ObjectiveThis paper aims to investigate the mechanism by which Erchentang improves body weight in obese mice by regulating the AMP‑activated protein kinase （AMPK）/peroxisome proliferator‑activated receptor γ coactivator‑1α （PGC‑1α） signaling pathway and inducing browning of inguinal white adipose tissue （iWAT）. MethodsObese mouse models were established by feeding a high‑fat diet. After successful modeling， mice were randomly divided into a model group and low‑， medium‑， and high‑dose Erchentang groups （7.5， 15， 30 g·kg^-1）， with six mice in each group. Another six normal mice were set as the normal group. Mice in the treatment groups were administered with corresponding doses of the drug by gavage， while those in the normal and model groups were administered with an equal volume of pure water by gavage for four consecutive weeks. Obesity was evaluated by body weight and Lee's index. The levels of low‑density lipoprotein cholesterol （LDL‑C） and high‑density lipoprotein cholesterol （HDL‑C） in serum were detected by biochemical assays. The leptin content in serum was measured by enzyme‑linked immunosorbent assay （ELISA）. Hematoxylin and eosin （HE） staining was used to observe the pathological morphology of the liver and iWAT. Immunofluorescence staining was applied to detect the protein expression levels of glucose transporter 4 （GLUT4） in the liver and iWAT. Molecular docking was performed to simulate the binding affinity between the key components of Erchentang （nobiletin， diosmetin， naringenin） and the key pathway proteins AMPK and PGC‑1α. Western blot was used to detect the protein expression levels of uncoupling protein‑1 （UCP‑1）， AMPK， phosphorylated AMP-activated protein kinase （p‑AMPK）， and PGC‑1α in iWAT. ResultsCompared with those in the normal group， the mice in the model group showed significantly increased body weight and Lee's index， elevated levels of HDL‑C， LDL‑C， and leptin in serum， enlarged adipocytes in iWAT， down‑regulated protein expression levels of GLUT4 in iWAT and liver， and decreased protein expression levels of UCP‑1 and PGC‑1α in iWAT（P<0.05， P<0.01）， the expression level of p-AMPK / AMPK protein was up-regulated， but the difference was not statistically significant. Compared with those in the model group， the mice in the Erchentang groups with different doses exhibited significantly reduced body weight and Lee's index， decreased levels of HDL‑C， LDL‑C， and leptin in serum， smaller adipocytes in iWAT， up‑regulated GLUT4 protein expression levels in iWAT and liver， and increased protein expression levels of UCP‑1， p‑AMPK/AMPK， and PGC‑1α in iWAT （P<0.05， P<0.01）. Molecular docking results show that nobiletin， diosmetin， and naringenin have strong binding energies with both AMPK and PGC‑1α. ConclusionErchentang may improve body weight in obese mice by regulating the AMPK/PGC‑1α signaling pathway and inducing iWAT browning.

