Diabetes mellitus,particularly type 2 diabetes mellitus(T2DM),poses a significant global health challenge.Traditional management strategies primarily focus on glycemic control;however,there is a growing need for compr...Diabetes mellitus,particularly type 2 diabetes mellitus(T2DM),poses a significant global health challenge.Traditional management strategies primarily focus on glycemic control;however,there is a growing need for comprehensive approaches addressing the complex pathophysiology of diabetes complications.The recent study by Attia et al explores the potential of a novel therapy combining metformin with cholecalciferol(vitamin D3)and taurine to mitigate T2DM-related complications in a rat model.The findings indicate that this treatment combination improves glycemic control and reduces oxidative stress,inflammation,and lipid abnormalities.However,the study is limited by a lack of safety profile data and in-depth molecular mechanism insights.This editorial critically highlights the study's strengths and weaknesses,compares it against other combination therapy research in T2DM,and underscores the need to explore further the mechanisms underpinning the observed therapeutic effects and investigate the safety profile of this novel approach.展开更多
The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tum...The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.展开更多
In recent years,the incidence of type 2 diabetes mellitus(T2DM)caused by obesity in China has been increasing continuously,which has become a risk factor for the onset of T2DM and seriously affects the quality of life...In recent years,the incidence of type 2 diabetes mellitus(T2DM)caused by obesity in China has been increasing continuously,which has become a risk factor for the onset of T2DM and seriously affects the quality of life of patients.The conventional treatment methods include weight loss and regulating the body’s metabolism.Semaglutide,as a glucagon-like peptide-1 receptor agonist(GLP-1RA),mainly reduces patients’appetite,decreases their craving for high-fat and high-sugar foods,regulates hypothalamic feeding behavior,inhibits gastric emptying and gastrointestinal motility,and ultimately leads to weight loss.Metformin mainly acts on extra-islet tissues,increasing glucose utilization,reducing glucose production,and ultimately lowering blood glucose levels.Based on this,this article reviews relevant literature on authoritative websites such as CNKI and Wanfang,organizes the data,and analyzes the research progress of semaglutide combined with metformin in the treatment of obese T2DM.The aim is to bring more treatment options for obese T2DM and promote better prognosis for patients.展开更多
Background:Polycystic ovary syndrome(PCOS)is one of the most common reproductive endocrine metabolic diseases.Combined use of metformin and diane-35 has better curative effect in regulating serum hormone level(LH,FSH,...Background:Polycystic ovary syndrome(PCOS)is one of the most common reproductive endocrine metabolic diseases.Combined use of metformin and diane-35 has better curative effect in regulating serum hormone level(LH,FSH,T and E2)than using metformin alone.Traditional Chinese medicine(TCM)can also be used to treat PCOS.According to some studies,the combined use of metformin and diane-35 and TCM have achieved better curative effect than combining metformin and diane-35 in the treatment of patients with PCOS.Methods:Computerized searches of the science,Medline,VIP,Wan Fang and China HowNet(CNKI)databases were conducted to identify eligible randomized controlled trials(RCTs)from the data obtained up to March 1,2022.The Cochrane Collaboration risk of bias tool was used to assess the risk of bias in individual RCTs,and R software(version 4.0.3)was used for data statistical analysis.Results:Nine RCTs involving 1035 patients were included.Comparing to D+M,significant reduce of LH(mean difference[MD]:-1.93,95%confidence interval[CI]:-3.44,-0.42;Unit:U/L P<0.01;I2=89%)、T(MD:-1.44,95%CI-2.59,-0.30;Unit:nmol/L P<0.01;I2=98%)and significant increase of E2(MD:31.43,95%CI 24.54,38.33;Unit:pmol/L P<0.01;I2=96%)were shown in TCM+D+M.Comparing to D+M,TCM+D+M group has higher ovulation rate(RR 1.1495%CI 1.07,1.22;P=0.42;I2=0%)and higher pregnancy rate(RR 1.2995%CI 1.15,1.44;P=0.37;I2=7%).There is no significant difference between the two therapies in FSH changes(MD:-1.00,95%CI-2.27,0.28;Unit:U/L P<0.01;I2=95%).Subgroup analysis showed that compared with the Guizhi Fuling capsule group,the Kuntai capsule group had more FSH reduction and E2 increase more.In other outcome indicators,the two subgroup did not show significant differences.Conclusion:Kuntai Capsule+Diane-35+Metformin is better than Guizhi Fuling Capsule in reducing FSH,and it is also better in increasing E2.There was no significant difference between the two in LH and T hormones.There was no significant difference between Kuntai Capsules+Diane-35+Metformin and Guizhi Fuling Capsules+Diane-35+Metformin.As for the effect in lessen insulin resistance,Kuntai Capsule+Diane-35+Metformin was significantly better than Guizhi Fuling Capsules+Diane-35+Metformin.展开更多
