ObjectiveThe primary objective of this study was to investigate the effects of carbohydrate intake order on post-exercise recovery and metabolic regulation under heat stress, particularly in models of exercise induced fatigue. Given the increasing significance of optimizing nutritional strategies to support performance in extreme environmental conditions, this study aimed to provide experimental evidence that contributes to a better understanding of how the sequence in which carbohydrates are consumed impacts exercise recovery, metabolic homeostasis, and fatigue alleviation in a high-temperature environment. MethodsA mouse model of exercise-induced fatigue was established under high-temperature (35°C) to simulate heat stress. The subjects were divided into 3 distinct groups based on their carbohydrate intake order: the “mixed intake” group (HOT_MIX), where all macronutrients (carbohydrates, proteins, and fats) were consumed in a balanced ratio; the “carbohydrate-first intake” group (HOT_CHO), where carbohydrates were consumed first followed by other macronutrients; the “carbohydrate-later intake” group (HOT_PRO), where proteins and fats were consumed prior to carbohydrates. Each group underwent a 7 d intervention period with daily intake according to their designated group. Exercise performance was assessed using rotarod retention time test, and biomarkers of muscle damage, such as lactate dehydrogenase (LDH), creatine kinase (CK), lactate (LD), alanine aminotransferase (ALT), and non-esterified fatty acids (NEFA), were measured. Furthermore, targeted metabolomics analyses were conducted to investigate metabolic shifts in response to different dietary strategies, and KEGG pathway enrichment analysis was employed to explore the biological mechanisms underlying these changes. ResultsThe findings demonstrated that the HOT_PRO group exhibited a significantly improved performance in the rotarod test, with a longer retention time compared to both the HOT_MIX and HOT_CHO groups (P<0.05). Additionally, this group showed significantly reduced levels of muscle damage markers such as LDH and CK, indicating that the carbohydrate-later intake strategy helped alleviate exercise-induced muscle injury. Metabolomic profiling of the HOT_PRO group showed marked increases in alanine, creatine, and flavin adenine dinucleotide (FAD), indicating shifts in amino acid metabolism and oxidative metabolism. Conversely, metabolites such as spermidine, cholesterol sulfate, cholesterol, and serine were significantly reduced in the HOT_PRO group, pointing to alterations in lipid and sterol metabolism. Further analysis of the differential metabolites revealed that these changes were primarily associated with key metabolic pathways, including glycine-serine-threonine metabolism, primary bile acid biosynthesis, taurine and hypotaurine metabolism, and steroid hormone biosynthesis. These pathways are essential for energy production, antioxidant defense, and muscle recovery, suggesting that the carbohydrate-later feeding strategy may promote metabolic homeostasis and improve exercise recovery by enhancing these critical metabolic processes. ConclusionThe results of this study support the hypothesis that consuming carbohydrates after proteins and fats during exercise recovery enhances metabolic homeostasis and accelerates recovery under heat stress. This strategy effectively modulates energy, amino acid, and lipid-related pathways, which are crucial for improving endurance performance and mitigating fatigue in high-temperature environments. The findings suggest that carbohydrate-later intake could be a promising nutritional strategy for athletes and individuals exposed to heat during physical activity. Furthermore, the study provides valuable insights into how different nutrient timing strategies can impact exercise recovery and metabolic regulation, paving the way for more personalized and effective nutritional interventions in extreme environmental conditions.

Eightly-four novel thioheterocyclic nucleoside derivatives were designed, synthesized, and evaluated for antitumor activity in vitro and in vivo. Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells in vitro, among them 33a and 36b exhibited potent activity against HCT116 cells (IC₅₀ = 0.27 and 0.49 μmol/L, respectively). Both compounds 33a and 36b inhibited cell metastasis, arrested the cell cycle in the G₂/M phase, and induced apoptosis in vitro. Mechanistic studies revealed that 33a and 36b increased ROS levels, led to DNA damage, ER stress, and mitochondrial dysfunction, and inhibited autophagy in HCT116 cells. Biological information analysis, RNA-sequencing, Gene Set Enrichment Analysis (GSEA), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and SPR experiments identified that compounds 33a and 36b showed antitumor activity by suppressing the c-MYC pathway. c-MYC silencing assays indicated that c-MYC proteins participated in 33a-mediated anticancer activities in HCT116 cells. More importantly, compound 33a presented favorable pharmacokinetic properties in mice (T _1/2 = 6.8 h) and showed significant antitumor efficacy in vivo without obvious toxicity, showing promising potential for further clinical development.

