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Haptic experience to significantly motivate anatomy learning in medical students | 73536371-2365-42b0-b28f-903d6ace1304 | 11363654 | Anatomy[mh] | Teaching anatomy to medical students represents a constant challenge, due to the complex structure of the human body, its importance during the early stages of medical education, and its implications in future clinical practice, as it provides understanding of the structure and its function . To obtain a clinical integration, the student must become proficient in anatomical structures and their respective function, which lead to acquiring medical terminology and prepares the future healthcare professional for determining diagnosis. In addition, it is especially advantageous in certain fields, such as surgery, where it has been described to offer patients greater safety . Although, to learn anatomy cadaver dissection is considered the gold standard , high maintenance costs, exposure to toxic chemical substances, the lack of professors trained in anatomy dissection, curricular limitations and integrative curricula, among others, have led to the implementation of different methods and tools to teach anatomy such as, lecture sessions, laboratories, prosection, videos, interactive screens (such as Sectra and Anatomage), plastination and others . To date, no teaching tool meets all curriculum requirements; therefore, the best way to teach modern anatomy is by combining multiple pedagogical resources to complement each other . Understanding 3D spatial anatomical relationships requires of the student to have a solid structure comprehension and 3D mental visualization skills . It has been described by Rizzolo and Stewart, 2006 and DeHoff et al. 2011 that tactile manipulation, in addition to involving other senses, is a great advantage provided by cadaver dissection. Therefore, it might be associated with better understanding and retention of spatial information . In this context, the haptic experience arises as an innovative tool, promising to increase the student’s motivation, and facilitate a significant learning process. It seems to have a positive effect on long term memory with an impact on cognitive ability, especially at the level of the student’s satisfaction . A haptic experience uses the sense of touch, associated with sight to explore and understand the form, texture, and the 3D characteristics of an object . Moreover, physical manipulation allows active control of a model; hence, permitting visualization from multiple perspectives, and the capacity to establish relationships . Collectively, 3D models have been demonstrated to be versatile and easy to manipulate. Diverse modalities of haptic experiences have been evaluated, such as interactive 3D models and advanced haptic technologies, to determine their impact on anatomical knowledge acquisition and their capacity to develop a connection between theory and practice, both for undergraduate and post-graduate education . Applying this focus on teaching anatomy not only seeks to surpass the limitations in traditional methods, which are usually centered on passive memorization, but to stimulate active participation by the student in his or her autonomous learning process. In post-graduate clinical training, various studies have used haptic cues with 3D prototypes to strengthen the understanding of anatomical and surgical procedures, as an aid in the clinical practice. Using 3D printed models helps to understand abstract concepts through spatial visualization and establish relationships. One such example is a study where a 3D printed liver with tumors model was utilized to understand surgical procedures and establish better cooperation at different training levels . Another study used a physical model of an acetabular fraction to evaluate the effect of a tactile feedback, allowing the residents to feel resistance, contours, textures, and edges of fractures . Acknowledging the importance of the haptic experience in the educational context, this research sought to provide several valuable insights to teachers, curriculum designers and healthcare professionals interested in optimizing human anatomy teaching, promoting a pedagogical approach that not only transmits information, but inspires a deep and long-term understanding of human anatomy. This study aimed to investigate the effectiveness of a haptic experience and painting on 3D plaster models as a motivating strategy to enhance meaningful learning of the shoulder’s anatomy. The following study evaluated a haptic experience to motivate meaningful learning in anatomy between March 2021 and March 2023. To this end, skeletal elements of the shoulder were modelled in plaster to determine if a tactile workshop and interaction with color markers would establish a better learning process, in comparison with the traditional method using a written 2D workshop. This study was carried out with undergraduate second year medical students from Pontificia Universidad Javeriana, Bogotá. Plaster bone model To elaborate realistic physical bone models from the human shoulder computed tomography (CT) images were obtained from volunteers after signing informed consent (FM-CIE-0113-18). Digital Imaging and Communication in Medicine (DICOM) files from CT scan were segmented with an on-house algorithm and converted into a CAD format, using an isocontour algorithm. Using a rapid prototype system, CAD files were used to 3D print a scapula, humerus and clavicle prototype in ABS plastic. Following, each prototype was employed to elaborate a silicone model into which plaster was poured into and allowed to set. The piece was released from the mold and the excess material was removed to have a replica of the skeletal element to be used in the 3D workshop with the students. At least 12 prototypes for each bone were created. Study design The study was approved by the Ethics committee of Pontificia Universidad Javeriana, Bogotá, School of Medicine project No. 8259 (FM-CIE-0113-18). To carry out this research, 85 second year undergraduate medical students were invited to take part in this study (62 female (73%) and 23 males (27%) between the ages of 19 and 25, where 77 participated in this study anonymously, representing 91% of the fourth semester class. Gender distribution was 71% females and 29% males. It was made clear it would not influence their grades, and they could withdraw from the study at any moment. Signed inform consent was obtained from all participants (Act No. FM-CIE-0010-23). At the time of the study, subjects had completed two hours of lecture on the anatomy of the shoulder, without any practical component. Subjects were divided into random groups, assuming students held a similar anatomical knowledge. A first group answered the conventional workshop ( n = 24, females: 21, males: 3), herein referred to as 2D. A second group of 28 students participated in the 3D workshop ( n = 28, females: 21, males: 7) and a third group, referred to as control, decided not to participate in either of the workshops ( n = 25, females: 13, males: 12), but did participate in taking a 10-question quiz at the end of the study. The same written workshop regarding the anatomy of the shoulder bones was distributed among the two groups (2D and 3D workshops). Students could organize themselves into subgroups with no more than four students per subgroup. The activity was first explained for both groups by one of the professors leading the study. Subjects were handed out a printed workshop with black and white photographs of the scapulae, clavicle and humerus and a table to fill in. Students had 90 min to provide answers regarding the name of the skeletal element, bone laterality, and the view of the bone based on the photograph. In addition, the workshop contained a table with the names of 18 shoulder muscles. Subjects had to determine bone marking, muscle origins and insertions, and function, according to a given color code. To this end, they could use anatomy atlases, and information from the internet (Fig. ). For the study, the 2D and 3D groups were divided into two different classrooms: The 2D group performed the workshop in a lecture classroom, whereas the 3D group carried out the activity in an anatomy laboratory, where each group worked on a table with scapulae, clavicle and humerus plaster models and color markers. For the 3D workshop, in addition to writing the answers on paper, bone markings (projections and depressions) and muscle insertions were painted on the plaster bone models using a color code. At the end of the activity, all three groups, 2D, 3D and those not participating in either workshop (control group) had to answer a 10-question quiz under examination conditions related to anatomical markings, bone laterality, view of the bone, muscle insertion, and muscle function. They had a 20-minute time span to answer the quiz, without access to any of their learning material. The maximum score achievable was 5.0 and the minimum 0. After this activity, a focus group was performed with the two groups. A week later, a graded survey was conducted for the 2D workshop group, consisting of six questions addressing how the workshop contributed to their understanding of anatomical landmarks, muscle insertions, and articular movements. In addition, they were asked to grade the overall experience, how it contributed to their learning process and if the quiz questions were related to what they had learned in the activity. For the 3D workshop group, two additional questions were included: if bone manipulation and painting on bone plaster models had an added value in their learning process. Moreover, to gather feedback from all participants, two open questions regarding the two main strengths and weaknesses of this activity were answered by all students who participated. Data analysis This was a descriptive cross-sectional study. Data for quiz results are presented as mean ± standard deviation (SD). To determine normal distribution a Shapiro-Wilk test was performed, and an ANOVA test was carried out to establish significant differences among groups with a p < 0.05. For survey, responses are presented as percentages from a six-degree Likert scale: 1: very poor, 2: poor, 3: fair, 4: good, 5: very good, 6: excellent, results are presented as percentages. Stata software (College Station, TX USA) version 17.0 was used to analyze all data. Graphs were made with GraphPad version 8.0 (Boston, MA USA). To elaborate realistic physical bone models from the human shoulder computed tomography (CT) images were obtained from volunteers after signing informed consent (FM-CIE-0113-18). Digital Imaging and Communication in Medicine (DICOM) files from CT scan were segmented with an on-house algorithm and converted into a CAD format, using an isocontour algorithm. Using a rapid prototype system, CAD files were used to 3D print a scapula, humerus and clavicle prototype in ABS plastic. Following, each prototype was employed to elaborate a silicone model into which plaster was poured into and allowed to set. The piece was released from the mold and the excess material was removed to have a replica of the skeletal element to be used in the 3D workshop with the students. At least 12 prototypes for each bone were created. The study was approved by the Ethics committee of Pontificia Universidad Javeriana, Bogotá, School of Medicine project No. 8259 (FM-CIE-0113-18). To carry out this research, 85 second year undergraduate medical students were invited to take part in this study (62 female (73%) and 23 males (27%) between the ages of 19 and 25, where 77 participated in this study anonymously, representing 91% of the fourth semester class. Gender distribution was 71% females and 29% males. It was made clear it would not influence their grades, and they could withdraw from the study at any moment. Signed inform consent was obtained from all participants (Act No. FM-CIE-0010-23). At the time of the study, subjects had completed two hours of lecture on the anatomy of the shoulder, without any practical component. Subjects were divided into random groups, assuming students held a similar anatomical knowledge. A first group answered the conventional workshop ( n = 24, females: 21, males: 3), herein referred to as 2D. A second group of 28 students participated in the 3D workshop ( n = 28, females: 21, males: 7) and a third group, referred to as control, decided not to participate in either of the workshops ( n = 25, females: 13, males: 12), but did participate in taking a 10-question quiz at the end of the study. The same written workshop regarding the anatomy of the shoulder bones was distributed among the two groups (2D and 3D workshops). Students could organize themselves into subgroups with no more than four students per subgroup. The activity was first explained for both groups by one of the professors leading the study. Subjects were handed out a printed workshop with black and white photographs of the scapulae, clavicle and humerus and a table to fill in. Students had 90 min to provide answers regarding the name of the skeletal element, bone laterality, and the view of the bone based on the photograph. In addition, the workshop contained a table with the names of 18 shoulder muscles. Subjects had to determine bone marking, muscle origins and insertions, and function, according to a given color code. To this end, they could use anatomy atlases, and information from the internet (Fig. ). For the study, the 2D and 3D groups were divided into two different classrooms: The 2D group performed the workshop in a lecture classroom, whereas the 3D group carried out the activity in an anatomy laboratory, where each group worked on a table with scapulae, clavicle and humerus plaster models and color markers. For the 3D workshop, in addition to writing the answers on paper, bone markings (projections and depressions) and muscle insertions were painted on the plaster bone models using a color code. At the end of the activity, all three groups, 2D, 3D and those not participating in either workshop (control group) had to answer a 10-question quiz under examination conditions related to anatomical markings, bone laterality, view of the bone, muscle insertion, and muscle function. They had a 20-minute time span to answer the quiz, without access to any of their learning material. The maximum score achievable was 5.0 and the minimum 0. After this activity, a focus group was performed with the two groups. A week later, a graded survey was conducted for the 2D workshop group, consisting of six questions addressing how the workshop contributed to their understanding of anatomical landmarks, muscle insertions, and articular movements. In addition, they were asked to grade the overall experience, how it contributed to their learning process and if the quiz questions were related to what they had learned in the activity. For the 3D workshop group, two additional questions were included: if bone manipulation and painting on bone plaster models had an added value in their learning process. Moreover, to gather feedback from all participants, two open questions regarding the two main strengths and weaknesses of this activity were answered by all students who participated. This was a descriptive cross-sectional study. Data for quiz results are presented as mean ± standard deviation (SD). To determine normal distribution a Shapiro-Wilk test was performed, and an ANOVA test was carried out to establish significant differences among groups with a p < 0.05. For survey, responses are presented as percentages from a six-degree Likert scale: 1: very poor, 2: poor, 3: fair, 4: good, 5: very good, 6: excellent, results are presented as percentages. Stata software (College Station, TX USA) version 17.0 was used to analyze all data. Graphs were made with GraphPad version 8.0 (Boston, MA USA). Survey results Regarding the question on how the students perceived the workshop overall (Fig. ), 3D students graded the workshop as very good (35.7%) and excellent (53.6%), whereas the 2D group graded it as fair (34.8%) and good (30.4%). On how it contributed to the learning process (Fig. A), the 3D group rated it as good 21.4%, very good 42.8% and excellent 28.6%. On the contrary, the majority of the 2D group considered it fair (43.5%). Understanding anatomical landmarks (Fig. B) was graded by the 3D group as good (39.3%), and excellent (50.0%), compared with poor (27.3%), fair (27.3%) and good (40.9%) grades given by the 2D workshop students. For the question regarding muscle insertions (Fig. C), 63% of the students in the 3D group gave it an excellent mark. In contrast, for this question 8.7% of the students in the 2D group considered it was very poor. Last, understanding joint movement was graded by 3D workshop students for the most part as good (35.7%), whereas 52.2% of the 2D group considered it was poor (Fig. D). Because of the nature of the study design, students in the 3D workshop group answered two additional questions: manipulating the bones and its impact on significant learning was graded as excellent (67.9%), and even though it received a high mark (excellent 64.3%), painting on the bones seemed to have a lower importance in their learning process (Fig. ). Focus group results In addition, based on the focus group, the 3D workshop students commented it was helpful to see structures in 3D and establish associations, which is difficult when working with 2D images. Most found it was useful to understand bone laterality view and muscle origin and insertion. It asserted their knowledge, as it allowed to dimension how the bone is structured, reinforcing spatial location. In comparison to working with 2D images, such as an anatomy atlas or the lecture on the subject, the students referred it to be different when one touches the structure vs. reading about it. The 3D workshop promoted learning through collaborative work between students, complementing each other’s knowledge. From the focus group, it was evident that the tactile models allowed for a three-dimensional appreciation of the bones, their landmarks and respective muscle insertions, contributing to spatial metacognition. This result was not as strong for the 2D workshop. In contrast, students in the 2D workshop said they had to rely more on the teacher’s help. The process was more related to memorization rather than understanding. Printed photographs of the bone do not allow for good identification of bone markings. For both workshops, an anatomy atlas was of great help. Moreover, bone articulation and clinical correlation was not sufficiently reinforced in this workshop, as evidenced by the results from the survey and the quiz. Regarding the question on how the students perceived the workshop overall (Fig. ), 3D students graded the workshop as very good (35.7%) and excellent (53.6%), whereas the 2D group graded it as fair (34.8%) and good (30.4%). On how it contributed to the learning process (Fig. A), the 3D group rated it as good 21.4%, very good 42.8% and excellent 28.6%. On the contrary, the majority of the 2D group considered it fair (43.5%). Understanding anatomical landmarks (Fig. B) was graded by the 3D group as good (39.3%), and excellent (50.0%), compared with poor (27.3%), fair (27.3%) and good (40.9%) grades given by the 2D workshop students. For the question regarding muscle insertions (Fig. C), 63% of the students in the 3D group gave it an excellent mark. In contrast, for this question 8.7% of the students in the 2D group considered it was very poor. Last, understanding joint movement was graded by 3D workshop students for the most part as good (35.7%), whereas 52.2% of the 2D group considered it was poor (Fig. D). Because of the nature of the study design, students in the 3D workshop group answered two additional questions: manipulating the bones and its impact on significant learning was graded as excellent (67.9%), and even though it received a high mark (excellent 64.3%), painting on the bones seemed to have a lower importance in their learning process (Fig. ). In addition, based on the focus group, the 3D workshop students commented it was helpful to see structures in 3D and establish associations, which is difficult when working with 2D images. Most found it was useful to understand bone laterality view and muscle origin and insertion. It asserted their knowledge, as it allowed to dimension how the bone is structured, reinforcing spatial location. In comparison to working with 2D images, such as an anatomy atlas or the lecture on the subject, the students referred it to be different when one touches the structure vs. reading about it. The 3D workshop promoted learning through collaborative work between students, complementing each other’s knowledge. From the focus group, it was evident that the tactile models allowed for a three-dimensional appreciation of the bones, their landmarks and respective muscle insertions, contributing to spatial metacognition. This result was not as strong for the 2D workshop. In contrast, students in the 2D workshop said they had to rely more on the teacher’s help. The process was more related to memorization rather than understanding. Printed photographs of the bone do not allow for good identification of bone markings. For both workshops, an anatomy atlas was of great help. Moreover, bone articulation and clinical correlation was not sufficiently reinforced in this workshop, as evidenced by the results from the survey and the quiz. Even though, students