Triptolide （TP）， the core active component of the traditional Chinese medicine Tripterygium wilfordii ， exhibits remarkable pharmacological activities including anti-inflammatory， immunosuppressive and anti-tumor effects， and holds broad application prospects in the treatment of major diseases such as autoimmune diseases and malignant tumors. However， TP has a narrow therapeutic window and causes multi-organ toxicities including liver， kidney and reproductive toxicities， which severely restrict its safe clinical application and new drug development. Therefore， toxicity reduction and efficacy enhancement has become a core scientific problem urgently to be solved in this field. This paper systematically reviews the four core strategies for TP toxicity reduction and efficacy enhancement， including structural modification， dosage form improvement， herbal compatibility， and external therapies of traditional Chinese medicine. Among them， structural modification optimizes the toxic and efficacy characteristics of TP from the molecular structure level， with typica l derivatives including （5 R ）-5-hydroxy triptolide， ZT01， PG490-88， etc. Dosage form modification achieves toxicity reduction and efficacy enhancement via targeted and sustained-controlled drug release of diverse delivery systems. It includes triptolide preparations such as nanoparticles， liposomes， microemulsion gels and liquid crystals， possessing favorable clinical transformation potential. The herbal compatibility and external therapies of traditional Chinese medicine conform to the holistic view of traditional Chinese medicine and have a profound clinical application foundation， but their mechanisms of action are insufficiently elucidated， and they lack unified standardized specifications and high-quality evidence-based proof. In the future， we should rely on multi-omics technology to elucidate the toxic and efficacy mechanisms， integrate technologies to optimize preparations， improve the evaluation system and promote clinical transformation.

The core pathogenesis of childhood IgA vasculitis nephritis （IgAVN） lies in the intermingled conditions of heat， stasis and deficiency. Deficiency is the fundamental cause， while heat acts as the predominant manifestation at the initial stage， and stasis serves as the key factor leading to protracted illness. Based on this understanding， the overall therapeutic principle of clearing heat and cooling blood， dissolving stasis and unblocking collaterals， reinforcing healthy qi and consolidating the root is established. A self-formulated Qingre Zhixue Formula （清热止血方） is used as the basic prescription. According to the characteristics of different disease stages， childhood IgAVN is further classified into three main syndrome types， including blood heat with stasis obstruction， deficiency of both qi and yin， and deficiency of both spleen and kidney， with corresponding syndrome-based treatments. Throughout the treatment process， emphasis is placed on dissolving stasis and unblocking collaterals， while protecting the spleen and stomach of children and maintaining healthy qi. This paper provides new perspectives for diagnosis and treatment of childhood IgAVN with traditional Chinese medicine.

The core pathogenesis of childhood IgA vasculitis nephritis （IgAVN） lies in the intermingled conditions of heat， stasis and deficiency. Deficiency is the fundamental cause， while heat acts as the predominant manifestation at the initial stage， and stasis serves as the key factor leading to protracted illness. Based on this understanding， the overall therapeutic principle of clearing heat and cooling blood， dissolving stasis and unblocking collaterals， reinforcing healthy qi and consolidating the root is established. A self-formulated Qingre Zhixue Formula （清热止血方） is used as the basic prescription. According to the characteristics of different disease stages， childhood IgAVN is further classified into three main syndrome types， including blood heat with stasis obstruction， deficiency of both qi and yin， and deficiency of both spleen and kidney， with corresponding syndrome-based treatments. Throughout the treatment process， emphasis is placed on dissolving stasis and unblocking collaterals， while protecting the spleen and stomach of children and maintaining healthy qi. This paper provides new perspectives for diagnosis and treatment of childhood IgAVN with traditional Chinese medicine.

