The Effectiveness of Glyburide Compared to Insulin in the Management of Gestational Diabetes Mellitus: A Systematic Review

Background: Insulin therapy has been the mainstay in managing women with gestational diabetes mellitus (GDM), but some disadvantages of insulin have led to the use of glyburide, which is inexpensive in some countries, to manage GDM. However, there has been debate over its effectiveness, efficacy and safety when compared to insulin for maternal glycaemic control, and some adverse neonatal outcomes in GDM. Method: A systematic review of eight randomised controlled trial (RCT) studies was undertaken to compare glyburide and insulin. Studies involving 849 participants were included in the quantitative analysis. Results: There was no significant difference between glyburide and insulin in maternal fasting (P = 0.09;SMD: 0.13;95% CI: ﹣0.02 to 0.28) and postprandial (P = 0.45;SMD: 0.05;95% CI: ﹣0.09 to 0.19) glycaemic control and glycosylated hae-moglobin (P = 0.35;SMD: 0.08;95% CI: ﹣0.08 to 0.24). When compared with insulin, glyburide had an increase risk ratio (RR) for neonatal hypoglycaemia (P = 0.0002;RR: 2.27;95% CI: 1.47 to 3.51) and large for gestational age babies (P = 0.03;RR: 1.60;95% CI: 1.06 to 2.41). Estimation of standard mean difference shows that neonatal birth weight was significantly higher in subjects receiving glyburide than in the insulin group (P = 0.002;SMD: 0.21;95% CI: 0.08 to 0.35). Conclusions: Glyburide was seen to be clinically effective and a safer alternative to insulin for maternal glycaemic control in GDM women. It is affordable, convenient and requires no comprehensive educative training at the time of initiation of therapy. However, its adverse outcomes—neonatal hypogly-caemia, high neonatal birth weight and large for gestational age babies—call for careful monitoring of GDM patients for any need for supplemental insulin.

Metformin and pancreatic neuroendocrine tumors:A systematic review and meta-analysis

BACKGROUND Most patients with advanced pancreatic neuroendocrine tumors(pNETs)die due to tumor progression.Therefore,identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant.In this perspective,metformin is emerging as a molecule of interest.Retrospective studies have described metformin,a widely used agent for the treatment of patients with type 2 diabetes mellitus(T2DM),to be effective in modulating different tumor-related events,including cancer incidence,recurrence and survival by inhibiting mTOR phosphorylation.This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.AIM To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and posttreatment outcomes of pNET.METHODS A systematic review of the published literature was undertaken,focusing on the role of T2DM and metformin in insurgence and prognosis of pNET,measured through outcomes of tumor-free survival(TFS),overall survival and progression free survival.RESULTS A total of 13 studies(5674 patients)were included in this review.Analysis of 809 pNET cases from five retrospective studies(low study heterogeneity with I^(2)=0%)confirms the correlation between T2DM and insurgence of pNET(OR=2.13,95%CI=1.56-4.55;P<0.001).The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients(hazard ratio=1.84,95%CI=0.78-2.90;P<0.001).The study heterogeneity was intermediate,with I^(2)=51%.A few studies limited the possibility of performing pooled analysis in the setting of metformin;therefore,results were heterogeneous,with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.CONCLUSION T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients.Unfortunately,a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Promising use of metformin in treating neurological disorders:biomarker-guided therapies

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

Metformin alleviates spinal cord injury by inhibiting nerve cell ferroptosis through upregulation of heme oxygenase-1 expression

Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.

Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy

Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvation induced by glucose oxidase(GOx),after their efficient delivery to tumor sites,GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ.Herein,a pH-responsive epigallocatechin gallate(EGCG)-conjugated low-molecular-weight chitosan(LC-EGCG,LE)nanoparticle(Met–GOx/Fe@LE NPs)was constructed.The coordination between iron ions(Fe3+)and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction.Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability.Moreover,this pH-responsive nanoplatform presents controllable drug release behavior.An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug.The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation.This triple-combination therapy approach is promising for efficient and targeted cancer treatment.