ObjectiveTo investigate the effects of Erchentang （ECD） on the body weight of the mouse model of simple obesity induced by a high-fat diet （HFD） and decipher the underlying mechanisms. MethodsFirstly， single-cell transcriptomics （Sc-RNAseq） was employed to analyze the transcriptional changes in the ileum tissue of mice in the normal group and model group. Then， a mouse model of simple obesity was established with a high-fat diet. The successfully modeled mice were randomly allocated into the following four groups （n=8）： model， low-dose （7.5 g·kg^-1） ECD， medium-dose （15 g·kg^-1） ECD， and high-dose （30 g·kg^-1） ECD. Additionally， 8 mice of the same age were selected as the normal group. The body weight was measured at fixed time points during the 4-week gavage period. The overall efficacy of ECD in alleviating obesity was evaluated through glucose tolerance testing， behavioral analysis， hematoxylin-eosin （HE） staining， and biochemical testing. Protein docking was employed to predict the degree of binding between corresponding proteins. Molecular docking was employed to predict the binding degree between key components of ECD and target proteins. Real-time PCR was employed to determine the mRNA levels of tumor necrosis factor-α （TNF-α）， inducible nitric oxide synthase （iNOS）， interleukin-1β （IL-1β）， CD68， CD206， zonula occludens-1 （ZO-1）， and Claudin-5 in the ileum. Immunofluorescence staining was used to observe the expression and distribution of Claudin-5 and ZO-1. ResultsThe Sc-RNAseq results indicated that the differentially expressed genes of immune cells in the model group in comparison with the normal group were primarily enriched in biological functions related to lipid metabolism and inflammatory metabolism. Additionally， these genes were associated with the janus kinases（JAK）/signal transducers and activators of transcription （STAT） signaling pathway， an inflammation-related pathway. Compared with the normal group， the model group showed increases in body weight （P<0.01） and blood glucose level （P<0.01）， a decrease in limb strength （P<0.01）， an increase in liver weight （P<0.05）， and elevated serum alanine amino-transferase （ALT） and aspartate transferase （AST） levels （P<0.05， P<0.01）. Additionally， the model group exhibited increased hepatic fat vacuoles， notably enlarged adipocytes in the epididymal and inguinal white adipose tissue， and increased inflammation. Compared with the model group， ECD groups showed reduced body weights （P<0.01） and blood glucose levels （P<0.01）， increased limb strength （P<0.05， P<0.01）， decreased liver weights （P<0.05， P<0.01）， and declined serum ALT and AST levels （P<0.05， P<0.01）. Additionally， ECD reduced hepatic fat vacuoles and the adipocyte volume in the epididymal and inguinal white adipose tissue， and alleviated inflammation. Potential interactions existed between CD68 and ZO-1/Claudin-5， as well as between CD206 and ZO-1/Claudin-5. The key components of ECD， nobiletin， diosmetin， and naringenin， all demonstrated strong binding affinity with the target proteins ZO-1 and Claudin-5. Compared with the normal group， the model group exhibited up-regulated mRNA levels of the pro-inflammatory cytokines TNF-α， iNOS， IL-1β， and CD68 （P<0.05， P<0.01） and down-regulated mRNA levels of the anti-inflammatory cytokine CD206 （P<0.01） and the tight junction proteins Claudin-5 and ZO-1 （P<0.05， P<0.01）. In comparison with the model group， the ECD groups showed down-regulated mRNA levels of TNF-α， iNOS， IL-1β， and CD68 （P<0.05， P<0.01） and up-regulated mRNA levels of CD206， Claudin-5， and ZO-1 （P<0.05， P<0.01）. Compared with the normal group， the model group exhibited down-regulated expression of tight junction proteins Claudin-5 and ZO-1 （P<0.01）. Compared with the model group， ECD groups showed up-regulated expression of Claudin-5 and ZO-1 （P<0.05， P<0.01）. ConclusionECD can significantly ameliorate HFD-induced obesity and excessive body weight gain in mice by improving the inflammatory microenvironment in the ileum and further restoring the integrity of the impaired ileal barrier.

