AIM:To study the mechanism of oxy-sophoridine(OSR)in relieving neuropathic pain(NP).METHODS:The analgesic effect of OSR was observed by measuring mechanical pain sensitivity.By combining OSR with agonists and antagonists re-lated to synthesis and metabolism of gamma ami-nobutyric acid(GABA),the mechanism related to analgesic effects of OSR and GABA nervous system is studied.The expression of c-Fos immunopositive cells and the expression of c-Fos and Glutamic acid decarboxylase(Glutamic acid decarboxylase 67)in brain and spinal cord were detected by immunoflu-orescence staining.Co-expression of GAD67,GABA transporter 1(gamma-Aminobutyric acid Transport-er 1,GAT-1)immunopositive cells.RESULTS:Com-pared with Sham group,spared nerve injury(SNI)group showed increased mechanical pain sensitivi-ty,increased expression of c-Fos immunopositive cells,decreased and increased co-expression of c-Fos and GAD67 and GAT-1 immunopositive cells,re-spectively.Compared with SNI group,mechanical algesia in OSR 500 and 1 000 mg/kg groups was de-creased,algesia in OSR 250 mg/kg combined with antagonist group was decreased,and algesia in OSR 500 mg/kg combined with agonist group was increased.The co-expression of c-Fos and GAD67 immunopositive cells in the brain and spinal cord of OSR 500 mg/kg group increased,while the co-ex-pression of c-Fos and GAT-1 decreased.CONCLU-SION:OSR has a good analgesic effect on NP mice induced by SNI.The mechanism is that OSR increas-es the content of central GABA by up-regulating GABAergic neurons in brain and spinal cord.

AIM:To investigate the protective ef-fect of sinomenine hydrochloride(SIN)on adjuvant arthritis(AA)rats by regulating the NLRP3/Gasder-min D/Caspase-1/Interleukin-1β pyroptosis path-way.METHODS:Sixty rats were randomly divided into 6 groups,10 rats in each group:Con group(normal rats),AA group(AA rat model),L-SIN group(AA rats were intragastrically administered with 100 mg/kg SIN),M-SIN group(AA rats were intra-gastrically administered with 200 mg/kg SIN),H-SIN group(AA rats were intragastrically administered with 400 mg/kg SIN),ACG group(positive drug group:AA rats were intragastrically administered with 150 mg/kg Wantong Jingu Tablets).Observe the degree of joint swelling and arthritis index.HE was used to observe the pathological changes of the right ankle joint tissue of rats.The levels of in-flammatory factors and oxidative stress-related in-dicators in synovial tissue were detected.Western Blot was used to detect the expression levels of NL-RP3/Gasdermin D/Caspase-1/Interleukin-1β pyrop-tosis pathway-related proteins.RESULTS:Com-pared with Con group,the degree of joint swelling,arthritis index,inflammatory factors and oxidative stress levels,NLRP3,GSDMD,Caspase-1 and IL-1β protein expression levels in AA group were signifi-cantly increased(P<0.05).Compared with AA group,the degree of joint swelling,arthritis index,inflammatory factors and oxidative stress levels,NL-RP3,GSDMD,Caspase-1 and IL-1β protein expres-sion levels were significantly decreased in SIN treat-ment group with the increase of treatment dose(P<0.05).Compared with AA group and L-SIN group,the degree of joint swelling,arthritis index,inflam-matory factors and oxidative stress levels,NLRP3,GSDMD,Caspase-1 and IL-1β protein expression levels in ACG group were significantly decreased(P<0.05).Compared with H-SIN group,the degree of joint swelling,arthritis index,inflammatory factors and oxidative stress levels,NLRP3,GSDMD,Cas-pase-1 and IL-1β protein expression levels in ACG group were significantly increased(P<0.05).CON-CLUSION:SIN can alleviate the inflammatory injury of AA rats and reduce the levels of inflammatory factors and oxidative stress,thus exerting a protec-tive effect on AA rats.The mechanism may be based on the NLRP3/Gasdermin D/Caspase-1/Inter-leukin-1β pyroptosis pathway.

As the incidence of diabetes in China continues to rise,its complications pose a serious threat to the life health of patients.New hypoglyce-mic agents are constantly emerging,with particular attention being paid to glucagon-like peptide-1 re-ceptor agonists(GLP-1RA)and sodium-glucose co-transporter 2 inhibitor(SGLT2i),which can not only effectively control blood glucose levels,but also sig-nificantly improve the cardiac and renal outcomes of diabetic patients.New technologies for diabetes management based on artificial intelligence(AI)are also developing rapidly,playing a crucial role in the diagnosis of diabetic retinopathy(DR)and insu-lin dose-assisted decision-making.Continuous glu-cose monitoring(CGM)and automated insulin de-livery system(AID)have already been used clinical-ly.This article reviews the progress in drug therapy and new technologies for type 2 diabetes mellitus T2DM,aiming to provide guidance for the treat-ment of T2DM patients.