Synergistic Effects of Glutamine Deprivation and Metformin in Acute Myeloid Leukemia

Objective The metabolic reprogramming of acute myeloid leukemia(AML)cells is a compensatory adaptation to meet energy requirements for rapid proliferation.This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells.Methods SKM-1 cells(an AML cell line)were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide(BPTES,a glutaminase inhibitor)or cytarabine.Cell viability was detected by Cell Counting Kit-8(CCK-8)assay,and cell apoptosis and reactive oxygen species(ROS)by flow cytometry.Western blotting was conducted to examine the levels of apoptotic proteins,including cleaved caspase-3 and poly(ADP-ribose)polymerase(PARP).Moreover,the human long noncoding RNA(lncRNA)microarray was used to analyze gene expression after glutamine deprivation,and results were confirmed with quantitative RT-PCR(qRT-PCR).The expression of metallothionein 2A(MT2A)was suppressed using siRNA.Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry,respectively,in cells with MT2A knockdown.Results Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells.The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation.MT2A knockdown increased apoptosis,while proliferation was not affected in SKM-1 cells.In addition,metformin inhibited cell growth and induced apoptosis in SKM-1 cells.Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine.Furthermore,the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells.Conclusion Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML.

Metformin administration in prevention of colorectal polyps in type 2 diabetes mellitus patients

BACKGROUND Colorectal polyps are frequently observed in patients with type 2 diabetes mellitus(DM),posing a significant risk for colorectal cancer.Metformin,a widely prescribed biguanidine drug for type 2 DM,has been suggested to have potential chemoprophylactic effects against various cancers.AIM To explore the correlation between colorectal polyps and metformin use in type 2 DM patients.METHODS Type 2 DM patients were categorized into polyp and non-polyp groups.Following this,all patients were categorized into the type 2 DM-metformin,type 2 DM-non-metformin,and non-type 2 DM groups.Based on the baseline colonoscopy results,we performed pairwise comparisons of the incidence of colorectal polyps among the three groups.Additionally,we analyzed the relationship between colorectal polyps and the duration of metformin use and between the size and number of polyps and metformin use.Simultaneously,we focused on the specific pathological types of polyps and analyzed their relationship with metformin use.Finally,we compared the incidence of polyps between metformin and non-metformin groups according to the interval colonoscopy results.RESULTS The rate of metformin use in patients with colorectal polyps was 0.502 times that of patients without colorectal polyps[odds ratio(OR)=0.502,95%confidence interval(CI):0.365-0.689;P<0.001].The incidence of colorectal polyps did not differ significantly between the type 2 DM-metformin and non-type 2 DM groups(P>0.05).Furthermore,the correlations between the duration of metformin use and the incidence of colorectal polyps and between the size and number of polyps and metformin use were not statistically significant(P>0.05).Metformin use did not affect the incidence of colorectal polyps during interval colonoscopy(P>0.05).CONCLUSION Metformin use and colorectal polyp incidence in type 2 DM patients showed a negative correlation,independent of the hypoglycemic effect of metformin.

Mitigating diabetes-related complications:Empowering metformin with cholecalciferol and taurine supplementation in type 2 diabetic rats

BACKGROUND Type 2 diabetes is one of the most prevalent chronic diseases worldwide,significantly impacting patients'quality of life.Current treatment options like metformin(MET)effectively counteract hyperglycemia but fail to alleviate diabetes-associated complications such as retinopathy,neuropathy,nephropathy,hepatopathy,and cardiovascular diseases.AIM To propose the supplementation of cholecalciferol(CHO)and taurine(TAU)to enhance MET efficacy in controlling diabetes while minimizing the risk of associated complications.METHODS The study involved sixty rats,including ten non-diabetic control rats and fifty experimental rats with type 2 diabetes induced by streptozotocin.The experimental rats were further subdivided into positive control and treatment subgroups.The four treatment groups were randomly allocated to a single MET treatment or MET combined with supplements either CHO,TAU,or both.RESULTS Diabetic rats exhibited elevated levels of glucose,insulin,Homeostasis Model Assessment of Insulin Resistance(HOMA-IR),glycated hemoglobin percentage,lipid markers,aspartate aminotransferase,and malondialdehyde,along with reduced levels of antioxidant enzymes(catalase and superoxide dismutase).The administration of CHO and TAU supplements alongside MET in diabetic rats led to a noticeable recovery of islet mass.The antioxidative,anti-inflammatory,and anti-apoptotic properties of the proposed combination therapy significantly ameliorated the aforementioned abnormalities.CONCLUSION The supplementation of CHO and TAU with MET showed the potential to significantly improve metabolic parameters and protect against diabetic complications through its antioxidative,anti-inflammatory,and antiapoptotic effects.

