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Learning 2D sectional anatomy facilitates the comprehension of 3D anatomical structures, anatomical relationships, and radiological anatomy. However, the efficacy of technology-enhanced collaborative instructional activities in sectional anatomy remains unclear, especially if theoretical frameworks, namely the Cognitive Theory of Multimedia Learning (CTML), are applied in instructional design. Thus, this study compared the educational impact of distinct 45-min-long technology-enhanced collaborative learning tasks in sectional anatomy. A sample of 115 first-year medical students was randomly divided into three experimental groups that used different supporting technologies to learn the sectional anatomy of the chest: IMAIOS e-learning platform and Microsoft Surface Hub (n = 37); anatomage table (n = 38); anatomage table with CTML-based presets (n = 40). Prelearning and postlearning tests revealed that significant knowledge gains in sectional anatomy were obtained by all groups even though no inter-group differences were found. Moreover, a five-point Likert scale questionnaire showed that the learning session was highly valued by all participants and that users of the anatomage with CTML-based presets reported higher enjoyment than users of the IMAIOS system (mean difference = 0.400; p = 0.037). In addition, students using the IMAIOS system and the anatomage with CTML-based presets provided System Usability Scale (SUS) scores of 67.64 and 67.69, respectively, reaching the benchmark of usability. By contrast, students using the anatomage table without presets awarded a SUS score of 64.14. These results suggest that the integration of multimedia technologies in anatomy teaching and learning should be grounded on CTML principles of instructional design. Otherwise, students' perceptions of ed-tech usability are potentially hindered., (© 2024 The Author(s). Clinical Anatomy published by Wiley Periodicals LLC on behalf of American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Background: Interprofessional education (IPE) incorporates healthcare students from various disciplines to learn with, about, and from one another, aiming to foster effective collaboration. However, the factors that promote these collaboration outcomes remain elusive. Recognizing this knowledge gap, this study utilizes self-determination theory applied in a ten-day IPE programme. The study aims are twofold: to clarify the potential influence of personal factors (autonomy, competence, and relatedness) and environmental factors (clear goals and technology support) on collaboration outcomes (team goal achievement and team effectiveness) and to examine the effect of the IPE on these outcomes., Methodology: The study utilized an IPE programme that integrated asynchronous and synchronous learning methods across two institutions in Hong Kong and the United Kingdom. This involved 147 students from diverse healthcare disciplines who were enrolled in the IPE programme. A pre- and post-test design was employed to examine programme effects. Multiple regression analysis was conducted to explore the factors influencing these outcomes, while paired samples t-tests were used to evaluate the effect of the IPE programme on collaboration outcomes., Results: Among the personal factors, a sense of relatedness emerged as an important predictor of team effectiveness and goal achievement. Clear goals and technology support positively influenced collaboration outcomes. A paired samples t-test indicated significant improvements in collaboration outcomes after the IPE simulation., Conclusion: These findings highlight the importance of designing a large IPE programme that meets basic psychological needs (especially the sense of relatedness) and provides clear goals and adequate technology support in the IPE context. This study is helpful to understand how personal and environmental factors promote the collaboration outcomes in medical education and provide insights for future IPE curriculum development., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Enhancing health professional students' effective learning and collaborative practice requires a deep understanding of strategies for facilitating interprofessional learning. While faculty members and clinical preceptors are recognized as facilitators in interprofessional education (IPE), there is limited knowledge about the impact of student facilitators' engagement in IPE. Accordingly, this study aims to explore the perceptions and experiences of student facilitators in IPE. Thirteen student facilitators were recruited to lead an interprofessional learning program, and they were subsequently invited to participate in one-on-one interviews. An interview guide was developed to explore their motivations, expectations, engagement, effectiveness, and achievements in IPE facilitation. Thematic analysis was conducted using MAXQDA software to analyze the student facilitators' experiences and perceptions. Eight interviewees from various disciplines, including Medicine, Nursing, Pharmacy, Speech and Hearing Sciences, and Social Work, took part in the study. The findings revealed that student facilitators highly valued their IPE facilitation experience, which aligned with their expectations and led to the creation of social networks, increased confidence, improved understanding of other professions, and the development of lifelong skills. Furthermore, the student facilitators demonstrated cognitive and social congruence by establishing a relaxed learning environment, displaying empathetic and supportive behaviors, and using inclusive language to engage IPE learners in group discussions. This study provides a comprehensive understanding of the role of student facilitators in IPE, contributing to the evolving literature on IPE. A conceptual framework was developed to explore the entire facilitation experience, encompassing the motivations and expectations of student facilitators, their engagement and effectiveness, and the observed achievements. These findings can inform the development of peer teaching training in IPE and stimulate further research in identifying relevant facilitator competencies for optimal delivery of IPE.

Background: Interprofessional education (IPE) has the potential to shape students' collaboration perception and interprofessional identity but remains understudied. This study aims to understand the effects of the IPE program as a contextual trigger to promote collaboration perception change and interprofessional identity formation among healthcare professional students., Methods: Using concurrent triangulation mixed-methods, we examined the relationship between collaboration perception and interprofessional identity change among health profession students (N = 263), and explored their perspectives on how their IPE experiences influenced their perception and identity. Participants completed the Interdisciplinary Education Perception Scale and Extended Professional Identity Scale and responded to open-ended questions before and after the IPE intervention. Pearson's correlation, t-tests, regression (quantitative), and thematic analysis (qualitative) were conducted., Results: Teams with initially lower collaboration perception (M = 3.59) and lower interprofessional identity (M = 3.59) showed a significant increase in collaboration perception (M = 3.76, t = 2.63; p = .02) and interprofessional identity (M = 3.97, t = 4.86; p < .001) after participating in IPE. The positive relationship between collaboration perception and interprofessional identity strengthened after participating in IPE, as evident from the correlation (Time 1: r = .69; p < .001; Time 2: r = .79; p < .001). Furthermore, collaboration perception in Time 1 significantly predicted the variance in interprofessional identity at Time 2 (β = 0.347, p < .001). Qualitative findings indicated that 85.2% of students expressed that IPE played a role in promoting their interprofessional identity and collaboration attitudes., Conclusions: Incorporating the IPE program into the curriculum can effectively enhance students' collaboration perception and interprofessional identity, ultimately preparing them for collaborative practice in the healthcare system. By engaging students in interprofessional teamwork, communication, and joint decision-making processes, the IPE program provides a valuable context for students to develop a sense of belonging and commitment to interprofessional collaboration., (© 2024. The Author(s).)