AIM:To appraise the bioequivalence and safety of the test preparation of ritonavir tab-lets and the reference preparation(trade name:Norvir?)in healthy adult subjects under fasting and postprandial conditions.METHODS:This study was a randomized,open-label,single-dose,four-period,fully repeated crossover design bioequivalence study protocol.Thirty-six healthy male and female volunteers were enrolled in the fasting and post-prandial conditions,and a single dose of the test preparation and reference preparation was orally administered.We used liquid chromatography-tan-dem mass spectrometry(LC-MS/MS)to finish the bioassay of the drug concentration of ritonavir in plasma.Pharmacokinetic parameters were statisti-cally analyzed using PhoenixWinNonlin8.1 software(Pharsight,USA)and a non-compartmental model.RESULTS:Under fasting conditions,the pharmacoki-netic parameters of the test and reference prepara-tions:Cmax(792.010±369.282)ng/mL and(856.939±394.427)ng/mL,AUC0-t(6 463.043±2 876.849)ng·mL-1·h and(6 907.690±3 046.132)ng·mL-1·h,AUC0-∞(6 603.617±2 916.352)ng·mL-1·h and(7 051.614±3 093.047)ng·mL-1·h.Here are the pharmacokinetic parameters for both the test prep-aration and the reference preparation in the post-prandial condition:Cmax(574.380±289.566)ng/mL and(615.796±297.382)ng/mL,AUC0-t(5 084.796±2 435.557)ng·mL-1·h and(5 414.167±2 416.952)ng·mL-1·h,AUC0-∞(5 219.144±2 487.793)ng·mL-1·h and(5 551.060±2 490.604)ng·mL-1·h.The 90%confidence interval of the geometric mean ratio of AUC0-t,AUC0-∞,and Cmax for the test preparation and reference preparation lied in the equivalent range of statistics.CONCLUSION:The tested preparation was bioequivalent to the reference preparation un-der fasting and postprandial conditions.

AIM:To compare the effects and effi-cacy of methoxyamine and norepinephrine on sub-lingual microcirculation in patients with high-alti-tude septic shock.METHODS:A total of forty-six patients with septic shock from the Xining area of Qinghai Province were randomized into two groups:the M-hydroxylamine group(Group M,n=22)and the norepinephrine group(Group N,n=24).Baseline data as well as the incidence of acute kid-ney injury(AKI),distal limb necrosis/ischemia,and 28-day survival rates were documented.Sublingual microcirculation parameters were monitored and recorded at four time points:before treatment(T0),24 hours post-treatment(T1),48 hours post-treatment(T2),and 72 hours post-treatment(T3)using side-flow dark-field(SDF)imaging.The pa-rameters included total vascular density(TVD),per-fused vascular density(PVD),perfused vessel ratio(PPV),microvascular flow index(MFI),and hetero-geneity index(HI).Additionally,changes in heart rate(HR),mean arterial pressure(MAP),blood urea nitrogen(BUN),serum creatinine(Cr),and lac-tate(Lac)levels were also recorded.RESULTS:There were no significant differences between the two groups in terms of baseline data,incidence of AKI,distal limb necrosis/ischemia,and 28-day sur-vival rate.Additionally,there were no significant differences in HR,MAP,and Lac indices between the two groups at any time point.However,within-group comparisons showed that HR,MAP,and Lac indices improved over the course of treatment,with statistically significant differences.The BUN level at the T3 time point was significantly lower in the mehydroxyamine group compared to the nor-epinephrine group(P<0.05).Similarly,Cr levels were significantly lower at both T2 and T3 time points(P<0.05).There were no significant differenc-es in sublingual microcirculation indices between the two groups at any time point.However,TVD,PVD,PPV,MIF,and HI in both groups improved over the course of treatment,with statistically sig-nificant differences.CONCLUSION:Both methoxy-amine and norepinephrine can enhance both the macrocirculation and sublingual microcirculation in patients with septic shock at high altitudes.Addi-tionally,methoxyamine leads to a faster recovery of creatinine levels within 72 hours.