from the 3D group graded the workshop as very good or excellent in its majority, quiz results (Fig. ) did not reveal a significant difference compared to 2D workshop performance or students who did not participate in any workshop (1.82 ± 0.88), 2D (2.05 ± 0.82) and 3D (2.09 ± 0.94). However, 21% of the 3D group had a passing grade, whereas only 16% from the 2D group and 8% from the control group had a passing grade. The highest grade (4.0 from a maximum of 5.0) were obtained by two subjects of the 3D group (7%). The best grade for the 2D group was 3.7 obtained by one person (4%). Last, for the control group the highest mark was and 3.5 from one student (4%). Moreover, for the 3D group, five of the 10 questions had a greater percentage of students selecting the correct answer. These included a question regarding the levator scapulae muscle insertion, to identify the view of the clavicle, an arrow pointing to a humerus landmark asking to identify the function of the muscle fibers inserting in the lesser crest of the humerus, an arrow pointing to the radial groove asking to identify the structure that associates to it. Last, an arrow pointing to the anatomical neck of the humerus, asking to identify the structure. For the 2D group, only one question had a greater percentage of students answering the right question (to identify the muscle inserting on the scapula bone landmark circled in red). Last, the control group had four questions for which a greater percentage of students answered correctly. The questions were related to the main function of the muscle inserting in the subscapular fossa, to identify the neck of the scapula, to identify the structure and function of the arrow pointing at the coronoid fossa, and to identify the crest of the lesser tubercle. This study aimed to develop new learning resources using bone plaster models to understand the shoulder’s skeletal anatomy, focusing on bone landmarks and muscle insertions and origins. To this end, a customized, highly accurate plaster skeletal element from a 3D printed prototype was used to assess the efficacy as an anatomical teaching aid. To evaluate what students had learned, a quiz was applied to all subjects at the end of the activity. Additionally, to collect the views of the two approaches evaluated (conventional 2D vs. 3D), a focus group and survey were conducted to determine the subjects’ educational benefits and perceptions. At present, objective evaluation on comparative efficacies using conventional teaching resources and novel pedagogical tools, such as 3D prototypes remains scarce in the literature, since most studies are based on student perception, attitude and enjoyment . The objective of the present study was to proof the hypothesis that students actively participating in the 3D workshop would obtain a significantly higher grade compared with 2D workshop or control subjects. However, results did not reveal significant differences (Fig. ). As was observed from the 3D focus group, students described it would be more beneficial to have a lecture followed by a lab session to interiorize the information. Furthermore, subjects recounted this was the first time studying this subject; if they had a review session, they would have benefited more from the activity. In addition, they attributed the low performance on the fact that they had high-stakes examinations in the two weeks prior. In contrast, in studies where a post-test objectively evaluated the efficacy of a 3D model, test conditions were different: For the Preece et al. study , subjects had access to their teaching aids, and for Bao et al. study , a training took place three times a week, with each session lasting 40 min for four continuous weeks. Therefore, for both formerly mentioned studies, test scores were significantly higher for the subjects learning by a haptic experience. Last, in the Huang et al. study, the subjective questionnaire demonstrated the 3D experience was considered the most valuable and enjoyable learning instrument , suggesting this positive quality using 3D models can be employed towards developing educational resources. In the present study, it was evidenced that a haptic experience involving painting on 3D plaster models of skeletal elements, aided in the learning process of the shoulder’s anatomy by enhancing the student’s anatomical spatial awareness. It is known that there has been limited development of activities that support visuospatial and metacognitive skills in anatomy . Therefore, with this innovative approach, the limitations that traditional methods, usually focused on a surface approach to learning such as memorization, might be overcome . Preece et al. suggested that 3D physical models have a significant advantage over textbooks and virtual reality by improving visuospatial understanding. Furthermore, appreciating complex spatial relationships in 3D increases visual skills . In their acetabular fracture study, Huang et al. described that by touching the anatomical landmarks and fracture lines in the 3D models, students could obtain spatial details of the morphology of the fracture that could not be acquired by the other methods evaluated. They concluded that 3D models are an efficient learning tool . Hence, haptic cues may be crucial in learning about complicated structures. In the present study, 3D group participants were able to identify bone landmarks by touching the structure. Students were made aware of bone landmark’s that may not be otherwise noticeable in a 2D format (photograph, drawing or virtual image). The hand-held interactive experience allows for active control, permitting visualization from multiple perspectives. As concluded by Wainman et al., a physical model is superior to a computer projection, because of stereoscopic vision in the 3D structure . In addition, the 3D model improves understanding, because the haptic experience develops the ability to integrate information, as described in the acetabular study: “form a complete chain from vision to touch, from plane to stereo, and from intact to fracture”. To achieve a deep learning approach, the student must understand the structure and manipulate the object to make sense of the relation between the elements. Hence, 3D plaster models of the shoulder skeleton were fabricated. Brumpt et al. carried out a systematic review describing the value of 3D printed anatomical models . From their work, they selected 68 articles, of which 47 were designed from CT scans, and 51 articles mentioned bone printing. However, the shoulder was only mentioned in one study . In the study of Garas and colleagues, 23 undergraduate students of health sciences were exposed to plastinated, 3D-printed models and cadaverous specimens of the external heart, shoulder, and thigh, where the shoulder was plastinated . The students then had to take a test with nine questions on a pinned structure, and were asked to identify it. Afterwards, they were provided a post-test survey with five questions on a Likert scale. Collectively, from the Garas’ study, it was concluded that 3D printing can be an asset in the process of learning anatomy . Furthermore, the level of understanding was very basic and not comparable with the present study. Ye et al. carried out a systematic review and meta-analysis for the last decade . They included studies using post-training tests, where 3D printed models of various systems, such as nervous system, and abdominal organs were used. Regarding student satisfaction, from their study it was observed that five of the six study results were significantly higher for the 3D group, in comparison with conventional groups. Likewise, concerning accuracy of answering questions, two studies showed the 3D group was significantly better in comparison with the conventional group. Collectively, subjective information obtained from survey can be as important as test scores. In the present work, students from the 3D group described how important it was to touch, feel the texture, see the structure and establish proportions in the plaster bone models. The students expressed the added value provided by manipulating the three skeletal elements to establish associations and anatomical relations. Additionally, anatomical information was not fully understood from textbook reading or from explanations in a lecture. One student described how the main difficulty was establishing dimensions. The 3D spatial perception view allowed to understand proportions and locations. Additionally, painting on bone landmarks and muscle insertions made it easier to recognize their locations. Wainman et al. described how a haptic experience manipulating a 3D model, enhanced the learning process by providing additional sensory spatial relationships, which cannot be acquired by learning from 2D images; thus, enhancing the learning process . To further this learning experience, painting was included in the 3D workshop, reinforcing the learning process. Other researchers have used 3D printing and painting to learn anatomy. McMenamin and collaborators reported on high resolution 3D prints of accurate color reproductions of prosections based on CT scan images . Their article described in depth the process of creating the models, yet no evaluation with students was carried out. In the present study, the overall experience was rated as very good or excellent by almost 90% of the 3D model group members. In contrast, 65% of the students in the 2D group rated the activity primarily as fair or good, and none of them rated it as excellent. Likewise, a study carried out by Pandya, Mistry and Owens , described the use of videoconferencing and use of tactile learning with 3D models to assess the differences in undergraduate students’ attitudes toward tactile and non-tactile learning. In their results, students believed tactile learning was statistically superior ( p = 0.017). Furthermore, Reid et al. described a study where five students participated in a special module entitled “Drawing and Anatomy” at the University of Cape Town . Reid’s study coupled exploring the skeletal element, such as a skull, with a haptic experience with one hand and drawing with the other hand. The students were then interviewed mid-way through their intervention. Collectively, the experience resulted in an increased comprehension of the 3D form and detail of anatomical landmarks and cavities. Likewise, herein we obtained similar answers from the 3D focus group. Other experiences using painting to learn anatomy were evaluated by Shapiro et al. . In their study, they employed haptic surface painting to support learner engagement and spatial awareness. They described that haptico-visual observation can support spatial, holistic anatomy learning. Haptic sensing involves perceiving a variety of object features, such as shape, size, weight, surface texture, compliance, and thermal characteristics . In this manner, somatosensory haptic acquired information is also subjected to detailed analysis . In our study, the students surveyed in the 3D model group perceived the haptic activity favored their overall learning process, rating it primarily between the very good and excellent, representing 71.5% of their answers; while in the group that used only 2D images, more than 60% perceived the contribution that the activity provided to their learning process as poor or fair. The haptic experiences in this study support the argument that their implementation favors meaningful, autonomous and collaborative learning, characteristics that are sought in all academic activities in current medical education. The opportunity to work with the 3D plaster models and actively participate in painting on them, demonstrated a significant impact on the learning of the medical students who scored 90% in the very good and excellent categories. It is evident that the bone plaster models provided 3D metacognition of the structures, consolidating knowledge and making learning more motivating and satisfactory. To achieve a comprehensive knowledge of bone markings, laterality, muscle insertions and joint movements, demands of the learner the correct spatial orientation of the structures involved. The group that worked with the 3D plaster bone models graded it in the survey as very good and excellent (between 85 and 90%). However, joint movement was not properly developed in this workshop. These same categories were rated between fair and poor (50–70%) for the 2D group. Collectively, haptic experiences in this study were shown to favor significant learning, characterized by an autonomous and collaborative approach. Although results in this study were satisfactory, one of the limitations observed was the duration of the workshop, which only lasted 90 min. As with the Waiman et al. study, learning time was brief . It could be expected that another 90-minute laboratory might allow students to recognize bone articulation and movements, rather than identifying a bone landmark without understanding its function. Even though, one of the learning objectives of this activity was to recognize different components of the shoulder in diagnostic images to establish associations between them, this was not achieved. Anatomical understanding must precede diagnostic images, as was the means of objectively evaluating the 3D tool in the Preece study . Therefore, radiological images should also be included in the workshop, to verify if learned concepts can be applied in a clinical setting. Moreover, a pre-test should have been carried out to assess the level of anatomy knowledge of all participants. Last, evaluations of this nature should not be implemented after midterm examination, as they might affect students’ performance. A highly accurate 3D plaster model was custom made, so students could appreciate the bones’ landmarks, identify muscle origins and insertions, and understand their function. Such tools contribute to the development of skills that allow students to face various future situations in clinical practice with greater proficiency and confidence. The results from our study demonstrated that a haptic experience increased motivation and satisfaction. Furthermore, painting on a particular bone landmark required from the student to combine the senses of touch and sight to establish spatial relationships; thus, reinforcing the learning process. Additionally, in the 3D workshop, students actively participated in their autonomous learning process. Furthermore, teamwork helped solve questions and complete tasks, while learning new concepts. Hence, new collaborative learning was stimulated, as evidenced from the 3D model focus group. However, this workshop must be complemented with activities that increase the understanding of muscle movement and bone articulation for better integration to clinical settings. Below is the link to the electronic supplementary material. Supplementary Material 1 Supplementary Material 2 Supplementary Material 3 Supplementary Material 4 |
When | 937a0697-4e7f-4ec8-85bb-45643c957395 | 11863445 | Forensic Medicine[mh] | Escherichia coli ( E. coli ) is the one of prevalent gram-negative species. The following three broad categories of E. coli strains are of biological significance to mammals: commensal, intestinal pathogenic (InPEC), and extraintestinal pathogenic (ExPEC) . Although E. coli is a benign commensal colonizing the mammalian intestine, some strains or pathotypes can cause a variety of intestinal and diarrheal disorders . For example, a minimum of the following six pathotypes have been described: enterohemorrhagic, enteropathogenic, enterotoxigenic, enteroaggregative, diffusely adherent, and enteroinvasive E. coli , respectively . Moreover, ExPEC can cause diseases such as urinary tract infections, bacteremia, septicemia, and meningitis . It is unclear how E. coli genetic diversity, virulence, and antimicrobial resistance affect biodiversity and wild animal conservation . Wild animals may get exposed to antimicrobial compounds and antimicrobial resistance bacteria by interaction with anthropogenic sources such as human waste (garbage and sewage) and polluted waterways , livestock activities , or predation on impacted prey, including livestock corpses . Giraffes ( Giraffa camelopardalis ) are the tallest living animals and are kept in many zoos worldwide. Despite the passionate interest in keeping captive giraffes healthy, the health management of the giraffe presents a significant challenge. Despite being routinely bred in zoos, giraffes continue to provide a problem, particularly when it comes to food. Because of the high risk of maternal rejection and death among both mother-reared and hand-reared calves . Although success rates have increased over time, intensive care therapy of compromised calves remains under documented . There are still no definitive feeding standards, predicted weight increase, or suggestions for veterinarian assistance. In addition, little research has been conducted on diseases affecting giraffes, which are primarily associated with its hoofs and musculoskeletal system . However, there are few reports of E. coli disease in young giraffes. ExPEC infections are a serious threat to public health worldwide . Urinary tract infections, severe newborn meningitis, major intra-abdominal infections, and, less frequently, pneumonia, intravascular device infections, osteomyelitis, soft tissue infections, or bacteremia are the most troublesome illnesses. Bacteremia can result in sepsis, which is defined as life-threatening organ dysfunction caused by an unregulated immune response to infection . In this study, we describe the case of a giraffe that developed septicemia after an umbilical cord infection caused by E. coli. This case study may serve as a valuable reference and caution for veterinarians in zoos. Clinical history A female giraffe’s mother died of severe trauma approximately 5 h after delivery; hence, the juvenile giraffe could not feed colostrum and had to be artificially administered milk powder (Holstein milk + 10% colostrum). The juvenile giraffe was able to stand on its own 3 days after birth and was in a good condition. However, on the eight day after birth, the juvenile giraffe began to show clinical signs of losing appetite, slow walking, and depression. Lactasin (LactaidⓇ, Johnson & Johnson Inc., Guelp, Canada; Take 3 caplets with their bite of daily food.) was administered orally twice a day for 4 days during the course of the disease, and the treatment was ineffective. On the 12th day after birth, the juvenile giraffe showed anorexia, tarsal joint swelling of the right hind limb, claudication, unwillingness to move, the presence of a small amount of dirty yellow loose stool around the anus, and eventually lying down, and died on the 14th day after birth. Necropsy A postmortem examination was performed within 2 h of the animal’s death. According to the naked eye observation, dark, red, and swollen umbilicus (Fig. A); and a small amount of dirty yellow sticky feces on the perianal coat. Serofibrinous arthritis and periarticular serous necrotizing inflammation: the swollen hock joint of the hind limb and the subcutaneous tissue near it was light yellow gelatinous material due to inflammatory edema, and the local skin is attached to the subcutaneous tissue and muscle (Fig. B). A cystic necrotic focus was formed at the adhesion site, with a red inflammatory response zone at the margin and yellow necrotic tissue in the central area. A large amount of pale yellow translucent inflammatory fluid and yellow flocculent fibrinous exudate accumulated in the joint cavity of the wrist, hock, and hip joints (Fig. C). Serous omphicitis with severe gelatinous swelling of the umbilical pore was obvious. The umbilical veins and bilateral umbilical arteries were thickened significantly, with black and red adventitia and gelatinous edema of the surrounding connective tissue. The umbilical arteries were full of dirty dark red necrosis, and the intima was rough (Fig. D). Severe serofibrinous pericarditis, pleuritis, and peritonitis: A large amount of pale-yellow translucent fluid and yellow white flocculent fibrinous exudates in the pericardial, chest, and abdominal cavities, and slight adhesion of the local serous membrane were observed (Fig. E and F). The kidneys and liver were swollen and dark red, with moist and glossy surfaces, and the submucosa of the renal pelvis was thickened and showed yellowish gelatinous edema. The lungs were enlarged, dark red in color, covered with flocculent fibrinous exudates, and the interstitium of the pulmonary lobule was generally widened and full of yellow translucent gelatinous exudate (Fig. A). The transverse diameter of the heart was significantly widened, and the epicardial membrane was attached to a flocculent yellowish-white fibrinous exudate. Hyperemia and edema of the abomasum mucosa and intestinal pneumatosis were observed. Histopathology Serous interstitial pneumonia and lobular interstitial pneumonia were significantly widened and filled with homogeneous pink stained serous fluid (Fig. A). A small amount of fibrous protein, diffused neutrophils, scattered or clustered small blue bacilli, and a large number of neutrophils within lymphatic vessels at all levels were observed (Fig. B). Pulmonary hyperemia and sporadic serous fluid, erythrocytes, and neutrophils were found in the alveolar and bronchial lumens near the lobular interstitium (Fig. C and D). Serous necrotizing umbilical arteritis with hyperemia, edema, and marked thickening of the tunica