ObjectiveType 2 diabetes mellitus (T2DM) often causes severe hepatic metabolic complications, dominated by metabolic associated fatty liver disease (MAFLD). Persistent hepatic steatosis and oxidative stress further trigger steatohepatitis and progressive liver damage, increasing the mortality risk of diabetic patients. Aerobic exercise effectively improves hepatic lipid metabolism and antioxidant capacity, but poor patient adherence restricts its long-term clinical application. Mitochondrial-derived mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a key peptide regulating insulin sensitivity and hepatic redox homeostasis. This study aimed to explore the protective mechanism of MOTS-c against T2DM-related liver injury and its combined beneficial effect with aerobic exercise via the NRF2/PPARγ signaling axis. This study aimed to investigate whether MOTS-c cooperates with aerobic exercise to alleviate T2DM-associated hepatic oxidative stress and metabolic dysfunction by activating the NRF2/PPARγ axis, and to clarify the molecular and transcriptomic characteristics of their combined intervention. MethodsStable MOTS-c overexpression and knockdown HepG2 cell lines were constructed using lentiviral transfection. An oleic acid-induced cellular lipid accumulation model and NRF2-knockout cell model were applied to verify the NRF2-dependent mechanism ofMOTS-c. Intracellular lipid deposition, triglyceride levels, antioxidant enzyme activities, and the expression of NRF2/PPARγ pathway-related genes and proteins were detected. In vivo, a T2DM rat model with obvious hepatic steatosis was established via a high-fat and high-sucrose diet combined with streptozotocin injection. Model rats received aerobic exercise, MOTS-c intraperitoneal injection, or combined intervention. We detected systemic glycolipid metabolic indicators, hepatic histopathological changes, and the expression of core proteins in the hepatic NRF2/PPARγ axis. Hepatic transcriptomic sequencing was performed to screen differentially expressed genes (DEGs) and enrich key pathways co-regulated by MOTS-c and aerobic exercise. ResultsCellular results showed that MOTS-c overexpression significantly reduced oleic acid-induced lipid deposition, enhanced antioxidant enzyme activity, and upregulated NRF2 and PPARγ expression. Conversely, MOTS-c knockdown aggravated hepatic lipid accumulation and oxidative damage and inhibited NRF2/PPARγ pathway activation. NRF2 knockout completely eliminated the protective effects of MOTS-c on lipid metabolism and redox balance, confirming its NRF2-dependent regulatory mechanism. In T2DM rats, both MOTS-c supplementation and aerobic exercise effectively improved insulin resistance, corrected glycolipid metabolic disorders, and alleviated hepatic steatosis, while consistently activating the hepatic NRF2/PPARγ axis. Compared with single intervention, the combined treatment showed a better improvement trend in hepatic metabolic and oxidative injury, without definitive synergistic effects. Transcriptomic analysis revealed that the co-regulated DEGs of MOTS-c and aerobic exercise were primarily enriched in lipid metabolism and PPAR signaling pathways, with multiple antioxidant and lipid-regulating genes significantly modulated by combined intervention. ConclusionMOTS-c exhibits obvious exercise-mimetic hepatoprotective effects in T2DM. It activates the hepatic NRF2/PPARγ axis to strengthen antioxidant defense, stabilize lipid metabolism, and relieve T2DM-associated hepatic steatosis and oxidative damage. Furthermore, MOTS-c produces additive beneficial effects with aerobic exercise, showing a superior intervention trend on diabetic liver dysfunction. This study identifies the NRF2/PPARγ axis as the core mechanism of MOTS-c-regulated hepatic protection, elucidates the transcriptomic basis of combined intervention, and provides a reliable theoretical basis and potential therapeutic target for clinical intervention in T2DM-complicated MAFLD.

Objective To investigate the comparative efficacy of different frequencies of pelvic floor electrical stimulation(PFES)on stress urinary incontinence(SUI)in rats.Methods Twenty female Sprague-Dawley rats were randomly divided into 6,15,30 and 50 Hz group by random number table method.All rats underwent vaginal dilatation(VD)to simulate postpartum SUI.One week after VD,the sneeze test was conducted to determine whether the modeling was successful.If the sneeze test was positive,the modeling was successful.The miniature and wireless electric pelvic floor stimulator were implanted into the pelvic floor muscle of the modeled rats,and PFES were treated for 2 weeks in each group at the rates of 6,15,30 and 50 Hz,respectively.The Leak point pressure(LPP)of all rats before VD,1 week after VD and 2 weeks after stimulation were measured by cystometrograms(CMGs)for comparison.Results LPP was significantly reduced in all groups of rats after VD 1 week(P<0.001).Compared with after VD 1 week,after two consecutive weeks of PFES at four different frequencies of 6,15,30 and 50 Hz,LPP was again significantly increased(P<0.001)and reached the baseline level(P>0.05)in all groups of rats.In the between-group comparison of the rats in each group,there was no significant difference in their LPP at baseline value,after VD 1 week and after stimulation 2 weeks(P>0.05).Conclusion The present study suggests that of the several stimulation frequencies explored so far,6 Hz may be a more appropriate choice for PFES.Further studies are still needed to evaluate more frequencies and the long-term efficacy of PFES.

