Lipid nanoparticles of quercetin (QU-Lip) alleviated pancreatic microenvironment in diabetic male rats: The interplay between oxidative stress - unfolded protein response (UPR) - autophagy, and their regulatory miRNA.

BACKGROUND: Autophagy is a well-preserved mechanism essential in minimizing endoplasmic reticulum stress (ER)-related cell death. Defects in ß-cell autophagy have been linked to type 1 diabetes, particularly deficits in the secretion of insulin, boosting ER stress sensitivity and possibly promoting pancreatic ß-cell death. Quercetin (QU) is a potent antioxidant and anti-diabetic flavonoid with low bioavailability, and the precise mechanism of its anti-diabetic activity is still unknown. Aim This study aimed to design an improved bioavailable form of QU (liposomes) and examine the impact of its treatment on the alleviation of type 1 diabetes induced by STZ in rats. METHODS: Seventy SD rats were allocated into seven equal groups 10 rats of each: control, STZ, STZ + 3-MA, STZ + QU-Lip, and STZ + 3-MA + QU-Lip. Fasting blood glucose, insulin, c-peptide, serum IL-6, TNF-α, pancreatic oxidative stress, TRAF-6, autophagy, endoplasmic reticulum stress (ER stress) markers expression and their regulatory microRNA (miRNA) were performed. As well as, docking analysis for the quercetin, ER stress, and autophagy were done. Finally, the histopathological and immunohistochemical analysis were conducted. SIGNIFICANCE: QU-Lip significantly decreased glucose levels, oxidative, and inflammatory markers in the pancreas. It also significantly downregulated the expression of ER stress and upregulated autophagic-related markers. Furthermore, QU-Lip significantly ameliorated the expression of several MicroRNAs, which both control autophagy and ER stress signaling pathways. However, the improvement of STZ-diabetic rats was abolished upon combination with an autophagy inhibitor (3-MA). The findings suggest that QU-Lip has therapeutic promise in treating type 1 diabetes by modulating ER stress and autophagy via an epigenetic mechanism.

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

The Antiproliferative Activity of Adiantum pedatum Extract and/or Piceatannol in Phenylhydrazine-Induced Colon Cancer in Male Albino Rats: The miR-145 Expression of the PI-3K/Akt/p53 and Oct4/Sox2/Nanog Pathways.

Colon cancer is one of the most common types of cancer worldwide, and its incidence is increasing. Despite advances in medical science, the treatment of colon cancer still poses a significant challenge. This study aimed to investigate the potential protective effects of Adiantum pedatum (AP) extract and/or piceatannol on colon cancer induced via phenylhydrazine (PHZ) in terms of the antioxidant and apoptotic pathways and histopathologic changes in the colons of male albino rats. The rats were randomly divided into eight groups: control, AP extract, piceatannol (P), PHZ, PHZ and AP treatments, PHZ and P treatments, PHZ and both AP and P, and PHZ and prophylaxis with both AP and P. The results demonstrated that PHZ induced oxidative damage, apoptosis, and histopathological changes compared to the control group. However, the administration of AP or P or AP + P as therapy or prophylaxis significantly ameliorated these changes and upregulated the colonic mir-145 and mRNA expression of P53 and PDCD-4 while downregulating the colonic mRNA expression of PI3K, AKT, c-Myc, CK-20, SOX-2, OCT-4, and NanoG compared to the PHZ group. These findings suggest that the candidate drugs may exert their anti-cancer effects through multiple mechanisms, including antioxidant and apoptotic activities.

Teaching, Learning and Assessing Anatomy with Artificial Intelligence: The Road to a Better Future.

