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1.
Eur Rev Med Pharmacol Sci ; 26(10): 3506-3513, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35647831

RESUMO

OBJECTIVE: Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). In this regard, the present study examined the potential effects of aerobic exercise on interleukin-6 (IL6), tumor necrosis factor (TNF), and C-reactive protein (CRP) in PCOS women. PATIENTS AND METHODS: This was a randomized clinical trial that included 40 females aged 25-35 years diagnosed with PCOS. The participants were divided into two groups equal in number: the aerobic exercise group (AEM), and the metformin group (M). The AEM group performed aerobic exercise three times a week for 12 weeks in addition to metformin treatment. The M group received metformin only. Participants were assessed for IL-6, TNF-α, and CRP at baseline and after 12 weeks of intervention. RESULTS: The findings showed a significant reduction in IL-6, TNF-α, and CRP values in both AEM and M groups (p=0.001, p=0.01, respectively) after the end of the 12 weeks of the intervention. However, the participants who received aerobic exercise plus metformin, group AEM, showed a greater reduction in IL-6, TNF-α, and CRP (p=0.01, p = 0.01 and p=0.001, respectively). CONCLUSIONS: Aerobic exercise is effective in lowering IL-6, TNF-α, and CRP in polycystic ovarian women. Further clinical trials are recommended to assess the potential effects of aerobic exercise on PCOS-associated risk factors.


Assuntos
Exercício Físico , Metformina , Síndrome do Ovário Policístico , Biomarcadores , Proteína C-Reativa/análise , Feminino , Humanos , Inflamação/tratamento farmacológico , Interleucina-6/metabolismo , Metformina/uso terapêutico , Síndrome do Ovário Policístico/terapia , Fator de Necrose Tumoral alfa/metabolismo
2.
Int J Clin Pract ; 2022: 9592969, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685604

RESUMO

Background: Previous observational studies and meta-analysis suggested a possible association between metformin use and reduced mortality in women with ovarian cancer (OC). However, clinical factors that may influence the relationship remain poorly evaluated. We performed an updated meta-analysis to systematically evaluate the above association and to observe the potential influences of study characteristics on the association. Methods: Relevant studies reporting the association between metformin use and mortality in women with OC in the multivariate adjusted model were identified by search of electronic databases that included PubMed, Embase, and Web of Science. The random-effects model was adopted to combine the results. Results: Nine studies including 10030 women with OC were included. Overall, metformin use was independently associated with reduced overall mortality (hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.55-0.93, P=0.01; I 2 = 62%). Consistent results were observed for studies comparing metformin users with nondiabetic women and studies comparing metformin users with diabetic women who did not use metformin (P for subgroup analysis = 0.70). Further subgroup analyses showed consistent results in studies with metformin use before or after the diagnosis of OC, with or without adjustment of body mass index (BMI) and with or without adjustment of concurrent medications (P for subgroup analyses all >0.10). Conclusion: Metformin use is associated with reduced mortality in women with OC, which may be independent of the diabetic status of the controls, timing of metformin use, or adjustment of BMI and concurrent medications. Clinical trials are needed to validate the potential benefits of metformin on survival of OC.


Assuntos
Diabetes Mellitus , Metformina , Neoplasias Ovarianas , Índice de Massa Corporal , Feminino , Humanos , Metformina/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Modelos de Riscos Proporcionais
3.
Int J Mol Sci ; 23(11)2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35682612

RESUMO

Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/ß-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/ß-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.