AIM:To explore the correlation be-tween trimethylamine N-oxide(TMAO)and Hashi-moto's thyroiditis(HT)and to provide new ideas for early clinical diagnosis of HT.METHODS:A total of 102 patients with Hashimoto's thyroiditis(HT group)and 204 healthy individuals(control group)were included in the study and clinical data were collected.Serum TMAO levels was determined by stable isotope dilution high-performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS).SPSS 26.0 was used for statistical analysis.RESULTS:Analysis of the baseline data revealed that there was a statistically significant difference between the TMAO levels and gender between the HT group and the control group(P<0.05).In the high-level TMAO group,the proportion of HT(63.7%)was significantly higher than that of the control group(18.6%),the regression analysis showed that high levels of TMAO were correlated with HT and positively correlated with the levels of thyroid peroxidase antibody(TPOAb),thyroglobulin antibody(TgAb),Logistic regression analysis further revealed that serum TMAO was a risk factor for the development of HT.CONCLUSION:In the TMAO>6.80 μmol/L group,the level of TMAO was correlat-ed with HT,and the high level of TMAO was posi-tively correlated with TPOAb and TgAb,which were risk factors for the occurrence of HT.It is suggested that TMAO can predict the risk of HT and has cer-tain clinical value.

Ivonescimab is a humanized bispecific antibody targeting human vascular endothelial growth factor-A(VEGF-A)and programmed death protein-1(PD-1).It was approved by National Medi-cal Products Administration on May 24th,2024,and can be used in combination with pemetrexed and carboplatin for locally advanced or positive EG-FR gene mutation after treatment with epidermal growth factor receptor(EGFR)tyrosine kinase inhib-itor.This paper mainly introduces the research progress of the world's first PD-1/VEGF bispecific antibody ivonescimab,and summarizes the mecha-nism of action,pharmacokinetics,phase Ⅰ-Ⅲ clinical trials and drug safety.

AIM:To explore the effects of Jianpi Huatan formula on regulating T cells and helper T cells 17(Th17)cells in patients with polycystic ova-ry syndrome(PCOS)due to spleen deficiency and phlegm dampness syndrome,and conduct a model evaluation.METHODS:Ninety-two patients with spleen deficiency phlegm dampness syndrome(PCOS)admitted to our hospital from January 2023 to October 2024 were selected as the research sub-jects.Propensity score matching(PSM)method was used to match them in a 1:1 ratio,with 46 pa-tients in each group.The control group received conventional treatment,while the observation group received treatment with Jianpi Huatan for-mula on the basis of the control group.Compared and analyze the differences in clinical data and lab-oratory indicators between two groups;Compared the changes of sex hormone,glucose metabolism and TCM syndrome score before and after treat-ment in the two groups,and focused on the chang-es of regulatory T cells(Treg)and Th17 cells in the two groups before and after treatment;And used the Generalized Estimation Equation(GEE)model to analyze its improvement.Multiple linear regres-sion analysis was used to examine its correlation with the score of traditional Chinese medicine syn-drome.A time effect model of Jianpi Huatan formu-la for treating PCOS with spleen deficiency and phlegm dampness syndrome was established using a nonlinear mixed effects model.The fitting effect of the final model was evaluated through the good-ness of fit.Bootstrap was used to test and evaluate the stability of model parameters.Visual prediction testing was used to evaluate the predictive perfor-mance of the model.Typical time effect curves of traditional Chinese medicine symptom scores was simulated based on the final model for each base-line.RESULTS:After treatment,the total effective rate of the observation group was significantly high-er than that of the control group(χ2=4.842,P=0.028);Compared with before treatment,after 1months and 3 months of treatment,TC,TG,LDL-C,T,LH,FSH,AMH,FPG,FINS,HOMA-IR,the score of traditional Chinese medicine syndrome were sig-nificantly reduced,while E2 and HDL-C were signifi-cantly increased,and the improvement in the ob-servation group was significantly greater than that in the control group(P<0.05);The results of repeat-ed measures ANOVA showed significant difference-sin the time effects,inter group effects,and interac-tion effects of Treg,Th17,and Treg/Th17 between the two groups of patients(P<0.05).The GEE anal-ysis results showed that the improvement of Treg,Th17,and Treg/Th17 in the observation group were better than that in the control group(P<0.05);The results of multiple linear regression analysis showed that the levels of TC,TG,LDL-C,T,LH,FSH,AMH,FPG,FINS,HOMA-IR,Th17 were significantly positively correlated with TCM syndrome score,while the levels of E2,HDL-C,Treg,and Treg/Th17 were significantly negatively correlated with TCM syndrome score(P<0.05);The decrease in tradition-al Chinese medicine symptom score compared to baseline gradually increases over time,eventually reaching the pharmacological platform,which was consistent with the classic Emax model.After gradu-ally screening covariates,it was found that the baseline value of traditional Chinese medicine symptom score had a significant impact on the effi-cacy parameter Emax.The final model was Emax,i=15.42+1.21×(Baselinei-24.41).The goodness of fit results showed that the final model had a good fit-ting effect on the measured data.The model pa-rameters obtained from Bootstrap testing were very consistent with the original model,indicated that the model parameter estimation was robust.The visual prediction test results showed that the model had good predictive performance.The typi-cal efficacy time curve showed that the higher the baseline value of TCM symptom score,the greater the decrease in score.At 3 months of treatment,the TCM symptom score at each baseline basically decreased to below 10 points.CONCLUSION:The formula for strengthening the spleen and resolving phlegm can effectively improve the levels of Treg and Th17 in PCOS patients with spleen deficiency and phlegm dampness syndrome,and has good therapeutic effects,which is worthy of clinical appli-cation.

