AIM:To examine the impact of the transcription factor 7 analogue 2(TCF7L2)gene polymorphism on the hypoglycaemic effect of ex-enatide in patients with type 2 diabetes mellitus(T2DM).METHODS:A total of 100 newly diagnosed Han Chinese patients with T2DM who had not re-ceived any drug treatment were selected from the Affiliated Hospital of Xuzhou Medical University and treated with exenatide monotherapy for 6 months.The TCF7L2 rs290487 was genotyped by SnaPshot method,and blood glucose levels,lipids profiles and pancreatic function evaluation indica-tors were measured at baseline,3 months and 6 months after exenatide treatment.Multiple linear regression analysis was employed to assess the cor-relation between each indicator and the reduction in glycated hemoglobin(HbA1c)levels after 6 months of exenatide treatment.The expression of TCF7L2 protein in the plasma of T2DM patients was detected by enzyme-linked immunosorbent assay(ELISA)kit.Furthermore,western blotting was con-ducted to ascertain TCF7L2 expression in pancreat-ic tissues obtained from db/db mice and INS-1 cells cultured under high glucose conditions.Lentivirus transfection was used to overexpress or knock down TCF7L2 in insulinoma cell line(INS-1)cells,followed by measurement of KSIS activity and insu-lin content after a 24-hour intervention with exena-tide.RESULTS:The distribution pattern of TCF7L2 rs290487 was found to be in accordance with Har-dy-Weinberg equilibrium(P＞0.05).Following 6 months of exenatide treatment,there was a nota-ble reduction in blood glucose levels and an im-provement in lipid profiles when compared to base-line values.Additionally,there was a significant in-crease in the homeostasis model assessment of be-ta-cell function(HOMA-B)values.Patients with the TT genotype exhibited significantly lower postpran-dial plasma glucose(PPG)levels and HbA1c values compared to those with the CC or CT genotypes(P＜0.05).After adjusting for age,gender,body mass in-dex(BMI),and waist to hip ratio(WHR)in the mul-tiple linear regression model,a significant associa-tion was observed between the rs290487 TT geno-type,baseline HbA1c levels,and family history of diabetes with the reduction in HbA1c after six months of exenatide treatment(P＜0.05).Further-more,individuals with the rs290487 TT genotype demonstrated a notable elevation in TCF7L2 expres-sion in plasma among T2DM patients in comparison to those with the CC genotype(P＜0.05).In particu-lar,pancreatic tissue from db/db mice exhibited markedly elevated TCF7L2 expression compared to db/m mice.However,this up-regulation was re-versed by exenatide treatment.Similarly,INS-1 cells cultured under high glucose conditions dem-onstrated an increase in TCF7L2 expression,which was ameliorated upon exenatide administration.The knockdown of TCF7L2 using shRNA enhanced the KSIS function of pancreatic β cells and aug-mented the insulinotropic effect of exenatide.Con-versely,the upregulation of TCF7L2 impaired the KSIS function of pancreatic β cells and attenuated the insulinotropic effect of exenatide.CONCLU-SION:The TCF7L2 rs290487 gene polymorphism is closely associated with the hypoglycaemic efficacy of exenatide therapy.The risk allele C may diminish the effectiveness of exenatide by impacting the lev-els of PPG and HbA1c in T2DM patients.The muta-tion at TCF7L2 rs290487 site(C→T)influenced the expression of TCF7L2 protein.By exerting its regula-tory effect,exenatide may be capable of regulating the impact of TCF7L2 on the function of pancreaticβ cells.