Diabetes mellitus is a substantial global health threat due to its high prevalence and its serious complications.The hyperglycemic state causes damage to vascular endothelial cells and disturbance of lipid metabolism,...Diabetes mellitus is a substantial global health threat due to its high prevalence and its serious complications.The hyperglycemic state causes damage to vascular endothelial cells and disturbance of lipid metabolism,thus contributing to the development of vascular disorders,especially atherosclerotic diseases.Aggressive glycemic control combined with vascular intervention is critical to the prevention and treatment of diabetes-associated atherosclerosis.It is suggested that metformin should be combined with hypoglycemic agents with proven vascular benefits for treating type 2 diabetes(T2DM)complicated with atherosclerotic diseases.Clinical studies indicates that the preferred combination is metformin with either glucagon-like peptide-1 receptor agonist or sodium/glucose cotransporter-2 inhibitor,which could offer additional vascular benefits and reduce the risk of atherosclerotic complications.Likewise,combination therapy with metformin and hypolipidemic agents has also shown additive effects on glucose control and lipid-lowering in patients with both diabetes and dyslipidemia,whereas extensive clinical trials using atherosclerotic-associated outcomes are required to support the vascular benefits.Moreover,co-administration of metformin with systemic antioxidant or anti-inflammatory therapy may also provide additional vascular benefits as indicated by several animal studies.For instance,a recent study found that additional supplementation of cholecalciferol and taurine enhanced metformin efficacy in controlling diabetes while reducing the risk of associated atherosclerotic complications.However,these potential benefits remain need validation by the evidence from clinical studies.Despite the limitations,such as heterogeneity across different patient populations,and deficiency in long-term outcomes,such efforts can contribute to finding optimal drug combinations to improve the management of T2DM and reduce its atherosclerotic complications.展开更多
The rapidly aging population directly contributes to the increasing cases of neurological disorders.Due to the chronic progressive nature of neurodegeneration,numerous neurological conditions are considered“multifact...The rapidly aging population directly contributes to the increasing cases of neurological disorders.Due to the chronic progressive nature of neurodegeneration,numerous neurological conditions are considered“multifactorial”with systemic metabolic alterations.Even so,treatments for neurological disorders have remained unchanged for the past decades.Recently,metabolic drugs such as metformin and glucagon-like peptide 1 agonists have demonstrated promising health outcomes for neurodegeneration.展开更多
Metformin-induced vitamin B12 deficiency is a prevalent condition among pa-tients with type 2 diabetes mellitus.In recent years,a growing body of evidence has demonstrated the association between vitamin B12 deficienc...Metformin-induced vitamin B12 deficiency is a prevalent condition among pa-tients with type 2 diabetes mellitus.In recent years,a growing body of evidence has demonstrated the association between vitamin B12 deficiency and the onset,progression,and worsening of diabetic neuropathy(DNP)as well as its im-provement with supplementation in cases of deficiency.Major clinical guidelines for diabetes and DNP remain vague in their recommendations for B12 measu-rement and supplementation,and some guidelines do not address it at all.Given that vitamin B12 therapy is an economical,safe,and widely available treatment in most countries and supported by emerging evidence of its potential benefits,greater efforts should be made to promote systematic screening for vitamin B12 deficiency in all patients with DNP before establishing a definitive diagnosis as well as in patients with diabetes with risk factors for deficiency.Vitamin B12 deficiency should be treated in all affected patients,and supplementation should be considered in those with borderline levels when confirmatory diagnostic tests for deficiency are unavailable.Clinical guidelines should place greater emphasis on the recommendations for measuring and supplementing vitamin B12 in these patients.展开更多