Background: Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes., Methods: Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H 2 O 2 . Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4)., Results: Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro . In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs., Conclusions: Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms., Competing Interests: The authors declare that there are no conflict of interests in this study., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Difficulty in visualizing anatomical structures has been identified as a challenge in anatomy learning and the emergence of three-dimensional printed models (3DPMs) offers a potential solution. This study evaluated the effectiveness of 3DPMs for learning the arterial supply of the head and neck region. One hundred eighty-four undergraduate medical students were randomly assigned to one of four learning modalities including wet specimen, digital model, 3DPM, and textbook image. Posttest scores indicated that all four modalities supported participants' knowledge acquisition, most significantly in the wet specimen group. While the participants rated 3DPMs lower for helping correct identification of structures than wet specimens, they praised 3DPMs for their ability to demonstrate topographical relationships between the arterial supply and adjacent structures. The data further suggested that the biggest limitation of the 3DPMs was their simplicity, thus making it more difficult for users to recognize the equivalent structures on the wet specimens. It was concluded that future designs of 3DPMs will need to consider the balance between the ease of visualization of anatomical structures and the degree of complexity required for successful transfer of learning. Overall, this study presented some conflicting evidence of the favorable outcomes of 3DPMs reported in other similar studies. While effective for anatomy learning as a standalone modality, educators must identify the position 3DPM models hold relative to other modalities in the continuum of undergraduate anatomy education in order to maximize their advantages for students., (© 2023 American Association for Anatomy.)

Introduction: Online interprofessional education is a collaborative process that emphasizes both individual reflection and shared discourses. A useful analytical tool for understanding the complex dynamics of online collaborative learning is the community of inquiry (CoI) framework, which originally held that there are three types of presence in such learning: teaching, cognitive, and social. However, it was later revised to include learning presence, which is characterized by self-regulated learning. Our study aims to refine the construct of learning presence through a clearer understanding of how self- and co-regulation jointly influence learning outcomes., Methods: We surveyed 110 people involved with an online interprofessional medical-education curriculum at a university in Hong Kong. Path analysis was adopted to explore the relationships among 1) the three original presences of CoI; 2) learning presence (i.e., for this purpose, a combination of self-regulation and co-regulation); and 3) two learning outcomes: perceived progress and learner satisfaction., Results: The results of path analysis indicated that teaching presence had a significant indirect effect, through co-regulation, on perceived progress. In terms of direct relationships, co-regulation significantly and positively influenced both self-regulation and cognitive presence; and social presence had both positive influence on learners' satisfaction and perceived progress., Discussion: This study's findings suggest the important role of co-regulation in supporting self-regulation, especially in online collaborative-learning environments. Learners' self-regulation skills are shaped by their social interactions and regulatory activities with others. This further implies that health-professions educators and instructional designers should create learning activities that facilitate the development of co-regulatory skills, as a means of improving learning outcomes. As self-regulation is an important skill for health professions learners' lifelong learning, and because their future workplaces will be interdisciplinary in nature, it is critical to provide interactive and collaborative learning environments that will promote co-regulation and self-regulation.

Background: The application of self-determination theory in explaining student achievement has been well-established in various contexts. However, its application to medical education, particularly in interprofessional education (IPE) remains underexplored. Understanding how students' motivation plays a role in students' engagement and achievement is essential to optimize efforts to improve learning and instruction., Objective: This two-stage study aims to contextualize the SDT framework to IPE through the adaptation of the Basic Psychological Need Satisfaction to IPE (Study 1) and to demonstrate how SDT can be applied in IPE by examining a model of SDT constructs (Study 2) in predicting outcomes (behavioral engagement, team effectiveness, collective dedication, goal achievement)., Design: In Study 1 ( n =996), we adapted and validated BPNS-IPE using confirmatory factor analysis and multiple linear regression using data from 996 IPE students (Chinese Medicine, Medicine, Nursing, and Pharmacy). In Study 2 ( n =271), we implemented an IPE program where we integrated SDT approaches and examined the relationship of SDT constructs with IPE outcomes using multiple linear regression., Results: Our data supported the three-factor structure (autonomy, competence, and relatedness) of BPNS-IPE, meeting the required model fit. Autonomy predicted team effectiveness (F=51.290, p <.05, R 2 =.580); competence predicted behavioral engagement (F=55.181, p <.05, R 2 =.598); while relatedness predicted significantly four IPE outcomes: behavioral engagement (F=55.181, p <.01, R 2 =.598), team effectiveness (F=51.290, p <.01, R 2 =.580), collective dedication (F=49.858, p <.01, R 2 =.573), goal achievement (F=68.713, p <.01, R 2 =.649)., Conclusions: The SDT motivational framework can be adapted and applied in the IPE context to understand and enhance student motivation in medical education. Potential studies with the use of the scale are provided to guide researchers.

Background: Interprofessional education (IPE) has been promoted as a breakthrough in healthcare because of the impact when professionals work as a team. However, despite its inception dating back to the 1960s, its science has taken a long time to advance. There is a need to theorize IPE to cultivate creative insights for a nuanced understanding of IPE. This study aims to propose a research agenda on social interaction by understanding the measurement scales used and guiding researchers to contribute to the discussion of social processes in IPE., Method: This quantitative research was undertaken in a cross-institutional IPE involving 925 healthcare students (Medicine, Nursing, Social Work, Chinese Medicine, Pharmacy, Speech Language Pathology, Clinical Psychology, Food and Nutritional Science and Physiotherapy) from two institutions in Hong Kong. Participants completed the Social Interaction Anxiety Scale (SIAS-6) and Social Phobia Scale (SPS-6). We applied a construct validation approach: within-network and between-network validation. We performed confirmatory factors analysis, t-test, analysis of variance and regression analysis., Results: CFA results indicated that current data fit the a priori model providing support to within-network validity [RMSEA=.08, NFI=.959, CFI=.965, IFI=.965, TLI=.955]. The criteria for acceptable fit were met. The scales were invariant between genders, across year levels and disciplines. Results indicated that social interaction anxiety and social phobia negatively predicted behavioural engagement ( F  = 25.093, p <.001, R 2 =.065) and positively predicted behavioural disaffection ( F  = 22.169, p <.001, R 2 =.057) to IPE, suggesting between-network validity., Conclusions: Our data provided support for the validity of the scales when used among healthcare students in Hong Kong. SIAS-6 and SPS-6 have sound psychometric properties based on students' data in Hong Kong. We identified quantitative, qualitative and mixed methods research designs to guide researchers in getting involved in the discussion of students' social interactions in IPE.Key MessagesThe Social Anxiety Scale (SIAS-6) and Social Phobia Scale (SPS-6) scales have sound psychometric properties based on the large-scale healthcare students' data in IPE in Hong Kong.Social interaction anxiety and social phobia negatively predicted students' behavioural engagement with IPE and positively predicted behavioural disaffection. The scales are invariant in terms of gender, year level and discipline.Quantitative, qualitative and mixed methods studies are proposed to aid researchers to contribute in healthcare education literature using the SIAS-6 and SPS-6.