adventitia of the umbilical artery filled with homogeneous pink serous fluid, scattered or diffused infiltrating neutrophils, and scattered or clustered small blue-stained bacilli were observed (Fig. E and F). Necrosis of the tunica intima and partial tunica media with diffused neutrophils and increased blue-stained bacterial clusters of varying sizes were observed; there was a large amount of serous fluid, necrotic neutrophils, and erythrocytes in the lumen of the artery (Fig. F). Mild hepatic sclerosis: hepatic interstitial connective tissue proliferated and widened mildly, with small bile duct increase; liver edema, obvious Disse space, incomplete wall of hepatic sinusoid, hemolysis, and hepatocytes separated from each other were seen. Mild steatosis and scattered necrosis of hepatocytes in the central area of the hepatic lobule were observed. Renal hyperemia and edema, mild to moderate cell swelling of the renal tubular epithelia, occasional necrosis of the renal tubular epithelia in some renal tubules, and increased neutrophil content in the pelvis were observed. Hyperemia and edema, loose capsules with scattered infiltrating neutrophils, and cells in the zona fasciculata separated from each other were observed in the adrenal glands. Lymphocyte reduction, fewer lymph nodules with inconspicuous germinal centers, and diffuse hemorrhage of the medulla were observed in the lymph nodes. Hyperemia and edema, significantly reduced lymphocytes, white pulp lymphocyte nodules with sparse lymphocytes of white pulp were observed in the spleen. Mild to moderate cellular swelling of cardiomyocytes was observed. Serous necrotizing enteritis: significant edema and thickening of the small intestine wall, large amount of serous fluid, diffuse infiltrating neutrophils, and necrotic mucosal layer were observed in the small intestine. The marginal acinar epithelial cells of the thyroid gland were partially necrotic. Blue-stained bacterial clusters of varying sizes or diffuse blue-stained small bacilli were present in the interstitium and serous membranes of most tissues and organs as well as in small blood vessels and lymphatic vessels (Fig. A). This was accompanied by scattered or diffuse infiltrating neutrophils, particularly in the lymphatic vessels of tissues filled with neutrophils (lymphatic spread). The endothelial cells separated severely from the media of the small vessels because of edema. Bacterial isolation and molecular identification Pleural fluid, pericardial exudate, ascites, joint fluid, lung, liver, and umbilical artery wall were aseptically collected with an inoculation loop and inoculated on MacConkey and eosin-methylene blue (EMB) medium and cultivated at 37 °C for 24 h. Many small pink colonies grew on the MacConkey medium. The EMB medium grew many small, round, shiny black colonies characteristic of E. coli . Using an inoculation loop, a small amount of the organism was collected to prepare a smear. Simple gram-negative small rods having the same morphology as that of E. coli were detected using Gram staining (Fig. B). In this study, the 16S rRNA of the cultured bacteria was sequenced. We selected ten colonies from each plate (total 70 colonies) for polymerase chain reaction (PCR) detection and sequencing. General primer sets (10Fx:5′-AGAGTTTGATCCTGGCTCAG-3′; 1509R:5′-GTTACCTTGTTACGACTTCAC-3′) were selected to amplify the 16S rRNA from all the colonies isolated from the baby giraffe samples . For amplification, the following conditions were used: initial denaturation at 95 °C for 3 min; 30 cycles of denaturation (30 s at 94 °C), annealing (30 s at 55 °C), extension (1.5 min at 72 °C), and final extension at 72 °C for 5 min. The amplified PCR products were analyzed on 1.5% agarose gels, purified, and sequenced. Through BLAST searches, the sequences were compared with those in the NCBI database. The results indicated that all the 70 colonies were of E. coli ; they also revealed a nucleotide sequence similarity of 99.16–99.79% to strains from human feces (CCFM8332), Yuncheng Salt Lake (YC-LK-LKJ9), poultry droppings (AKP_87), marine (CSR-33, CSR-59), wetland (CH-8), and wastewater treatment plant (WTPii241) (Fig. C). The phylogenetic groups of E. coli isolates were identified using a PCR-based method developed by Clermont et al. E. coli was classified into four main phylogenetic groups (A, B1, B2, and D) based on the presence of three markers (chuA, yjaA, and TSPE4.C2) in their DNA. Crude DNA was extracted from colonies by lysing them in sterile water at 100 °C for 15 min, followed by centrifugation. The lysis supernatant was utilized for the polymerase chain reaction, following the conditions outlined by Clermont et al. . The primers utilized in this investigation are detailed in Supplementary Table 1. PCR analysis of the isolate indicated its classification within phylogenetic group B1 (Fig. A). A total of twenty-five virulence genes were identified, including PAI, pap A, fm H, kps MT III, pap EF, ibe A, fyu A, bma E, sfa / foc DE, iut A, pap G allele III, hly A, rfc , nfa E, pap G allele I, kps MT II, pap C, gaf D, cva C, foc G, tra T, pap G allele I, pap G allele II, afa / dra BC, cnf 1, and sfas . Each virulence gene was amplified using specific primers in PCR. The primers utilized in this investigation are detailed in Supplementary Table 1. Thermal cycling conditions included an initial denaturation cycle at 94 °C for 2 min, followed by 35 cycles at 94 °C for 1 min, annealing at a specific temperature for 1 min, and extension at 72 °C for 1 min, with a final cycle at 72 °C for 2 min. In this strain, 6 virulence genes (PAI, iut A, pap G allele III, cva C, sfas , afa / dra BC) associated with adhesion, toxicity, and environmental response were identified (Fig. B). E. coli strains were tested for antibiotic susceptibility using CLSI guidelines and a disc diffusion method with 16 antibiotics . The resistance profiles of the E. coli strains to the antibiotics tested are outlined in Table , with interpretation of all susceptibility results based on the CLSI guidelines . The strains exhibited resistance to ceftazidime, ceftriaxone, ciprofloxacin, levofloxacin, amoxicillin, and azithromycin, while demonstrating susceptibility to penicillin, oxacillin, lincomycin, clindamycin, ampicillin, and cotrimoxazole. A female giraffe’s mother died of severe trauma approximately 5 h after delivery; hence, the juvenile giraffe could not feed colostrum and had to be artificially administered milk powder (Holstein milk + 10% colostrum). The juvenile giraffe was able to stand on its own 3 days after birth and was in a good condition. However, on the eight day after birth, the juvenile giraffe began to show clinical signs of losing appetite, slow walking, and depression. Lactasin (LactaidⓇ, Johnson & Johnson Inc., Guelp, Canada; Take 3 caplets with their bite of daily food.) was administered orally twice a day for 4 days during the course of the disease, and the treatment was ineffective. On the 12th day after birth, the juvenile giraffe showed anorexia, tarsal joint swelling of the right hind limb, claudication, unwillingness to move, the presence of a small amount of dirty yellow loose stool around the anus, and eventually lying down, and died on the 14th day after birth. A postmortem examination was performed within 2 h of the animal’s death. According to the naked eye observation, dark, red, and swollen umbilicus (Fig. A); and a small amount of dirty yellow sticky feces on the perianal coat. Serofibrinous arthritis and periarticular serous necrotizing inflammation: the swollen hock joint of the hind limb and the subcutaneous tissue near it was light yellow gelatinous material due to inflammatory edema, and the local skin is attached to the subcutaneous tissue and muscle (Fig. B). A cystic necrotic focus was formed at the adhesion site, with a red inflammatory response zone at the margin and yellow necrotic tissue in the central area. A large amount of pale yellow translucent inflammatory fluid and yellow flocculent fibrinous exudate accumulated in the joint cavity of the wrist, hock, and hip joints (Fig. C). Serous omphicitis with severe gelatinous swelling of the umbilical pore was obvious. The umbilical veins and bilateral umbilical arteries were thickened significantly, with black and red adventitia and gelatinous edema of the surrounding connective tissue. The umbilical arteries were full of dirty dark red necrosis, and the intima was rough (Fig. D). Severe serofibrinous pericarditis, pleuritis, and peritonitis: A large amount of pale-yellow translucent fluid and yellow white flocculent fibrinous exudates in the pericardial, chest, and abdominal cavities, and slight adhesion of the local serous membrane were observed (Fig. E and F). The kidneys and liver were swollen and dark red, with moist and glossy surfaces, and the submucosa of the renal pelvis was thickened and showed yellowish gelatinous edema. The lungs were enlarged, dark red in color, covered with flocculent fibrinous exudates, and the interstitium of the pulmonary lobule was generally widened and full of yellow translucent gelatinous exudate (Fig. A). The transverse diameter of the heart was significantly widened, and the epicardial membrane was attached to a flocculent yellowish-white fibrinous exudate. Hyperemia and edema of the abomasum mucosa and intestinal pneumatosis were observed. Serous interstitial pneumonia and lobular interstitial pneumonia were significantly widened and filled with homogeneous pink stained serous fluid (Fig. A). A small amount of fibrous protein, diffused neutrophils, scattered or clustered small blue bacilli, and a large number of neutrophils within lymphatic vessels at all levels were observed (Fig. B). Pulmonary hyperemia and sporadic serous fluid, erythrocytes, and neutrophils were found in the alveolar and bronchial lumens near the lobular interstitium (Fig. C and D). Serous necrotizing umbilical arteritis with hyperemia, edema, and marked thickening of the tunica adventitia of the umbilical artery filled with homogeneous pink serous fluid, scattered or diffused infiltrating neutrophils, and scattered or clustered small blue-stained bacilli were observed (Fig. E and F). Necrosis of the tunica intima and partial tunica media with diffused neutrophils and increased blue-stained bacterial clusters of varying sizes were observed; there was a large amount of serous fluid, necrotic neutrophils, and erythrocytes in the lumen of the artery (Fig. F). Mild hepatic sclerosis: hepatic interstitial connective tissue proliferated and widened mildly, with small bile duct increase; liver edema, obvious Disse space, incomplete wall of hepatic sinusoid, hemolysis, and hepatocytes separated from each other were seen. Mild steatosis and scattered necrosis of hepatocytes in the central area of the hepatic lobule were observed. Renal hyperemia and edema, mild to moderate cell swelling of the renal tubular epithelia, occasional necrosis of the renal tubular epithelia in some renal tubules, and increased neutrophil content in the pelvis were observed. Hyperemia and edema, loose capsules with scattered infiltrating neutrophils, and cells in the zona fasciculata separated from each other were observed in the adrenal glands. Lymphocyte reduction, fewer lymph nodules with inconspicuous germinal centers, and diffuse hemorrhage of the medulla were observed in the lymph nodes. Hyperemia and edema, significantly reduced lymphocytes, white pulp lymphocyte nodules with sparse lymphocytes of white pulp were observed in the spleen. Mild to moderate cellular swelling of cardiomyocytes was observed. Serous necrotizing enteritis: significant edema and thickening of the small intestine wall, large amount of serous fluid, diffuse infiltrating neutrophils, and necrotic mucosal layer were observed in the small intestine. The marginal acinar epithelial cells of the thyroid gland were partially necrotic. Blue-stained bacterial clusters of varying sizes or diffuse blue-stained small bacilli were present in the interstitium and serous membranes of most tissues and organs as well as in small blood vessels and lymphatic vessels (Fig. A). This was accompanied by scattered or diffuse infiltrating neutrophils, particularly in the lymphatic vessels of tissues filled with neutrophils (lymphatic spread). The endothelial cells separated severely from the media of the small vessels because of edema. Pleural fluid, pericardial exudate, ascites, joint fluid, lung, liver, and umbilical artery wall were aseptically collected with an inoculation loop and inoculated on MacConkey and eosin-methylene blue (EMB) medium and cultivated at 37 °C for 24 h. Many small pink colonies grew on the MacConkey medium. The EMB medium grew many small, round, shiny black colonies characteristic of E. coli . Using an inoculation loop, a small amount of the organism was collected to prepare a smear. Simple gram-negative small rods having the same morphology as that of E. coli were detected using Gram staining (Fig. B). In this study, the 16S rRNA of the cultured bacteria was sequenced. We selected ten colonies from each plate (total 70 colonies) for polymerase chain reaction (PCR) detection and sequencing. General primer sets (10Fx:5′-AGAGTTTGATCCTGGCTCAG-3′; 1509R:5′-GTTACCTTGTTACGACTTCAC-3′) were selected to amplify the 16S rRNA from all the colonies isolated from the baby giraffe samples . For amplification, the following conditions were used: initial denaturation at 95 °C for 3 min; 30 cycles of denaturation (30 s at 94 °C), annealing (30 s at 55 °C), extension (1.5 min at 72 °C), and final extension at 72 °C for 5 min. The amplified PCR products were analyzed on 1.5% agarose gels, purified, and sequenced. Through BLAST searches, the sequences were compared with those in the NCBI database. The results indicated that all the 70 colonies were of E. coli ; they also revealed a nucleotide sequence similarity of 99.16–99.79% to strains from human feces (CCFM8332), Yuncheng Salt Lake (YC-LK-LKJ9), poultry droppings (AKP_87), marine (CSR-33, CSR-59), wetland (CH-8), and wastewater treatment plant (WTPii241) (Fig. C). The phylogenetic groups of E. coli isolates were identified using a PCR-based method developed by Clermont et al. E. coli was classified into four main phylogenetic groups (A, B1, B2, and D) based on the presence of three markers (chuA, yjaA, and TSPE4.C2) in their DNA. Crude DNA was extracted from colonies by lysing them in sterile water at 100 °C for 15 min, followed by centrifugation. The lysis supernatant was utilized for the polymerase chain reaction, following the conditions outlined by Clermont et al. . The primers utilized in this investigation are detailed in Supplementary Table 1. PCR analysis of the isolate indicated its classification within phylogenetic group B1 (Fig. A). A total of twenty-five virulence genes were identified, including PAI, pap A, fm H, kps MT III, pap EF, ibe A, fyu A, bma E, sfa / foc DE, iut A, pap G allele III, hly A, rfc , nfa E, pap G allele I, kps MT II, pap C, gaf D, cva C, foc G, tra T, pap G allele I, pap G allele II, afa / dra BC, cnf 1, and sfas . Each virulence gene was amplified using specific primers in PCR. The primers utilized in this investigation are detailed in Supplementary Table 1. Thermal cycling conditions included an initial denaturation cycle at 94 °C for 2 min, followed by 35 cycles at 94 °C for 1 min, annealing at a specific temperature for 1 min, and extension at 72 °C for 1 min, with a final cycle at 72 °C for 2 min. In this strain, 6 virulence genes (PAI, iut A, pap G allele III, cva C, sfas , afa / dra BC) associated with adhesion, toxicity, and environmental response were identified (Fig. B). E. coli strains were tested for antibiotic susceptibility using CLSI guidelines and a disc diffusion method with 16 antibiotics . The resistance profiles of the E. coli strains to the antibiotics tested are outlined in Table , with interpretation of all susceptibility results based on the CLSI guidelines . The strains exhibited resistance to ceftazidime, ceftriaxone, ciprofloxacin, levofloxacin, amoxicillin, and azithromycin, while demonstrating susceptibility to penicillin, oxacillin, lincomycin, clindamycin, ampicillin, and cotrimoxazole. Among neonatal hand-reared giraffes, failure of passive transfer of immunity (FPI) continues to be a problem . The cotyledonary placentas in giraffes transfer negligible antibodies. Therefore, newborns rely on colostrum consumption and the absorption of maternal antibodies across the intestines during the first 24–48 h after birth . FPI increases the risk of diarrhea, enteritis, septicemia, arthritis, omphalitis, and pneumonia in domestic ungulates . Passive immunity transfer during the newborn’s first week is crucial for the successful rearing of ruminant neonates. To ensure optimal and steady growth, milk replacers must have a composition similar to that of giraffe milk. Bovine milk and colostrum have been effectively utilized and advised for hand-rearing giraffes despite the lower fat and protein contents of cow’s milk and milk substitutes than that of giraffe milk . Until the regular consumption of solid food, milk should be consumed daily in amounts of 7–10% of the body weight (19,000–25,000 kcal/day) . A hand-fed giraffe calf (which did not receive colostrum) died of septicemia caused by E. coli in the present study. Septic arthritis and phlegmon are caused by trauma or systemic infection. No trauma was recorded in this giraffe pup. Therefore, systemic infection may have contributed to the septic polyarthritis and/or phlegmon observed in this study. Enteritis, pneumonia, and funisitis are common sources of infection in giraffe calves; enteritis and pneumonia were not recorded in giraffe calves before the development of arthritis . Furthermore, the lack of immunocompetence might have put the calves at a risk of the infection spreading systemically through the umbilical cord. Septic polyarthritis and/or phlegmon may be caused by systemic infection. A PCR and sequence analysis confirmed that E. coli was the cause of bacteremia in the present case. E. coli colonizes newborn pups’ gastrointestinal tract shortly after birth and typically coexists with its host without causing disease. However, certain strains with specific virulence attributes can cause a range of illnesses in immunocompromised hosts or when gastrointestinal barriers are compromised. Extraintestinal pathogenic E. coli (ExPEC) are characterized primarily by their site of isolation, with the most clinically significant groups being uropathogenic E. coli (UPEC), neonatal meningitis-associated E. coli (NMEC), avian pathogenic E. coli (APEC), and septicemic E. coli (SEPEC) . ExPEC strains have the ability to cause infections in various extraintestinal locations. In the present case, the ExPEC strain resulted in pneumonia, umbilical arteritis, hepatitis, nephritis, hemorrhagic lymphadenitis, necrotizing enteritis, and necrotizing thyroiditis in the baby giraffe. There is no doubt that this is a direct result of E. coli bacteremia. In order to initiate bacteremia, the ExPEC strain must successfully infiltrate initial sites of infection or colonization, disseminate throughout the bloodstream, and persist within the blood. Nevertheless, the ExPEC strain has the capability to access the bloodstream through various pathways. Bacteremia lacking a discernible origin is classified as primary, while secondary bacteremia may result from dissemination originating from an existing infection, such as pneumonia or urinary tract infections, or from contaminated medical equipment . In this case, however, the bacteremia was likely a result of an umbilical cord infection. Improper handling of the umbilical cord presents a potential risk of infection, as it serves as a significant entry point for pathogens in newborns. Therefore, it is strongly advised that veterinarians adhere to proper disinfection, sterilization, isolation, and other cleaning protocols to ensure optimal umbilical cord hygiene when handling neonates. ExPEC uses various factors to cause disease in animals, including adhesins, invasins, protectins, iron acquisition systems, and toxins . These factors help ExPEC adhere, invade, evade the immune system, colonize, proliferate, and spread throughout the body, leading to infection in animals . Other bacterial factors such as secretion systems, quorum sensing systems, transcriptional regulators, and two-component systems also play a role in ExPEC pathogenesis . In this study, the virulotyping revealed that the E. coli strain was positive for PAI, iut A, pap G allele III, cva C, sfa s, and afa / dra BC. Adhesins are bacterial components that help them stick to other cells or surfaces, increasing their virulence. Specific adhesins are adapted to colonize different environments. Virulence genes linked to adhesion include pap G allele III, sfas , and afa / dra BC. Iron is a crucial micronutrient necessary for the growth and proliferation of bacteria within the host following successful colonization and/or invasion. Among the most significant virulence plasmids associated with ExPEC virulence are ColV and ColBM, particularly those containing the aerobactin operon ( iut A/ iuc ABCD). This operon codes for high-affinity iron-transport systems that enable bacteria to acquire iron in low-iron environments, such as those found in host fluids and tissues. Our isolates carrying virulence genes were found to possess the iut A gene, which facilitates survival in low iron conditions. Antibiotics are commonly utilized for the prevention and treatment of ExPEC infections. However, the widespread use of antibiotics has been linked to the development of multidrug-resistant bacteria. The high levels of antibiotic resistance observed in ExPEC strains present a significant risk to human health, as antibiotic-resistant bacteria and genes can be transmitted through the food chain. Previous research has shown that ExPEC isolates exhibit resistance to multiple antibiotics , underscoring the importance of conducting antibiotic susceptibility testing to identify the most effective treatment option. In this particular instance, the E. coli strain exhibited broad-spectrum beta-lactamase production. β-Lactam antibiotics, particularly 3rd generation cephalosporins, are commonly prescribed for the treatment of serious community-onset or hospital-acquired infections caused by E. coli . Regrettably, β-lactamase production in E. coli continues to be a significant factor in the development of resistance to β-lactam antibiotics . β-lactamases are bacterial enzymes that render β-lactam antibiotics ineffective through hydrolysis. This study presents findings on septic polyarthritis and/or septicemia in juvenile giraffes, potentially attributed to insufficient colostrum intake and E. coli infection via the umbilical cord. Furthermore, the study elucidates the diverse array of virulence factors exhibited by the E. coli strain and underscores the pathogenic significance of these pathogens in animal health. Continued research is warranted to identify additional virulence factors and elucidate the pathogenic mechanisms, ultimately aiding in the development of an effective diagnosis and treatment strategy for managing giraffe colibacillosis. Supplementary Material 1. Supplementary Material 2. Supplementary Material 3. |