Dengue is an arboviral disease caused by the dengue virus,with 390 million infections reported annually worldwide.It is classified into two categories:dengue without or with warning signs and severe dengue.[1]Given th...Dengue is an arboviral disease caused by the dengue virus,with 390 million infections reported annually worldwide.It is classified into two categories:dengue without or with warning signs and severe dengue.[1]Given the moderate efficacy of the dengue vaccine,[2]there is an urgent necessity to design host-directed therapeutic strategies,such as the repurposing of FDA-approved drugs,to combat dengue virus infection.展开更多
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 esta...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.展开更多
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...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.展开更多
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 exert...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.展开更多
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...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.展开更多
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),cerebr...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.展开更多
Metformin is a commonly prescribed drug used to treat type 2 diabetes. The drug works by decreasing the amount of glucose the liver produces, increasing the sensitivity of muscle cells to insulin, and delaying the abs...Metformin is a commonly prescribed drug used to treat type 2 diabetes. The drug works by decreasing the amount of glucose the liver produces, increasing the sensitivity of muscle cells to insulin, and delaying the absorption of glucose in the intestines. Approximately 50% - 55% of metformin is absorbed in the small intestines. Most of the drug is excreted in the urine, so a patient with renal impairment may need a lower dose of the drug. Common side effects include nausea, vomiting, and diarrhea. Metformin may increase the risk of vitamin B12 deficiency. A rare but serious complication of metformin treatment is lactic acidosis, which is characterized by a blood pH of less than 7.35 and a plasma lactate concentration of greater than 5.0 mmol/L. The risk of lactic acidosis increases with the dose of metformin. The current recommended maximum dose of metformin is 2.0 g per day.展开更多
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 starvatio...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.展开更多
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 glutami...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.展开更多
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 ...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.展开更多
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 c...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.展开更多
文摘Diabetes mellitus,particularly type 2 diabetes mellitus(T2DM),poses a significant global health challenge.Traditional management strategies primarily focus on glycemic control;however,there is a growing need for comprehensive approaches addressing the complex pathophysiology of diabetes complications.The recent study by Attia et al explores the potential of a novel therapy combining metformin with cholecalciferol(vitamin D3)and taurine to mitigate T2DM-related complications in a rat model.The findings indicate that this treatment combination improves glycemic control and reduces oxidative stress,inflammation,and lipid abnormalities.However,the study is limited by a lack of safety profile data and in-depth molecular mechanism insights.This editorial critically highlights the study's strengths and weaknesses,compares it against other combination therapy research in T2DM,and underscores the need to explore further the mechanisms underpinning the observed therapeutic effects and investigate the safety profile of this novel approach.
文摘The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.
文摘In recent years,the incidence of type 2 diabetes mellitus(T2DM)caused by obesity in China has been increasing continuously,which has become a risk factor for the onset of T2DM and seriously affects the quality of life of patients.The conventional treatment methods include weight loss and regulating the body’s metabolism.Semaglutide,as a glucagon-like peptide-1 receptor agonist(GLP-1RA),mainly reduces patients’appetite,decreases their craving for high-fat and high-sugar foods,regulates hypothalamic feeding behavior,inhibits gastric emptying and gastrointestinal motility,and ultimately leads to weight loss.Metformin mainly acts on extra-islet tissues,increasing glucose utilization,reducing glucose production,and ultimately lowering blood glucose levels.Based on this,this article reviews relevant literature on authoritative websites such as CNKI and Wanfang,organizes the data,and analyzes the research progress of semaglutide combined with metformin in the treatment of obese T2DM.The aim is to bring more treatment options for obese T2DM and promote better prognosis for patients.
