Background: High-mobility group box protein 1 (HMGB1) is a chromatin-binding protein involved in arthritis, ischemia, sepsis, atherosclerosis, neurodegenerative disorders, meningitis, and cancer. HMGB1 exhibits dual roles in cancer, acting as either a tumor suppressor or oncoprotein depending on context. Objective: This research aimed to elucidate HMGB1’s functional significance in cutaneous squamous cell carcinoma (cSCC). Methods: We overexpressed HMGB1 in cSCC cell lines using recombinant adenovirus and examined its effects on cell proliferation, colony formation, and cell migration. Results: Immunohistochemical analysis revealed elevated HMGB1 expression levels in cSCC tissue relative to normal epidermis. To assess the influence of HMGB1, we employed recombinant adenoviruses expressing HMGB1 to transduce SCC cell lines (SCC12 and SCC13). Enhanced HMGB1 expression significantly promoted cellular proliferation and colony formation capacity.Notably, HMGB1 overexpression elevated the levels of proliferation regulators, including P63, SOX2, CDK4 and CDK6. Furthermore, HMGB1 overexpression substantially enhanced tumor invasiveness, accompanied by upregulation of epithelial-mesenchymal transition (EMT) biomarkers. Mechanistically, overexpression of HMGB1 enhanced transforming growth factor-β signaling by increasing phosphorylation of SMAD2/3, the key mediators of EMT. Conclusion These data imply that HMGB1 acts as a tumor-promoting factor in cSCC.

At present,reforming and innovating the public health talent training model are the challenges that the construc-tion of new medical in our country.Medical Immunology is the initial driving force in preventive medicine.Based on the course con-struction of Medical Immunology and centering on the core link of post competency of preventive medicine undergraduates,this study comprehensively reshapes the course system of Medical Immunology from the aspects of theoretical courses,practical courses,experi-mental courses,ideological and political courses and assessment methods,so as to provide reference for improving the teaching quality of preventive healthcare undergraduates.

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

AIM:This study aims to investigate the synergistic cytotoxic effects of chrysin and venetoclax on acute myeloid leukemia(AML)cells and to elucidate the underlying mechanisms.METHODS:Human AML cell lines MV411 and MOLM13 were cultured in vitro and treated with chrysin in combination with venetoclax.Cell viability was as-sessed using the CCK8 assay,while flow cytometry was employed to measure cell cycle distribution and apoptosis rates.Western blot was used to detect the expression of apoptosis-related proteins and protein kinase B(PKB/Akt)/nuclear factor-κB(NF-κB)signaling pathway-related proteins.RESULTS:The results from the CCK8 assay and flow cytometry demon-strated that treatment with 16 and 32 μmol/L chrysin significantly inhibited the viability of AML cells and increased the proportion of cells in G1 phase,as well as the apoptosis rate.Notably,the cells in combination treatment group exhibited a marked reduction in proliferation and an elevated apoptosis rate compared with either chrysin or venetoclax group alone.Western blot analysis indicated that increasing concentrations of chrysin led to an elevation in cleaved poly(ADP-ribose)polymerase(PARP)level,alongside a down-regulation of proteins associated with the Akt/NF-κB signaling pathway.Fur-thermore,the combination treatment significantly up-regulated cleaved PARP level and down-regulated Akt/NF-κB path-way-related proteins compared with the treatment with chrysin or venetoclax alone.CONCLUSION:Chrysin and veneto-clax synergistically inhibit the proliferation of AML cells and promote apoptosis by modulating the Akt/NF-κB signaling pathway.

At present,reforming and innovating the public health talent training model are the challenges that the construc-tion of new medical in our country.Medical Immunology is the initial driving force in preventive medicine.Based on the course con-struction of Medical Immunology and centering on the core link of post competency of preventive medicine undergraduates,this study comprehensively reshapes the course system of Medical Immunology from the aspects of theoretical courses,practical courses,experi-mental courses,ideological and political courses and assessment methods,so as to provide reference for improving the teaching quality of preventive healthcare undergraduates.