Anatomy is taught in the early years of an undergraduate medical curriculum. The subject is volatile and of voluminous content, given the complex nature of the human body. Students frequently face learning constraints in these fledgling years of medical education, often resulting in a spiraling dwindling academic performance. Hence, there have been continued efforts directed at developing new curricula and incorporating new methods of teaching, learning and assessment that are aimed at logical learning and long-term retention of anatomical knowledge, which is a mainstay of all medical practice. In recent years, artificial intelligence (AI) has gained in popularity. AI uses machine learning models to store, compute, analyze and even augment huge amounts of data to be retrieved when needed, while simultaneously the machine itself can be programmed for deep learning, improving its own efficiency through complex neural networks. There are numerous specific benefits to incorporating AI in education, which include in-depth learning, storage of large electronic data, teaching from remote locations, engagement of fewer personnel in teaching, quick feedback from responders, innovative assessment methods and user-friendly alternatives. AI has long been a part of medical diagnostics and treatment planning. Extensive literature is available on uses of AI in clinical settings, e.g., in Radiology, but to the best of our knowledge there is a paucity of published data on AI used for teaching, learning and assessment in anatomy. In the present review, we highlight recent novel and advanced AI techniques such as Artificial Neural Networks (ANN), or more complex Convoluted Neural Networks (CNN) and Bayesian U-Net, which are used for teaching anatomy. We also address the main advantages and limitations of the use of AI in medical education and lessons learnt from AI application during the COVID-19 pandemic. In the future, studies with AI in anatomy education could be advantageous for both students to develop professional expertise and for instructors to develop improved teaching methods for this vast and complex subject, especially with the increasing paucity of cadavers in many medical schools. We also suggest some novel examples of how AI could be incorporated to deliver augmented reality experiences, especially with reference to complex regions in the human body, such as neural pathways in the brain, complex developmental processes in the embryo or in complicated miniature regions such as the middle and inner ear. AI can change the face of assessment techniques and broaden their dimensions to suit individual learners.

Location-Linked QR Code as a Safe Tool for Recording Classroom Attendance During COVID-19 Pandemic: Perspectives of Medical Students.

COVID-19 lockdowns affected educational programs. Online learning has suddenly become the main form of medical education. However, attendance enhances a student's competency and professionalism. Rising student numbers and the COVID-19 pandemic make in-class learning challenging. This study investigates medical students' perceptions of a recently implemented tool for recording attendance using a QR code that detects students' location while scanning. An online questionnaire was designed to collect responses. One hundred thirty-two students completed the survey. Students agreed that the method was usable, reliable, accurate, secure, and convenient. This method should be investigated as a standard tool for attendance recording. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01625-7.

Genetic Interpretation of the Impacts of Honokiol and EGCG on Apoptotic and Self-Renewal Pathways in HEp-2 Human Laryngeal CD44high Cancer Stem Cells.

Most current larynx cancer therapies are generally aimed at the global mass of tumor, targeting the non-tumorigenic cells, and unfortunately sparing the tumorigenic cancer stem cells (CSCs) that are responsible for sustained growth, metastasis, and chemo- and radioresistance. Phytochemicals and herbs have recently been introduced as therapeutic sources for eliminating CSCs. Therefore, we assessed the anti-tumor effects of two herbal ingredients, the green tea extract "Epigallocatechin-3-gallate (EGCG)" and Honokiol (HNK), on parental cells or CD44high CSCs of the human laryngeal squamous cell carcinoma cell line HEp-2. Results revealed that EGCG had a preeminent apoptotic potential on HEp-2 laryngeal CSCs. HNK conferred higher cytotoxic impacts on parental cells mostly by necrosis induction, especially with higher doses, but apoptosis induction with lower doses was also observed. The Notch signaling pathway genes were more potently suppressed by EGCG than HNK. However, HNK surpassed EGCG in downregulating the ß-catenin and the Sonic Hedgehog signaling pathways genes. On a genetic basis, both agents engaged the BCL-2 family-regulated and caspase-dependent intrinsic apoptotic pathway, but EGCG and HNK triggered apoptosis via p53-independent and p53-dependent pathways, respectively. Taken together, EGCG and HNK eradicated HEp-2 human larynx cancer cells through targeting multiple self-renewal pathways and activating diverse cell death modalities.

Correlation Between Enrollment of Students in Mentoring Program and Their Academic Achievements: A Cross-Sectional Study.