Objective To analyze trend changes of disease burden of hypertensive nephropathy (HTN) between 2012 and 2023 in Chongqing, and to provide the suggestion for HTN prevention and treatment. Methods Death cases of HTN from Chongqing death registration data between 2012 and 2023 were analyzed to calculate indicators such as mortality, age standardization mortality rate (ASMR), rate of years of life lost (YLL) and Average years of life lost. The mortality of HTN between male and female, urban and rural were compared by Chi-square test. The trend change was explained by average annual percent of change (AAPC). Results The mortality and standardized mortality of HTN in Chongqing decreased from 5.44/100 000 and 3.13/100 000 in 2012 to 2.76/100 000 and 1.07/100,000 in 2023 respectively. The average annual percent change (AAPC) was -5.41% and -8.35% respectively, and the differences in the change trends were statistically significant (P<0.01). The mortality and standardized mortality of HTN in males and females decreased with AAPC of 5.50%, 8.07%, 5.27% and 8.69% respectively, and the differences in the change trends were all statistically significant (all P< 0.05). From 2012 to 2014, 2019 and 2021, the mortality rate of HTN in rural areas was higher than that in urban areas (all P < 0.05). The mortality and standardized mortality of HTN in rural areas decreased with AAPC of 6.58% and 9.46% respectively, and the differences in the change trends were all statistically significant (all P<0.05). The rate of YLL and standardized YLL of HTN in Chongqing decreased from 96.02/100 000 and 60.42/100 000 in 2012 to 44.98/100 000 and 21.49/100 000 in 2023 respectively. The AAPC was -5.83% and -7.80% respectively, and the differences in the change trends were statistically significant (both P < 0.05). AYLL of HTN were 17.88 years in 2012, and it was 17.08 years in 2023. There were no statistically significant differences in the changes (both P > 0.05). The standardized AYLL of HTN in rural areas increased at an average annual rate of 1.14%, and the difference was statistically significant (P < 0.05). Conclusion The mortality and YLL rate of HNT in Chongqing was lower than it in China. Moreover, its trend was decreased. It should be strengthened early screening and healthy management of HNT.

BACKGROUND:Various proteins,signaling pathways,and inflammatory mediators are involved in the pathophysiological process of osteoarthritis.The development of small molecule drugs targeting these proteins,signaling pathways,and inflammatory mediators can effectively delay the progression of osteoarthritis and ameliorate its clinical manifestations. OBJECTIVE:To review the research progress of small molecule drugs in the treatment of osteoarthritis based on the pathogenesis of osteoarthritis. METHODS:PubMed,CNKI,and WanFang databases were searched with English search terms"osteoarthritis,arthritis,osteoarthrosis,degenerative,arthritides,deformans,small molecule drugs,small molecule inhibitors,small molecule agents"and Chinese search terms"osteoarthritis,small molecule drugs,small molecule inhibitors."A total of 68 articles were included for review according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION:(1)Currently,studies concerning the pathogenesis of osteoarthritis remain unclear.The occurrence and development of osteoarthritis are strongly associated with proteins,cytokines,and signal transduction pathways,so its therapeutic mechanism is relatively complex.Currently,targeting proteins,cytokines,and signal transduction pathways related to osteoarthritis with small molecule drugs has become a major research focus.(2)Small molecule drugs frequently possess visible intracellular or extracellular targets and efficacy,containing enhancing cartilage repair,resisting joint degradation,attenuating inflammation,and relieving pain.Other anti-osteoarthritis small molecule drugs have shown promise in promoting stem cell chondrogenic differentiation and cartilage matrix reconstruction.(3)At present,small molecule drugs targeting the pathophysiological process of osteoarthritis to delay the progression of osteoarthritis are still in the experimental stage,but most of these small molecule drugs have shown the expected results in the experimental process,and there are no relevant studies to illustrate the efficacy of small molecule drugs in the treatment of osteoarthritis.(4)Small molecule drugs for the treatment of osteoarthritis have reached the expected experimental results in the basic experimental stage.Numerous studies have exhibited that small molecule drugs can target the suppression of specific proteins,cytokines,and signal transduction pathways that cause osteoarthritis,so as to treat osteoarthritis.Nevertheless,its safety and effectiveness still need to be identified by further basic and clinical studies.This process needs to be investigated and studied by more scholars.(5)At present,many scholars in and outside China have made contributions to the treatment of osteoarthritis.Compared with traditional treatment methods,small molecule drugs reveal better efficacy and safety in the basic experimental stage,and it is expected to become an emerging method for the treatment of osteoarthritis in the future to rid patients of pain.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age intogroup I (donor age ≤17 years, n=647); group II (donor age 18–59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were com-pared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001).When we analyzed the different effects of donor age on OS with different ACLF grades, in groupsII and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions Donor age is related to OS and graft survival of ACLF patients after transplanta-tion, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