This article investigates the level of anatomical knowledge of the Hong Kong public and uses the data to help suggest public engagement activities and health campaigns to raise health literacy in the general population. In the annual public engagement event organized by the University of Hong Kong, 250 attendees took a survey assessing basic anatomical knowledge by putting organs/structures in their correct positions. Description analysis, correlation analysis, independent sample t-test, and one-way ANOVA analysis were conducted by SPSS 27.0. Overall, a mean score of 6.5 out of 20 was achieved. Differences between various demographic parameters were analyzed, and the results showed that better performance on the survey was associated with younger age, higher educational levels, and having healthcare experience. There was also a statistically significant difference in correctly positioning the thyroid between males and females. Interestingly, some misconceptions were thought to arise from the bespoke use of the Chinese language in the survey. The data reflected room for improvement in the level of anatomical knowledge among the public, notably in the older age groups. This was attributed partially to a lack of public outreach initiatives and established anatomy-focused programs, which has restricted public exposure to anatomical knowledge and hindered the development of anatomical sciences in Hong Kong. In conclusion, the knowledge of the public on the human body needs to be improved and possible solutions to improve public awareness of health were raised., (© 2023 The Authors. Anatomical Sciences Education published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

The usefulness of virtual reality (VR) technology in physiology education is largely unexplored. Although VR has the potential to enrich learning experience by enhancing the spatial awareness of students, it is unclear whether VR contributes to active learning of physiology. In the present study, we used a mixed-method research approach to investigate students' perceptions of physiology learning based on VR simulations. Quantitative and qualitative data indicate that the implementation of VR learning environments improves the quality of physiology education by promoting active learning in terms of interactive engagement, interest, problem-solving skills, and feedback. In the Technology-Enabled Active Learning Inventory, which consisted of 20 questions to which students responded along a 7-point Likert scale, the majority of students agreed that VR learning of physiology not only stimulated their curiosity (77%; P < 0.001) but also allowed them to obtain knowledge through diverse formats (76%; P < 0.001), participate in thought-provoking dialogue (72%; P < 0.001), and interact better with peers (72%; P < 0.001). Positive responses in the social, cognitive, behavioral, and evaluative domains of active learning were received from students across different disciplines, including medicine, Chinese medicine, biomedical sciences, and biomedical engineering. Their written feedback showed that VR enhanced their interest in physiology and facilitated the visualization of physiological processes to improve their learning. Overall, this study supports that the integration of VR technology into physiology courses can be an effective teaching strategy. NEW & NOTEWORTHY Virtual reality (VR) improves physiology education by promoting active learning in terms of interactive engagement, interest, problem-solving skills, and feedback. Positive responses toward multiple components of active learning were received from students across different disciplines. The majority of students agreed that VR learning of physiology not only stimulated their curiosity but also allowed them to obtain knowledge through diverse formats, participate in thought-provoking dialogue, and interact better with peers.

Objectives: A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available., Methods: This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students' data., Results: We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest-posttest differences in students' readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students' social interaction anxiety after the IPE simulation., Conclusions: The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education., (© 2023. The Author(s).)

The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis (NASH) remain largely unknown. We aimed to elucidate the roles of hepatic cyclooxygenase 1 (COX1) in autophagy and the pathogenesis of diet-induced steatohepatitis in mice. Human nonalcoholic fatty liver disease (NAFLD) liver samples were used to examine the protein expression of COX1 and the level of autophagy. Cox1 Δhepa mice and their wildtype littermates were generated and fed with 3 different NASH models. We found that hepatic COX1 expression was increased in patients with NASH and diet-induced NASH mice models accompanied by impaired autophagy. COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy. Mechanistically, COX1 directly interacted with WD repeat domain, phosphoinositide interacting 2 (WIPI2), which was crucial for autophagosome maturation. Adeno-associated virus (AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1 Δhepa mice, indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy. In conclusion, we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2. Targeting the COX1-WIPI2 axis may be a novel therapeutic strategy for NASH., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although previous study demonstrated the neuroprotective effects of Hericium erinaceus ( H.E. ), the mechanisms of H.E . treatment on the neuroinflammatory response, neurotransmission, and related metabolites remain largely unknown. We demonstrated that 3-AP rats treated with 25 mg/kg H.E. extracts had improved motor coordination and balance in the accelerated rotarod and rod tests. We showed that the H.E . treatment upregulated the expression of Tgfb1, Tgfb2, and Smad3 genes to levels comparable to those in the non-3-AP control group. Interestingly, we also observed a significant correlation between Tgfb2 gene expression and rod test performance in the 3-AP saline group, but not in the non-3-AP control or H.E .+3-AP groups, indicating a relationship between Tgfb2 gene expression and motor balance in the 3-AP rat model. Additionally, we also found that the H.E . treatment increased mitochondrial COX-IV protein expression and normalized dopamine-serotonin neurotransmission and metabolite levels in the cerebellum of the H.E .+3-AP group compared to the 3-AP saline group. In conclusion, our findings suggest that the H.E . treatment improved motor function in the 3-AP rat model, which was potentially mediated through neuroprotective mechanisms involving TGFB2-Smad3 signaling via normalization of neurotransmission and metabolic pathways.

Declining global DNA methylation and cognitive impairment are reported to occur in the normal aging process. It is not known if DNA methylation plays a role in the efficacy of memory-enhancing therapies. In this study, aged animals were administered prelimbic cortical deep brain stimulation (PrL DBS) and/or L-methionine (MET) treatment. We found that PrL DBS and MET (MET-PrL DBS) co-administration resulted in hippocampal-dependent spatial memory enhancements in aged animals. Molecular data suggested MET-PrL DBS induced DNA methyltransferase DNMT3a-dependent methylation, robust synergistic upregulation of neuroplasticity-related genes, and simultaneous inhibition of the memory-suppressing gene calcineurin in the hippocampus. We further found that MET-PrL DBS also activated the PKA-CaMKIIα-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. We next inhibited the activity of DNA methyltransferase (DNMT) by RG108 infusion in the hippocampus of young animals to establish a causal relationship between DNMT activity and the effects of PrL DBS. Hippocampal DNMT inhibition in young animals was sufficient to recapitulate the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS. Our findings implicate hippocampal DNMT as a therapeutic target for PrL DBS and pave way for the potential use of non-invasive neuromodulation modalities against dementia., Competing Interests: Competing interests The authors declare no competing financial interests., (copyright: © 2022 Poon et al.)