文摘Background:Polycystic ovary syndrome(PCOS)is one of the most common reproductive endocrine metabolic diseases.Combined use of metformin and diane-35 has better curative effect in regulating serum hormone level(LH,FSH,T and E2)than using metformin alone.Traditional Chinese medicine(TCM)can also be used to treat PCOS.According to some studies,the combined use of metformin and diane-35 and TCM have achieved better curative effect than combining metformin and diane-35 in the treatment of patients with PCOS.Methods:Computerized searches of the science,Medline,VIP,Wan Fang and China HowNet(CNKI)databases were conducted to identify eligible randomized controlled trials(RCTs)from the data obtained up to March 1,2022.The Cochrane Collaboration risk of bias tool was used to assess the risk of bias in individual RCTs,and R software(version 4.0.3)was used for data statistical analysis.Results:Nine RCTs involving 1035 patients were included.Comparing to D+M,significant reduce of LH(mean difference[MD]:-1.93,95%confidence interval[CI]:-3.44,-0.42;Unit:U/L P<0.01;I2=89%)、T(MD:-1.44,95%CI-2.59,-0.30;Unit:nmol/L P<0.01;I2=98%)and significant increase of E2(MD:31.43,95%CI 24.54,38.33;Unit:pmol/L P<0.01;I2=96%)were shown in TCM+D+M.Comparing to D+M,TCM+D+M group has higher ovulation rate(RR 1.1495%CI 1.07,1.22;P=0.42;I2=0%)and higher pregnancy rate(RR 1.2995%CI 1.15,1.44;P=0.37;I2=7%).There is no significant difference between the two therapies in FSH changes(MD:-1.00,95%CI-2.27,0.28;Unit:U/L P<0.01;I2=95%).Subgroup analysis showed that compared with the Guizhi Fuling capsule group,the Kuntai capsule group had more FSH reduction and E2 increase more.In other outcome indicators,the two subgroup did not show significant differences.Conclusion:Kuntai Capsule+Diane-35+Metformin is better than Guizhi Fuling Capsule in reducing FSH,and it is also better in increasing E2.There was no significant difference between the two in LH and T hormones.There was no significant difference between Kuntai Capsules+Diane-35+Metformin and Guizhi Fuling Capsules+Diane-35+Metformin.As for the effect in lessen insulin resistance,Kuntai Capsule+Diane-35+Metformin was significantly better than Guizhi Fuling Capsules+Diane-35+Metformin.
基金Supported by the Natural Science Research Project of Anhui Province,No.2023AH053172National Natural Science Foundation of Anhui Province,No.2408085QH260+1 种基金Projects of Administration of Traditional Chinese Medicine of Anhui Province,No.2024CCCX082National Natural Science Foundation Incubation Program of The Second Hospital of Anhui Medical University,No.2022GMFY08.
文摘Diabetes mellitus is a substantial global health threat due to its high prevalence and its serious complications.The hyperglycemic state causes damage to vascular endothelial cells and disturbance of lipid metabolism,thus contributing to the development of vascular disorders,especially atherosclerotic diseases.Aggressive glycemic control combined with vascular intervention is critical to the prevention and treatment of diabetes-associated atherosclerosis.It is suggested that metformin should be combined with hypoglycemic agents with proven vascular benefits for treating type 2 diabetes(T2DM)complicated with atherosclerotic diseases.Clinical studies indicates that the preferred combination is metformin with either glucagon-like peptide-1 receptor agonist or sodium/glucose cotransporter-2 inhibitor,which could offer additional vascular benefits and reduce the risk of atherosclerotic complications.Likewise,combination therapy with metformin and hypolipidemic agents has also shown additive effects on glucose control and lipid-lowering in patients with both diabetes and dyslipidemia,whereas extensive clinical trials using atherosclerotic-associated outcomes are required to support the vascular benefits.Moreover,co-administration of metformin with systemic antioxidant or anti-inflammatory therapy may also provide additional vascular benefits as indicated by several animal studies.For instance,a recent study found that additional supplementation of cholecalciferol and taurine enhanced metformin efficacy in controlling diabetes while reducing the risk of associated atherosclerotic complications.However,these potential benefits remain need validation by the evidence from clinical studies.Despite the limitations,such as heterogeneity across different patient populations,and deficiency in long-term outcomes,such efforts can contribute to finding optimal drug combinations to improve the management of T2DM and reduce its atherosclerotic complications.