Resistance to poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi) presents a considerable obstacle in the treatment of ovarian cancer. F-box and tryptophan-aspartic (WD) repeat domain containing 11 (FBXW11) modulates the ubiquitination of growth-and invasion-related factors in lung cancer, colorectal cancer, and osteosarcoma. The function of FBXW11 in PARPi therapy is still ambiguous. In this study, RNA sequencing (RNA-seq) showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi. FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer (HGSOC) tissues, and low levels of FBXW11 were associated with shorter overall survival (OS) and progression-free survival (PFS) in HGSOC patients. Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi, while knocking down FBXW11 made it less sensitive. The four-dimensional (4D) label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11 (S100A11) and promoted its degradation through ubiquitination. The increased degradation of S100A11 led to less efficient DNA damage repair, which in turn contributed to increased PARPi-induced DNA damage. The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models. In summary, our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.

Objective:To evaluate clinical efficacy and safety of immunotherapy by retrospectively analyzing clinical medica-tion of patients with recurrent pregnancy loss(RPL)complicated with abnormal immune factors.Methods:A retrospective cohort study was conducted on RPL cases in outpatient department of Hebei Reproductive Health Hospital from January 2021 to April 2022.Efficacy and safety of immunotherapy were evaluated from pregnancy outcome,adverse reactions and birth defects of offspring.Results:According to guidelines,192 cases with abnormal autoimmunity and/or immune indicators were included.Early abortion rate was 4.16%in group of two lost pregnancies,which was lower than that in group of three lost pregnancies(16.66%).Twelve week sus-tained pregnancy rate was 89.58%in the former group,and 28 week sustained pregnancy rate was 86.45%,which were significantly higher than those in the latter group(75.00%,71.87%).RPL patients were divided into groups according to their exposure to immuno-modulatory drugs before 12 weeks of pregnancy.There was no significant difference in pregnancy outcome,adverse reaction rate and birth defect rate of their offspring(P>0.05).Conclusion:Immunotherapy can effectively reduce risk of recurrent abortion and increase rate of persistent pregnancy in patients with immune RPL.Personalized immunotherapy can make RPL patients with immune factors achieve expected effect of fetal protection.

Objective To identify the clinical characteristics and prognostic factors of young patients with sporadic rectal cancer liver metastasis(RCLM).Methods The clinical data of young RCLM patients at 45 years or under(n=40,as younger patient group)in Peking University First Hospital from January 2016 to January 2021 were reviewed,meanwhile,elder RCLM patient group were comprised of 82 patients older than 45-year-old in a 1:2 ratio.Proportions of categorical variables were compared between young patients and old patients.The clinicopathologic parameters were analyzed with univariate and multivariate Cox regression models and Kaplan-Meier method for demonstrating survival differences between the maximum diameter of liver metastasis and local therapy.Results One hundred and twenty-two RCLM patients were identified,the 1-,3-and 5-year survival rates of young patient group were 97.5%,47.5%,15.0%,those of elder patient group were 84.1%,26.8%,9.8%,respectively.The differences in BMI(P=0.008),primary tumor with obstruction and bleeding(P=0.006),synchronous rectal cancer liver metastases(P=0.005),the maximum diameter of liver metastasis>3 cm(P=0.019)were statistically significant between the two groups.And univariate and multivariate analyses showed that age(P=0.003),N stage(P=0.007),local therapy for liver metastases(P=0.047)and the maximum diameter of liver metastasis(P=0.030)were independent risk factors for influencing the prognosis of RCLM patients;curative resection or not of primary tumor(P=0.035)and the maximum diameter of liver metastasis(P=0.041)were independent risk factors for influencing the prognosis of young RCLM patients.Kaplan-Maier curve demonstrated survival differences between the maximum diameter of liver metastasis and local therapy for liver metastasis in RCLM patients(log-rank P=0.000).Conclusions Although with later staging of initial tumor station,young RCLM patients may obtain better survival benefit compared with old patients.Higher degree of lymph node metastasis,local therapy for liver metastases and the maximum diameter of liver metastasis>3 cm indicates poor prognosis in RCLM patients,and without curative resection of primary tumor and maximum diameter of liver metastasis are also considered as the independent poor prognostic factors of young RCLM patients.Local therapy for liver metastases appears to play an important role in the treatment strategy of RCLM patients.