AIM:To investigate the effects of semaglutide on inflammation and autophagy in hu-man AC16 cardiomyocytes under hypoxia/reoxy-genation conditions.METHODS:AC16 cells were randomly divided into four groups:control(CON),hypoxia/reoxygenation(H/R),hypoxia/reoxygen-ation+semaglutide(H/R+SEM),and hypoxia/reoxy-genation+semaglutide+3-MA(H/R+SEM+3-MA).All groups except CON underwent 8 hours of hypoxia followed by 12 hours of reoxygenation.Cell viabili-ty was measured by CCK-8.Levels of IL-1β and TNF-α were assessed by ELISA.Western blot analysis evaluated AMPK,p-AMPK,mTOR,p-mTOR,ULK1,p-ULK1,Beclin-1,and LC3.Autophagosomes were an-alyzed using laser confocal microscopy and trans-mission electron microscopy.The structure of au-tophagosome and autolysosome was observed by transmission electron microscopy.RESULTS:IL-1βand TNF-α levels increased significantly in the H/R group compared to CON(P＜0.01)but decreased in the H/R+SEM group(P＜0.01).In the H/R+SEM+3-MA group,inflammatory levels increased com-pared to the H/R+SEM(P＜0.05).Compared with the CON group,p-AMPK/AMPK and p-ULK1/ULK1 ratios increased significantly in the H/R group(P＜0.05,P＜0.01).The ratios further increased in the H/R+SEM group compared to H/R(P＜0.05,P＜0.01).But the two ratios decreased in the H/R+SEM+3-MA group compared to H/R+SEM(P＜0.01,P＜0.05).The pmTOR/mTOR had the opposite trend to the two previous ratios.The expression of Beclin1 and LC3 were significantly increased in group H/R com-pared to CON(P＜0.05),and which further in-creased in the H/R+SEM group compared to H/R(P＜0.01).But the two indicators decreased in the H/R+SEM+3-MA group compared to H/R+SEM(P＜0.01,P＜0.05).Laser confocal microscopy revealed increased autophagosome numbers in H/R group compared to CON(P＜0.05),and which further in-creased in the H/R+SEM group compared to H/R(P＜0.01).While the H/R+SEM+3-MA group showed a decrease compared to H/R+SEM(P＜0.05).CON-CLUSION:Semaglutide may moderate regulate au-tophagy through AMPK/mTOR/ULK1 pathway,re-duce the release of inflammatory factors,and alle-viate hypoxia/reoxygenation-induced inflammatory injury.

AIM:To investigate the appropriate dose of intravenous dexmedetomidine(Dex)for se-dation in minimally invasive breast surgery under regional block.METHODS:A total of 120 patients with multiple breast masses were selected and di-vided into Dex 0.5 μg/kg group(group D1),Dex 0.75 μg/kg group(group D2),Dex 1.0 μg/kg group(group D3)and normal saline group(group C)ac-cording to the random number table method.After intravenous injection of test drugs,minimally inva-sive rotary cutting under retromammary space an-esthesia was performed.The optimal sedation rate during operation,the optimal sedation rate after operation,Ramsay sedation scores were recorded before anesthesia,at the end of intravenous admin-istration,at the retromammary space anesthesia,at the beginning of surgery,5 min after surgery,at the end of surgery,30 min after administration,and 60 min after administration,visual analogue scale(VAS),vital signs(SBP,DBP,HR,SpO2),the inci-dence of moderate and above pain(VAS＞3)and ad-verse reactions were observed.The optimal seda-tion was defined as intraoperative Ramsay score 2-4 points and postoperative Ramsay score 2-3 points.RESULTS:Dex had a dose-dependent seda-tive and analgesic effect.The optimal sedation rate during operation in group D2 and D3 was significant-ly higher than that in group C and D1,and the opti-mal sedation rate after operation in group D2 was the highest.The rate of VAS score greater than 3 points in group D2 and group D3 was significantly lower than that in group C and group D1,and there was no statistical difference between group D2 and group D3.The incidence of dizziness in group D2and group D3 was higher than that in group C and group D1.There was no significant difference in the inci-dence of hypotension,hypertension,severe brady-cardia,hypoxemia and nausea among the groups.CONCLUSION:Preoperative single intravenous ap-plication of 0.75 μg/kg dexmedetomidine has a def-inite sedative and analgesic effect,and the optimal sedation rate during and after operation is high.It is an appropriate dose for sedation assisted by min-imally invasive breast surgery under regional block.