The anti-neoplastic effects of metformin modulate the acquired phenotype of fbroblast cells in the breast cancer-normal fbroblast co-culture system

Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation,growth,and therapy resitance.The hallmarks of cancer fibroblast interactions,consisting of caveolin 1(Cav1)and mono-carboxylate ransporter 4(MCT4)(metabolic coupling markers),along with IL-6,TGFB,and lactate secretion,are considered robust biomarkers predicting recurrence and metastasis.In order to promote a novel phenotype in normal fibroblasts,we predicted that breast cancer cells could be able to cause loss of Cavl and increase of MCT4,as well as elevate IL 6 and TGF in nearby nomal fibroblasts.We created a co culture model using breast cancer(4T1)and normal fibroblast(NIH3T3)cell lines cultured under specific experimental conditions in order to directly test our theory.Moreover,we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cavl and gain of MCT4 in adjacent fibroblasts and increase lactate secretion.These results were validated using the monoculture of each group separately as a control.In this system,we show that me tformin inhibits IL-6 and TGFB secretion and re expresses Cavl in both cells.However,MCT4 and lactate stayed high after treatment with metformin.In conclusion,our work shows that co-culture with breast cancer cells may cause signifcant alterations in the phenotype and secretion of normal fibroblasts.Metformin,however,may change this state and affect fibroblasts'acquired phenotypes.Moreover,mitochondrial inhibition by metformin after 8 days of treatment,signi ficantly hinders tumor growth in mouse model of breast cancer.

Metformin:A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.However,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive relationship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met’s anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early-stage endometrial adenocarcinoma: a prospective study

Objective To evaluate the efficacy of medroxyprogesterone acetate(MA)plus metformin as the primary fertility-sparing treatment for atypical endometrial hyperplasia(AEH)and early-stage grade 1 endometrial adenocarcinoma(G1 EAC)and the recurrence rate after treatment.Methods Sixty patients(aged 20-42 years)with AEH and/or grade 1 EAC limited to the endometrium were enrolled prospectively and randomized into two groups(n=30)to receive oral MA treatment at the daily dose of 160 mg(control)or MA plus oral metformin(850 mg,twice a day)for at least 6 months.The treatment could extend to 12 months until a complete response(CR)was achieved,and follow-up hysteroscopy and curettage were performed every 3 months.For all the patients who achieved CR,endometrial expressions of IGFBP-rP1,p-Akt and p-AMPK were detected immunohistochemically.Results A total of 58 patients completed the treatment.After 9 months of treatment,23(76.7%)patients in the combined treatment group and 20(71.4%)in the control group achieved CR;two patients in the control group achieved CR after converting to the combined treatment.The recurrence rate did not differ significantly between the control group and combined treatment group(30.0%vs 22.7%,P>0.05).Ten(35.7%)patients in the control group experienced significant weight gain of 5.7±6.1 kg,while none of the patients receiving the combined treatment exhibited significant body weight changes.Compared with the control group,the patients receiving the combined treatment showed enhanced endometrial expressions of IGFBP-rP1 and p-AMPK with lowered p-Akt expression.Conclusion Metformin combined with MA may provide an effective option for fertility-sparing treatment of AEH and grade 1 stage IA EAC,and the clinical benefits of metformin for controlling MA-induced weight gain and promoting endometrial expressions of IGFBP-rP1 and p-AMPK while inhibiting p-Akt expression warrants further study.

Metformin promotes anti-tumor immunity in STK11 mutant NSCLC through AXIN1-dependent upregulation of multiple nucleotide metabolites

Background:Metformin has pleiotropic effects beyond glucose reduction,including tumor inhibition and immune regulation.It enhanced the anti-tumor effects of programmed cell death protein 1(PD-1)inhibitors in serine/threonine kinase 11(STK11)mutant non-small cell lung cancer(NSCLC)through an axis inhibition protein 1(AXIN1)-dependent manner.However,the alterations of tumor metabolism and metabolites upon metformin administration remain unclear.Methods:We performed untargeted metabolomics using liquid chromatography(LC)-mass spectrometry(MS)/MS system and conducted cell experiments to verify the results of bioinformatics analysis.Results:According to the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway database,most metabolites were annotated into metabolism,including nucleotide metabolism.Next,the differentially expressed metabolites in H460(refers to H460 cells),H460_met(refers to metformin-treated H460 cells),and H460_KO_met(refers to metformin-treated Axin1-/-H460 cells)were distributed into six clusters based on expression patterns.The clusters with a reversed expression pattern upon metformin treatment were selected for further analysis.We screened out metabolic pathways through KEGG pathway enrichment analysis and found that multiple nucleotide metabolites enriched in this pathway were upregulated.Furthermore,these metabolites enhanced the cytotoxicity of activated T cells on H460 cells in vitro and can activate the stimulator of the interferon genes(STING)pathway independently of AXIN1.Conclusion:Relying on AXIN1,metformin upregulated multiple nucleotide metabolites which promoted STING signaling and the killing of activated T cells in STK11 mutant NSCLC,indicating a potential immunotherapeutic strategy for STK11 mutant NSCLC.