ObjectiveTo analyze the changes in CD4⁺T lymphocyte (CD4 cells) levels and influencing factors in patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) before and after highly active anti-retroviral therapy (HAART) in Xining City, Qinghai Province, so as to provide a scientific basis for formulating corresponding follow-up intervention strategies. MethodsFrom February to July, 2023, 468 HIV/AIDS patients who received HAART in Xining, Qinghai Province were selected using a convenient sampling method for a questionnaire survey. Venous blood was collected and CD4 cell levels were detected by flow cytometry. SPSS 22.0 was used for t-test, analysis of variance and χ²⁃test, and multiple linear regression analysis was used to explore the level of CD4 cells and its main influencing factors in HIV/AIDS population after HAART. ResultsUnivariate analysis showed significant differences in baseline CD4 cell levels among people of different ages, nationalities, residential types and annual income (P<0.05). There were statistically significant differences in the most recent CD4 cell levels among people of different nationalities, different marital statuses, with or without regular physical exercise, with or without hypertension, different baseline CD4 cell count, different years since HIV diagnosis, different years of HAART treatment, and different treatment programs (P<0.05). Multiple linear regression analysis showed that the baseline CD4 cell count was 350‒499 (t=7.40) and ≥500 (t=6.69), the number of years of HAART treatment was 5‒9 (t=3.59) and ≥10 (t=4.54), the number of years of HIV diagnosis was ≥10 (t=-2.58), the number of people receiving second-line treatment (t=-2.49) and the latest CD4 cell levels after HAART were statistically correlated (P<0.05). ConclusionThe CD4 cell levels of HIV/AIDS population in Xining city of Qinghai Province are affected by many factors. Comprehensive health intervention should be carried out for this population, the implementation of early detection and treatment strategy should be strengthened, relevant physiological and biochemical indicators should be monitored regularly, and health education should be carried out, so as to encourage this population group to choose a healthy lifestyle, improving their quality of life from multiple dimensions.

Inflammatory bowel disease (IBD) is characterized by chronic relapsing intestinal inflammation and encompasses ulcerative colitis (UC) and Crohn's disease (CD). IBD has emerged as a global healthcare problem. Clinically efficacious therapeutic agents are deficient. This study concentrates on models of ulcerative colitis with the objective of discovering novel therapeutic strategies. Previous investigations have established that schisandrin A demonstrates anti-inflammatory effects in vitro, concurrently enhancing the transcriptional activity of farnesoid X receptor (FXR). FXR inversely modulates the transcriptional activity of NF-κB, which has an important role in regulating inflammatory responses. Consequently, the current study was to explore the safeguarding influence of schisandrin A on ulcerative colitis and delineate the mechanism by which it regulates this effect through the FXR signaling pathway. The effect of schisandrin A on the mRNA levels of inflammatory factors was evaluated in RAW264.7 cells. The dual luciferase reporter gene assay was used to verify the relationship between schisandrin A and FXR targeting. The animal experiments were performed in accordance with the regulations of the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (approval No. PZSHUTCM2304250005). Acute ulcerative colitis was induced in wild-type or FXR knockout C57BL/6 mice by drinking 3% dextran sodium sulfate (DSS) for 7 days, and schisandrin A was administered via gavage for a continuous treatment period of 7 days. The body weight and faecal were monitored daily. The mRNA levels of inflammatory factors in colon tissue and FXR target genes were measured by RT-qPCR. The findings revealed that schisandrin A, in vitro, impeded the lipopolysaccharide (LPS)-induced elevation in mRNA levels of inflammatory factors and schisandrin A could augment transcriptional activity of FXR. In wild-type mice, schisandrin A significantly improved weight loss, colon shortening, loose stools and blood in stools in mice with acute ulcerative colitis, and schisandrin A significantly reduced the expression of pro-inflammatory factors genes and significantly increased the expression of FXR target genes in colon tissues. In FXR knockout mice, the administration of schisandrin A failed to yield ameliorative effect on acute ulcerative colitis in mice. In conclusion, schisandrin A can reduce intestinal inflammation through the FXR signaling pathway to alleviate acute ulcerative colitis in mice. Implications arise that Schisandra lignans could serve as lead compounds for drug development aimed at inflammatory bowel disease.