Objective:To explore the structural equation model to explore the levels of work-related musculoskeletal disorders (WMSDs) and various risk factors in the feet and ankle of China's occupational population, providing scientific basis for for preventing WMSDs in feet and ankles.Methods:Data of 73497 national occupational epidemiological cases were selected from June 2018 to December 2023 used the Chinese version of the Electronic Questionnaire on Musculoskeletal Disorders. The adverse ergonomic factors and their source classification standard and confirmatory factor analysis were used to investigate foot and ankle WMSDs and their related risk factors (including individual factors, work organization, work posture, work type, fatigue, etc.) in key occupational groups in China, and structural equation model hypothesis, fitting, verification, and path and intermediary effect analysis were carried out. The model fit evaluation indexes included Chi-square specific degrees of freedom ( χ2/ df), gauge fit index (NFI), Tucker Lewis index (TLI), goodness of Fit index (GFI), adjusted Goodness of Fit index (AGFI) and approximate root mean square error (RMSEA) . Results:A total of 73497 occupational workers were surveyed, with local muscle fatigue and WMSDs incidence rates in the feet and ankles being 17.17% and 12.06%, respectively. The fitting index of the adjusted structural equation model basically meets the standard (GFI=1, AGFI=1, RMESA=0.042, NFI=0.716, TLI=0.663). The top three factors affecting feet and ankle WMSDs are feet and ankle muscle fatigue, work type, and work organization, with standardized path coefficients of 0.221, 0.105, and 0.095, respectively. The top two factors affecting feet and ankle muscle fatigue are work organization and work type, with standardized path coefficients of 0.548 and 0.383, respectively. Feet and ankle muscle fatigue, work type, work organization, and work posture have a direct effect on feet and ankle WMSDs, with effect values of 0.221, 0.105, 0.095, and 0.077, respectively. The organization and type of work can also have indirect effects through feet and ankle muscle fatigue, with effect values of 0.121 and 0.084, respectively.Conclusion:Feet and ankle muscle fatigue has a direct impact on WMSDs, and plays a mediating role between ankle and ankle WMSDs caused by work organization and work type. Feet and ankle muscle fatigue is an important pathway leading to feet and ankle WMSDs. It is recommended that employers and managers detect job fatigue early and take corresponding prevention and intervention measures, which can play a key role in preventing feet and ankle WMSDs.

BACKGROUND:Apoptosis and autophagy imbalance in the hippocampal region of perimenopausal depressed rats are closely related to cognitive decline.Whether aerobic exercise can reduce apoptosis by promoting hippocampal autophagy and thus improve the learning and memory abilities of perimenopausal depressed rats is not clear.OBJECTIVE:To investigate the possible mechanism by which 4-week moderate-intensity treadmill exercise improves learning memory ability in ovariectomized stressed rats.METHODS:Forty Sprague-Dawely rats were randomly divided into four groups,namely,sham operation group(n=10),ovariectomized group(n=10),ovariectomized stress group(n=10)and ovariectomized stress exercise group(n=10).Except for the sham operation group,the ovaries were removed in the other three groups to establish a perimenopausal rat model,and then a depressed rat model was established by chronic unpredictable stress in the latter two groups.The rats in the ovariectomized stress exercise group underwent a 4-week moderate-intensity treadmill exercise.Tail suspension test and sucrose preference test were performed to text depression-like behaviors in rats after exercise and stress.The eight-arm maze experiment was used to test the learning and memory behaviors of rats after exercise and stress.Western blot was used to detect the protein levels of AMP-activated protein kinase/UNC-51 like autophagy activating kinase 1/mammalian target of rapamycin(AMPK/mTOR/ULK1),hippocampus apoptotic factor Caspase-3 and the protein expression of autophagy markers LC-3II/Beclin-1 in the hippocampus.RESULTS AND CONCLUSION:(1)Compared with the sham operation group,rats in the ovariectomized and ovariectomized stress groups had prolonged resting time in the tail suspension test and decreased sugar-water intake and sugar-water preference in the sucrose preference test.(2)Ovary removal reduced the learning memory capacity of rats,as evidenced behaviorally by a significant increase in the number of working memory errors,the number of reference memory errors,and the completion time,and an even more pronounced increase in the above measures in the ovariectomized stress group.(3)Compared with the ovariectomized group,there was a significant reduction in the number of working memory errors,the number of reference memory errors,and the completion time in the ovariectomized stress group.(4)Compared with the sham operation group,in the ovariectomized and ovariectomized stress groups,the expression of hippocampal apoptotic factor Caspase 3 protein was significantly elevated,the expression of autophagy-related factors proteins Beclin-1 and LC3II,as well as the protein expression of AMPK and ULK1,was decreased,whereas the expression of mTOR protein was elevated.Changes in the above indicators were more significant in the ovariectomized stress group.(5)Compared with the ovariectomized stress group,in the ovariectomized stress exercise group,the protein expression of Caspase 3 was significantly decreased,the protein expression of Beclin-1 and LC3II was significantly increased,the protein expression of AMPK and ULK1 was significantly increased,and the protein expression of mTOR was significantly reduced.To conclude,4-week moderate-intensity treadmill exercise may promote cellular autophagy and reduce apoptosis through the AMPK/mTOR/ULK1 autophagy signaling pathway,thereby enhancing the learning and memory capacity of rats with ovariectomized depression