null | e814789b-ddb6-4c6e-9a90-40082890bdd3 | 10819464 | Pharmacology[mh] | Trollius chinensis Bunge, a perennial herb of the Ranunculaceae family, falls under the genus Trollius . Widely distributed in Northern China, T. chinensis is recognized for its high ornamental and medicinal value . Its dried flowers, known as Flos Trollii, serve as the medicinal component . There are more than 20 identified species in the genus Trollius . They are distributed mainly in the temperate and arctic regions of Asia, Europe, and North America, of which 16 are in China . It usually grows in peatlands, swamps, wet meadows, and banks of reservoirs, as well as in mountain areas up to the alpine zone . T. chinensis , with its significant ornamental and health-related compounds, is highly esteemed for applications in the food, medicine, and cosmetic industries . Traditionally, the Chinese have employed T. chinensis for medicinal and tea purposes, dating back to the Qing Dynasty and recorded in Supplements to the Compendium of Materia Medica (Qing Dynasty) as “bitter in taste, cold in nature, non-toxic, mainly used for heat-clearing and detoxicating” . It holds a prominent place in pharmacies, is frequently referenced in medical literature, and is listed in the Chinese Pharmacopoeia (Edition 2020) with five Chinese patent medicines. Pharmacological tests have substantiated T. chinensis ’s anti-inflammatory, anti-oxidant, anti-bacterial, and anti-viral properties, correlating closely with its chemical composition . Over 100 compounds have been isolated from Trollius species, including flavonoids, organic acids, coumarins, alkaloids, terpenoids, and prenyl flavonoids in T. chinensis , boasting diverse biological activities . To date, more than 100 compounds have been isolated from Trollius species. Phytochemical investigations of this plant have demonstrated the presence of flavonoids, organic acids, coumarins, alkaloids, terpenoids, and prenylflavonoids as main constituents of T. chinensis with diverse biological activities . For instance, the flavonoid metabolite(s) Orientin and poncirin found in T. chinensis exhibited significant antiviral activity against parainfluenza type 3 (Para 3) . Additionally, researchers have identified seventeen new labdane diterpenoid glycosides A–Q (1–17) in the dried flowers of T. chinensis , possessing therapeutic, antiviral, and antibacterial properties, establishing T. chinensis as a common anti-inflammatory drug and health tea . The flowers have traditional uses in treating respiratory infections, pharyngitis, tonsillitis, and bronchitis in Chinese medicine . The exploration of T. chinensis holds immense potential for novel medication research and therapeutic advancements . This review article aims to provide comprehensive information and highlight the potential values associated with the development of T. chinensis . Relevant literature was obtained from scientific databases such as TCMSP ( https://old.tcmsp-e.com/tcmsp.php , accessed on 21 April 2023), Pubchem ( https://pubchem.ncbi.nlm.nih.gov , accessed on 23 April 2023), Scientific Database of China Plant Species ( http://db.kib.ac.cn , accessed on 10 April 2023), Google Scholar ( https://xs.scqylaw.com , accessed on 5 April 2023), PubMed ( https://pubmed.ncbi.nlm.nih.gov , accessed on 5 April 2023), Baidu Scholar ( https://xueshu.baidu.com , accessed on 3 April 2023), Vip site (China Science and Technology Journal Database) ( http://www.cqvip.com , accessed on 3 April 2023), and CNKI site (Chinese National Knowledge Infrastructure) ( https://www.cnki.net , accessed on 3 April 2023). The most extensive collection of publicly available chemical data in the world is found on PubChem. Chemicals can be found using their names, structures, molecular formulas, and other identifiers. Discover information about biological activity, safety and toxicity, chemical and physical qualities, patents, literature citations, et al. The PubChem Compound, Substance, and Bioassay sub-databases are the three sub-databases that make up the PubChem database. TCMSP, which includes 499 Chinese herbal medicines, a total of 29,384 ingredients, 3311 targets, and 837 related diseases. TCMSP is a unique systematic pharmacology platform for Chinese herbal medicines, where we can find the relationship between drugs, targets, and diseases. This database platform provides information that includes identifying active ingredients, compounds, drug target networks, et al. . The Database of China Plant Species is jointly constructed by the Kunming Institute of Botany, Chinese Academy of Sciences (KIB), the Institute of Botany, Chinese Academy of Sciences (IBS), the Wuhan Botanical Garden, Chinese Academy of Sciences (WBG), and the South China Botanical Garden, Chinese Academy of Sciences (SCBG). There are more than 31,000 species of higher plants in more than 3400 genera in more than 300 families, and the data content mainly includes standard names of plant species, basic information, systematic taxonomic information, ecological information, physiological and biochemical characteristic description information, habitat and distribution information, literature information, and other information. TCMSP, Pubchem, and Web of Huayuan were used to find the chemical composition of T. chinensis . Most of the active components were obtained by searching for T. chinensis in TCMSP. Then, PubChem and Web of Huayuan were used to obtain and validate information related to the chemical structure of organic small molecules contained in the herb and their biological activities. The Web of China Plant Species Information Database is the primary source for the botanical collection of the genus Trollius . All the sites listed above are public databases and have access to the public database. The article is summarized using other websites that gather literature about the development of T. chinensis research. Diverse studies have been published in recent years. Therefore, a comprehensive review is necessary. This paper reviewed the research progress of T. chinensis from six aspects, including botany, materia medica, ethnopharmacological use, phytochemistry, pharmacology, and quality control, with the keywords of chemical constituents such as flavonoids, phenolic acids, anti-inflammatory effects, and antimicrobial effects, as well as related words such as pharmacological effects. We reviewed 350 related papers. This paper draws on over 120 articles on T. chinensis and documents some of the literature on chemical composition and pharmacological studies conducted from 1991 to 2023. Based on the search results from the Chinese herbal medicine series of the Chinese herbal medicine resource dictionary , Flora of China ( https://www.plantplus.cn/foc , accessed on 10 April 2023), Scientific Database of China Plant Species (DCP) ( http://db.kib.ac.cn , accessed on 10 April 2023), and other websites, and complemented by an extensive array of references, the genus Trollius comprises 26 species, as detailed in . T. chinensis , a perennial herb of medicinal significance, features dried flowers as its medicinal components . The geographical distribution of T. chinensis mainly spans Asia, Europe, the temperate zones of North America, and the Arctic region. In China, it is located in Tibet, Yunnan, Sichuan, Qinghai, Xinjiang, Gansu, Shaanxi, Shanxi, Henan, Hebei, Liaoning, Jilin, Heilongjiang, Inner Mongolia, and Taiwan . Additionally, it is prevalent in Russia (Far East, Siberia, and Central Asia), North Korea, Inner Mongolia, Sakhalin Island (Sakhalin Island), Nepal, and Northern Europe . Thriving in light and moist conditions, T. chinensis flourishes best in deep, preferably heavy, and consistently moist soil, exhibiting resilience in full sun or partial shade. Typically growing at elevations between 1000 and 2000 m, it is frequently observed at approximately 1400 m in habitats with ample water and optimal light conditions, such as peatlands, marshes, wet meadows, reservoir banks, mountainous areas, and alpine areas . T. chinensis plants are glabrous, boasting columns reaching up to 70 cm in height . The stems, numbering 1–3, range from 3.5–100 cm tall, either unbranched or branched above the middle, with occasional basal or distal branching and sparse foliage featuring 2–4 leaves. Basal leaves, numbering 1–4, measure 16–36 cm in length and are characterized by long stalks, occasionally accompanied by 1–3 rosette leaves. The leaf blade is pentagonal, with dimensions of 3.8–12.5 cm, exhibiting a cordate, trilobated base; the petiole, measuring 12–30 cm, has a narrowly sheathed base. Cauline leaves mirror basal leaves, with lower leaves possessing long stalks and upper leaves being smaller, short-stalked, or sessile. The pedicel, mostly grey-green, extends 5–9 cm in length. Flowers appear solitarily terminal or in 2–3 cymes, with a diameter ranging from 3.8–5.5 cm. Sepals, numbering 6–19, measure 1.6–2.8 cm and exhibit varying colors among species, including pale purple, pale blue, white, golden yellow, yellow, or orange-yellow. The leaf blade is not green when dried and is isobovate or elliptic-obovate in shape. Petals, numbering 18–21, are narrowly linear, slightly longer than sepals or subequal to sepals apically attenuate, measuring 1.8–2.2 cm in length and 1.2–1.5 mm in width. Stamens, numerous and spirally arranged, range from 0.5–1.1 cm in length. Carpels, numbering 20–30, are sessile, and follicles are 1–1.2 cm in length and approximately 3 mm in width. Seeds are subobovoid, around 1–1.5 mm in length, black, and glossy. Flowering June–July, fruiting August–September . T. chinensis has various nicknames. T. chinensis was recorded in the Annals of Shan Xi Traditional Chinese Medicine as Golden Pimple. It has been recorded in Wild Plants of Shan Xi under Asian T. chinensis. Tropaeolum majus, T. chinensis was recorded as a Supplement to the Compendium of Materia Medica (Thirty Years of Qianlong, 1765) by Shanxi Tong Zhi. Liao’s History is also recorded in the Annals of Wu Tai Mountain and the Sea of Humanity under Nasturtium. In Liao’s History Ying Wei Zhi, T. chinensis is recorded as T. chinensis , and The Book of Pictorial Guide of Chinese Plants calls it a globeflower . T. chinensis was initially recognized as an ornamental plant. It was not until the Qing Dynasty that the medicinal value of T. chinensis was widely developed. The Record of Ennin’s Diary: The Record of a Pilgrimage to China in Search of the Law mentions that T. chinensis blooms in June and July . After that, in the Yuan Dynasty, the poet Zhou Boqi used T. chinensis as the title of the Book of the Squire of Shangdu Poems, left heroic verses with the objects, and recorded the characteristics of the flowers of T. chinensis in the notes of the Book of the Squire of Shangdu Poems. In the Qing Dynasty, the origin of T. chinensis was recorded in the Shanxi Tong Zhi. In the Annals of Mount Wu Tai, under the name of nasturtium, T. chinensis was associated with miracles to record articles. The Widely Manual of Aromatic Plants describes the golden yellow color of the flower, seven petals, and two layers; the heart of the flower is also yellow; there are several flowers on one stem; and so on, describing in detail the flowering period, flowering characteristics, and other botanical characteristics of T. chinensis . It appeared as a companion botanical drug to licorice in the description of licorice in the Bencao ZhengYao (Ming Dynasty, AD 1368–1644) but was not included in the book in its entirety . T. chinensis ’s medicinal functions were first recorded in Supplements to the Compendium of Materia Medica (Thirty Years of Qianlong, 1765) . Modern character descriptions and fluorescence identification of T. chinensis have been included in the Chinese Pharmacopeia (1977 edition). T. chinensis is a traditional Mongolian medicine and not a widely used medicinal herb. Initially, its sources of medicinal herbs were mainly wild, and due to the lack of commercial supply, fewer applications, regional herbs, and relatively limited clinical applications and research, as well as the cold nature of T. chinensis , some potential safety and efficacy issues, and other factors, it has not been included in the Pharmacopoeia of China since 1985 . The Chinese Pharmacopoeia (2020 edition) includes only five proprietary Chinese medicines: Jinlianhua Tablets, Jinlianhua Runhou Tablets, Jinlianhua Mixture, Jinlianhua Capsules, and Jinlianhua Granules . 5.1. Traditional Uses T. chinensis serves as both a traditional Chinese medicine and a frequently used ethnomedicine. The herb can improve heat clearance, detoxification, alleviation of oral/throat soreness, earache, eye pain, cold-induced fever, and vision improvement . Furthermore, it can effectively treat boils, poisons, and winds. The Shanhai Caozhuan briefly mentions T. chinensis as a remedy for boils, poisons, and all kinds of winds. Flowers are used in the Hebei Handbook of Traditional Chinese Medicine (1970) for chronic tonsillitis. T. chinensis is combined with Juhua and Guanaco, doubled in acute cases, or added with Yazhicao in equal parts. To treat acute otitis media, acute conjunctivitis, and other inflammatory diseases of the upper focus, T. chinensis and Juhua are each taken with three qian, and raw Gancao with one qian. Zhaobing Nan Fang records combining Nanshashen and Beishashen with 12 g of T. chinensis to promote yin and diminish fire, reducing spleen and kidney yin deficiency and inflammation caused by fire inadequacy. It is noted in the Manual of Chinese Herbal Medicine Commonly Used in Guangxi Folklore: Book I that T. chinensis has been utilized for alleviating eye inflammation and pain. Furthermore, T. chinensis , along with Wushuige and Mufurong, are recommended for treating malignant sores via compressing and pounding the affected site . 5.2. Current Use In 2003, the Administration of Traditional Chinese Medicine of China announced a prescription for preventing atypical pneumonia. The prescription, T. chinensis Tang, combined six botanical drugs, including T. chinensis , to clear away heat, detoxify toxins, disperse wind, and penetrate evil spirits. This prescription had a significant effect on atypical pneumonia and is now commonly used to prevent and treat “plague”, such as the new coronavirus . Its principal effects and clinical use for acute and chronic tonsillitis and other inflammatory conditions are recorded in the National Compendium of Chinese Herbal Medicine (1975). The pharmacological effects of T. chinensis are summarized in the Dictionary of Traditional Chinese Medicine (2006). To cope with the contemporary and rapidly changing lifestyle, the utilization of T. chinensis medicinal decoctions has diminished compared with previous times. Instead, they are now commonly consumed as patented medications—for example, Jinlianhua soft capsules and health products . Moreover, the petals and stamens of T. chinensis are widely employed as a flavoring agent in culinary contexts, imparting a distinctive taste to salads, desserts, and beverages. Moreover, it can be used as a coloring agent, food additive, and dyeing agent . It is also valued as an antioxidant component in cosmetics, including T. chinensis Pure Lotion and T. chinensis Spray. The ethnopharmacological uses of T. chinensis are shown in . T. chinensis serves as both a traditional Chinese medicine and a frequently used ethnomedicine. The herb can improve heat clearance, detoxification, alleviation of oral/throat soreness, earache, eye pain, cold-induced fever, and vision improvement . Furthermore, it can effectively treat boils, poisons, and winds. The Shanhai Caozhuan briefly mentions T. chinensis as a remedy for boils, poisons, and all kinds of winds. Flowers are used in the Hebei Handbook of Traditional Chinese Medicine (1970) for chronic tonsillitis. T. chinensis is combined with Juhua and Guanaco, doubled in acute cases, or added with Yazhicao in equal parts. To treat acute otitis media, acute conjunctivitis, and other inflammatory diseases of the upper focus, T. chinensis and Juhua are each taken with three qian, and raw Gancao with one qian. Zhaobing Nan Fang records combining Nanshashen and Beishashen with 12 g of T. chinensis to promote yin and diminish fire, reducing spleen and kidney yin deficiency and inflammation caused by fire inadequacy. It is noted in the Manual of Chinese Herbal Medicine Commonly Used in Guangxi Folklore: Book I that T. chinensis has been utilized for alleviating eye inflammation and pain. Furthermore, T. chinensis , along with Wushuige and Mufurong, are recommended for treating malignant sores via compressing and pounding the affected site . In 2003, the Administration of Traditional Chinese Medicine of China announced a prescription for preventing atypical pneumonia. The prescription, T. chinensis Tang, combined six botanical drugs, including T. chinensis , to clear away heat, detoxify toxins, disperse wind, and penetrate evil spirits. This prescription had a significant effect on atypical pneumonia and is now commonly used to prevent and treat “plague”, such as the new coronavirus . Its principal effects and clinical use for acute and chronic tonsillitis and other inflammatory conditions are recorded in the National Compendium of Chinese Herbal Medicine (1975). The pharmacological effects of T. chinensis are summarized in the Dictionary of Traditional Chinese Medicine (2006). To cope with the contemporary and rapidly changing lifestyle, the utilization of T. chinensis medicinal decoctions has diminished compared with previous times. Instead, they are now commonly consumed as patented medications—for example, Jinlianhua soft capsules and health products . Moreover, the petals and stamens of T. chinensis are widely employed as a flavoring agent in culinary contexts, imparting a distinctive taste to salads, desserts, and beverages. Moreover, it can be used as a coloring agent, food additive, and dyeing agent . It is also valued as an antioxidant component in cosmetics, including T. chinensis Pure Lotion and T. chinensis Spray. The ethnopharmacological uses of T. chinensis are shown in . According to the search results of TCMSP ( old.tcmsp-e.com/tcmsp.php , accessed on 21 April 2023), the Huayuan website ( www.chemsrc.com , accessed on 23 April 2023), PubChem ( https://pubchem.ncbi.nlm.nih.gov , accessed on 23 April 2023), and other websites combined with much of the literature review, the main components of T. chinensis include flavonoids, fatty acids, alkaloids, sterols, coumarins, tannins, and polysaccharides. 6.1. Flavonoids Flavonoids stand out as the predominant bioactive metabolites within Trollius chinensis flowers. Numerous studies have substantiated the manifold advantageous biological properties of flavonoids, encompassing anti-oxidation, anti-inflammatory, anti-viral, and anti-tumor characteristics . The flavonoids in T. chinensis consist primarily of flavone C-glycoside, flavone O-glycoside, dihydroflavone, and flavonols. Notably, flavone C-glycosides, predominantly hexose glycosides, exhibit unique stability due to a direct connection between the sugar group and the flavonoid parent nucleus via a c-c bond , forming a remarkably stable glycoside structure. The majority of flavone C-glycosides are situated at the flavone C-glycoside C-6 or C-8 positions, with a few occurring at the a-ring C-3 or C-4 positions. In T. chinensis , the flavone C-glycoside is positioned at the flavonoid A-ring C-8 positions . Polyphenols, mainly flavonoids, including Orientin, Vitexin, and isoflavin, are highly abundant among T. chinensis and are responsible for antiviral, antimicrobial, and antioxidant activities. The flavone C-glycoside includes Orientin, Vitexin, and isodoxanthin. Notably, Orientin, Vitexin, and Orientin -2″- O -β- l -galactoside emerge as the most abundant flavonoids in T. chinensis . Vitexin and Orientin glycosyl exhibit robust inhibitory effects against influenza virus, Staphylococcus aureus , and epidermis . In addition to flavone C-glycosides, flavone O-glycosides, such as Quercetin and Isoquercetin, are also discernible in T. chinensis . Noteworthy is the enhanced stability and reduced hydrolysis susceptibility of flavonoid carbosides like Orientin . The therapeutic potential of these constituents extends to the treatment of age-related macular degeneration, cancer, cardiovascular disease, and skin repair following UV damage. Refer to and for further details. 