AIM:To explore the relationship be-tween the level of myeloid-derived suppressor cell(MDSC)infiltration in tumor tissues and the clinical efficacy and prognosis of combined PD-1 inhibitor and chemotherapy in the treatment of advanced non-small cell lung cancer(NSCLC).METHODS:A retrospective analysis was conducted on 92 NSCLC patients who received PD-1 inhibitor combined with chemotherapy at the First Affiliated Hospital of Anhui Medical University from June 2019 to June 2024.Tumor tissue samples were examined using immunohistochemistry to detect the level of MDSC infiltration,dividing the patients into high-in-filtration group(MDSC≥2)and low-infiltration group(MDSC＜2).The objective response rate(iORR),disease control rate(iDCR),progression-free survival(PFS),and overall survival(OS)were compared between the two groups.Kaplan-Meier survival analysis and Log-rank test were used to plot PFS and OS survival curves,and Cox regression analysis was applied to identify factors influencing prognosis.RESULTS:Among the 92 patients,53 were in the low MDSC infiltration group,and 39 were in the high MDSC infiltration group.The low MDSC infiltration group showed significantly better treatment responses compared to the high MDSC infiltration group.The objective response rate(iORR)was 77.3％in the low MDSC infiltration group,higher than the 56.4％in the high MDSC in-filtration group(P=0.033).The disease control rate(iDCR)was 94.3％,also significantly higher than the 66.7％in the high MDSC infiltration group(P=0.001).Moreover,the median progression-free sur-vival(PFS)and overall survival(OS)in the low MD-SC infiltration group were 16.9 months and 27.6 months,respectively,which were significantly lon-ger than those in the high MDSC infiltration group(PFS 12.6 months,OS 22.3 months).Kaplan-Meier analysis revealed that both PFS and OS in the low MDSC infiltration group were significantly longer than those in the high MDSC infiltration group.Cox univariate analysis showed that smoking,PD-L1 ex-pression levels,tumor stage,and MDSC infiltration level were closely associated with PFS and OS.Mul-tivariate Cox regression analysis further indicated that high MDSC infiltration was an independent risk factor for both PFS(HR=2.678,P=0.013)and OS(HR=2.254,P=0.022).CONCLUSION:The level of MDSC infiltration in tumor tissues is closely related to the efficacy and prognosis of PD-1 inhibitor com-bined with chemotherapy in NSCLC patients.High MDSC infiltration suggests reduced treatment sen-sitivity and poor prognosis.MDSC infiltration level may serve as a predictive biomarker for the effica-cy and prognosis of PD-1 inhibitor combined with chemotherapy in advanced NSCLC.

Pulmonary hypertension(PH)is a seri-ous disease characterized by abnormally high pul-monary arterial pressure(PAP),which leads to in-creased cardiac burden and may eventually lead to right heart failure.Levosimendan,as a calcium sen-sitizer,has the dual role of enhancing cardiac con-striction force and promoting vascular dilation.It shows a good prospect in the treatment of PH com-bined with right heart failure by reducing PAP,in-creasing RV contractile force and reducing anterior and posterior cardiac load without increasing myo-cardial oxygen consumption.Since it does not in-crease the intracellular Ca2+concentration,it avoids the arrhythmia-inducing,reduced coronary perfu-sion and other side effects of other positive inotro-pic drugs.At present,levosimandan is mainly trans-fused intravenically,which may lead to systemic hy-potension,arrhythmia and other side effects,while inhalation administration can reduce the occur-rence of adverse reactions,but its effectiveness and safety in the treatment of PH combined with right heart failure remains to be studied.The pur-pose of this review was to investigate the role of in-haled levosimendan in PH combined with right heart failure.

AIM:To investigate the role of lectin-like oxidized low-density lipoprotein receptor-1(LOX-1)in hypoxia-induced autophagy and apopto-sis in endothelial cells.METHODS:Human umbili-cal vein endothelial cells(HUVECs)were exposed to hypoxia(1％O2)for varying durations(0,6,12,24 h)to evaluate autophagy and apoptosis levels.LOX-1 was further intervened to explore its effects on autophagy and apoptosis.GFP-LC3B adenovirus in-fection was observed under fluorescence microsco-py to assess LC3B expression.Autophagosomes were detected by transmission electron microscopy(TEM).LOX-1 mRNA levels were measured using re-al-time PCR.Protein expression of LOX-1,LC3Ⅱ/Ⅰ,Beclin-1,Atg5,cleaved-caspase 3,Bax,and Bcl-2 was analyzed by Western blot.Reactive oxygen spe-cies(ROS)levels were quantified using the DCFH-DA fluorescent probe.Apoptosis was assessed via Hoechst staining and flow cytometry(Annexin V-PI double staining).RESULTS:Hypoxia(1％O2,24 h)significantly increased LC3Ⅱ puncta under fluores-cence microscopy,upregulated LC3Ⅱ/Ⅰ protein ex-pression,and induced autophagosome formation observed by TEM.Hypoxia elevated ROS produc-tion and promoted apoptosis.LOX-1 mRNA and protein expression were upregulated in hypoxic HU-VECs.LOX-1 siRNA intervention markedly reversed hypoxia-induced autophagy,downregulating au-tophagy-related proteins(Beclin-1,Atg5,LC3Ⅱ/Ⅰ).LOX-1 siRNA also suppressed ROS generation and inhibited apoptosis,as evidenced by decreased ex-pression of cleaved-caspase 3 and Bax,and in-creased Bcl-2 levels.CONCLUSION:Hypoxia in-duced upregulation of LOX-1 expression to produce ROS,thereby promoting autophagy and apoptosis in endothelial cells.