Neuropathic pain(NP)is a type of chronic pain caused by damage or disease of the nervous system.It is mainly characterized by spontaneous pain,hyperalgesia,and allodynia,which seriously af-fect the quality of life of patients.The pathogenesis of NP is complex,involving abnormal regulation such as peripheral sensitization,central sensitization,ion channel changes,and glial cell activation.In recent years,the role of m6A in NP has attracted extensive attention.However,the research on the role of m6A modification in different diseases and pain models is still limited.Therefore,it is particularly important to clarify the role of m6A modification in different diseases and pain models.This article reviews the re-search progress on the role and mechanism of m6A methylation modification in the pathogenesis of NP in recent years,especially the role mechanism of the five classical m6A modification factors,METTL3,METTL14,FTO,ALKBH5 and YTHDF1,in mediating the formation of NP in different diseases and pain models,with the expectation of providing new insights and ideas for the drug development and pre-vention of NP from the perspective of m6A modification.

To investigate the impact of high salt stress on the metabolic pathways and regulatory mecha-nisms involved in synthesizing hydroxyectoine(5-HE)in Virgibacillus salexigens,cultures were supple-mented with 1.5 and 2.5 mol/L NaCl as control and experimental groups,respectively.High-perform-ance liquid chromatography(HPLC)was used to detect the difference in the amount of 5-HE synthesis.Transcriptomic and metabolomic analyses identified differential genes and metabolites under varying salt concentrations.Key differential gene expressions related to 5-HE synthesis were validated using qRT-PCR.Results showed that 5-HE synthesis reached 121.9 mg/L at 2.5 mol/L NaCl.Transcriptomic anal-ysis identified 652 differentially expressed genes across 348 KEGG pathways,with 210 upregulated and 442 downregulated,primarily enriched in pathways such as purine metabolism,amino acid biosynthesis,sulfur metabolism,and biotin metabolism.Validation of 13 genes,including lysC,asd,ectA,ectB,ectC,ectD,thrB,thrC,ilvA,ilvE,AGXT,YckA and GlnQ,showed expression trends consistent with transcriptome data.Metabolomic analysis identified 1153 metabolites predominantly enriched in histidine metabolism,lysine degradation,and arginine and proline metabolism.This study preliminarily elucidated the effect of high salt on the 5-HE synthesis pathway,and provided a basis for the subsequent construc-tion of 5-HE high-yielding strains.

Background and Aims:Single-incision laparoscopic cholecystectomy(LC)has become increasingly popular due to its minimal invasiveness and cosmetic advantages,but challenges remain in biliary identification and limited operative space.Indocyanine green(ICG)fluorescence navigation enables real-time visualization of the biliary tract and may enhance surgical safety and efficiency.This study aimed to evaluate the clinical application value of ICG fluorescence navigation in single-incision LC.Methods:A retrospective analysis was conducted on 59 patients with benign gallbladder diseases who underwent elective single-incision LC at Yixing Hospital affiliated to Jiangsu University from January 2023 to December 2024.Patients were divided into a fluorescence group(n=27)and a white-light group(n=32)according to whether ICG fluorescence navigation was applied.The two groups were compared in terms of Calot's triangle dissection time,operative time,intraoperative blood loss,surgeon satisfaction,hospital stay,and postoperative complications.Results:No significant differences were observed in baseline clinical characteristics between the two groups(all P＞0.05).In the fluorescence group,the cystic duct,common hepatic duct,and common bile duct were all successfully visualized.Compared with the white-light group,the fluorescence group had significantly shorter Calot's triangle dissection time[(25.56±3.49)min vs.(38.81±5.59)min],shorter operative time[(44.67±3.06)min vs.(61.31±4.96)min],and less intraoperative blood loss[(13.44±1.70)mL vs.(14.50±2.11)mL](all P＜0.05),with significantly higher surgeon satisfaction(P＜0.05).No intraoperative bile duct injury,conversion to three-port surgery,or postoperative complications occurred in either group.Conclusion:ICG fluorescence navigation can significantly improve biliary identification efficiency in single-incision LC,shorten operative time,reduce blood loss,and enhance surgeon satisfaction,demonstrating promising clinical application prospects.