6.2. Organic Acids The concentration of phenolic acids in T. chinensis surpasses only that of flavonoids. Specifically, Veratric acid stands out with a notably high concentration of 0.86–0.91 mg.g −1 . Intriguingly, a distinct study revealed that the bioavailability of phenolic acid constituents in T. chinensis surpassed that of its flavonoid counterparts . Organic acids in T. chinensis encompass both phenolic and fatty acids. Phenolic acids predominantly constitute derivatives of benzoic acid, further classified into two categories. The first category lacks a free hydroxyl group, including Veratric acid, benzonic acid, methyl veratrate, globeflower acid, etc. The second category possesses free hydroxyl groups, including vanillic acid, methyl-p-hydroxybenzoate, p-hydroxybenzonic acid, etc. . T. chinensis houses a repertoire of 21 fatty acids, with saturated fatty acids as the primary components, and a total of 21 elements, constituting 57.95% of the detected substances. Palmitic acid and tetradecanoic acid exhibit relatively substantial content within saturated fatty acids. Additionally, nine types of unsaturated fatty acids comprise 30.35% of the total, featuring oleic acid, linoleic acid, palmitoleic acid, 3-(4-hydroxy-3-methoxybenzene) -2-acrylic acid, 3-(4-hydroxy-benzene) -2-acrylic acid, 4-phenyl-2-butenic acid, 3-phenyl-2-acrylic acid, (E) -11-eicosanoic acid, and (Z, Z, Z) -9, 12, 15-octadecanotrioleic acid . Of significant note, three crucial phenolic acids—proglobeflowery acid (PA), globeflowery acid (GA), and trolloside (TS)—have been isolated from the flowers of T. chinensis . Pharmacological investigations have underscored their diverse biological activities, strongly correlated with the flower’s efficacy in treating respiratory infections, tonsillitis, bronchitis, and pharyngitis . Refer to and for detailed insights. 6.3. Alkaloids Alkaloids, a prominent category of nitrogenous phytochemicals widely distributed in medicinal plants, stand out as crucial constituents in T. chinensis . The exploration of T. chinensis alkaloids remains limited, with only five of these compounds identified thus far. The principal pyrrolidine alkaloids include Senecionine and Integerrimine, the isoquinoline Trolline and Indole (R)-nitrile-methyl-3-hydroxy-oxyindole), and adenine . Notably, Trolline emerges as the most abundant among these five ingredients . Investigations indicate that T. chinensis flowers possess the highest total alkaloid content, while roots and branches exhibit the lowest concentrations. Among them, Trolline, an isoquinoline first discovered in T. chinensis , demonstrates significant antiviral and antibacterial activities. Refer to and for detailed data. 6.4. Other Chemical Components In addition to the aforementioned three primary active components, the flowers contain trace amounts of sterols, coumarins, tannins, and polysaccharides. Although these components exist in relatively low concentrations, their pharmacological effects are manifold, holding substantial potential for development. T. chinensis polysaccharides consist of neutral and acidic monosaccharides, predominantly comprising mannose (Man), rhamnose (Rha), galacturonic acid (GalA), glucose (Glu), galactose (Gal), arabinose (Ara), and fucose (Fuc) . T. chinensis also harbors compounds like xantho-phyll-Epoxyde (C 40 H 56 O 3 ) and trollixanthin (C 40 H 56 O 3 ). The yellow pigment in T. chinensis , characterized as a fat-soluble pigment, exhibits remarkable stability under neutral and acidic conditions . An undescribed phenolic glycoside, phenol A, isolated from T. chinensis flowers via spectroscopic methods, has revealed both its structural composition and pharmacological actions, including anti-inflammatory and antibacterial properties . Furthermore, T. chinensis encompasses eight trace elements: Fe, Mg, Cu, Zn, Mn, Cr, Pb, and As. Research indicates minimal variations in Ca and Fe levels across T. chinensis from different regions, while more pronounced differences exist in Mn, Cu, and Zn levels . For a comprehensive overview, consult and . Flavonoids stand out as the predominant bioactive metabolites within Trollius chinensis flowers. Numerous studies have substantiated the manifold advantageous biological properties of flavonoids, encompassing anti-oxidation, anti-inflammatory, anti-viral, and anti-tumor characteristics . The flavonoids in T. chinensis consist primarily of flavone C-glycoside, flavone O-glycoside, dihydroflavone, and flavonols. Notably, flavone C-glycosides, predominantly hexose glycosides, exhibit unique stability due to a direct connection between the sugar group and the flavonoid parent nucleus via a c-c bond , forming a remarkably stable glycoside structure. The majority of flavone C-glycosides are situated at the flavone C-glycoside C-6 or C-8 positions, with a few occurring at the a-ring C-3 or C-4 positions. In T. chinensis , the flavone C-glycoside is positioned at the flavonoid A-ring C-8 positions . Polyphenols, mainly flavonoids, including Orientin, Vitexin, and isoflavin, are highly abundant among T. chinensis and are responsible for antiviral, antimicrobial, and antioxidant activities. The flavone C-glycoside includes Orientin, Vitexin, and isodoxanthin. Notably, Orientin, Vitexin, and Orientin -2″- O -β- l -galactoside emerge as the most abundant flavonoids in T. chinensis . Vitexin and Orientin glycosyl exhibit robust inhibitory effects against influenza virus, Staphylococcus aureus , and epidermis . In addition to flavone C-glycosides, flavone O-glycosides, such as Quercetin and Isoquercetin, are also discernible in T. chinensis . Noteworthy is the enhanced stability and reduced hydrolysis susceptibility of flavonoid carbosides like Orientin . The therapeutic potential of these constituents extends to the treatment of age-related macular degeneration, cancer, cardiovascular disease, and skin repair following UV damage. Refer to and for further details. The concentration of phenolic acids in T. chinensis surpasses only that of flavonoids. Specifically, Veratric acid stands out with a notably high concentration of 0.86–0.91 mg.g −1 . Intriguingly, a distinct study revealed that the bioavailability of phenolic acid constituents in T. chinensis surpassed that of its flavonoid counterparts . Organic acids in T. chinensis encompass both phenolic and fatty acids. Phenolic acids predominantly constitute derivatives of benzoic acid, further classified into two categories. The first category lacks a free hydroxyl group, including Veratric acid, benzonic acid, methyl veratrate, globeflower acid, etc. The second category possesses free hydroxyl groups, including vanillic acid, methyl-p-hydroxybenzoate, p-hydroxybenzonic acid, etc. . T. chinensis houses a repertoire of 21 fatty acids, with saturated fatty acids as the primary components, and a total of 21 elements, constituting 57.95% of the detected substances. Palmitic acid and tetradecanoic acid exhibit relatively substantial content within saturated fatty acids. Additionally, nine types of unsaturated fatty acids comprise 30.35% of the total, featuring oleic acid, linoleic acid, palmitoleic acid, 3-(4-hydroxy-3-methoxybenzene) -2-acrylic acid, 3-(4-hydroxy-benzene) -2-acrylic acid, 4-phenyl-2-butenic acid, 3-phenyl-2-acrylic acid, (E) -11-eicosanoic acid, and (Z, Z, Z) -9, 12, 15-octadecanotrioleic acid . Of significant note, three crucial phenolic acids—proglobeflowery acid (PA), globeflowery acid (GA), and trolloside (TS)—have been isolated from the flowers of T. chinensis . Pharmacological investigations have underscored their diverse biological activities, strongly correlated with the flower’s efficacy in treating respiratory infections, tonsillitis, bronchitis, and pharyngitis . Refer to and for detailed insights. Alkaloids, a prominent category of nitrogenous phytochemicals widely distributed in medicinal plants, stand out as crucial constituents in T. chinensis . The exploration of T. chinensis alkaloids remains limited, with only five of these compounds identified thus far. The principal pyrrolidine alkaloids include Senecionine and Integerrimine, the isoquinoline Trolline and Indole (R)-nitrile-methyl-3-hydroxy-oxyindole), and adenine . Notably, Trolline emerges as the most abundant among these five ingredients . Investigations indicate that T. chinensis flowers possess the highest total alkaloid content, while roots and branches exhibit the lowest concentrations. Among them, Trolline, an isoquinoline first discovered in T. chinensis , demonstrates significant antiviral and antibacterial activities. Refer to and for detailed data. In addition to the aforementioned three primary active components, the flowers contain trace amounts of sterols, coumarins, tannins, and polysaccharides. Although these components exist in relatively low concentrations, their pharmacological effects are manifold, holding substantial potential for development. T. chinensis polysaccharides consist of neutral and acidic monosaccharides, predominantly comprising mannose (Man), rhamnose (Rha), galacturonic acid (GalA), glucose (Glu), galactose (Gal), arabinose (Ara), and fucose (Fuc) . T. chinensis also harbors compounds like xantho-phyll-Epoxyde (C 40 H 56 O 3 ) and trollixanthin (C 40 H 56 O 3 ). The yellow pigment in T. chinensis , characterized as a fat-soluble pigment, exhibits remarkable stability under neutral and acidic conditions . An undescribed phenolic glycoside, phenol A, isolated from T. chinensis flowers via spectroscopic methods, has revealed both its structural composition and pharmacological actions, including anti-inflammatory and antibacterial properties . Furthermore, T. chinensis encompasses eight trace elements: Fe, Mg, Cu, Zn, Mn, Cr, Pb, and As. Research indicates minimal variations in Ca and Fe levels across T. chinensis from different regions, while more pronounced differences exist in Mn, Cu, and Zn levels . For a comprehensive overview, consult and . 7.1. Antiviral Effect A study exploring the antiviral properties of T. chinensis revealed that its five active components—Vitexin, Orientin, Trolline, Veratric acid, and Vitexin-2″- O -β- l -galorientin—exert their effects by modulating Toll-like receptors (a critical class of protein molecules associated with non-specific immunity/natural immunity). Specifically, the T. chinensis soft capsule demonstrated in vitro inhibition of human coronavirus OC43 replication, accomplished through the regulation of TLRs to suppress elevated expression of host cell cytokines such as IL-1B, IL-6, and IFN-a mRNA induced by viral infection. These findings substantiate the inhibitory mechanism of the T. chinensis soft capsule against the virus . Examining 26 active components such as Rutin, Luteolin-7- O -glucoside, Kaempferol, Genistin, Apigenin, Scutellarin, Orientin, Daidzin, Vitexin, 3′-Hydroxy Puerarin, Puerarin, Daidzein, 3′-Methoxypuerarin, 2″- O -Beta- l -Galactoside, Rosmarinic acid, Progloboflowery acid, Caffeic acid, Protocatechuic acid, Ferulic acid, Veratric acid, Indirubin E, Oleracein E, Trollioside, Carbenoside I, 2″- O -(2‴-methyl butanol)isodangyloxanthin, 2″- O -(2‴-methylbutyryl) Vitexin, and glucose veratrate in T. chinensis, were observed to bind to the Mpro protein (2019-nCoV novel coronavirus pneumonia hydrolase Mpr0 protein) primarily through hydrogen bonds. This binding showcased Mpro protein-binding activity, affirming the potential of T. chinensis against novel coronaviruses . Influencing pivotal anti-inflammatory and immunomodulatory targets, T. chinensis , when combined with multiple inflammatory and immunomodulatory pathways such as tumor necrosis factor-α (TNF-α), HIF-1, and Toll-like receptors (TLR), exhibits anti-influenza viral effects, particularly against influenza A . The antiviral action of T. chinensis has been scrutinized through cyberpharmacology. While cyberpharmacological analyses offer valuable insights into pharmacological research, their reliance on network interactions between biomolecules and extensive databases introduces challenges related to data quality and reliability. Furthermore, the intricate nature of biological systems, limited experimental data, and the evolving understanding of drugs and targets require cautious consideration of credibility, necessitating further validation through pharmacological experiments . Chicken embryos served as the medium for influenza virus cultivation, with the inhibitory effect of T. chinensis alcohol extract on viral proliferation in chicken embryo allantoic fluid evaluated through a chicken erythrocyte agglutination test. The results substantiated the direct inactivation of the influenza A virus by T. chinensis alcohol extract in vitro. In a parallel experiment involving influenza A virus inoculation into chicken embryos, the T. chinensis alcohol extract effectively curbed the proliferation of the virus within the embryos . In a mouse model infected with influenza A (H1N1) virus, the study categorized the subjects into the control group, TGC group ( T. chinensis crude extract gavage group), VI1~3 groups (virus infection model 1~3 groups), and VI + TGC 1~3 groups (treatment 1~3 groups), each comprising 10 mice. Notably, the aqueous extract of T. chinensis exhibited the potential to enhance the antiviral ability of mice. Subsequent comparative analyses validated the initial findings, establishing that aqueous extracts of T. chinensis augmented antiviral capacity in mice. Conversely, alcoholic extracts of T. chinensis directly deactivated the influenza A virus . Furthermore, the aqueous extract of T. chinensis demonstrated potent inhibitory activity against the Cox B3 virus, achieving an inhibitory concentration of 0.318 mg/mL. The total flavonoids in this study displayed varying inhibitory activity against the respiratory syncytial virus, influenza A virus, and parainfluenza virus, with inhibitory concentrations of the viruses being 20.8 μg/mL and 11.7 μg/mL for Vitexin and Orientin, respectively . Notably, 60% ethanolic extracts of T. chinensis and total flavonoids exhibited weak effects, with Protopanaxanthic acid among the organic acids demonstrating the weakest antiviral ability. While T. chinensis showed effectiveness against the influenza A virus, its impact on the influenza B virus was not significant . Comparative assessments revealed that the alcoholic extract solution of T. chinensis soup displayed greater antiviral effects than the aqueous decoction of T. chinensis soup. Additionally, higher-purity T. chinensis soup extract exhibited a more robust inhibitory effect on the influenza virus. Specifically, 80% T. chinensis soup extract and secondary 95% T. chinensis soup extract demonstrated superior antiviral effects compared with 60% T. chinensis soup extract . A study delved into the material basis of the UPLC-DAD-TOF/MS fingerprinting profile (ultra-performance liquid chromatography-tandem diode array detector-time-of-flight mass spectrometry) of T. chinensis , establishing its potential as the active agent against EV71 (enterovirus 71). The key active ingredients of T. chinensis in combating EV71 included Guaijaverin acid, an unidentified alkaloid, P-hydroxybenzene-malic acid, and 2″- O -acetyl Orientin . In the broader context, T. chinensis flowers emerged as a valuable contributor to the anti-influenza virus activity of the overall formula, exhibiting relatively few side effects. The synergistic effect of T. chinensis , particularly in formulations like T. chinensis soup, has proven effective as a treatment for influenza virus . In recapitulation, the findings indicate that the antiviral mechanism of T. chinensis predominantly revolves around impeding the virus-receptor binding process and restraining the cytokines/chemokines response. The unrefined flower extract derived from T. chinensis shields the host from inflammatory damage by intervening in the TLRs, encompassing TLR3, TLR4, and TLR7. This intervention leads to a reduction in the secretion of inflammatory factors, ultimately manifesting antiviral effects . 7.2. Antioxidant Effect The varied pharmacological impacts of Orientin in T. chinensis , particularly its potent antioxidant effect, surpass those attributed to Vitexin. This discrepancy may be attributed to the structural disparity between Orientin and Vitexin. The oxidative activity of flavonoids with an o-diphenol hydroxyl group on the B-ring is notably more robust compared with those flavonoids possessing a singular phenol hydroxyl group attached to the B-ring . To assess the antioxidant capacity of Orientin and Vitexin in T. chinensis concerning D-galactose-induced subacute senescence in mice, D-galactose was administered intraperitoneally . The experimental outcomes revealed that Orientin and Bauhinia glycosides in T. chinensis effectively elevated the total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GPGP), and glutathione peroxidase (GPP) in the tissues of the kidneys, livers, and brains of senescent mice. Additionally, these compounds increased SOD, glutathione peroxidase (GSH-Px), Na + -K + -ATPase, and Ca 2+ -Mg 2+ -ATPase activities in kidney, liver, and brain tissues. Notably, Orientin demonstrated superior efficacy over Oryza sativa in augmenting T-AOC activity within the organism . The former mitigates impaired sodium ion transport and associated metabolic disorders , while the latter, elevated levels of Ca 2+ , adversely impact the cytoskeleton and membrane structure of neuronal cells, culminating in diminished stability and heightened membrane permeability, thereby contributing to the senescence process . In contrast, the glycosides of Orientin and Vitexin pruriens act as antioxidants by positively modulating the activity of membrane transporter enzymes within tissue cells. Remarkably, Orientin exhibited greater efficacy than Vitexin in enhancing the activity of these tissue cell membrane transporter enzymes . The robust antioxidant potential of Orientin, exceeding that of poncirin and further surpassing total flavonoids, has been corroborated in various studies. Both Orientin and Vitexin demonstrate the ability to scavenge superoxide anion, hydroxyl radical, and DPPH radical, effectively safeguarding the erythrocyte membrane. Specifically, Orientin displayed notable scavenging efficacy within the concentration range of 2.0–12.0 μg/mL. In contrast, Vitexin exhibited hydroxyl radical scavenging within the concentration range of 0–1.0 μg/mL, achieving maximum scavenging efficiency at 1.0 μg/mL, followed by a decline in scavenging effect with increasing Vitexin concentration . The pharmacological mechanism underlying the antioxidant action of T. chinensis encompasses several key facets: (1) Scavenging of free radicals: The active constituents in T. chinensis , particularly flavonoids, exhibit potent free radical scavenging capabilities. This capacity enables the neutralization of free radicals both inside and outside the cell, thereby mitigating oxidative stress-induced damage . (2) Stimulation of antioxidant enzyme activity: the active ingredients in T. chinensis stimulate the activity of antioxidant enzymes by stimulating the intracellular antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, etc. . This stimulation enhances the efficacy of the antioxidant system, fortifying cells against oxidative damage. In conclusion, T. chinensis safeguards cells from oxidative damage through the dual mechanisms of scavenging free radicals and enhancing antioxidant enzyme activity. These combined actions underscore the efficacy of T. chinensis as a potent antioxidant therapeutic agent. 