Objective:To screen the optimal machine learning model for predicting the recurrence condition of hepatocellular carcinoma (HCC) at different time points post-surgery, based on the cutoff value of the Ki67 positive proliferation index condition calculated from recurrence-free survival and combined with various clinical features.Methods:retrospective study included initially treated patients with solitary HCC who underwent radical surgery at the Fifth Medical Center of the PLA General Hospital from January 2013 to March 2023. Data included general clinical data, preoperative laboratory parameters, and surgical pathology information about the subjects. The postoperative recurrence status was assessed by querying the medical record system or by telephone follow-up. The Ki67 positive index cutoff value was determined by the X-tile software based on the patient's recurrence-free survival status and time analysis. Survival rates were calculated using the Kaplan-Meier method, and survival curves were plotted. The study population was randomly divided into training and testing groups in a 7:3 ratio using a computer-generated random number method. The minimum redundancy maximum relevance (mRMR) method was used for feature variable selection. Predictive models for postoperative HCC recurrence conditions in patients with HCC were constructed using random forest, support vector machine, logistic regression, and gradient boosting decision tree machine learning algorithms. Inter-group comparisons for continuous data were performed using the t-test or Mann-Whitney U test. Inter-group comparisons of enumeration data were performed using the Pearson χ2 test, continuity-corrected χ2 test, or Fisher's exact test. Results:The cutoff values for the Ki67 positivity index were 0.3 and 0.5 in 510 cases, with a follow-up time ranging from 1.2 to 11.4 years (median: 6.2 years). The recurrence-free survival time was between 1 and 135 months (median: 32 months), with recurrence-free survival rates post-surgery at 1, 2, 3, and 5 years were 87.5%, 77.1%, 61.2%, and 54.5%, respectively. The top five variables predicted HCC recurrence and non-recurrence conditions following surgical follow-up at 6 months, 1 year, 2 years, and beyond 2 years, in accordance with information obtained by the mRMR screen out. The Ki67 positivity index screened a successfully constructed machine learning model to predict HCC recurrence and non-recurrence conditions following surgical follow-up at 6 months, 1 year, 2 years, and beyond 2 years. The machine learning model based on the gradient boosting decision tree algorithm had the best prediction performance among them (areas under the receiver operating characteristic curves for predicting HCC recurrence within six months in the training and validation sets were 0.996 and 0.946, and accuracies were 0.972 and 0.935, respectively).Conclusion:A machine learning model was successfully constructed using the Ki67 positivity index combined with four readily available clinical features to predict HCC recurrence. The machine learning model based on the gradient boosting decision tree algorithm demonstrated the best performance in terms of predicting HCC recurrence within six months after surgery.

Objective To systematically evaluate the level of proteus mirabilis(PM)infection in patients with rheumatoid arthritis(RA)and to investigate its potential association with the development of RA.Methods Based on Meta-analysis of observational studies in epidemiology and preferred reporting items for systematic review and Meta-analysis guide,a comprehensive search of PubMed,Web of Science and Embase databases was conducted to screen relevant literature published up to December 2024 for studies comparing the levels of anti-PM antibodies between RA patients and healthy populations,and the quality of the included studies was assessed by using the Newcastle-Ottawa scale.Heterogeneity among studies was assessed by Q-test and I2-test,and accordingly,fixed-effects or random-effects models were selected,and the robustness of the results was assessed by sensitivity analyses,Begg's test,and clipping and patching method.Results Finally,18 eligible articles were included,involving 753 RA patients and 716 healthy controls.The total antibody levels[weighted mean difference(WMD)=0.86,95％CI:0.38-1.34,I2=98.3％,P=0.000]and IgA antibody levels(WMD=0.17,95％CI:0.06-0.28,I2=96.7％,P=0.000)of RA patients were higher than those of healthy controls,and subgroup analyses revealed significant heterogeneity among geographic regions and testing methods.Conclusion Prevention and treatment of PM infections may be a complementary strategy for RA management and provide evidence-based support for the"PM antigen-genitourinary tract mucosa-autoimmunity"pathology hypothesis.