Chronic alcohol consumption causes liver steatosis, cell death, and inflammation. Melatonin (MLT) is reported to alleviate alcoholic liver disease (ALD)-induced injury. However, its direct regulating targets in hepatocytes are not fully understood. In the current study, a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT. MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models (optimal doses of 10 μmol/L and 5 mg/kg, respectively), including lowered liver steatosis, cell death, and inflammation. RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase (TERT) was a key downstream effector of MLT. Biophysical assay found that epidermal growth factor receptor (EGFR) on the hepatocyte surface was a direct binding and regulating target of MLT. Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection, partly through the regulation of nuclear brahma-related gene-1 ( BRG1 ). Long-term administration (90 days) of MLT in healthy mice did not cause evident adverse effect. In conclusion, MLT is an efficacious and safe agent for ALD alleviation. Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis. MLT might be used as a complimentary agent for alcoholics., Competing Interests: The authors declare no conflicts of interest., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Objectives: Despite the popularity of interprofessional education, the empirical and theoretical development of its scholarship and science is just emerging. This may be caused in part by the non-availability of measures that can be used by researchers in this field. This study aimed to contribute to the psychological theorizing of interprofessional education by uncovering the psychometric properties of Perceived Locus of Causality adapted to Interprofessional Education (PLOC-IPE) in healthcare education and provide a comprehensive guide on how this can be used to advance the IPE research agenda., Methods: Confirmatory factor analysis (quantitative design) was used to examine the acceptability of psychometric properties of PLOC-IPE. Data were collected through questionnaires administered at two different time points. The participants consisted of 345 students from Chinese Medicine, Clinical Psychology, Medicine, Nursing, Pharmacy, and Social Work from a university in Hong Kong., Results: Based on confirmatory factor analysis, results of within-network construct validity showed good psychometric properties of PLOC-IPE while between-network validity indicated that the scale can predict IPE-related outcomes. Students' intrinsic motivation in IPE positively predicted emotional engagement and negatively predicted emotional disaffection, demonstrating the applicability of the newly validated PLOC-IPE. Amotivation was a negative predictor of emotional engagement and a positive predictor of emotional disaffection., Conclusions: Findings support the acceptability of PLOC when adapted to IPE. PLOC-IPE obtained acceptable psychometric properties as a measure of students' academic motivation in IPE. It is an adapted scale that can be used to understand self-determined motivation in the context of IPE in health and social care education. A guide on how PLOC-IPE can be a means by which researchers can contribute to the advancement of scholarship of IPE was provided., Competing Interests: Declaration of competing interest We have no known conflict of interest to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The COVID-19 pandemic has exacerbated the pre-existing global crisis of physician burnout. Physician and particularly medical educator well-being, has come into focus as educators can influence their own and learners' well-being. Measuring this construct is one important step towards promoting well-being in the work and learning environments. The 5-item World Health Organization Well-Being Index (WHO-5) has been validated in different populations worldwide for assessing well-being. Yet, its psychometric acceptability remains unexplored among medical educators in Asia including Hong Kong (HK). This study evaluates the validity of the WHO-5 when used among HK medical educators., Method: Using data from 435 medical educators, we employed combined within-network (confirmatory factor analysis; CFA) and between-network approaches (correlation and regression) to scale validation., Results: CFA results indicated that our data fit the a priori WHO-5 model, suggesting structural validity. Results of comparison of means indicated no gender differences, but there were significant differences when participants were compared by age and professional backgrounds. Resilience predicted well-being as measured by the WHO-5, suggesting construct criterion validity., Conclusions: Our findings extend the validity evidence for the WHO-5 to HK medical educators examined in this study. This enables their well-being to be assessed when evaluating the impact of future well-being programmes.

Background: Team cohesiveness and collective efficacy have been construed as important characteristics of a high-functioning team. However, the psychological mechanism through which they promote positive outcomes remains unknown. Understanding this psychological process is important to teachers and programme implementers to yield actionable interventions that can be used to craft effective practices for optimizing team outcomes. This is especially true in interprofessional education (IPE) in medical education, where a team-based approach to patient management is promoted. Drawing from the social-cognitive theory, we examined a hypothesized model where team cohesiveness predicts collaboration outcomes (teamwork satisfaction, overall satisfaction with the team experience, and IPE goal attainment) via collective efficacy., Methods: We used data from Chinese medicine, medicine, nursing, and social work students in Hong Kong (n = 285) who were enrolled in IPE. They were invited to respond to scales in two time points. We performed mediation analysis using structural equations modelling to test the indirect effect model: team cohesiveness → collective efficacy → outcomes., Results: Results of structural equation modelling revealed that collective efficacy fully mediated the relationships between team cohesiveness and all three team outcomes, providing support for the hypothesised model [RMSEA = 0.08, NFI = 0.90, CFI = 0.93, IFI = 0.93, TLI = 0.93]. Team cohesiveness predicted the achievement of collaboration outcomes via collective efficacy., Conclusion: The findings demonstrated the important roles of team cohesiveness and collective efficacy in promoting successful team collaboration. Team cohesiveness predicted collective efficacy, and collective efficacy, in turn, predicted collaboration outcomes. This study contributed to theorising the pathways towards successful team collaboration outcomes., (© 2022. The Author(s).)