Introduction Mentoring is a process in which a mentor guides his mentee to achieve specific academic goals and an array of objectives. We conducted this study to detect the correlation between the active participation of the students in the mentoring program and their academic achievements.  Methods This is a comparative cross-sectional study. The data were collected through an online questionnaire. One hundred participants were enrolled randomly in the study. The data included the number of meetings between the mentor and students and their cumulative grade point average (CGPA). Results The response rate was 83.3% (100 students). Fifty percent (n = 50) of the respondents had never met with their mentors while the other 50% (n = 50) had met with their mentors at least once in a semester. For this group, overall, positive response rates regarding the value and effectiveness of the mentoring program exceeded 78%. The correlation between participation in the mentoring program and the academic achievements of students was calculated (R2 was 0.007, p-value = 0.757). Conclusions This study demonstrated a non-significant correlation between the degree of involvement in the mentoring program and students' overall academic achievements as students from both sections. Those who were enrolled in the program, and those students who were not, still achieved high scores.

Effect of Intermittent Fasting on Glucose Homeostasis and Bone Remodeling in Glucocorticoid-Induced Osteoporosis Rat Model.

BACKGROUND: The present study examined the effect of intermittent fasting (IF) on bone mineral content (BMC) and bone mineral density (BMD) and the markers of bone remodeling in a glucocorticoid-induced osteoporosis (GIO) rat model. METHODS: Forty male rats were allocated to 4 groups (N=10 per group): control group of normal rats; control+IF group (normal rats subjected to IF for 16-18 hr daily for 90 days); dexamethasone (DEX) group: (DEX [0.5 mg i.p.] for 90 days); and DEX+IF group (DEX and IF for 90 days). By the end of the experiment, BMD and BMC in the right tibia were measured. Serum levels of the following were measured: glucose; insulin; triglycerides (TGs); total cholesterol; parathyroid hormone (PTH); osteoprotegerin (OPG); receptor activator of nuclear factor-κB (RANK); bone-resorbing cytokines, including bone deoxypyridinoline (DPD), N-terminal telopeptide of collagen type I (NTX-1), and tartrate-resistant acid phosphatase 5b (TRAP-5b); and bone-forming cytokines, including alkaline phosphatase (ALP) and osteocalcin (OC). RESULTS: DEX administration for 90 days resulted in significantly increased serum levels of glucose, insulin, TGs, cholesterol, PTH, OPG, DPD, NTX-1, and TRAP-5b and significantly decreased BMD, BMC, and serum levels of RANK, OC, and ALP (all P<0.05). IF for 90 days significantly improved all these parameters (all P<0.05). CONCLUSIONS: IF corrected GIO in rats by inhibiting osteoclastogenesis and PTH secretion and stimulating osteoblast activity.

Time Spent in Practicing Dissection Correlated with Improvement in Anatomical Knowledge of Students: Experimental Study in an Integrated Learning Program.

Introduction and aim Cadaveric dissection has long been used as the main domain for teaching anatomy in medical schools. However, recently with a limited number of cadavers and time for practicing dissection, prosections and anatomical models are widely used and may replace traditional dissection. We aimed to explore the possible association between practicing dissection and test results among medical students and to determine whether there are differences in achievements between students who studied anatomy by cadaveric dissection and those who used prosections and anatomical models. Methods The study was conducted at the University of Bisha, College of Medicine, Saudi Arabia, during the period from March to August 2017. Students were randomly assigned to one of two groups (50 in each). The first group studied anatomy (upper limb course) by practicing dissection while the other studied it by using prosections and anatomical models. Both groups were subjected to the same final assessments. Scores of both groups were compared by using the Student's t-test. Correlation analysis between time spent in practicing dissection (carefully registered using a predesigned portfolio and an attendance logbook) and assessment grades was implemented using the rank-based Pearson correlation coefficient. Results Students practicing dissection achieved higher grades (169 ± 1.99) than those who studied anatomy by only using prosections and anatomical models (142 ± 1.78, p<0.001). There was an association between the time spent in practicing dissections and overall anatomy summative assessments (r2=0.841, p<0.001). Students expressed positive responses towards the effectiveness and value of practicing dissection. Conclusions We concluded that practicing dissection helps students to achieve higher results than learning using only models and prosections. Time spent in practicing dissection correlated with final assessment results. Further research is required to measure not only the statistical significance of results but also their educational effectiveness and long term learning outcomes.

Effect of blueprinting methods on test difficulty, discrimination, and reliability indices: cross-sectional study in an integrated learning program.