AIM:To construct a network calcula-tor based on machine learning(ML)models to pre-dict the risk of delayed awakening from anaesthesia in breast cancer(BC)patients.METHODS:A total of 435 BC patients surgically treated at our hospital from January 2023 to June 2024 were selected.The Boruta algorithm was used to screen for important characteristic variables for the risk of delayed awak-ening from anaesthesia.All patients were randomly assigned to a training set(n=261)and a test set(n=174)based on a 3:2 ratio and nine ML models were constructed and trained.Nine ML models were evaluated on the basis of receiver operating charac-teristic(ROC)curves for a random sample of 10 sub-jects and the clinical utility of the models was as-sessed using decision curve analysis.Combined with SHapley Additive exPlanations(SHAP)bar graphs,summary graphs and force diagrams additional in-terpretation and visualization of the ML model.Con-struction of a network calculator for predicting the risk of delayed awakening from anesthesia in BC pa-tients using the R package.RESULTS:Of the 435 BC patients,25.1%experienced delayed awakening from anesthesia.Boruta algorithm screened seven feature variables.The ROC curve shows that the XG-Boost model has the highest area under the curve(AUC)for 10 random samples among the 9 ML mod-els,and the decision curve shows that the XGBoost model has a significant clinical net benefit.The SHAP bar graph shows the importance of ASA classi-fication,surgery time,anesthesia time,intraopera-tive blood loss,propofol,preoperative anemia,and intraoperative hypothermia,and the SHAP summa-ry graph reflects the distribution of the ranges of in-fluence of the seven important characteristic vari-ables,which are"separated at the ends."The SHAP force diagram visualization XGBoost model predict-ed the risk of delayed awakening from anesthesia for individual patients with a predictive value of 0.998 for patients with delayed awakening from an-esthesia and 0.008 91 for patients without delayed awakening from anesthesia.A web-based calculator(https://xz-nomogram.shinyapps.io/DE_web/)based on an interpretable XGBoost model effective-ly predicts the risk of delayed awakening from anes-thesia in BC patients.CONCLUSION:ASA classifica-tion,surgery time,propofol,intraoperative blood loss,anaesthesia time,preoperative anaemia and intraoperative hypothermia are important charac-teristic variables for the risk of delayed awakening from anaesthesia in BC patients.The network calcu-lator based on the interpretable XGBoost model can accurately and quickly quantify the risk of de-layed awakening from anaesthesia,which can help clinicians to effectively adjust the treatment strate-gy and better improve the prognosis of patients.

Diabetic erectile dysfunction is a com-mon complication of diabetes that severely affects the quality of life of men and their sexual partners.Active participation in scientific research on diabet-ic erectile dysfunction is particularly important,and animal models are an important basis for exploring the pathogenesis of the disease,evaluating the effi-cacy of drug treatments,and developing new drugs.The pathogenesis of diabetic erectile dys-function is complex,and current treatments mainly focus on regulating blood sugar,anti-oxidative stress,PDE5 inhibitors,stem cell therapy,inhibiting neurovascular injury,anti-fibrosis,traditional Chi-nese medicine,and other aspects.In particular,cor-recting hyperglycemia is crucial for preventing or stopping the progression of the disease.This article summarizes and updates existing treatment meth-ods by reviewing the latest literature,and reviews the animal models used in different treatment methods,in order to provide a reference for animal experiments and clinical treatment.