AIM:To investigate how the stearoyl-CoA desaturase-1(SCD1)inhibitor CAY-10566 induc-es ferroptosis in oral squamous cell carcinoma(OS-CC)cells and enhances their sensitivity to cisplatin,with preliminary exploration of the underlying mo-lecular mechanisms.METHODS:Bioinformatics analysis and clinical specimens were used to evalu-ate SCD1 expression in OSCC tissues.OSCC cell lines(Cal27 and HSC3)were treated with CAY-10566,cis-platin,the ferroptosis inhibitor Ferrostatin-1(Fer-1),or their combinations.Cell viability was assessed using the CCK-8 assay,while reactive oxygen spe-cies(ROS)and lipid ROS levels were measured by flow cytometry.Malondialdehyde(MDA)and re-duced glutathione(GSH)levels were quantified us-ing commercial assay kits.Western blotting was performed to analyze the protein expression of glu-tathione peroxidase 4(GPX4),mechanistic target of rapamycin(mTOR),mature sterol regulatory ele-ment-binding protein 1(m-SREBP1),SCD1,and heme oxygenase 1(HMOX1).RESULTS:SCD1 was significantly overexpressed in OSCC tissues(P＜0.01).Combined treatment with CAY-10566 and cis-platin markedly reduced OSCC cell viability(P＜0.01)and increased lipid peroxidation(P＜0.001),while suppressing GPX4 expression-effects that were re-versed by Fer-1(P＜0.001).CAY-10566 upregulated HMOX1 expression and inhibited mTOR,m-SREBP1,and SCD1 protein levels(P＜0.001).CONCLUSION:CAY-10566 promotes ferroptosis and cisplatin sensi-tivity in OSCC cells,potentially through HMOX1 up-regulation and suppression of the mTOR/SREBP1/SCD1 axis.

Hedysari radix is the characteristic chi-nese medicine of Gansu Province,with"MiCang Hedysari radix"as the best.Modern pharmacologi-cal research has shown that it has polysaccharides and flavonoids,which have good anti-tumor effects and can inhibit the occurrence and development of various cancers,such as lung cancer,liver cancer,and breast cancer.Cancer is ranked as the second leading cause of death in the world,and the mor-bidity and mortality rates are increasing year by year,seriously affecting the quality of life.At pres-ent,with the modernization of Traditional Chinese Medicine(TCM),there has been a significant break-through in the treatment of malignant tumors with TCM.Based on this,by collating the relevant litera-ture at home and abroad in recent years,the anti-tumor effects and mechanisms of Hedysari radix and its active ingredients are summarized to pro-vide a scientific basis for the study of elucidating the material basis of the anti-tumor effects of He-dysari radix and to promote the development of the Hedysari radix industry.

AIM:Xiongshi Shiwei Wendan decoc-tion(SWD)comes from Xiong Jibai,a master of tra-ditional Chinese medicine,and has been widely used in the treatment of AS.ABCA1 is an important pathway for macrophages to export cholesterol and plays a protective role in the occurrence and development of AS.The purpose of this study was to study the effects of SWD on ABCA1 expression and cholesterol efflux through network pharmacol-ogy,molecular docking and in vitro experiments,and explore the pathway mechanism of promoting reverse cholesterol transport(RCT).METHODS:The active components of SWD drugs were screened by TCMSP and HERB databases,RCT targets were pre-dicted,the component-target network map was constructed,the PPI network was constructed and the GO and KEGG pathways were enriched and ana-lyzed by STRING database,and the key active com-ponents of SWD were selected for molecular dock-ing with ABCA1 protein and miR-33 by AutoDockVi-na.In vitro,RAW264.7 was used to establish foam cell model,oil red O staining,NBD-cholesterol staining and lentivirus overexpression cell miRNA-33 were used to study the effect of SWD on lipid accumulation and cholesterol outflow rate of RAW264.7 cells.Western blotting was used to de-tect the expression of ABCA1.RESULTS:According to network pharmacology,336 active components of SWD,267 targets of RCT and 46 targets of inter-section of RCT and SWD were obtained,which in-volved multiple signal pathways such as lipid and atherosclerosis.Molecular docking showed that the main active components had stable conforma-tion with ABCA1 and miR-33.In vitro experiment,it was found that the lipid content was significantly decreased(P＜0.01),the cholesterol outflow rate was significantly increased(P＜0.01)and the expres-sion of ABCA1 protein was up-regulated in SWD group(P＜0.01),but the expression of ABCA1 in miR-33 overexpression group was significantly de-creased(P＜0.01).CONCLUSION:SWD has the char-acteristics of multi-components and multi-targets,which can promote RCT and treat AS through miR-NA-33-ABCA1 pathway.