Statin, aspirin and metformin use and risk of hepatocellular carcinoma related outcomes following liver transplantation: A retrospective study

BACKGROUND Liver transplantation(LT)is a potentially curative therapy for patients with hepatocellular carcinoma(HCC).HCC-recurrence following LT is associated with reduced survival.There is increasing interest in chemoprophylaxis to improve HCC-related outcomes post-LT.AIM To investigate whether there is any benefit for the use of drugs with proposed chemoprophylactic properties against HCC,and patient outcomes following LT.METHODS This was a retrospective study of adult patients who received Deceased Donor LT for HCC from 2005-2022,from a single Australian centre.Drug use was defined as statin,aspirin or metformin therapy for≥29 days,within 24 months post-LT.A cox proportional-hazards model with time-dependent covariates was used for survival analysis.Outcome measures were the composite-endpoint of HCC-recurrence and all-cause mortality,HCC-recurrence and HCC-related mortality.Sensitivity analysis was performed to account for immortality time bias and statin dosing.RESULTS Three hundred and five patients were included in this study,with 253(82.95%)males with a median age of 58.90 years.Aetiologies of liver disease were 150(49.18%)hepatitis C,73(23.93%)hepatitis B(HBV)and 33(10.82%)non-alcoholic fatty liver disease(NAFLD).56(18.36%)took statins,51(16.72%)aspirin and 50(16.39%)metformin.During a median follow-up time of 59.90 months,34(11.15%)developed HCC-recurrence,48(15.74%)died,17(5.57%)from HCC-related mortality.Statin,aspirin or metformin use was not associated with statistically significant differences in the composite endpoint of HCC-recurrence or all-cause mortality[hazard ratio(HR):1.16,95%CI:0.58-2.30;HR:1.21,95%CI:0.28-5.27;HR:0.61,95%CI:0.27-1.36],HCC-recurrence(HR:0.52,95%CI:0.20-1.35;HR:0.51,95%CI:0.14-1.93;HR 1.00,95%CI:0.37-2.72),or HCC-related mortality(HR:0.32,95%CI:0.033-3.09;HR:0.71,95%CI:0.14-3.73;HR:1.57,95%CI:0.61-4.04)respectively.Statin dosing was not associated with statist-ically significant differences in HCC-related outcomes.CONCLUSION Statin,metformin or aspirin use was not associated with improved HCC-related outcomes post-LT,in a largely historical cohort of Australian patients with a low proportion of NAFLD.Further prospective,multicentre studies are required to clarify any potential benefit of these drugs to improve HCC-related outcomes.

Exploring the anti-osteoporotic potential of simvastatin and metformin: a comprehensive Mendelian randomization and animal experiment investigation