Objectives: Interprofessional education (IPE) harnesses the power of teams to facilitate collaborative learning across disciplines. However, prior research has not paid sufficient attention to the role of team-level factors on IPE outcomes, posing a major theoretical and methodological limitation. In response to this, using social interdependence theory (SIT), this study aimed to delineate the independent contributions of both team-level and student-level interprofessional attitudes (teamwork, roles, and responsibilities; patient-centeredness; and community-centeredness) in predicting IPE collaboration outcomes (goal achievement, team effectiveness, and team performance) employing multi-level analysis., Methods: To test whether interprofessional attitudes at the team and student levels predict IPE collaboration outcomes, conducted multilevel modeling. We used the pretest and posttest data from 323 healthcare students in Hong Kong from Chinese medicine, medicine, nursing, pharmacy, and social work programmes enrolled in the IPE Cancer module., Results: Among the interprofessional attitudes, "teamwork, roles, and responsibilities" was found to be the best predictor of IPE outcomes, both at the student and team levels. Students who recognized the benefits of shared learning had better goal achievement and team effectiveness. Furthermore, teams that emphasized shared learning also had better overall team performance., Conclusions: Students' attitudes towards teamwork, roles, and responsibilities in interprofessional collaborative practice, both at the student and team levels, are important to attaining positive student- and team-level outcomes. The study contributes to the expansion of existing knowledge in medical education, theoretically, by adopting SIT as a lens through which collaborative learning in healthcare teams can be understood, and methodologically, by applying multi-level approaches and delineating important student- and team-level predictors of IPE outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Calls to promote team-based interprofessional collaborative practice in managing patients with complex health problems are ubiquitous. However, the literature remains silent on what characterises successful teams in interprofessional education (IPE) and on profiling successful teams. To help conceptualise successful teams, this study investigated the differences in attitudes and achievement between high- and low-performing teams in an online asynchronous and synchronous IPE programme, and the role of autonomous motivation in determining team membership., Methods: Using extreme case sampling involving health and social care students, we identified ten high-performing teams and seven low-performing teams based on their team composite scores on three interprofessional collaborative outcomes: team effectiveness, goal achievement, and scores on the readiness assurance test. Each team had five to seven members of diverse backgrounds. Independent t-tests were performed to identify differences in interprofessional collaborative outcomes, namely teamwork and collaboration, patient-centredness, diversity and ethics, community-centeredness, and interprofessional biases for the affective domain and application exercise for the cognitive domain. We employed logistic regression in which autonomous motivation was used to predict group membership., Results: High-performing teams were characterised as those whose members endorsed or valued "teamwork and collaboration" in IPE simulations. Compared with the low-performing groups, they better recognised and endorsed diversity and ethics, patient-centeredness, and community-centeredness. Membership to high- and low-performing teams was linked to autonomous motivation., Conclusions: High-performing teams have higher favourable valuing of important interprofessional collaborative competencies, and membership to which is predicted by autonomous motivation. The results suggest the need to pay special attention to struggling teams to facilitate desirable collaborative competencies, especially in terms of members' motivation. Theoretical, methodological, and practical implications are discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Benefits of intercalation during an undergraduate medical degree are well-recognized. The University of Hong Kong implemented a compulsory Enrichment Year (EY) in its Bachelor of Medicine and Bachelor of Surgery degree programme (MBBS) in 2016. In their third year of study, students could work on an area of interest in any of three programme categories (i) intercalation/ university exchange (IC); (ii) research (RA); (iii) service/ humanitarian work (SH). This study aimed to explore the barriers, enablers, and overall student learning experiences from the first cohort of EY students in order to inform future development of the EY., Methods: An exploratory sequential mixed-method study in 2019-20. Twenty students were purposively selected to attend three semi-structured focus group interviews. Conventional thematic analysis was employed and results assisted the design of a cross-sectional questionnaire. Sixty-three students completed the questionnaire. ANOVA or chi-square test was used to compare the difference in student's characteristics, barriers, enablers and perspectives on EY between programme categories. Adjusting student's characteristics, logistic regressions were conducted to identify the effect of programme categories on the EY experience., Results: Most students (95% in the questionnaire) agreed that EY was worthwhile and more rewarding than expected. EY was positively regarded for enhancing personal growth and interpersonal relationships. The main barriers were financial difficulties, scholarship issues and insufficient information beforehand. A few students had practical (i.e. accommodation, cultural adaptation) problems. Potential enablers included better financial support, more efficient information exchange and fewer assignments and preparation tasks. Similar barriers were encountered by students across all three categories of EY activities., Conclusions: Personal growth was the most important benefit of the EY. Barriers were consistent with those identified in the literature except for cultural adaptation, which could be related to Hong Kong's unique historical context. Financial limitation was the most concerning barrier, as it could result in unequal access to educational opportunities. Better and timely access to scholarships and other funding sources need to be considered., Trial Registration: Ethics approval was obtained from the local Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 19-585 )., (© 2022. The Author(s).)

Melatonin and novel melatonin-based therapies such as melatonin-containing hybrid molecules, melatonin analogues, and melatonin derivatives have been investigated as potential therapeutics against Alzheimer's disease (AD) pathogenesis. In this review, we examine the developmental trends of melatonin therapies for AD from 1997 to 2021. We then highlight the neuroprotective mechanisms of melatonin therapy derived from preclinical studies. These mechanisms include the alleviation of amyloid-related burden, neurofibrillary tangle accumulation, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, and impaired neuroplasticity and neurotransmission. We further illustrate the beneficial effects of melatonin on behavior in animal models of AD. Next, we discuss the clinical effects of melatonin on sleep, cognition, behavior, psychiatric symptoms, electroencephalography findings, and molecular biomarkers in patients with mild cognitive impairment and AD. We then explore the effectiveness of novel melatonin-based therapies. Lastly, we discuss the limitations of current melatonin therapies for AD and suggest two emerging research themes for future study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Students' attitudes toward interprofessional teamwork can be linked to successful interprofessional education. This points to the importance of identifying a scale that may be useful in keeping track of the change in students' attitudes over time. In response to this, using a combination of within- and between-network approaches to construct validity, we examined the psychometric acceptability of the Interprofessional Attitude Scale (IPAS) involving 274 Chinese healthcare and social care pre-licensure students in Hong Kong. Overall results indicated that IPAS had good internal consistency. Results of the confirmatory factor analysis provided support to the overall five-factor solution although one negatively worded item obtained non-significant factor loading. Results of the between-network analysis suggest that various subscales of IPAS correlated systematically with other theoretically relevant variables: teamwork attitudes, communication, and team effectiveness. The IPAS is a valid measure to examine predominantly Chinese healthcare and social care students' interprofessional attitudes in online interprofessional education.

The Students' Perceptions of Physician-Pharmacist Interprofessional Clinical Education and its revision (SPICE, SPICE-R) were designed to understand medicine and pharmacy students' perceptions of interprofessional education and collaborative practice in managing complex health problems. The SPICE-R authors, however, suggested for additional items for subscales "roles and responsibilities for collaborative care" and "patient outcomes from collaborative practice". We added two items and introduced SPICE-R3 to differentiate it from the 10-item SPICE-R2 and to adapt the scale to a wider range of healthcare members. We administered the SPICE-R3 to healthcare students at the height of the COVID-19 outbreak in Hong Kong in February 2020. Using data from 225 students from Chinese medicine, medicine, nursing, and pharmacy, confirmatory factor analysis indicated nine items having acceptable item coefficients. Our data obtained a good fit to the three-factor, nine-item model suggesting construct validity. Results of the between-network analysis suggest that the three subscales of SPICE-R3 correlated systematically with other theoretically relevant variables in the nomological network suggesting convergent validity. The SPICE-R3 is a valid measure to examine Hong Kong healthcare students' interprofessional attitudes in online interprofessional education even during the pandemic. Implications and directions for future research are provided.