AIM:Hepatotoxicity of Brucea javani-ca picryl with broad-spectrum anticancer effect in nude mice based on hepatic drug metabolizing en-zyme CYP450 activity.METHODS:Fifty-six nude mice were randomly divided into blank group,Bru-cea javanica low-dose group(2 mg/kg),Brucea ja-vanica high-dose group(4 mg/kg),and cisplatin group(2 mg/kg),with 14 mice in each group.The blank group was injected with the same amount of normal saline every 3 days for 6 weeks.Calculate the mortality rate of nude mice in each group,ob-serve the general growth state of nude mice,re-cord the weight change of nude mice before and af-ter administration,weigh and record the liver weight after taking materials,and calculate the liv-er coefficient(liver weight/weight mass×100％),ob-serve and record the liver color and morphology.Hematoxylin-eosin(HE)staining was used to ob-serve the pathological changes of liver tissue.De-tection of alanine aminotransferase(ALT),aspar-tate aminotransferase(AST),lactate dehydrogenase(LDH),alkaline phosphatase(AKP)and albumin(ALB)levels in serum of nude mice by ELISA.Real-time PCR and Western blot were used to detect the mRNA and protein expression levels of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6 and CYP2C9,which were key enzymes of drug metabolism in nude mice liver.RESULTS:Compared with the blank group,the mortality rate of nude mice in the low-dose Brucea javanica bitter alcohol group was 0,the growth state was good,the diet,movement,and mental state were normal,the weight change and liver coefficient ratio were consistent,the liver color was ruddy,the liver lobule morphology was complete under the microscope,the structure was clear,the liver cells were arranged regularly,and there was no inflammatory cell infiltration.There was no significant difference in the content of ALT,AST,LDH,AKP,and ALB.There was no significant difference in the mRNA and protein expression of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9(all P＞0.05).Compared with the blank group,the mortality rate of nude mice in the high-dose group of Brucea javanica bitter alcohol was 14.3％,the growth state was slightly poor,the diet,movement,and mental state were reduced,the weight growth was slow,the liver coefficient ratio was increased,the liver color was reddish brown,some liver lobule boundaries were unclear,a small number of liver cells were loosely arranged,the contents of ALT,AST,LDH,AKP,and ALB were signif-icantly increased,the mRNA levels of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9 were significantly reduced,and the protein expres-sions of CYP2E1,CYP3A11,CYP1A2,and CYP2D6 were significantly reduced(all P＜0.05 or P＜0.01),but there was no statistical difference in the mRNA and protein expression of CYP2C19,and the pro-tein expression of CYP2C9(P＞0.05).Compared with the blank group,the mortality rate of nude mice in the cisplatin group was 35.7％,the growth state was poor,the diet,action,and mental state were low,the weight gain was less,the liver coefficient ratio was significantly increased,the liver color was dark red,the liver sinusoids and central veins were congested,the hepatocytes were disordered,the nuclei were consolidated and contracted,and the arrangement was loose,the contents of ALT,AST,LDH,AKP,and ALB were significantly increased,and the mRNA and protein expressions of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9 were significantly reduced(all P＜0.05 or P＜0.01).CONCLUSION:The dose of Brucea javanica bitter alcohol is correlated with hepatotoxicity to nude mice.High doses of Brucea javanica bitter alcohol have hepatotoxicity to nude mice,which may be re-lated to reducing serum levels of ALT,AST,LDH,AKP,and ALB,inhibiting the expression of multiple subtypes of enzymes in the key enzyme CYP450 of liver drug metabolism,and then reducing the me-tabolism of toxic substances.