Objectives:This study aims to evaluate the causal relationship between plasma proteins and myocardial infarction(MI)using two-sample bidirectional Mendelian randomization(MR)analysis,identify key biomarkers,and validate their expression.Methods:The study utilized publicly available genome-wide association study(GWAS)data of 4 907 plasma proteins as the exposure factor,with single nucleotide polymorphisms(SNPs)as instrumental variables,and four MI datasets as outcomes.Two-sample MR analysis was performed using the inverse variance weighted(IVW)method,complemented by simple model,weighted model,weighted median estimator(WME),and MR-Egger regression methods to assess the causal relationship between exposure factors and outcomes.Venn diagrams and word clouds were used to screen proteins associated with MI as candidate biomarkers.Reverse MR analysis was conducted to evaluate reverse causality.Sensitivity analysis was performed to assess the robustness of the results.Immunohistochemistry(IHC)was used to validate the expression of proteasome activator subunit 1(PSME1)and vacuolar protein sorting 29(VPS29)in the aorta of mice,and enzyme-linked immunosorbent assay(ELISA)was used to verify the expression of PSME1 and VPS29 in plasma from patients with acute myocardial infarction(AMI).Results:The two-sample MR analysis indicated that PSME1 was significantly negatively associated with myocardial infarction in all four datasets,with OR(95%CI)of 0.684(0.557-0.839),0.990(0.987-0.993),0.579(0.448-0.748),and 0.993(0.990-0.996),respectively,with all P<0.001.Similarly,VPS29 also showed a significant negative association with MI in all four datasets,with OR(95%CI)of 0.902(0.862-0.945),0.998(0.997-0.999),0.866(0.808-0.929),and 0.998(0.997-0.999),respectively,with all P<0.001.Reverse MR analysis did not detect reverse causality,and sensitivity analysis confirmed the robustness of the results.IHC results showed significantly reduced expression of PSME1 and VPS29 in the aortas of AMI mice with an atherosclerotic background compared to control mice(both P<0.05).ELISA results indicated significantly lower plasma levels of PSME1 and VPS29 in AMI patients compared to healthy controls(both P<0.05).Conclusions:Higher levels of PSME1 and VPS29 are negatively associated with the risk of MI,suggesting that PSME1 and VPS29 may serve as protective biomarkers for cardiovascular diseases.

Objectives:This study aims to evaluate the causal relationship between plasma proteins and myocardial infarction(MI)using two-sample bidirectional Mendelian randomization(MR)analysis,identify key biomarkers,and validate their expression.Methods:The study utilized publicly available genome-wide association study(GWAS)data of 4 907 plasma proteins as the exposure factor,with single nucleotide polymorphisms(SNPs)as instrumental variables,and four MI datasets as outcomes.Two-sample MR analysis was performed using the inverse variance weighted(IVW)method,complemented by simple model,weighted model,weighted median estimator(WME),and MR-Egger regression methods to assess the causal relationship between exposure factors and outcomes.Venn diagrams and word clouds were used to screen proteins associated with MI as candidate biomarkers.Reverse MR analysis was conducted to evaluate reverse causality.Sensitivity analysis was performed to assess the robustness of the results.Immunohistochemistry(IHC)was used to validate the expression of proteasome activator subunit 1(PSME1)and vacuolar protein sorting 29(VPS29)in the aorta of mice,and enzyme-linked immunosorbent assay(ELISA)was used to verify the expression of PSME1 and VPS29 in plasma from patients with acute myocardial infarction(AMI).Results:The two-sample MR analysis indicated that PSME1 was significantly negatively associated with myocardial infarction in all four datasets,with OR(95%CI)of 0.684(0.557-0.839),0.990(0.987-0.993),0.579(0.448-0.748),and 0.993(0.990-0.996),respectively,with all P<0.001.Similarly,VPS29 also showed a significant negative association with MI in all four datasets,with OR(95%CI)of 0.902(0.862-0.945),0.998(0.997-0.999),0.866(0.808-0.929),and 0.998(0.997-0.999),respectively,with all P<0.001.Reverse MR analysis did not detect reverse causality,and sensitivity analysis confirmed the robustness of the results.IHC results showed significantly reduced expression of PSME1 and VPS29 in the aortas of AMI mice with an atherosclerotic background compared to control mice(both P<0.05).ELISA results indicated significantly lower plasma levels of PSME1 and VPS29 in AMI patients compared to healthy controls(both P<0.05).Conclusions:Higher levels of PSME1 and VPS29 are negatively associated with the risk of MI,suggesting that PSME1 and VPS29 may serve as protective biomarkers for cardiovascular diseases.