7.3. Anti-Inflammatory Effect The anti-inflammatory prowess of T. chinensis primarily targets the upper segment of the triple energizer, encompassing the area above the diaphragm within the human body. This region predominantly involves organs such as the stomach and throat, extending through the diaphragm and chest, including the heart, lungs, viscera, head, and face. Both the aqueous extract and 95% ethanol extracts of T. chinensis manifest robust anti-inflammatory activities. Notably, within the repertoire of compounds contained in T. chinensis , flavonoids such as Robinin, Quercetin, Vitexin, and Orientin exhibit heightened anti-inflammatory efficacy. Particularly, Vitexin and Orientin, due to their anti-inflammatory and soothing properties, along with peptide anti-histamine attributes, are deemed suitable for managing acute allergic skin conditions such as rash and eczema, as well as respiratory allergic diseases . Current domestic research on T. chinensis underscores its potential in treating upper respiratory tract infectious diseases, including nasal mucosal diseases, by deploying an anti-inflammatory mechanism that engages multiple metabolites, targets, and pathways. Among the identified core targets, TNF and mitogen-activated protein kinase 1(MAPK1) take precedence, with the cancer factor pathway emerging as a pivotal route . Additionally, Toll-like receptors 3, 4, and 7 (TLR3/4/7) have been proposed as promising common anti-inflammatory targets for T. chinensis constituents. This includes Vitexin, Orientin, Trolline, Veratric acid, and Vitexin-2″- O -galactoside, as discerned through the integration of network pharmacology and molecular docking techniques . Respiratory inflammation, arising from diverse pathogens, microbial infections, influenza, nitroative stress, and compromised immune systems, can be effectively addressed by T. chinensis . Its therapeutic spectrum extends beyond treating nasal mucosa inflammation to positively impacting upper respiratory infections. Leveraging data mining, an enriched analysis of the top 20 pathways linked to the targets and metabolites of T. chinensis in upper respiratory tract infection treatment identified quercetin as a highly probable compound. This conclusion was derived from the “metabolite-target-signaling pathway” network analysis . Moreover, T. chinensis preparations exhibit therapeutic potential against upper respiratory tract infections by reducing serum inflammatory factors in patients. These factors include IL-8, IL-6, TNF-alpha, C-reactive protein, and procalcitonin, along with the modulation of T-cell subpopulation ratios . Additionally, Orientin-2″- O -β- l -galactoside and Veratric acid have been identified for their anti-inflammatory effects . In the clinical realm, the combination of amoxicillin, sodium, and potassium clavulanate has demonstrated the potential to reduce treatment duration and enhance therapeutic efficacy in children with acute tonsillitisn ratios . In summary, T. chinensis harbors a repertoire of anti-inflammatory compounds, including Vitexin, Orientxin, Trolline, Veratric acid, and Vitexin-2″- O -galactoside. Notably, Quercetin may also contribute significantly to its anti-inflammatory activity . Specifically, Orientin demonstrates efficacy in attenuating LPS-induced inflammation by impeding the production of inflammatory mediators and suppressing the expression of Cyclooxygenase 2 (COX-2) and Inducible nitric oxide synthase (iNOS) . Vitexin-2″- O -galactoside exhibits substantial inhibitory effects on lipopolysaccharide (LPS)-induced inflammation, as evidenced by its impact on key factors such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), iNOS, and COX-2 expression. Additionally, it mitigates the production of reactive oxygen species and exerts an anti-neurogenic role by inhibiting the NF-κB and extracellular signal-regulated kinase (ERK) signaling pathways, leading to anti-neuroinflammatory activity. However, the pharmacological mechanisms underlying the anti-inflammatory effects of the other components remain elusive. 7.4. Antitumour Flavonoids derived from T. chinensis exhibit notable inhibitory effects on active cancer cells. Specifically, the total flavonoids from T. chinensis demonstrate the capacity to impede the proliferation of tumor cells by activating the mitochondrial pathway . T. chinensis extracts exerted strong inhibitory effects on Leukemia K562 cells (K562), and HeL T. chinensis extracts manifest robust inhibitory influences on various cancer cell lines, including Leukemia K562 cells (K562), HeLa cells (He La), esophageal cancer cellsEc-109 (Ec-109), lung cancer cells NCI-H446 (NCI-H446), human non-lung cancer cells NCI-H446 (NCI-H446), human non-small cell lung cancer cell line A549 (A549), and human carcinoma cells HT-29 (HT-29), MCF-7, and HepG2, among others . Moreover, the total flavonoid extract of T. chinensis significantly retards the growth and proliferation of MCF-7 cells. This involvement is characterized by the activation of caspase-3 and caspase-9, leading to induced cell apoptosis within a concentration range of 0.0991 to 1.5856 mg/mL . Non-alcoholic fatty liver disease (NAFLD) stands as a clinical pathologic syndrome , with its incidence in China reaching a significant 29.2%, demonstrating an annual increase . The complex interplay of metabolic disorders, such as dyslipidemia, hypertension, hyperglycemia, and persistent abnormalities in liver function tests, is closely associated with NAFLD . Elevated lipid levels induce expression changes in HepG2 cells (hepatoma cells) . In an investigation into the impact of total flavonoids from T. chinensis on HepG2 cell function induced by high sugar levels, it was observed that oxidative stress levels in hepatocytes and the metabolic balance of reactive oxygen species (ROS) in HepG2 cells were intricately linked to intracellular fat accumulation. The study conclusively demonstrated that total flavonoids from T. chinensis exhibit a specific therapeutic effect on HepG2 cells by influencing disease-associated processes. Tissue cultures were employed to compare the effects of high glucose concentrations and varying doses of total flavonoids from T. chinensis on HepG2 cells. The proliferative tendencies of lipid substances are directly correlated with ROS levels; higher lipid accumulation corresponds to elevated ROS levels. Elevated glucose concentrations intensified ROS levels, while total flavonoids from T. chinensis effectively attenuated ROS levels, thereby influencing HepG2 cells. In vitro, total flavonoids from T. chinensis demonstrated a capacity to reduce lipid substance accumulation, presenting a promising avenue for the improved treatment of NAFLD . The ethanol extract derived from the total flavonoids of T. chinensis has been observed to induce apoptosis in HT-2 cells through the endogenous mitochondrial pathway. In addition, specific constituents of T. chinensis, namely Orientin and Vitexin, have demonstrated inhibitory effects on human esophageal cancer EC-109 cells. The apoptotic induction of EC-109 cells by both Orientin and Vitexin was found to correlate with increased drug action time and elevated drug concentrations. Significantly, Orientin surpassed Vitexin in effectively inhibiting the growth and apoptosis of EC-109 cells . At the administration dose of 80 μM, Orientin demonstrated a more potent apoptotic effect on EC-109 cells compared with Vitexin at the same concentration, registering apoptotic rates of 28.03% and 12.38%, respectively, within the concentration range of 0.91 to 1.5856 mg/mL. Elucidating the pharmacological mechanism underlying Orientin’s action, specifically in the context of esophageal cancer cells (EC-109), involves the up-regulation of P53 expression and concomitant down-regulation of Bcl-2 expression. This dual modulation positions Orientin as a prospective therapeutic agent for esophageal cancer. Utilizing the total flavonoids of T. chinensis as a model drug, our exploration delved into the molecular-level relationship and mechanism of these flavonoids, shedding light on their antitumor activity. A pertinent discovery was that Orientin affected HeLa, augmenting the Bax/Bcl-2 protein ratio. This manifested as an increase in Bax protein levels coupled with a decrease in Bcl-2 protein levels, thereby triggering apoptotic protease activation. Consequently, this inhibition of HeLa cell proliferation underscores the therapeutic potential of Orientin in cervical cancer treatment. While the notable anti-tumor activity of T. chinensis extract is evident, the specific mechanistic intricacies remain elusive. Putatively, this metabolite’s impact on the signaling pathways within tumor cells plays a pivotal role. T. chinensis is observed to down-regulate anti-apoptotic genes Bcl and Bcl-xL while concurrently up-regulating pro-apoptotic genes such as Bax, caspase-9 , and caspase-3 at the mRNA levels. This concomitant suppression of COX-2 gene expression in tumor cells is linked to inhibiting the proliferation of diverse tumor cell lines. The inhibitory effect extends to the HT-29 of human colon cancer cells, with T. chinensis flavonoids proving efficacious in restraining cell proliferation. The concentration-dependent inhibition of human non-small cell lung cancer A549 cells, the induction of apoptosis in lung cancer A549 cells, and the anti-lung cancer role demonstrated by these flavonoids underscore their potential therapeutic relevance. Moreover, the ability of T. chinensis flavonoids to impede the progression of K562 cells, retaining them in the Go/G1 phase, elucidates their protective role against leukemia. Additionally, beyond the total flavonoid components, the total saponins of T. chinensis showcase robust antitumor activity, albeit without significant advantages over other pharmaceutical agents . 7.5. Antibacterial Effect T. chinensis manifests broad-spectrum bacteriostatic activity against both Gram-positive cocci and Gram-negative Bacilli, including Pseudomonas aeruginosa, Staphylococcus aureus , Diplococcus pneumoniae, and Shigella dysenteriae. The pivotal antibacterial constituents of T. chinensis are its flavonoids, notably Orientin and Vitexin . In vitro assessments utilized Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) as benchmarks for analyzing Escherichia coli , Salmonella , Staphylococcus aureus , Bacillus subtilis , Streptococcus mutans , Streptomyces , Rhodotorula , Aspergillus niger , and Candida albicans . The 30% ethanolic extract of T. chinensis exhibited notable antibacterial efficacy, particularly inhibiting Streptococcus mutans, suggesting a potential therapeutic avenue for dental caries. T. chinensis total flavonoids, along with Orientin and Vitexin, exhibited notable inhibitory effects on Gram-positive cocci while demonstrating no discernible impact on Gram-negative Bacilli and fungi. Their most pronounced inhibitory activity was observed against Staphylococcus aureus , with the order of inhibitory strength being Orientin = Total flavonoids > Vitexin. Specifically, the lowest inhibitory and bactericidal concentrations were determined to be 0.15625 mg·mL −1 and 0.625 mg·mL −1 for Orientin and total flavonoids, respectively. Additionally, these components demonstrated considerable inhibitory activity against Streptococcus mutans, with the antibacterial efficacy ranking as Orientin > Total flavonoids > Vitexin. Notably, the lowest inhibitory concentration and bactericidal concentration of Orientin were 0.15625 mg·mL −1 and 0.625 mg·mL −1 , surpassing the efficacy of Vitexin . In investigations exploring the bacteriostatic activity of various T. chinensis preparations, the Staphylococcus aureus solution clarified at concentrations of 225 mg/mL for Jinlianhua Tablets, 56.25 mg/mL for Jinlianhua Jiaonang, 450 mg/mL for Jinlianhua Granules, and 56.25 mg/mL for T. chinensis oral solution. For Bacillus subtilis , clarification occurred at concentrations of 56.25 mg/mL for Jinlianhua tablets, 14.0625 mg/mL for T. chinensis capsule, 225 mg/mL for T. chinensis granules, and 28.125 mg/mL for T. chinensis oral solution. Notably, the T. chinensis oral solution displayed no inhibitory effect against Escherichia coli . These experiments revealed that the antibacterial activities of the four T. chinensis preparations followed the order of strength as Bacillus subtilis > Staphylococcus aureus > Escherichia coli , with varying minimum inhibitory concentrations (MICs) against Staphylococcus aureus and Bacillus subtilis for different T. chinensis preparations, ranked from strongest to weakest as Jinlianhua capsules, Jinlianhua mixture, Jinlianhua tablets, and Jinlianhua granules . In the in vitro bacteriostatic efficacy assessment, the total flavonoids extracted from T. chinensis exhibited robust inhibitory effects against common pathogenic organisms, including Staphylococcus epidermidis , Staphylococcus aureus , Escherichia coli , Streptococcus viridans , Salmonella paratyphi A , and Salmonella paratyphi B . Notably, the total demonstrated considerable protective effects in Staphylococcus aureus -infected mice, showcasing a dose-dependent reduction in the 48-h mortality of the infected mice . The yellow pigment of T. chinensis , composed of xantho-phyll epoxyde and trollixanthin, also displayed bacteriostatic properties, with varying degrees of inhibition against Staphylococcus aureus , Bacillus subtilis , and Escherichia coli , showing increased activity with escalating concentrations. Tecomin, a glucose ester of Veratric acid, exhibited effective inhibition against Staphylococcus aureus and Pseudomonas aeruginosa, with MICs of 0.256 and 0.128 mg/mL, respectively . Progloboflowery acid has emerged as an effective treatment for Pseudomonas aeruginosa-induced inflammatory skin reactions. Inhibitory effects were observed for proglobeflowery acid, Vitexin, and Orientin against Bacillus subtilis , Staphylococcus epidermidis , Staphylococcus aureus , and Micrococcus luteus . T. chinensis total flavonoids, Vitexin, Orientin, and proglobeflowery acid displayed inhibitory effects on Staphylococcus aureus and Staphylococcus epidermidis , with MICs of 50 and 25 μg/mL, 100 and 25 μg/mL, 25 and 25 μg/mL, and 200 and 200 μg/mL. For Micrococcus luteus and Bacillus subtilis , the MICs were higher than 200 μg/mL . In the investigation, T. chinensis extract and its three metabolites exhibited potent inhibitory effects on four Gram-positive cocci. Total flavonoids and Vitexin, having the highest content, demonstrated strong inhibition, especially Orientin, against Staphylococcus aureus and Staphylococcus epidermidis , while PA demonstrated relatively weak inhibition against these two bacteria . The study further revealed that PA had robust inhibitory action against Pseudomonas aeruginosa and Staphylococcus aureus , with MIC rates of 16 and 200 mg/L, respectively. Additionally, PA exhibited modest antiviral activity (IC50 of 184.2 μg/mL) against Para 3. Conversely, GA displayed significant antiviral efficacy against influenza A, as evidenced by its IC50 value of 42.1 μg/mL. With a MIC rate of 128 mg/L, TS demonstrated moderate inhibitory activity against Streptococcus pneumonia . The antibacterial pharmacological mechanism underlying the action of T. chinensis predominantly revolves around impeding regular bacterial growth processes. This is accomplished by elevating extracellular nucleic acid and soluble protein levels within bacteria. The resultant damage to the cell membrane influences membrane permeability, inducing the efflux of vital metabolic substances crucial for cellular viability or the influx of detrimental medicinal fluids. Such interactions significantly impact bacterial growth, thereby realizing the intended inhibitory effects. The drug concentration exhibits a positive correlation with both the rate of inhibition of bacterial growth and the rate of inhibition of biofilm formation . 7.6. Others The main active components of T. chinensis , total flavonoids, also have analgesic and antipyretic effects. Studies have shown that flavonoids can significantly reduce ET (the lipid and polysaccharide substances produced by the cell wall of G-bacteria-ET are a standard model for screening antipyretic drugs and exploring antipyretic mechanisms). Total flavonoids can also reduce the contents of endogenous heat sources TNF-α and IL-1β in the serum of febrile rabbits and then inhibit the production and release of PGE2 in the cerebrospinal fluid of rabbits by inhibiting the production or release of TNF-α and IL-1β induced by ET to reduce fever, increase heat loss, and restore body temperature to normal. Reducing the production of endogenous pyrogens such as IL-1 and TNF-α is the pharmacological basis of the antipyretic effect of total flavonoids . The experiment was divided into two parts: the blank group, the positive group, the water extract from stem and leaf (low), the water extract from stem and leaf (high), the alcohol extract from stem and leaf (low), and the alcohol extract from stem and leaf (high). The control group was used to investigate the anti-inflammatory effect of T. chinensis . A part of the control group was divided into the blank group (distilled water 20 mL/kg), positive group (100 mg/kg), low (12 g/kg), and high (24 g/kg) water extract groups, and low (12 g/kg) and high (24 g/kg) alcohol extract groups as the control group to verify the analgesic effect of T. chinensis . The extracts of T. chinensis stem and leaf have anti-inflammatory and analgesic effects . One study further investigated the antitussive, anti-inflammatory, and analgesic effects of T. chinensis . The study showed that all dose groups of total flavonoid extract of T. chinensis could significantly prolong the therapeutic effect of antitussive; with the increase in total flavonoid extract dose, the incubation period of cough in mice was prolonged, and the number of coughs was reduced—the more significant the tracheal phenol red excretion, the more pronounced the antitussive and expectorant effects. The antitussive and expectorant effects were more evident in the high-dose group of total flavone extract of T. chinensis than in patent medicine cough syrup. In addition, the high-dose group treated with the whole flavonoid extract of T. chinensis showed significantly reduced ear swelling caused by xylenes, reduced reaction times, and an improved hot plate pain threshold. Moreover, statistical analysis showed that the total flavonoid extract of this drug had effects similar to those of nonsteroidal anti-inflammatory drugs commonly used in clinics. It was confirmed that the total flavone extract had sound anti-inflammatory and analgesic effects and that the total flavones of T. chinensis were helpful in myocardial ischemia-reperfusion injury. Experimental studies have shown that its mechanism of action is to inhibit the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), reduce the content of malondialdehyde (MDA), reduce the area of myocardial infarction, inhibit the release of myocardial enzymes, reduce the apoptosis of myocardial cells, and play a corresponding therapeutic and relieving role . In addition, Orientin and Vitexin in T. chinensis could improve membrane transport in d-galactose-induced aging mice, which may be helpful for clinical applications in treating acute respiratory distress syndrome . A study exploring the antiviral properties of T. chinensis revealed that its five active components—Vitexin, Orientin, Trolline, Veratric acid, and Vitexin-2″- O -β- l -galorientin—exert their effects by modulating Toll-like receptors (a critical class of protein molecules associated with non-specific immunity/natural immunity). Specifically, the T. chinensis soft capsule demonstrated in vitro inhibition of human coronavirus OC43 replication, accomplished through the regulation of TLRs to suppress elevated expression of host cell cytokines such as IL-1B, IL-6, and IFN-a mRNA induced by viral infection. These findings substantiate the inhibitory mechanism of the T. chinensis soft capsule against the virus . Examining 26 active components such as Rutin, Luteolin-7- O -glucoside, Kaempferol, Genistin, Apigenin, Scutellarin, Orientin, Daidzin, Vitexin, 3′-Hydroxy Puerarin, Puerarin, Daidzein, 3′-Methoxypuerarin, 2″- O -Beta- l -Galactoside, Rosmarinic acid, Progloboflowery acid, Caffeic acid, Protocatechuic acid, Ferulic acid, Veratric acid, Indirubin E, Oleracein E, Trollioside, Carbenoside I, 2″- O -(2‴-methyl butanol)isodangyloxanthin, 2″- O -(2‴-methylbutyryl) Vitexin, and glucose veratrate in T. chinensis, were observed to bind to the Mpro protein (2019-nCoV novel coronavirus pneumonia hydrolase Mpr0 protein) primarily through hydrogen bonds. This binding showcased Mpro protein-binding activity, affirming the potential of T. chinensis against novel coronaviruses . Influencing pivotal anti-inflammatory and immunomodulatory targets, T. chinensis , when combined with multiple inflammatory and immunomodulatory pathways such as tumor necrosis factor-α (TNF-α), HIF-1, and Toll-like receptors (TLR), exhibits anti-influenza viral effects, particularly against influenza A . The antiviral action of T. chinensis has been scrutinized through cyberpharmacology. While cyberpharmacological analyses offer valuable insights into pharmacological research, their reliance on network interactions between biomolecules and extensive databases introduces challenges related to data quality and reliability. Furthermore, the intricate nature of biological systems, limited experimental data, and the evolving understanding of drugs and targets require cautious consideration of credibility, necessitating further validation through pharmacological experiments . Chicken embryos served as the medium for influenza virus cultivation, with the inhibitory effect of T. chinensis alcohol extract on viral proliferation in chicken embryo allantoic fluid evaluated through a chicken erythrocyte agglutination test. The results substantiated the direct inactivation of the influenza A virus by T. chinensis alcohol extract in vitro. In a parallel experiment involving influenza A virus inoculation into chicken embryos, the T. chinensis alcohol extract effectively curbed the proliferation of the virus within the embryos . In a mouse model infected with influenza A (H1N1) virus, the study categorized the subjects into the control group, TGC group ( T. chinensis crude extract gavage group), VI1~3 groups (virus infection model 1~3 groups), and VI + TGC 1~3 groups (treatment 1~3 groups), each comprising 10 mice. Notably, the aqueous extract of T. chinensis exhibited the potential to enhance the antiviral ability of mice. Subsequent comparative analyses validated the initial findings, establishing that aqueous