Background & Aims: CREB-H is a key liver-enriched transcription factor governing lipid metabolism. Additional targets of CREB-H remain to be identified and characterized. Here, we identified a novel fasting- and CREB-H-induced (FACI) protein that inhibits intestinal lipid absorption and alleviates diet-induced obesity in mice., Methods: FACI was identified by reanalysis of existing transcriptomic data. Faci -/- mice were generated by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)-mediated genome engineering. RNA sequencing was performed to identify differentially expressed genes in Faci -/- mice. Lipid accumulation in the villi was assessed by triglyceride measurement and Oil red O staining. In vitro fatty acid uptake assay was performed to verify in vivo findings., Results: FACI expression was enriched in liver and intestine. FACI is a phospholipid-binding protein that localizes to plasma membrane and recycling endosomes. Hepatic transcription of Faci was regulated by not only CREB-H, but also nutrient-responsive transcription factors sterol regulatory element-binding protein 1 (SREBP1), hepatocyte nuclear factor 4α (HNF4α), peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), and CREB, as well as fasting-related cyclic adenosine monophosphate (cAMP) signaling. Genetic knockout of Faci in mice showed an increase in intestinal fat absorption. In accordance with this, Faci deficiency aggravated high-fat diet-induced obesity, hyperlipidemia, steatosis, and other obesity-related metabolic dysfunction in mice., Conclusions: FACI is a novel CREB-H-induced protein. Genetic disruption of Faci in mice showed its inhibitory effect on fat absorption and obesity. Our findings shed light on a new target of CREB-H implicated in lipid homeostasis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The shift in the way how health care is delivered from exclusive (disciplinary) to a more collective and inclusive (interprofessional) has recently been gaining traction in health care. The need for this shift is even magnified when the health care system face unprecedented challenges that single expertise is no more enough. The promise of transformative power of collaboration in health care suggests that collective intelligence achieves tasks more effectively than a single expertise could achieve., (© 2021 Association for the Study of Medical Education and John Wiley & Sons Ltd.)

The impact of the medical curricular reform on anatomy education has been inconclusive. A pervasive perception is that graduates do not possess a sufficient level of anatomical knowledge for safe medical practice; however, the reason is less well-studied. This qualitative study investigated the perceived challenges in learning anatomy, possible explanations, and ways to overcome these challenges. Unlike previous work, it explored the perceptions of multiple stakeholders in anatomy learning. Semi-structured interviews were conducted and the transcripts were analyzed by a grounded theory approach. Three main themes emerged from the data: (1) visualization of structures, (2) body of information, and (3) issues with curriculum design. The decreasing time spent in anatomy laboratories forced students to rely on alternative resources to learn anatomy but they lacked the opportunities to apply to human specimens, which impeded the "near" transfer of learning. The lack of clinical integration failed to facilitate the "far" transfer of learning. Learners also struggled to cope with the large amount of surface knowledge, which was pre-requisite to successful deep and transfer of learning. It was theorized that the perceived decline in anatomical knowledge was derived from this combination of insufficient surface knowledge and impeded "near" transfer resulting in impeded deep and "far" transfer of learning. Moving forward, anatomy learning should still be cadaveric-based coupled with complementary technological innovations that demonstrate "hidden" structures. A constant review of anatomical disciplinary knowledge with incremental integration of clinical contexts should also be adopted in medical curricula which could promote deep and far transfer of learning., (© 2021 American Association for Anatomy.)

Alzheimer's disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.

Objectives: In response to the observations that interprofessional education (IPE) is seemingly atheoretical or under-theorised, this quantitative research seeks to uncover students' motivational mechanisms which could explain their behavioural and collaborative outcomes using self-determination theory (SDT). While SDT has been studied in various contexts, its applicability to IPE remains underexplored. This study aims to integrate a new perspective in understanding students' motivation in IPE by exploring how the fulfilment of a need for sense of autonomy, competence and relatedness is linked to desirable IPE outcomes., Methods: Utilising quantitative methods, we involved 255 health care students in Hong Kong from the medical, nursing and pharmacy disciplines enrolled in IPE anticoagulation therapy module. They were invited to respond to the Psychological Need Satisfaction Questionnaire and other measures as part of the post-test., Results: Sense of autonomy emerged as the strongest positive predictor of behavioural (collective dedication, behavioural engagement) and collaboration outcomes (team effectiveness, goal achievement). There were no significant program-level differences across these outcomes except for behavioural engagement for which nursing students had a higher perception than medicine students., Conclusions: We were able to demonstrate that SDT is a meaningful framework in understanding behavioural and collaboration outcomes in IPE. The major theoretical contribution of this study refers to the ability of students' motivation to explain variance in their behavioural outcomes. That is, sense of autonomy consistently predicted team effectiveness, collective dedication, behavioural engagement and goal achievement. Autonomous motivation among a sample of health care students can explain behavioural outcomes. Theoretical, methodological and practical implications are discussed., (© 2020 John Wiley & Sons Ltd and The Association for the Study of Medical Education.)

Background: Percutaneous insertion of third-generation straight humeral nails is a recent alternative to the conventional open method. Rather than splitting, retracting and subsequently repairing the supraspinatus fibers to visualize the humeral head entry site, the percutaneous approach utilizes a cannulated awl to enter the intramedullary canal through the supraspinatus fibers without visualizing internal shoulder structures. Despite recent evidence demonstrating satisfactory outcomes in the percutaneous method, the potential for iatrogenic injury to the rotator cuff and other shoulder structures is not fully understood., Materials and Methods: We performed an anatomical study of 46 shoulders in 23 cadavers to compare damage caused to internal shoulder structures between the open and percutaneous techniques. Dimensions and morphologies of supraspinatus and humeral head perforations were recorded., Results: The percutaneous technique produced greater latitudinal tearing ( p = 0.002) and less longitudinal tearing ( p < 0.001) of muscle fibers, however there was no difference in supraspinatus hole area ( p = 0.748). The long head biceps tendon was within 3 mm of the bone entry hole in 13 (28%) shoulders, with one shoulder in the open group exhibiting full tendon transection., Conclusions: Percutaneous insertion of intramedullary nails using a cannulated awl appears to produce similar soft tissue and bone entry site morphology as compared to the conventional open technique. The percutaneous method was associated with slightly greater latitudinal tearing, however the effects of this remain to be clarified through clinical studies. External rotation should be avoided during instrumentation to reduce the risk of biceps tendon transection.

Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S -allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3 β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3 β pathway., Competing Interests: The authors declare no conflicts of interest., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Purpose: To investigate the novel molecular mechanisms of the antioxidant and anti-inflammatory properties of S-allylmercaptocysteine (SAMC) based on a transcriptomic study in a nonalcoholic steatohepatitis (NASH) rat model METHODS: NASH was induced in Sprague-Dawley rats by feeding with a high fat diet (HFD) for 12 weeks. 200 mg/kg SAMC was fed by oral gavage for 4 weeks from 9 to 12 week., Results: SAMC co-administration attenuated HFD-induced liver injury, including the increased serum ALT, hepatic oxidative stress and inflammation. Transcriptomic analysis revealed that SAMC dramatically induced the XRE- and ARE-driven drug metabolising enzymes (DMEs) including Akr7a3, Akr1b8, and Nqo1. The nuclear translocation of the upstream regulator of xenobiotics metabolism, AHR, and regulator of antioxidant responses, NRF2, were significantly increased by SAMC treatment. Furthermore, SAMC counteracted the effects of HFD on NF-κB/IκB and NLRP3/6 pathways with decreasing protein levels of ASC, cleaved caspase-1, IL-18, and IL-1β. These results were further verified in another mice NASH model induced by an MCD diet with SAMC co-administration., Conclusion: We propose that SAMC triggers AHR/NRF2-mediated antioxidant responses which may further suppress the NLRP3/6 inflammasome pathway and NF-κB activation, contributing to the improvement of NASH.

Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although several studies have demonstrated the neuroprotective effects of Hericium erinaceus (H.E.), its mechanisms in cerebellar ataxia remain largely unknown. Here, we investigated the neuroprotective effects of H.E. treatment in an animal model of 3-acetylpyridine (3-AP)-induced cerebellar ataxia. Animals administered 3-AP injection exhibited remarkable impairments in motor coordination and balance. There were no significant effects of 25 mg/kg H.E. on the 3-AP treatment group compared to the 3-AP saline group. Interestingly, there was also no significant difference in the 3-AP treatment group compared to the non-3-AP control, indicating a potential rescue of motor deficits. Our results revealed that 25 mg/kg H.E. normalised the neuroplasticity-related gene expression to the level of non-3-AP control. These findings were further supported by increased protein expressions of pERK1/2-pCREB-PSD95 as well as neuroprotective effects on cerebellar Purkinje cells in the 3-AP treatment group compared to the 3-AP saline group. In conclusion, our findings suggest that H.E. potentially rescued behavioural motor deficits through the neuroprotective mechanisms of ERK-CREB-PSD95 in an animal model of 3-AP-induced cerebellar ataxia.

Purpose: This study aimed to investigate the role of cathepsin B dependent autophagy induced by chronic aerobic exercise on a high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) in rats., Methods: Healthy female (Sprague-Dawley) SD rats (8-10 weeks old; 180g-200g; n=6 per group) were divided into: (1) control group; (2) HFD group; (3) Exercise group; (4) HFD + exercise group. Rats were fed with a normal chow or an HFD for 12 weeks. Rats with exercise ran on a rotarod for 30 min per day from weeks 9-12., Results: Exercise training significantly (1) upregulated the levels of autophagy markers Beclin1, ATG5 and LC3II partly through inhibiting the p-AKT/mTOR pathway; (2) ameliorated HFD-mediated accumulation of fat mass by upregulating β-oxidation regulator PPAR-α and downregulating fatty acid synthesis marker SREBP-1c via lipophagy; (3) diminished the HFD-induced hepatic pro-inflammatory mediators TNF-α and IL-1β via NF-κB inactivation; (4) decreased the NASH-induced hepatic apoptotic marker caspase-3 activation caused by the upstream oxidative stress and by cytochrome P450 2E1 (CYP2E1); (5) mitigated the HFD-mediated lysosomal membrane permeabilisation and cathepsin B release partly via the reduction of reactive oxygen species (ROS)., Conclusions: Chronic aerobic exercise reduces oxidative stress/ROS and ROS may cause lysosomal membrane destabilisation and disrupts the autophagic process. The beneficial effect of chronic exercise may further inhibit the process of lysosome membrane permeabilisation and facilitate lysosome fusion with autophagosomes to trigger autophagy. This process may possibly contribute to the inhibition of cathepsin B released into cytosol which further reduces inflammation and mitochondrial-dependent apoptosis.

PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85β are poorly understood. Here we report that p85β upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85β activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85β alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85β, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85β expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85β-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.

Background & Aims: Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood., Methods: ALD-associated liver injury were induced in TLR2 knockout (TLR2 -/- ), TLR3 -/- , TLR2 -/- bone marrow transplanted (BMT), TLR3 -/- BMT, IL-10 -/- mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl 3 injection to evaluate their pathogenic roles in ALD., Results: We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG's actions., Conclusions: Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study aimed to investigate the molecular mechanisms of the ameliorative effects of chronic aerobic exercise on non‑alcoholic steatohepatitis (NASH) in rat skeletal muscle. Female Sprague‑Dawley rats (n=6‑9 per group) were divided into four groups: i) Rats fed with normal chow; ii) exercise rats fed with normal chow + exercise (run on a rotarod for 30 min per day from 9‑12 weeks); iii) rats fed with a high‑fat diet (HFD); iv) rats fed with an HFD + exercise. All HFD rats were fed with an HFD consisting of 30% fat from fish oil throughout the study for 12 weeks. Exercise decreased the levels of hepatic lipogenic markers carbohydrate‑responsive element‑binding protein, fat‑specific protein 27 and liver X receptor and improved systemic glucose and insulin intolerance in the NASH animal model. The beneficial effects may have been mediated partly via the tripartite motif‑containing family protein 72 (TRIM72)/PI3K/Akt/mTOR pathway, accompanied with an upregulation of glucose transporter 4 in the skeletal muscle. The exercise regimen activated the master regulator of antioxidant enzymes, nuclear factor erythroid 2‑related factor 2, with upregulation of superoxide dismutase [Cu‑Zn] expression and a corresponding decrease in kelch‑like ECH‑associated protein 1 expression, but failed to decrease the levels of the oxidative marker malondialdehyde in the HFD rat skeletal muscle. Chronic exercise decreased the expression of the inflammation marker NF‑κB, followed by a decrease in interleukin‑6 and tumor necrosis factor‑α levels, as verified by a corresponding increase in the level of NF‑κB inhibitor α expression. Exercise may exert its beneficial effects by improving muscle insulin sensitivity via the TRIM72/PI3K/Akt/mTOR pathway, contributing to the improvement of systemic insulin intolerance, and finally leading to decreased hepatic lipogenesis during NASH. The attenuation of insulin resistance by exercise may be partly achieved through a decrease in the level of inflammation and an increased antioxidant response.