PURPOSE: Exam blueprinting achieves valid assessment of students by defining exactly what is intended to be measured in which learning domain and defines what level of competence is required. We aimed to detect the impact of newly applied method for blueprinting that depends on total course credit hours and relate the results with item analysis reports for students' performance. PARTICIPANTS AND METHODS: A new method for blueprint construction was created. This method utilizes course credit hours for blueprint creation. Survey analysis was conducted for two groups of students (n=80); one utilized our new method (credit hours based) for blueprinting and the other used traditional method depending on exam duration and time for individual test items. RESULTS: Results of both methods were related to item analysis of students' achievements. No significant difference was found between both groups in terms related to test difficulty, discrimination, or reliability indices. Both achieved close degrees of test validity and reliability measures. CONCLUSION: We concluded that our method using credit hours system for blueprinting could be considered easy and feasible and may eventually be utilized for blueprint construction and implementation.

Effect of human umbilical cord blood derived CD34+ hematopoietic stem cell on the expression of Wnt4 and P53 genes in a rat model of hepatocellular carcinoma.

BACKGROUND AND AIM OF THE WORK: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy. Chronic liver injuries as chronic hepatitis C and hepatitis B viruses, aflatoxins consumption and nonalcoholic fatty liver disease are well-established causes of HCC. HCC is associated with a series of molecular changes, as alternation in glypican-3, P53 expression and Wnt/ß-catenin pathway. Hepatic cancer progenitor cells could contribute to HCC development. This research aimed to study the effectiveness of human CD34+ hematopoietic stem cell on Wnt4 and P53 genes expression, histopathological grading and hepatic progenitor cells percentage in HCC rat model. MATERIALS AND METHODS: HCC was induced in the experimental group of outbred Sprague Dawley rats by administration of 50 mg/L N-nitroso-Di-Ethylamine (DEN) in drinking water for 15 weeks. Forty-six animals were used in total, they were initially subdivided into two groups; control (n = 6) and experimental (n = 40), the latter consisting of 4 DEN-unaffected, 6 DEN-lethalities and 30 surviving DEN-animals with elevated AFP. These 30 animals with elevated AFP were then subdivided into a new HCC control group (n = 15) and the stem cell treated group (n = 15). The latter group was injected with CD34+ human hematopoietic stem cell (1 × 106 cells/rat) in the rat's tail vein. Cyclosporine A (10 mg/kg) was injected intraperitoneal, starting 24 h before human stem cell transplantation. After 20 weeks passing since the beginning of the experiment, all rats were sacrificed and liver specimens were subjected to histopathological examination, RT-PCR in order to examine Wnt4 and P53 gene expression and flow cytometry to measure hepatic progenitor OV6 positive cells percentage. RESULTS: The saline-treated HCC group (with prior 15 week DEN exposure) showed higher levels of wnt4 and p53 gene expression (1.59 and 1.36 fold, respectively) and increased percentage in OV6+ progenitor cells (+4.9% in absolute terms) compared to saline-treated controls (p < 0.01, ANOVA). Compared with the saline HCC-group, transplantation with CD34+ human hematopoietic stem cells produced a further increase in the levels of wnt4 (+19.4%) and p53 gene expression (+53%), a 2-fold increase in the percentage of cancer progenitor cells and increased HCC pathology grading (all p < 0.01). The positive correlation between p53 and HCC grade (Spearman rho +0.73, p < 0.05) and negative correlation between wnt and OV6+% levels (rho -0.65, p < 0.05) in the saline-HCC group were not observed in the CD34+ HCC group. CONCLUSIONS: Human CD34+ cells transplantation has a deteriorating effect on HCC.

Circulating CD34+ hematopoietic stem/progenitor cells paralleled with level of viremia in patients chronically infected with hepatitis B virus.