Outer membrane vesicles (OMVs) are nanoscale vesicles secreted by Gram-negative bacteria. As a unique bacterial secretion, OMV secretion can help bacteria maintain the outer membrane stability or remove harmful substances. Studies have shown that local separation of outer membrane and peptidoglycan layers led by abnormalities in outer membrane protein function, abnormal structure or excessive accumulation of LPS, and erroneous accumulation of phospholipids in the outer leaflet, which can all lead to bacterial outer membrane protrusion and eventually bud formation of OMVs. Since OMVs are mainly composed of bacterial outer membrane and periplasmic components, the pathogen associated molecular patterns (PAMPs) on their surface can trigger strong immune responses. For example, OMVs can recruit and activate neutrophils, polarize macrophages to secrete large amounts of inflammatory factors. More importantly, OMVs can act as adjuvants to induce dendritic cell (DC) maturation to enhance adaptive immune response in the body. At the same time, OMVs are derived from bacteria, which make it easy to modify. The methods by genetic engineering and others can improve their tumor targeting, give them new functions, or reduce their immunotoxicity, which is conducive to their application in tumor therapy. OMVs not only induce apoptosis or pyroptosis of tumor cells, but also regulate the host immune system, which makes OMVs themselves have a certain killing effect on tumors. In addition, the tendency of neutrophils to inflammatory tumor sites and the formation of neutrophil extracellular traps enable OMVs to target tumor sites, and the suitable size and the characteristic that they are easily taken up by DCs give OMVs a certain lymphatic targeting ability. Therefore, OMVs are often employed as excellent drug or vaccine carriers in tumor therapy. This review mainly discusses the biological mechanism of OMVs, the regulatory effects of OMVs on immune cells, the functional modification strategies of OMVs, and their research progress in tumor therapy.

Objective:To evaluate the clinical and prognostic value of prothrombin time(PT)and activated partial thromboplastin time(APTT)in newly diagnosed patients with multiple myeloma(MM).Methods:The clinical data of 116 newly diagnosed MM patients in the Second Hospital and Third Hospital of Shanxi Medical University from October 2014 to March 2022 were analyzed retrospectively,and the patients were divided into two groups:normal PT and APTT group and prolonged PT or APTT group.The differences in sex,age,classification,staging,bleeding events,laboratory indicators[including hemoglobin(Hb),platelet count(PLT),serum calcium,serum albumin(ALB),lactate dehydrogenase(LDH),serum creatinine and β 2-microglobulin],and cytogenetic characteristics between the two groups of patients were compared.The effect of prolonged PT or APTT on survival of patients with MM was analyzed.Results:Compared with patients in normal PT and APTT group,patients in prolonged PT or APTT group were more likely to experience bleeding events(x2=5.087,P=0.024),with lower ALB levels(x2=4.962,P=0.026)and PLT levels(x2=4.309,P=0.038),and higher serum calcium levels(x2=5.056,P=0.025).The positive rates of del17p,del13q and 1q21+in prolonged PT or APTT group were higher than those in normal PT and APTT group,but the difference was not statistically significant(P＞0.05).K-M survival analysis showed that the prolonged PT or APTT group had a shorter median progression-free survival(PFS)(P=0.032)and overall survival(OS)(P=0.032).Multivariate Cox analysis showed that prolonged PT or APTT(HR=2.1 16,95％CI:1.025-4.372,P=0.043)and age ≥65 years(HR=2.403,95％CI:1.195-4.836,P=0.014)were independent risk factor for OS in newly diagnosed MM patients.However,prolonged PT or APTT had no significant effect on PFS of newly diagnosed MM patients(HR=1.162,95％CI:0.666-2.026,P=0.597).Conclusion:Newly diagnosed MM patients with prolonged PT or APTT have worse clinical indicators,shorter PFS and OS.Prolonged PT or APTT is an independent risk factor for OS in MM patients.