extracts of T. chinensis augmented antiviral capacity in mice. Conversely, alcoholic extracts of T. chinensis directly deactivated the influenza A virus . Furthermore, the aqueous extract of T. chinensis demonstrated potent inhibitory activity against the Cox B3 virus, achieving an inhibitory concentration of 0.318 mg/mL. The total flavonoids in this study displayed varying inhibitory activity against the respiratory syncytial virus, influenza A virus, and parainfluenza virus, with inhibitory concentrations of the viruses being 20.8 μg/mL and 11.7 μg/mL for Vitexin and Orientin, respectively . Notably, 60% ethanolic extracts of T. chinensis and total flavonoids exhibited weak effects, with Protopanaxanthic acid among the organic acids demonstrating the weakest antiviral ability. While T. chinensis showed effectiveness against the influenza A virus, its impact on the influenza B virus was not significant . Comparative assessments revealed that the alcoholic extract solution of T. chinensis soup displayed greater antiviral effects than the aqueous decoction of T. chinensis soup. Additionally, higher-purity T. chinensis soup extract exhibited a more robust inhibitory effect on the influenza virus. Specifically, 80% T. chinensis soup extract and secondary 95% T. chinensis soup extract demonstrated superior antiviral effects compared with 60% T. chinensis soup extract . A study delved into the material basis of the UPLC-DAD-TOF/MS fingerprinting profile (ultra-performance liquid chromatography-tandem diode array detector-time-of-flight mass spectrometry) of T. chinensis , establishing its potential as the active agent against EV71 (enterovirus 71). The key active ingredients of T. chinensis in combating EV71 included Guaijaverin acid, an unidentified alkaloid, P-hydroxybenzene-malic acid, and 2″- O -acetyl Orientin . In the broader context, T. chinensis flowers emerged as a valuable contributor to the anti-influenza virus activity of the overall formula, exhibiting relatively few side effects. The synergistic effect of T. chinensis , particularly in formulations like T. chinensis soup, has proven effective as a treatment for influenza virus . In recapitulation, the findings indicate that the antiviral mechanism of T. chinensis predominantly revolves around impeding the virus-receptor binding process and restraining the cytokines/chemokines response. The unrefined flower extract derived from T. chinensis shields the host from inflammatory damage by intervening in the TLRs, encompassing TLR3, TLR4, and TLR7. This intervention leads to a reduction in the secretion of inflammatory factors, ultimately manifesting antiviral effects . The varied pharmacological impacts of Orientin in T. chinensis , particularly its potent antioxidant effect, surpass those attributed to Vitexin. This discrepancy may be attributed to the structural disparity between Orientin and Vitexin. The oxidative activity of flavonoids with an o-diphenol hydroxyl group on the B-ring is notably more robust compared with those flavonoids possessing a singular phenol hydroxyl group attached to the B-ring . To assess the antioxidant capacity of Orientin and Vitexin in T. chinensis concerning D-galactose-induced subacute senescence in mice, D-galactose was administered intraperitoneally . The experimental outcomes revealed that Orientin and Bauhinia glycosides in T. chinensis effectively elevated the total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GPGP), and glutathione peroxidase (GPP) in the tissues of the kidneys, livers, and brains of senescent mice. Additionally, these compounds increased SOD, glutathione peroxidase (GSH-Px), Na + -K + -ATPase, and Ca 2+ -Mg 2+ -ATPase activities in kidney, liver, and brain tissues. Notably, Orientin demonstrated superior efficacy over Oryza sativa in augmenting T-AOC activity within the organism . The former mitigates impaired sodium ion transport and associated metabolic disorders , while the latter, elevated levels of Ca 2+ , adversely impact the cytoskeleton and membrane structure of neuronal cells, culminating in diminished stability and heightened membrane permeability, thereby contributing to the senescence process . In contrast, the glycosides of Orientin and Vitexin pruriens act as antioxidants by positively modulating the activity of membrane transporter enzymes within tissue cells. Remarkably, Orientin exhibited greater efficacy than Vitexin in enhancing the activity of these tissue cell membrane transporter enzymes . The robust antioxidant potential of Orientin, exceeding that of poncirin and further surpassing total flavonoids, has been corroborated in various studies. Both Orientin and Vitexin demonstrate the ability to scavenge superoxide anion, hydroxyl radical, and DPPH radical, effectively safeguarding the erythrocyte membrane. Specifically, Orientin displayed notable scavenging efficacy within the concentration range of 2.0–12.0 μg/mL. In contrast, Vitexin exhibited hydroxyl radical scavenging within the concentration range of 0–1.0 μg/mL, achieving maximum scavenging efficiency at 1.0 μg/mL, followed by a decline in scavenging effect with increasing Vitexin concentration . The pharmacological mechanism underlying the antioxidant action of T. chinensis encompasses several key facets: (1) Scavenging of free radicals: The active constituents in T. chinensis , particularly flavonoids, exhibit potent free radical scavenging capabilities. This capacity enables the neutralization of free radicals both inside and outside the cell, thereby mitigating oxidative stress-induced damage . (2) Stimulation of antioxidant enzyme activity: the active ingredients in T. chinensis stimulate the activity of antioxidant enzymes by stimulating the intracellular antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, etc. . This stimulation enhances the efficacy of the antioxidant system, fortifying cells against oxidative damage. In conclusion, T. chinensis safeguards cells from oxidative damage through the dual mechanisms of scavenging free radicals and enhancing antioxidant enzyme activity. These combined actions underscore the efficacy of T. chinensis as a potent antioxidant therapeutic agent. The anti-inflammatory prowess of T. chinensis primarily targets the upper segment of the triple energizer, encompassing the area above the diaphragm within the human body. This region predominantly involves organs such as the stomach and throat, extending through the diaphragm and chest, including the heart, lungs, viscera, head, and face. Both the aqueous extract and 95% ethanol extracts of T. chinensis manifest robust anti-inflammatory activities. Notably, within the repertoire of compounds contained in T. chinensis , flavonoids such as Robinin, Quercetin, Vitexin, and Orientin exhibit heightened anti-inflammatory efficacy. Particularly, Vitexin and Orientin, due to their anti-inflammatory and soothing properties, along with peptide anti-histamine attributes, are deemed suitable for managing acute allergic skin conditions such as rash and eczema, as well as respiratory allergic diseases . Current domestic research on T. chinensis underscores its potential in treating upper respiratory tract infectious diseases, including nasal mucosal diseases, by deploying an anti-inflammatory mechanism that engages multiple metabolites, targets, and pathways. Among the identified core targets, TNF and mitogen-activated protein kinase 1(MAPK1) take precedence, with the cancer factor pathway emerging as a pivotal route . Additionally, Toll-like receptors 3, 4, and 7 (TLR3/4/7) have been proposed as promising common anti-inflammatory targets for T. chinensis constituents. This includes Vitexin, Orientin, Trolline, Veratric acid, and Vitexin-2″- O -galactoside, as discerned through the integration of network pharmacology and molecular docking techniques . Respiratory inflammation, arising from diverse pathogens, microbial infections, influenza, nitroative stress, and compromised immune systems, can be effectively addressed by T. chinensis . Its therapeutic spectrum extends beyond treating nasal mucosa inflammation to positively impacting upper respiratory infections. Leveraging data mining, an enriched analysis of the top 20 pathways linked to the targets and metabolites of T. chinensis in upper respiratory tract infection treatment identified quercetin as a highly probable compound. This conclusion was derived from the “metabolite-target-signaling pathway” network analysis . Moreover, T. chinensis preparations exhibit therapeutic potential against upper respiratory tract infections by reducing serum inflammatory factors in patients. These factors include IL-8, IL-6, TNF-alpha, C-reactive protein, and procalcitonin, along with the modulation of T-cell subpopulation ratios . Additionally, Orientin-2″- O -β- l -galactoside and Veratric acid have been identified for their anti-inflammatory effects . In the clinical realm, the combination of amoxicillin, sodium, and potassium clavulanate has demonstrated the potential to reduce treatment duration and enhance therapeutic efficacy in children with acute tonsillitisn ratios . In summary, T. chinensis harbors a repertoire of anti-inflammatory compounds, including Vitexin, Orientxin, Trolline, Veratric acid, and Vitexin-2″- O -galactoside. Notably, Quercetin may also contribute significantly to its anti-inflammatory activity . Specifically, Orientin demonstrates efficacy in attenuating LPS-induced inflammation by impeding the production of inflammatory mediators and suppressing the expression of Cyclooxygenase 2 (COX-2) and Inducible nitric oxide synthase (iNOS) . Vitexin-2″- O -galactoside exhibits substantial inhibitory effects on lipopolysaccharide (LPS)-induced inflammation, as evidenced by its impact on key factors such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), iNOS, and COX-2 expression. Additionally, it mitigates the production of reactive oxygen species and exerts an anti-neurogenic role by inhibiting the NF-κB and extracellular signal-regulated kinase (ERK) signaling pathways, leading to anti-neuroinflammatory activity. However, the pharmacological mechanisms underlying the anti-inflammatory effects of the other components remain elusive. Flavonoids derived from T. chinensis exhibit notable inhibitory effects on active cancer cells. Specifically, the total flavonoids from T. chinensis demonstrate the capacity to impede the proliferation of tumor cells by activating the mitochondrial pathway . T. chinensis extracts exerted strong inhibitory effects on Leukemia K562 cells (K562), and HeL T. chinensis extracts manifest robust inhibitory influences on various cancer cell lines, including Leukemia K562 cells (K562), HeLa cells (He La), esophageal cancer cellsEc-109 (Ec-109), lung cancer cells NCI-H446 (NCI-H446), human non-lung cancer cells NCI-H446 (NCI-H446), human non-small cell lung cancer cell line A549 (A549), and human carcinoma cells HT-29 (HT-29), MCF-7, and HepG2, among others . Moreover, the total flavonoid extract of T. chinensis significantly retards the growth and proliferation of MCF-7 cells. This involvement is characterized by the activation of caspase-3 and caspase-9, leading to induced cell apoptosis within a concentration range of 0.0991 to 1.5856 mg/mL . Non-alcoholic fatty liver disease (NAFLD) stands as a clinical pathologic syndrome , with its incidence in China reaching a significant 29.2%, demonstrating an annual increase . The complex interplay of metabolic disorders, such as dyslipidemia, hypertension, hyperglycemia, and persistent abnormalities in liver function tests, is closely associated with NAFLD . Elevated lipid levels induce expression changes in HepG2 cells (hepatoma cells) . In an investigation into the impact of total flavonoids from T. chinensis on HepG2 cell function induced by high sugar levels, it was observed that oxidative stress levels in hepatocytes and the metabolic balance of reactive oxygen species (ROS) in HepG2 cells were intricately linked to intracellular fat accumulation. The study conclusively demonstrated that total flavonoids from T. chinensis exhibit a specific therapeutic effect on HepG2 cells by influencing disease-associated processes. Tissue cultures were employed to compare the effects of high glucose concentrations and varying doses of total flavonoids from T. chinensis on HepG2 cells. The proliferative tendencies of lipid substances are directly correlated with ROS levels; higher lipid accumulation corresponds to elevated ROS levels. Elevated glucose concentrations intensified ROS levels, while total flavonoids from T. chinensis effectively attenuated ROS levels, thereby influencing HepG2 cells. In vitro, total flavonoids from T. chinensis demonstrated a capacity to reduce lipid substance accumulation, presenting a promising avenue for the improved treatment of NAFLD . The ethanol extract derived from the total flavonoids of T. chinensis has been observed to induce apoptosis in HT-2 cells through the endogenous mitochondrial pathway. In addition, specific constituents of T. chinensis, namely Orientin and Vitexin, have demonstrated inhibitory effects on human esophageal cancer EC-109 cells. The apoptotic induction of EC-109 cells by both Orientin and Vitexin was found to correlate with increased drug action time and elevated drug concentrations. Significantly, Orientin surpassed Vitexin in effectively inhibiting the growth and apoptosis of EC-109 cells . At the administration dose of 80 μM, Orientin demonstrated a more potent apoptotic effect on EC-109 cells compared with Vitexin at the same concentration, registering apoptotic rates of 28.03% and 12.38%, respectively, within the concentration range of 0.91 to 1.5856 mg/mL. Elucidating the pharmacological mechanism underlying Orientin’s action, specifically in the context of esophageal cancer cells (EC-109), involves the up-regulation of P53 expression and concomitant down-regulation of Bcl-2 expression. This dual modulation positions Orientin as a prospective therapeutic agent for esophageal cancer. Utilizing the total flavonoids of T. chinensis as a model drug, our exploration delved into the molecular-level relationship and mechanism of these flavonoids, shedding light on their antitumor activity. A pertinent discovery was that Orientin affected HeLa, augmenting the Bax/Bcl-2 protein ratio. This manifested as an increase in Bax protein levels coupled with a decrease in Bcl-2 protein levels, thereby triggering apoptotic protease activation. Consequently, this inhibition of HeLa cell proliferation underscores the therapeutic potential of Orientin in cervical cancer treatment. While the notable anti-tumor activity of T. chinensis extract is evident, the specific mechanistic intricacies remain elusive. Putatively, this metabolite’s impact on the signaling pathways within tumor cells plays a pivotal role. T. chinensis is observed to down-regulate anti-apoptotic genes Bcl and Bcl-xL while concurrently up-regulating pro-apoptotic genes such as Bax, caspase-9 , and caspase-3 at the mRNA levels. This concomitant suppression of COX-2 gene expression in tumor cells is linked to inhibiting the proliferation of diverse tumor cell lines. The inhibitory effect extends to the HT-29 of human colon cancer cells, with T. chinensis flavonoids proving efficacious in restraining cell proliferation. The concentration-dependent inhibition of human non-small cell lung cancer A549 cells, the induction of apoptosis in lung cancer A549 cells, and the anti-lung cancer role demonstrated by these flavonoids underscore their potential therapeutic relevance. Moreover, the ability of T. chinensis flavonoids to impede the progression of K562 cells, retaining them in the Go/G1 phase, elucidates their protective role against leukemia. Additionally, beyond the total flavonoid components, the total saponins of T. chinensis showcase robust antitumor activity, albeit without significant advantages over other pharmaceutical agents . T. chinensis manifests broad-spectrum bacteriostatic activity against both Gram-positive cocci and Gram-negative Bacilli, including Pseudomonas aeruginosa, Staphylococcus aureus , Diplococcus pneumoniae, and Shigella dysenteriae. The pivotal antibacterial constituents of T. chinensis are its flavonoids, notably Orientin and Vitexin . In vitro assessments utilized Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) as benchmarks for analyzing Escherichia coli , Salmonella , Staphylococcus aureus , Bacillus subtilis , Streptococcus mutans , Streptomyces , Rhodotorula , Aspergillus niger , and Candida albicans . The 30% ethanolic extract of T. chinensis exhibited notable antibacterial efficacy, particularly inhibiting Streptococcus mutans, suggesting a potential therapeutic avenue for dental caries. T. chinensis total flavonoids, along with Orientin and Vitexin, exhibited notable inhibitory effects on Gram-positive cocci while demonstrating no discernible impact on Gram-negative Bacilli and fungi. Their most pronounced inhibitory activity was observed against Staphylococcus aureus , with the order of inhibitory strength being Orientin = Total flavonoids > Vitexin. Specifically, the lowest inhibitory and bactericidal concentrations were determined to be 0.15625 mg·mL −1 and 0.625 mg·mL −1 for Orientin and total flavonoids, respectively. Additionally, these components demonstrated considerable inhibitory activity against Streptococcus mutans, with the antibacterial efficacy ranking as Orientin > Total flavonoids > Vitexin. Notably, the lowest inhibitory concentration and bactericidal concentration of Orientin were 0.15625 mg·mL −1 and 0.625 mg·mL −1 , surpassing the efficacy of Vitexin . In investigations exploring the bacteriostatic activity of various T. chinensis preparations, the Staphylococcus aureus solution clarified at concentrations of 225 mg/mL for Jinlianhua Tablets, 56.25 mg/mL for Jinlianhua Jiaonang, 450 mg/mL for Jinlianhua Granules, and 56.25 mg/mL for T. chinensis oral solution. For Bacillus subtilis , clarification occurred at concentrations of 56.25 mg/mL for Jinlianhua tablets, 14.0625 mg/mL for T. chinensis capsule, 225 mg/mL for T. chinensis granules, and 28.125 mg/mL for T. chinensis oral solution. Notably, the T. chinensis oral solution displayed no inhibitory effect against Escherichia coli . These experiments revealed that the antibacterial activities of the four T. chinensis preparations followed the order of strength as Bacillus subtilis > Staphylococcus aureus > Escherichia coli , with varying minimum inhibitory concentrations (MICs) against Staphylococcus aureus and Bacillus subtilis for different T. chinensis preparations, ranked from strongest to weakest as Jinlianhua capsules, Jinlianhua mixture, Jinlianhua tablets, and Jinlianhua granules . In the in vitro bacteriostatic efficacy assessment, the total flavonoids extracted from T. chinensis exhibited robust inhibitory effects against common pathogenic organisms, including Staphylococcus epidermidis , Staphylococcus aureus , Escherichia coli , Streptococcus viridans , Salmonella paratyphi A , and Salmonella paratyphi B . Notably, the total demonstrated considerable protective effects in Staphylococcus aureus -infected mice, showcasing a dose-dependent reduction in the 48-h mortality of the infected mice . The yellow pigment of T. chinensis , composed of xantho-phyll epoxyde and trollixanthin, also displayed bacteriostatic properties, with varying degrees of inhibition against Staphylococcus aureus , Bacillus subtilis , and Escherichia coli , showing increased activity with escalating concentrations. Tecomin, a glucose ester of Veratric acid, exhibited effective inhibition against Staphylococcus aureus and Pseudomonas aeruginosa, with MICs of 0.256 and 0.128 mg/mL, respectively . Progloboflowery acid has emerged as an effective treatment for Pseudomonas aeruginosa-induced inflammatory skin reactions. Inhibitory effects were observed for proglobeflowery acid, Vitexin, and Orientin against Bacillus subtilis , Staphylococcus epidermidis , Staphylococcus aureus , and Micrococcus luteus . T. chinensis total flavonoids, Vitexin, Orientin, and proglobeflowery acid displayed inhibitory effects on Staphylococcus aureus and Staphylococcus epidermidis , with MICs of 50 and 25 μg/mL, 100 and 25 μg/mL, 25 and 25 μg/mL, and 200 and 200 μg/mL. For Micrococcus luteus and Bacillus subtilis , the MICs were higher than 200 μg/mL . In the investigation, T. chinensis extract and its three metabolites exhibited potent inhibitory effects on four Gram-positive cocci. Total flavonoids and Vitexin, having the highest content, demonstrated strong inhibition, especially Orientin, against Staphylococcus aureus and Staphylococcus epidermidis , while PA demonstrated relatively weak inhibition against these two bacteria . The study further revealed that PA had robust inhibitory action against Pseudomonas aeruginosa and Staphylococcus aureus , with MIC rates of 16 and 200 mg/L, respectively. Additionally, PA exhibited modest antiviral activity (IC50 of 184.2 μg/mL) against Para 3. Conversely, GA displayed significant antiviral efficacy against influenza A, as evidenced by its IC50 value of 42.1 μg/mL. With a MIC rate of 128 mg/L, TS demonstrated moderate inhibitory activity against Streptococcus pneumonia . The antibacterial pharmacological mechanism underlying the action of T. chinensis predominantly revolves around impeding regular bacterial growth processes. This is accomplished by elevating extracellular nucleic acid and soluble protein levels