Background:Both simvastatin and metformin have demonstrated potential efficacy in osteoporosis(OP)treatment.However,there is a lack of systematic studies comparing their anti-osteoporotic effects.This study aims to compare the effects of simvastatin and metformin on OP through Mendelian randomization(MR)studies and animal experiments.Methods:Initially,we will analyze the causal impact of simvastatin or metformin treatment on OP prevalence and three common clinical OP diagnostic markers(bone mineral density(BMD),serum osteocalcin(OCN),and tartrate-resistant acid phosphatase(TRAP)levels)using genome-wide association study(GWAS)summary statistics.Additionally,we established animal models to further analyze and compare the anti-osteoporosis effects of simvastatin and metformin.8 male C57BL/6J mice(3-month-old)and 24 male C57BL/6J mice(18-month-old)were treated with simvastatin or metformin for 12 weeks.OP pathology was assessed using histology,immunohistochemistry,biomechanical tests,micro-computed tomography,and osteogenic differentiation assays.Results:In the MR analysis,metformin treatment was significantly associated with lower OP prevalence(OR(95%CI)=0.933(0.902–0.965),β=-0.0694,P<0.001)and higher BMD(OR(95%CI)=3.719(1.750–7.908),β=1.3136,P<0.001).In the animal experiment,both drugs increased bone mass,improved bone microstructure,and promoted osteoblast differentiation.However,metformin appeared more effective in several aspects.It significantly inhibited bone marrow adipocyte and osteoclast differentiation in aged mice compared to simvastatin.Additionally,metformin better promoted the expression of osteoprotegerin(OPG)and collagen type I(Col-I)in bone tissue and maintained the structure and biomechanical properties of cancellous bone.Conclusion:Both drugs significantly preserved bone homeostasis.Particularly,compared with simvastatin,metformin exhibited superior effects in inhibiting adipogenesis,enhancing the OPG/RANKL pathway,and promoting cancellous bone reconstruction.Metformin may serve as a valuable adjunct in preventing and treating OP in the elderly.

二甲双胍通过NLRP3炎症小体通路对皮肤角质形成细胞增殖和凋亡的双向调节研究

背景扁平苔藓是一种皮肤-黏膜慢性炎症性疾病。因其病因不明,许多患者治疗效果欠佳,严重影响生活质量,有必要深入研究扁平苔藓的发病机制,为其药物筛选提供新靶点。目的探讨二甲双胍通过NLRP3炎症小体通路对皮肤角质形成细胞增殖和凋亡的调控作用。方法实验时间为2020—2023年。体外实验以人永生化角质形成细胞株HaCaT为研究对象,分为4组:对照组、脂多糖(LPS)组(5μg/mL)、二甲双胍组(Met组:10 mmol/L)、LPS与二甲双胍联合组(LPS+Met组:LPS 5μg/mL刺激2 h后,再给予二甲双胍10 mmol/L处理)。体内实验以BALB/c小鼠为研究对象,利用咪喹莫特涂抹小鼠背部皮肤诱导了银屑病样皮炎模型,并制备了二甲双胍乳膏进行治疗,将小鼠随机分为3组:对照组、咪喹莫特组(IMQ组)、咪喹莫特与二甲双胍联合组(IMQ+Met组),每组10只;对照组小鼠于背部涂抹凡士林,IMQ组小鼠于背部涂抹咪喹莫特软膏,IMQ+Met组小鼠于背部涂抹IMQ软膏12 h后再涂抹二甲双胍乳膏;1次/d,连续7 d。采用细胞增殖试剂盒(CCK-8)和流式细胞术检测二甲双胍对HaCaT细胞增殖和凋亡的影响;采用Western Blotting、酶联免疫吸附实验(ELISA)和半胱氨酸天冬氨酸蛋白酶1(Caspase-1)活性实验检测二甲双胍处理HaCaT细胞后NOD样受体蛋白3(NLRP3)炎症小体通路的蛋白表达情况及活性水平;最后采用皮肤组织切片苏木素-伊红(HE)染色和免疫组化检测二甲双胍对咪喹莫特诱导银屑病小鼠皮炎的抗炎效果。结果CCK-8实验结果显示:LPS组、Met组、LPS+Met组HaCaT细胞48 h存活率均低于对照组,而LPS+Met组HaCaT细胞48 h存活率高于LPS组(P<0.05)。流式细胞术结果显示:LPS组、Met组HaCaT细胞48 h G2/M期细胞、细胞凋亡比例均高于对照组,而LPS+Met组HaCaT细胞48 h G2/M期细胞、细胞凋亡比例低于LPS组(P<0.05)。Western Blotting结果显示:LPS组、Met组HaCaT细胞NLRP3炎症小体通路Caspase-1 p40、Caspase-1 p20、白介素(IL)-1β、IL-18蛋白表达均高于对照组,而LPS+Met组HaCaT细胞NLRP3炎症小体通路Caspase-1 p40、Caspase-1 p20、IL-1β、IL-18蛋白表达低于LPS组(P<0.05)。ELISA实验结果显示:LPS组、Met组HaCaT细胞NLRP3炎症小体通路IL-1β、IL-18水平、Caspase-1相对活性均高于对照组,而LPS+Met组HaCaT细胞NLRP3炎症小体通路IL-1β、IL-18水平、Caspase-1相对活性低于LPS组(P<0.05)。皮肤组织切片HE染色显示:IMQ+Met组小鼠二甲双胍涂抹明显改善了咪喹莫特对皮肤的损害。免疫组化结果显示:IMQ+Met组小鼠则显著降低了NLRP3、Caspase-1、IL-1β和IL-18的表达。结论二甲双胍通过NLRP3炎症小体通路双向调节皮肤角质形成细胞的增殖和凋亡,并能够改善咪喹莫特诱导的银屑病样小鼠的皮肤损害,有望为二甲双胍临床上用于治疗扁平苔藓提供理论依据。