Scope: Besides abstinence and nutritional support, there is no proven clinical treatment for patients with alcoholic fatty liver disease (AFLD). Here, the therapeutic effects and mechanisms of action of wolfberry-derived zeaxanthin dipalmitate (ZD) on AFLD models are demonstrated., Methods and Results: The hepatoprotective effects of ZD are evaluated in vitro and in vivo. Direct interacting receptors of ZD on cell membranes are identified by liver-specific knockdown and biophysical measurements. Downstream signaling pathways are delineated using molecular and cellular biological methods. It is demonstrated that ZD attenuates hepatocyte and whole-liver injury in ethanol-treated cells (dose: 1 µm) and a chronic binge AFLD rat model (dose: 10 mg kg -1 ), respectively. The direct targets of ZD on the cell membrane include receptor P2X7 and adiponectin receptor 1 (adipoR1). Signals from P2X7 and adipoR1 modulate the phosphatidylinositide 3-kinase-Akt and/or AMP-activated protein kinase-FoxO3a pathways, to restore mitochondrial autophagy (mitophagy) functions suppressed by ethanol intoxication. In addition, ZD alleviates hepatic inflammation partially via the inhibition of Nod-like receptor 3 inflammasome, whose activation is a direct consequence of suppressed mitophagy. Liver-specific inhibition of receptors or mitophagy significantly impairs the beneficial effects of ZD., Conclusions: ZD is an effective and promising agent for the potential treatment of AFLD., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: This study compares median nerve cross-sectional area (CSA) measurements at the wrist obtained with ultrasound (US) and magnetic resonance imaging (MRI) using cadaveric measurements as the gold standard., Methods: Median nerve CSA was measured using US and MRI in 9 cadaveric wrists obtained from 5 subjects at 5 locations: distal forearm, proximal to tunnel inlet, at tunnel inlet, at tunnel outlet, and distal to tunnel outlet and then on identical cadaveric transverse sections obtained with a bandsaw. All US, MRI, and cadaveric measurements were repeated to determine reliability. Median nerves of 10 patients with clinical carpal tunnel syndrome (CTS) were measured with US and MRI using an identical method US., Results: Median nerve CSA MRI measurements correlated better (Pearson correlation: 0.80-0.95, P < .05) with cadaveric measurements than with US measurements (Pearson correlation: 0.61-0.79, P < .05). Median nerve CSA US measurements (8.6-12.5 mm 2 , P < .05) were smaller at all levels than MRI (11.3-14.7 mm 2 ) or cadaveric (11.0-14.9 mm 2 ) measurements while MRI and cadaver measurements were similar at all levels. Median nerve CSA MRI measurements in CTS patients were larger than US measurements at all levels., Conclusion: Median nerve CSA measurements by MRI are larger than US measurements and correlated better with cadaveric measurements. Median nerve CSA criteria used for diagnosing CTS on US are not likely to be applicable to MRI., (© 2018 Wiley Periodicals, Inc.)

Lycium barbarum polysaccharides (LBP) are major bioactive constituents of wolfberry which possess several pharmacological effects such as antioxidant and immunomodulatory activities. We aimed to evaluate how LBP attenuated the hepatic injury in a non-alcoholic steatohepatitis (NASH) methionine-choline deficient (MCD) mouse model. NASH was induced in C57BL/6N mice by feeding with MCD diet for 6 weeks. During the experiments, 1 mg/kg LBP was intragastrically fed on a daily basis with or without MCD diet lasting from the 4th to 6th week. Control and vehicle-control (LBP + PBS) were fed with a regular animal chow. LBP significantly ameliorated NASH-induced injuries, including the increase of serum ALT and AST levels, hepatic oxidative stress, fibrosis, inflammation, and apoptosis. The hepatoprotective effects of LBP were accompanied by the attenuation of thioredoxin interacting protein, nod-like receptor protein 3/6 (NLRP3/6) and reduced NF-κB (nuclear factor-kappa B) activity. Vehicle LBP fed mice showed no adverse effect on the liver. In conclusion, the suppression of the NLRP3/6 inflammasome pathway and NF-κB activation may partly contribute to the reduction of the hepatic injury during the progression of NASH by therapeutic LBP treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Whether and how garlic-derived S -allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of β -catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.

Scope: Lycium barbarum polysaccharide (LBP) is a water fraction of wolfberry, which has been demonstrated to possess a hepatoprotective effect in several liver disease models. However, the anti-alcoholic liver disease (anti-ALD) mechanism of LBP has not been investigated thoroughly. Its protective effects on both male and femal mice are investigated in the current study., Methods and Results: A chronic ethanol-fed ALD in vivo model is applied to study the effect of LBP in both male and female mice. It is observed that ethanol causes more severe liver injury in female than male mice, and the ameliorative effects of LBP are also more significant in female mice, which are impaired after complete bilateral oophorectomy. The hepatic SCD1 expression is found to be positively correlated with the severity of the liver damage and the main mediator of LBP inducer of protection. The AMPK-CPT pathway is also activated by LBP to rebalance the dysregulated lipid metabolism during ALD development. By using concurrent sodium palmitate and an ethanol-induced in vitro cell damage model in AML-12 cell line, it is characterized that LBP directly interacts with ERα instead of ERβ to activate the SCD1-AMPK-CPT pathway., Conclusions: LBP is an effective and safe hepatoprotective agent against ALD primarily through the SCD1-AMPK-CPT pathway after ERα agonist., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Co-morbid depression is prevalent in patients with obstructive sleep apnea. Here we report that monoamine oxidase A (MAO-A) plays pathogenic roles in the comorbidity. We found that chronic intermittent hypoxia significantly increased the MAO-A expression in the rat hippocampus and markedly decreased the dendritic length and spine density in the pyramidal neurons with less pre- and post-synaptic proteins. The MAO-A upregulation resulted in increased 5-hydroxyindoleacetic acid/serotonin ratio, oxidative stress, leading to NF-κB activation, inflammation and apoptosis. Also, the expression of cytokine-responsive indoleamine 2,3-dioxygenase-1 (IDO-1) was significantly augmented in hypoxia, resulting in increased kynurenine/tryptophan ratio and lowered serotonin level in the hippocampus. Moreover, depressive-like behaviors were observed in the hypoxic rat. Administration of M30, a brain-selective MAO-A inhibitor with iron-chelating properties, prior to hypoxic treatment prevented the aberrant changes in the hippocampus and depressive behavior. In human SH-SY5Y cells expressing MAO-A but not MAO-B, hypoxia significantly increased the MAO-A expression, which was blocked by M30 or clorgyline. Collectively, the MAO-A upregulation induced by chronic intermittent hypoxia plays significant pathogenic role in oxidative stress, inflammation and IDO-1 activation resulting in serotonin depletion and neurodegeneration.