文摘The rapidly aging population directly contributes to the increasing cases of neurological disorders.Due to the chronic progressive nature of neurodegeneration,numerous neurological conditions are considered“multifactorial”with systemic metabolic alterations.Even so,treatments for neurological disorders have remained unchanged for the past decades.Recently,metabolic drugs such as metformin and glucagon-like peptide 1 agonists have demonstrated promising health outcomes for neurodegeneration.
文摘Metformin-induced vitamin B12 deficiency is a prevalent condition among pa-tients with type 2 diabetes mellitus.In recent years,a growing body of evidence has demonstrated the association between vitamin B12 deficiency and the onset,progression,and worsening of diabetic neuropathy(DNP)as well as its im-provement with supplementation in cases of deficiency.Major clinical guidelines for diabetes and DNP remain vague in their recommendations for B12 measu-rement and supplementation,and some guidelines do not address it at all.Given that vitamin B12 therapy is an economical,safe,and widely available treatment in most countries and supported by emerging evidence of its potential benefits,greater efforts should be made to promote systematic screening for vitamin B12 deficiency in all patients with DNP before establishing a definitive diagnosis as well as in patients with diabetes with risk factors for deficiency.Vitamin B12 deficiency should be treated in all affected patients,and supplementation should be considered in those with borderline levels when confirmatory diagnostic tests for deficiency are unavailable.Clinical guidelines should place greater emphasis on the recommendations for measuring and supplementing vitamin B12 in these patients.
基金funded by grants Pronaii 302979A1-S-9005 CONACyT (México) from RMDA。
文摘Dengue is an arboviral disease caused by the dengue virus,with 390 million infections reported annually worldwide.It is classified into two categories:dengue without or with warning signs and severe dengue.[1]Given the moderate efficacy of the dengue vaccine,[2]there is an urgent necessity to design host-directed therapeutic strategies,such as the repurposing of FDA-approved drugs,to combat dengue virus infection.
文摘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.
文摘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.
基金supported by the National Natural Science Foundation of China(Grant Nos.:81973377,81903689,82073906 and 82273987)the Key Natural Science Foundation of Jiangsu Higher Education Institutions of China(Grant Nos.:19KJB350006 and 19KJA460008)+1 种基金Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),the initializing Fund of Xuzhou Medical University(Grant No.:D2018011)Postgraduate Research Practice Innovation Program of Jiangsu Province(Grant Nos.:KYCX21-2733 and KYCX22-2966).
文摘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.
文摘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.
文摘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.
文摘Metformin is a commonly prescribed drug used to treat type 2 diabetes. The drug works by decreasing the amount of glucose the liver produces, increasing the sensitivity of muscle cells to insulin, and delaying the absorption of glucose in the intestines. Approximately 50% - 55% of metformin is absorbed in the small intestines. Most of the drug is excreted in the urine, so a patient with renal impairment may need a lower dose of the drug. Common side effects include nausea, vomiting, and diarrhea. Metformin may increase the risk of vitamin B12 deficiency. A rare but serious complication of metformin treatment is lactic acidosis, which is characterized by a blood pH of less than 7.35 and a plasma lactate concentration of greater than 5.0 mmol/L. The risk of lactic acidosis increases with the dose of metformin. The current recommended maximum dose of metformin is 2.0 g per day.
基金the National Natural Science Foundation of China(Grant Nos.:82102767 and 82002655)the 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project,West China Hospital,Sichuan University,China(Grant No.:2020HXFH036)+2 种基金the Knowledge Innovation Program of the Chinese Academy of Sciences,China(Grant No.:JH2022007)the Cultivation Project of Basic Medical College of Xinxiang Medical University,China(Grant No.:JCYXYKY202112)the Key Project of Science and Technology of Henan Province,China(Grant No.:222102310260).
文摘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.
基金supported by the National Natural Science Foundation of China(No.82270177).
文摘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.
基金The International Institute of Population Health,Peking University Health Science Center,No.JKCJ202102The National Key Clinical Specialty Construction Projects,No.2199000764。
文摘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.
基金the National Institute for Medical Research Development(NIMADGrant No.995813).
文摘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.