Mechanism of Drug Release from Compound Metformin/Glipizide Elementary Osmotic Pump Tablets

In previous studies, compound mefformin/glipizide was developed. Aim To discover the mechanism of drug release from factors influencing drug release from dosage form （the semi-permeable cry orifice） were investigated. Results The influx of water that elementary osmotic pump tablet it. Methods Three rate-limiting membrane, tablet core and delivpassed the osmotic pump tablet was almost equal to the metformin release rate, while it was greatly less than the drug dissolution rate from tablet core. The size of orifice from 0. 4 mm to 0.8 mm had no influence on drug release. The osmotic pressure of tablet core was mainly caused by mefformin. Conclusion From the developed model of osmotic pump systems, it can be seen that only the water influx through the membrane is a rate-limiting step, not tablet core dissolution rate and solution influx, and only when the core dissolution rate is equal to the solution influx, the zero order release is seen in the osmotic pump systems.

Compound Metformin/Glipizide Bilayer Extended Release Tablets: Development and in Vitro Release

Aim In this study, compound metformin/glipizide bilayer extended release tablets were formulated with hydroxypropyl methylcellulose （HPMC） by wet granulation technique in order to tackle the problems associated with the muhidrug therapy of non-insulin dependent diabetes mellitus. Me^ls High-dose metformin is difficult to formulate into a tablet dosage form due to its poor compressibility and compactibility. In this study, the way to overcome the difficulty was to utilize stearic alcohol to prepare the tablet formulation. The influences of viscosity, amount of HPMC, and weight of fillers were investigated. The optimal formulation had acceptable physicochemical properties and released metformin and glipizide over 10 h. Results The data of metformin obtained from in vitro release fitted Higuchi kinetics best, while the release of glipizide in vitro was found to follow zero kinetics. Conclusion Compound metformin/glipizide bilayer extended release tablets have been successfully developed.

Development of Prolonged Release Microspheres of Metformin Hydrochloride Using Ion Exchange Resins

Aim To prepare the prolonged-released microspheres of mefformin hydrochloride. Methods Ion-exchange resin-drug mefformin hydrochloride complexes were prepared as core materials, and followed by coating using ethylcellulose （EC） by the emulsion solvent diffusion technique. The release rate of mefformin from the microcapsules was highly dependent on the encapsulating formulation, thus being used as an index for formulation screening. Orthogonal experiments were performed to optimize the coating formulation. Results The final chosen formulation for coating of mefformin microcapsules were as follows： （ 1 ） the ratio of EC （20cps） to EC （45cps） was 50：50; （2） the ratio of plasticizer to coating materials was 20% ;and （3） the ratio of resin-mefformin complexes to coating materials was 5 ： 1. Conclusion The prolonged release microspheres of mefformin hydrochloride were successfully prepared.

Autophagy-targeting modulation to promote peripheral nerve regeneration

Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

Metformin与AMPKγ亚基结合位点的探究

目的:基于前期Metformin与AMPKγ亚基结合的研究,进一步确认二者间的结合机制。方法:采用分子对接方法模拟Metformin与AMPKγ亚基潜在的结合位点,通过定点突变技术对AMPKγ亚基进行修饰,以荧光滴定法为检测方法,检测Metformin对突变前后的AMPKγ内源荧光猝灭的改变。结果:获得一系列AMPKγ亚基的突变体AMPKγM84A、T88A、D89A、R117A、K126A及I149A,比较发现Metformin与AMPKγ的解离常数KD值为(3.76±0.45)μmol/L,与突变体AMPKγT88A的KD值约为未突(36.15±6.91)μmol/L,约为变前的10倍,提示88位中的苏氨酸T可能是Metformin的结合位点之一。结论:该结果一方面阐明Metformin与AMPKγ的结合情况,另一方面也为以AMPKγ亚基为靶点的抗肿瘤药物设计提供理论指导。