within bacteria. The resultant damage to the cell membrane influences membrane permeability, inducing the efflux of vital metabolic substances crucial for cellular viability or the influx of detrimental medicinal fluids. Such interactions significantly impact bacterial growth, thereby realizing the intended inhibitory effects. The drug concentration exhibits a positive correlation with both the rate of inhibition of bacterial growth and the rate of inhibition of biofilm formation . The main active components of T. chinensis , total flavonoids, also have analgesic and antipyretic effects. Studies have shown that flavonoids can significantly reduce ET (the lipid and polysaccharide substances produced by the cell wall of G-bacteria-ET are a standard model for screening antipyretic drugs and exploring antipyretic mechanisms). Total flavonoids can also reduce the contents of endogenous heat sources TNF-α and IL-1β in the serum of febrile rabbits and then inhibit the production and release of PGE2 in the cerebrospinal fluid of rabbits by inhibiting the production or release of TNF-α and IL-1β induced by ET to reduce fever, increase heat loss, and restore body temperature to normal. Reducing the production of endogenous pyrogens such as IL-1 and TNF-α is the pharmacological basis of the antipyretic effect of total flavonoids . The experiment was divided into two parts: the blank group, the positive group, the water extract from stem and leaf (low), the water extract from stem and leaf (high), the alcohol extract from stem and leaf (low), and the alcohol extract from stem and leaf (high). The control group was used to investigate the anti-inflammatory effect of T. chinensis . A part of the control group was divided into the blank group (distilled water 20 mL/kg), positive group (100 mg/kg), low (12 g/kg), and high (24 g/kg) water extract groups, and low (12 g/kg) and high (24 g/kg) alcohol extract groups as the control group to verify the analgesic effect of T. chinensis . The extracts of T. chinensis stem and leaf have anti-inflammatory and analgesic effects . One study further investigated the antitussive, anti-inflammatory, and analgesic effects of T. chinensis . The study showed that all dose groups of total flavonoid extract of T. chinensis could significantly prolong the therapeutic effect of antitussive; with the increase in total flavonoid extract dose, the incubation period of cough in mice was prolonged, and the number of coughs was reduced—the more significant the tracheal phenol red excretion, the more pronounced the antitussive and expectorant effects. The antitussive and expectorant effects were more evident in the high-dose group of total flavone extract of T. chinensis than in patent medicine cough syrup. In addition, the high-dose group treated with the whole flavonoid extract of T. chinensis showed significantly reduced ear swelling caused by xylenes, reduced reaction times, and an improved hot plate pain threshold. Moreover, statistical analysis showed that the total flavonoid extract of this drug had effects similar to those of nonsteroidal anti-inflammatory drugs commonly used in clinics. It was confirmed that the total flavone extract had sound anti-inflammatory and analgesic effects and that the total flavones of T. chinensis were helpful in myocardial ischemia-reperfusion injury. Experimental studies have shown that its mechanism of action is to inhibit the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), reduce the content of malondialdehyde (MDA), reduce the area of myocardial infarction, inhibit the release of myocardial enzymes, reduce the apoptosis of myocardial cells, and play a corresponding therapeutic and relieving role . In addition, Orientin and Vitexin in T. chinensis could improve membrane transport in d-galactose-induced aging mice, which may be helpful for clinical applications in treating acute respiratory distress syndrome . 8.1. Analysis Methods Currently, the market for Chinese herbal medicine T. chinensis has not been unified into varieties, in addition to Trollius chinensis Bunge. as the primary source of medicinal botanical drugs, Trollius ledebourii Reichenbach. Trollius macropetalus Fr. et al. have also done more research on resource exploitation and utilization for medicinal use. Hence, the quality of T. chinensis on the market is confusing, and it is difficult to distinguish the good from the bad. The 1977 edition of the Chinese Pharmacopoeia analyzes the quality of botanical drugs from two perspectives: physical identification and chemical identification. The 1998 edition of the Beijing Standards for Chinese Materia Medica (1998) also includes a microscopic identification method for determining authenticity. The 2019 edition of the Anhui Provincial Standard for the Preparation of Chinese Medicinal Tablets (2019) records the method of identification by thin-layer chromatography, in which the chromatograms of the test article obtained by experimental treatment and the chromatogram of the control botanical drug show spots of the same color at the corresponding positions of the thin-layer plate. The evaluation method in the 2018 edition of the Hubei Quality Standard for Traditional Chinese Medicinal Materials (2018) specifies that the moisture content of T. chinensis should not exceed 13.0%. The total ash content should not exceed 9.0%. The leachate content shall not be less than 35.0%. The content of Orientin (C 21 H 20 O 11 ) must not be less than 1.0% when measured by high-performance liquid chromatography and calculated on the dry product. In addition to the identification methods recorded in pharmacopeia and local standards, the fluorescence reaction identification method, micro-sublimation test, FTIR identification, and DNA barcode molecular identification method of Chinese herbal medicines can also be used to identify the authenticity of T. chinensis . A micro-sublimation test can be seen on the slide of yellowish snow-like crystals . The FTIR profile of T. chinensis was obtained by using FTIR identification, and the differences in peak shape, peak position, and peak intensity of the peaks in the profile can elucidate the differences in the components, compositions, and ratios of T. chinensis botanical drugs extracted from different origins, habitats, varieties, growth years, and different drying methods and extraction solvents to carry out a more accurate quality analysis to determine the authenticity of T. chinensis . DNA barcode molecular identification of Chinese herbal medicines is a method to identify herbal medicines through the study of the polymorphism of the genetic material of Chinese herbal medicines, which can quickly identify the species . At present, with the rapid development of molecular identification technology and in-depth plant genetic information mining, molecular identification methods in the standardization of traditional Chinese medicine identification have been widely used. For example, the early DNA molecular identification technique of T. chinensis , random amplified polymorphic DNA labeling (RAPD), was used to identify T. chinensis by observing the electrophoretic results of the DNA bands by PCR amplification, and the samples of T. chinensis could be classified according to their origins by using the RAPD technique . The DNA barcode identification method of T. chinensis was established by using ITS2 sequences, and the neighbor-joining (NJ) phylogenetic tree was constructed to accurately identify T. chinensis , Trollius lilacinus Bunge, and Artemisia annua L. In addition, high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS) can be used to identify the chemical composition and characteristics of TCM. Based on the different information of protein bands of different varieties as the basis for the identification of TCM with protein as the informative substance, it is observed that the protein bands of different varieties of T. chinensis differ significantly in the number of bands, levels, and distribution . In addition to the above methods, X-ray diffraction and X-ray fluorescence analysis can also be used to identify the grain characteristics of T. chinensis and establish a primary X-ray diffraction database for rapid identification of the authenticity of T. chinensis and its powder . 8.2. Quality Evaluation Method To ensure the quality and therapeutic efficacy of T. chinensis , the key to quality control of the active ingredients is also to establish quality analysis methods. The quality of T. chinensis can be identified and evaluated through the establishment of content determination standards, the use of fingerprinting evaluation methods, and other methods that can provide reference for the further development and utilization of T. chinensis . At present, the quality evaluation method of T. chinensis is mainly based on chemical content determination, i.e., HPLC fingerprinting, with Orientin and Vitexin as the index components of the method . In some studies, these two metabolites are combined with phenolic acid or alkaloid and other metabolites as quality evaluation indexes to improve the comprehensiveness of evaluation, and HPLC is the main evaluation method at present . Currently, the market for Chinese herbal medicine T. chinensis has not been unified into varieties, in addition to Trollius chinensis Bunge. as the primary source of medicinal botanical drugs, Trollius ledebourii Reichenbach. Trollius macropetalus Fr. et al. have also done more research on resource exploitation and utilization for medicinal use. Hence, the quality of T. chinensis on the market is confusing, and it is difficult to distinguish the good from the bad. The 1977 edition of the Chinese Pharmacopoeia analyzes the quality of botanical drugs from two perspectives: physical identification and chemical identification. The 1998 edition of the Beijing Standards for Chinese Materia Medica (1998) also includes a microscopic identification method for determining authenticity. The 2019 edition of the Anhui Provincial Standard for the Preparation of Chinese Medicinal Tablets (2019) records the method of identification by thin-layer chromatography, in which the chromatograms of the test article obtained by experimental treatment and the chromatogram of the control botanical drug show spots of the same color at the corresponding positions of the thin-layer plate. The evaluation method in the 2018 edition of the Hubei Quality Standard for Traditional Chinese Medicinal Materials (2018) specifies that the moisture content of T. chinensis should not exceed 13.0%. The total ash content should not exceed 9.0%. The leachate content shall not be less than 35.0%. The content of Orientin (C 21 H 20 O 11 ) must not be less than 1.0% when measured by high-performance liquid chromatography and calculated on the dry product. In addition to the identification methods recorded in pharmacopeia and local standards, the fluorescence reaction identification method, micro-sublimation test, FTIR identification, and DNA barcode molecular identification method of Chinese herbal medicines can also be used to identify the authenticity of T. chinensis . A micro-sublimation test can be seen on the slide of yellowish snow-like crystals . The FTIR profile of T. chinensis was obtained by using FTIR identification, and the differences in peak shape, peak position, and peak intensity of the peaks in the profile can elucidate the differences in the components, compositions, and ratios of T. chinensis botanical drugs extracted from different origins, habitats, varieties, growth years, and different drying methods and extraction solvents to carry out a more accurate quality analysis to determine the authenticity of T. chinensis . DNA barcode molecular identification of Chinese herbal medicines is a method to identify herbal medicines through the study of the polymorphism of the genetic material of Chinese herbal medicines, which can quickly identify the species . At present, with the rapid development of molecular identification technology and in-depth plant genetic information mining, molecular identification methods in the standardization of traditional Chinese medicine identification have been widely used. For example, the early DNA molecular identification technique of T. chinensis , random amplified polymorphic DNA labeling (RAPD), was used to identify T. chinensis by observing the electrophoretic results of the DNA bands by PCR amplification, and the samples of T. chinensis could be classified according to their origins by using the RAPD technique . The DNA barcode identification method of T. chinensis was established by using ITS2 sequences, and the neighbor-joining (NJ) phylogenetic tree was constructed to accurately identify T. chinensis , Trollius lilacinus Bunge, and Artemisia annua L. In addition, high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS) can be used to identify the chemical composition and characteristics of TCM. Based on the different information of protein bands of different varieties as the basis for the identification of TCM with protein as the informative substance, it is observed that the protein bands of different varieties of T. chinensis differ significantly in the number of bands, levels, and distribution . In addition to the above methods, X-ray diffraction and X-ray fluorescence analysis can also be used to identify the grain characteristics of T. chinensis and establish a primary X-ray diffraction database for rapid identification of the authenticity of T. chinensis and its powder . To ensure the quality and therapeutic efficacy of T. chinensis , the key to quality control of the active ingredients is also to establish quality analysis methods. The quality of T. chinensis can be identified and evaluated through the establishment of content determination standards, the use of fingerprinting evaluation methods, and other methods that can provide reference for the further development and utilization of T. chinensis . At present, the quality evaluation method of T. chinensis is mainly based on chemical content determination, i.e., HPLC fingerprinting, with Orientin and Vitexin as the index components of the method . In some studies, these two metabolites are combined with phenolic acid or alkaloid and other metabolites as quality evaluation indexes to improve the comprehensiveness of evaluation, and HPLC is the main evaluation method at present . Based on ancient texts and modern research, this paper reviews the herbal testimonies, traditional uses, phytochemistry, pharmacological activities, and quality standards of T. chinensis to provide new ideas for future research on T. chinensis . According to ancient texts, T. chinensis can reduce inflammation, eliminate heat and toxins, and enhance visual clarity. It is particularly effective in managing sore throats, swollen gums, and oral gingival pain caused by heat. Based on recent phytochemical and pharmacological studies, T. chinensis possesses anti-inflammatory, antiviral, antitumor, antibacterial, and antimicrobial effects, which are especially good for treating virus-induced colds and various types of inflammation, such as respiratory inflammation. It was initially recorded as an ornamental plant in various ancient books. Since its initial inclusion in the Compendium of Materia Medica as a traditional Chinese medicine in 1765 during the Qing Dynasty, T. chinensis has been widely developed for its medicinal properties and employed in health care products and various dosage forms following current processing technology. Over 180 compounds from T. chinensis have been isolated and identified. The main active components of T. chinensis are flavonoids, alkaloids, and organic acids. Objective evaluations are emphasized in recent studies of T. chinensis , where the focus is mainly on the flavonoids Orientin and Vitexin. These two compounds are the most important and representative of T. chinensis , with less research on the other active components. Various domestic and international investigations indicate that flavonoids account for most of the pharmacological effects of T. chinensis . First of all, regarding the medicinal employment of T. chinensis , historical records specify that its dried flower is the primary constituent. Additionally, contemporary experimental research concentrates on the flower of T. chinensis ; however, chemical makeup and pharmacology evaluations of its roots, stems, and leaves are limited. Moreover, most research on the phytochemical metabolites of T. chinensis concentrates on crude extracts and flavonoids, including Vitexin, Orientin, and Orientin-2″- O -β- l -galactopyranoside. However, there is a lack of studies on the alkaloids and organic acids present in T. chinensis, with only a limited number of articles on this topic. Second, studies have shown that both crude extracts and active constituents of T. chinensis have a wide range of pharmacological activities, and these modern pharmacological studies support most of the traditional uses of T. chinensis as a folk medicine. However, there is still a gap in the systematic research on T. chinensis . Many pharmacological studies on its crude extracts or active constituents are not in-depth enough, and fewer in vitro experiments exist. These pharmacological activities must be further confirmed by in vivo animal experiments and combined with clinical applications. This direction will provide a solid foundation for developing novel drug-lead compounds. For example, relevant animal experiments did not verify the antitumor effect of T. chinensis . Third, most studies on the pharmacological activities of T. chinensis have focused on uncharacterized crude extracts, making it difficult to clarify the link between the isolated compounds and their biological activities. Systematic pharmacological studies on compounds isolated from T. chinensis are considerable. In addition, many pharmacological activities of crude extracts or compounds of T. chinensis , such as the anti-inflammatory pharmacological effects of T. chinensis, are currently focused on network pharmacology and molecular docking techniques, with only very few relevant in vitro experiments for further validation, and the exact mechanism of the inhibitory activity is still unclear; therefore, further studies to reveal better the precise molecular mechanism of the pharmacological activity of the drug appear to be necessary. Fourth, in some ancient texts, T. chinensis was used with other botanical drugs, thereby treating chronic inflammation. However, almost no studies have been carried out to investigate the formulae of T. chinensis or to reveal the effects of synergistic or antagonistic actions. The area of this piece is almost blank. Therefore, drug interactions between certain botanical drugs and T. chinensis seem to be a new direction worth further exploration. Fifth, T. chinensis was included in the 1977 edition of the Chinese Pharmacopoeia, but this variety was not included in the 1985–2020 edition. Although this paper summarizes the identification methods of T. chinensis in other pharmacopeias, the provisions on authenticity identification and quality evaluation methods of T. chinensis are not comprehensive compared with other Chinese medicinal materials. For example, Trollius ledebourii Rchb. It is an alternative source of T. chinensis . However, the different base plants of T. chinensis have not been included in the pharmacopeia like other Chinese botanical drugs, which limits the further development and utilization of T. chinensis . In addition, although other plants of the same genus have been used as substitutes for T. chinensis in some places, there is no unified standard in the market for evaluation, confusing product types, specifications, and grades of Chinese medicinal materials in the medicinal materials market, which easily leads to problems in efficacy and safety. At present, the commonly used identification methods for T. chinensis are different. Microscopic identification and character identification make it difficult to distinguish the difference between T. chinensis and different species of T. chinensis . Molecular identification technology still needs to be further improved, and new DNA molecular marker technology must be developed. By analyzing and comparing the ribosomal DNA of biological species, species identification methods such as ITS barcode technology still need to collect more T. chinensis from different places and species to improve relevant studies and further verify the applicability of this method. In summary, T. chinensis serves not only as an ornamental plant and a tea source but also as a significant medicinal and food crop, possessing wide-ranging pharmacological and nutritional value. Nonetheless, more in-depth and comprehensive clinical utility studies are needed to establish the plant’s safety and effectiveness. Various compounds have been identified in T. chinensis , although the work done so far has been insufficient. Furthermore, additional research is necessary to determine the precise molecular mechanisms of these active ingredients in specific diseases. Future investigations should emphasize active metabolites other than flavonoids to uncover novel compounds and pharmacological effects. Thus, systematic studies on the phytochemistry and bioactivity of T. chinensis are essential for future research endeavors. This review is intended to serve as a valuable reference for developing and applying T. chinensis. |
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