INTRODUCTION: Liver regeneration is a heterogeneous process involving proliferation of different cell types in response to injury. Bone marrow derived stem cells may be involved in this process, by making contribution to parenchymal restoration and cellular replacement. We aimed to investigate the correlation between level of circulating mobilized CD34+ hematopoietic stem progenitor cells (HSPCs) and viremia level in patients chronically infected with hepatitis B virus (HBV). METHODS: Blood samples were prospectively collected for assessing percentage and absolute counts of circulating CD34+ HSPCs and viral load level using flow cytometry and RT-PCR respectively. Patients with chronic hepatitis B (CHB) (n = 30), Entecavir (ETV) treated subjects (n = 30) and 20 age and gender matched healthy controls were enrolled in this study. Results were expressed as mean ± SD. RESULTS AND DISCUSSION: A significant increase in circulating CD34+ HSPCs level was observed in CHB patients (5 ± 3.1, 324 ± 195 × 103/ml) as compared to ETV treated subjects (0.57 ± 0.27,1022 ± 325) and healthy controls (0.53 ± 0.37, 694 ± 254, P < 0.001) in regards to percentage and absolute counts respectively. Levels of CD34+ HSPCs strongly and positively correlated with HBV DNA viral load levels in CHB patients (r2 = 0.8417, 0.649, P < 0.001).Thus, in chronic liver disorders (CHB), when reduced regenerative capacity of hepatocytes is reached, BMSCs mobilization occurs and their level increases in peripheral blood. The level of circulating CD34+ cells in peripheral blood of CHB patients paralleled with the hepatitis B viral load.

PD-L1 Expression on Circulating CD34＋ Hematopoietic Stem Cells Closely Correlated with T-cell Apoptosis in Chronic Hepatitis C Infected Patients.

BACKGROUND AND OBJECTIVES: Lack of understanding of the interplay between hematopoietic stem cells (HSCs) and the immune system has severely hampered stem cell research. Programmed death-1 (PD-L1) has been reported on parenchymal cells in patients with chronically inflamed livers and found to play an essential role in T cell homeostasis regulation. However, the bidirectional interaction between HSCs and lymphocytes remains elusive. Here, we aimed to get more insight into circulating CD34+ HSCs PD-L1 expression and T cell apoptosis in chronic HCV infected patients. METHODS: CD34＋ HSCs were isolated and purified by immunomagnetic separation. PD-L1 expression was analyzed by quantitative PCR and flow cytometry. Furthermore, co-culture experiments between CD34＋ HSCs and T-lymphocytes were established. T-cell lymphocyte apoptosis in peripheral blood and in cultures was detected. RESULTS: CD34＋ HSCs constitutively express low levels of PD-L1. Its expression is up-regulated in chronic HCV infected patients. Moreover, PD-L1 expression on circulating CD34＋ HSCs enhanced T cell apoptosis in peripheral blood and co-culture. CONCLUSION: Our results suggest novel bidirectional interplay between HSCs and lymphocytes mediated by PD-L1 expression on CD34＋ HSCs. PD-L1 expression correlated with T-cell lymphocyte apoptosis. This may contribute to immunomodulatory properties of HSCs which improves its use for allogeneic transplantation.

Effect of human umbilical cord blood stem cell transplantation on oval cell response in 2-AAF/CCL4 liver injury model: experimental immunohistochemical study.

BACKGROUND: Oval cells, specific liver progenitors, are activated in response to injury. The human umbilical cord blood (hUCB) is a possible source of transplantable hepatic progenitors and can be used in cases of severe liver injury. We detected the effect of hUCB stem cell transplantation on natural response of oval cells to injury. METHODS: Twenty-four female albino rats were randomly divided into three groups: (A) control, (B) liver injury with hepatocyte block, and (C) hUCB transplanted group. Hepatocyte block was performed by administration of 2-acetylaminofluorene (2-AAF) for 12 days. CCL4 was administrated at day 5 from experiment start. Animals were sacrificed at 9 days post CCL4 administration, and samples were collected for biochemical and histopathological analysis. Oval cell response to injury was evaluated by the percentage of oval cells in the liver tissue and frequency of cells incorporated into new ducts. RESULTS: Immunohistochemical analysis of oval cell response to injury was performed. There was significant deviation in the hUCB-transplanted (4.9 ± 1.4) and liver injury groups (2.4 ± 0.9) as compared to control (0.89 ± 0.4) 9 days post injury. Detection of oval cell response was dependant on OV-6 immunoreactivity. For mere localization of cells with human origin, CD34 antihuman immunoreactivity was performed. There was no significant difference in endogenous OV-6 immunoreactivity following stem cell transplantation as compared to the liver injury group. CONCLUSIONS: In vivo transplantation of cord blood stem cells (hUCB) does not interfere with natural oval cell response to liver injury.