Aim To explore the mechanism of luteolin in alleviating hepatic fibrosis.Methods C57BL/6 mice were randomly divided into the control group,CCl4 group,silybin group(100 mg·kg-1)and luteo-lin group(100 mg·kg-1).After 10-week modeling and 2-week treatment,the serum levels of aminotrans-ferase and liver histopathology were examined.Hepatic fibrosis and autophagy-related gene expression were as-sessed using immunohistochemistry and immunofluores-cence.Human hepatic stellate cell line(LX2)was cultured and divided into control,TGF-β1(10 mg·L-1),TGF-β1+silybin(40 μmol·L-1),TGF-β1+luteolin(40 μmol·L-1).Fibrotic and autophagy-re-lated markers were analyzed using quantitative real-time PCR,Western blot,immunofluorescence and MDC staining.Results Compared with the CCl4 group,the treatment groups showed significantly improved liver function and reduced hepatic fibrosis,with markedly downregulated COL1A1 and α-SMA expression,and luteolin demonstrated superior efficacy.Compared with TGF-β1 group,luteolin treatment significantly de-creased mRNA levels of COL1A1,ACTA2 and MAP1LC3B,while increasing the mRNA level of SQSTM1,the protein levels of COL1A1 and α-SMA de-creased,p62 was enhanced,the LC3Ⅱ/Ⅰ ratio was downregulated,and autophagy was reduced.These effects of luteolin were reversed by autophagy inducer rapamycin.Conclusion Luteolin alleviates liver fi-brosis by decreasing the autophagy of hepatic stellate cells.

AIM To prepare anisamide-modified ursolic acid self-assembled nanoparticles,and to evaluate their anti-drug resistance effect of enzalutamide on prostate cancer.METHODS Nanoparticle precipitation method was adopted in the preparation of anisamide-modified and non-anisamide-modified self-assembled nanoparticles,respectively,after which the particle size,Zeta potential and encapsulation efficiency were determined,and the morphology was observed under transmission electron microscope.The intake of cancer-associated fibroblasts(CAFs)was investigated,after which the model for enzalutamide resistance in prostate cancer was established,CCK8 assay was applied to analyzing the sensitization effect of self-assembled nanoparticles on enzalutamide,and Western blot was used for the detection of NRG1,HER3,AKT expressions.RESULTS The anisamide-modified self-assembled nanoparticles demonstrated the average particle size,Zeta potential and encapsulation efficiency of(195.13±8.06)nm,(-29.07±0.55)mV and(94.58±0.84)％,respectively.CAFs displayed higher intake in the anisamide-modified self-assembled nanoparticles than that in the non-modified preparation and free Cy5(P＜0.05).Meanwhile,anisamide-modified self-assembled nanoparticles were able to inhibit enzalutamide resistance caused by CAFs,reduce NRG1 expression on CAFs,and anisamide-modified self-assembled nanoparticles-treated conditioned medium of CAFs could reduce HER3 and AKT expression on LNCaP cells(P＜0.05,P＜0.01).CONCLUSION Anisamide-modified ursolic acid self-assembled nanoparticles can enhance the targeting of CAFs,alleviate the drug resistance effect of enzalutamide on prostate cancer caused by CAFs,and reduce NRG1 expression in CAFs.

OBJECTIVES: To evaluate the effectiveness of single-balloon and double-balloon enteroscopy in diagnosing pediatric small bowel diseases and assess the diagnostic efficacy of computed tomography enterography (CTE) for small bowel diseases using enteroscopy as the reference standard. METHODS: Clinical data from 576 children who underwent enteroscopy at Hunan Children's Hospital between January 2017 and December 2023 were retrospectively collected. The children were categorized based on enteroscopy type into the single-balloon enteroscopy (SBE) group (n=457) and double-balloon enteroscopy (DBE) group (n=119), and the clinical data were compared between the two groups. The sensitivity and specificity of CTE for diagnosing small bowel diseases were evaluated using enteroscopy results as the standard. RESULTS: Among the 576 children, small bowel lesions were detected by enteroscopy in 274 children (47.6%).There was no significant difference in lesion detection rates or complication rates between the SBE and DBE groups (P>0.05), but the DBE group had deeper insertion, longer procedure time, and higher complete small bowel examination rate (P<0.05). The complication rate during enteroscopy was 4.3% (25/576), with 18 cases (3.1%) of mild complications and 7 cases (1.2%) of severe complications, which improved with symptomatic treatment, surgical, or endoscopic intervention. Among the 412 children who underwent CTE, the sensitivity and specificity for diagnosing small bowel diseases were 44.4% and 71.3%, respectively. CONCLUSIONS SBE and DBE have similar diagnostic efficacy for pediatric small bowel diseases, but DBE is preferred for suspected deep small bowel lesions and comprehensive small bowel examination. Enteroscopy in children demonstrates relatively good overall safety. CTE demonstrates relatively low sensitivity but comparatively high specificity for diagnosing small bowel diseases.
Retrospective Studies ; Treatment Outcome ; Double-Balloon Enteroscopy/statistics & numerical data* ; Single-Balloon Enteroscopy/statistics & numerical data* ; Humans ; Male ; Female ; Child ; Operative Time ; Tomography, X-Ray Computed/statistics & numerical data* ; Sensitivity and Specificity ; Intestine, Small/surgery* ; Intestinal Diseases/surgery*