Assuntos
Enteropatias , Metformina , Animais , Proliferação de Células , Células Caliciformes/metabolismo , Enteropatias/metabolismo , Mucosa Intestinal/metabolismo , Intestinos , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , beta Catenina/metabolismo
4.
Int J Mol Sci ; 23(11)2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35682666

RESUMO

Metformin is still being investigated due to its potential use as a therapeutic agent for managing overweight or obesity. However, the underlying mechanisms are not fully understood. Inhibiting the adipogenesis of adipocyte precursors may be a new therapeutic opportunity for obesity treatments. It is still not fully elucidated whether adipogenesis is also involved in the weight loss mechanisms by metformin. We therefore used adipose-derived stem cells (ADSCs) from inguinal and epididymal fat pads to investigate the effects and mechanisms of metformin on adipogenesis in vitro. Our results demonstrate the similar effect of metformin inhibition on lipid accumulation, lipid droplets fusion, and growth in adipose-derived stem cells from epididymal fat pads (Epi-ADSCs) and adipose-derived stem cells from inguinal fat pads (Ing-ADSCs) cultures. We identified that cell death-inducing DFFA-like effector c (Cidec), Perilipin1, and ras-related protein 8a (Rab8a) expression increased ADSCs differentiation. In addition, we found that metformin inhibits lipid droplets fusion and growth by decreasing the expression of Cidec, Perilipin1, and Rab8a. Activation of AMPK pathway signaling in part involves metformin inhibition on Cidec, Perilipin1, and Rab8a expression. Collectively, our study reveals that metformin inhibits lipid storage, fusion, and growth of lipid droplets via reduction in Cidec and its regulatory factors in ADSCs cultures. Our study supports the development of clinical trials on metformin-based therapy for patients with overweight and obesity.


Assuntos
Gotículas Lipídicas , Metformina , Adipócitos/metabolismo , Adipogenia , Tecido Adiposo/metabolismo , Animais , Humanos , Gotículas Lipídicas/metabolismo , Lipídeos , Metformina/metabolismo , Metformina/farmacologia , Obesidade/metabolismo , Sobrepeso/metabolismo , Proteínas/metabolismo , Ratos , Células-Tronco/metabolismo
5.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682699

RESUMO

Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (Ito). In vitro, incubation with metformin for 24 h also reduced Ito, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced IhERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of Ito and IhERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration.


Assuntos
Diabetes Mellitus Tipo 2 , Células-Tronco Pluripotentes Induzidas , Metformina , Potenciais de Ação , Animais , Arritmias Cardíacas/tratamento farmacológico , Células HEK293 , Humanos , Metformina/farmacologia , Miócitos Cardíacos , Potássio/farmacologia , Ratos
6.
Pathol Res Pract ; 235: 153951, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35644046

RESUMO

Endometriosis is a common gynecological hurting disorder in which tissue is similar to the tissue that normally lines the inner layer of the uterus. It often causes fertility problems. Unfortunately, effective treatments are limited. Therefore it's important to explore an imperative and easily accessible treatment to alleviate the probable pathologies and preserve fertility in endometriosis. Consequently, we aimed to investigate the effects of metformin, letrozole, and atorvastatin on inflammation and apoptosis in experimentally induced ovarian and peritoneal endometriosis in rat models. In the present study, 35 rats were randomly divided into five groups. Group 1: sham-operated control group. Group 2: untreated endometriosis group. Group 3: given 100 mg/kg/day of oral metformin. Group 4: given 0.1 mg/kg/day of oral letrozole. Group 5: given 2.5 mg/kg/day of oral atorvastatin. At the end of the 28 days, we examined Ki67, Bax and Bcl-2 immunoexpressions in ovarian and peritoneal tissues, and IL-6, IL-8, and TNF-α levels were evaluated from the peritoneal fluid. All medical treatment groups showed a significant decrease in Ki67 expression. A significant increase in Bax expression was also observed in all samples from all medical treatment groups (other than the untreated endometriosis groups). Further, a significant decrease in Bcl-2 expression was found in all medical treatment groups. IL-6, IL-8, and TNF-α levels were significantly lower in all medical treatment groups than in the endometriosis groups. In conclusion; Metformin, letrozole, and atorvastatin showed apoptosis induction and anti-inflammatory effects on both ovarian and peritoneal endometriosis in experimental models.


Assuntos
Endometriose , Metformina , Animais , Apoptose , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Endometriose/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Interleucina-6 , Interleucina-8 , Antígeno Ki-67 , Letrozol , Metformina/farmacologia , Metformina/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2
7.
Sci Rep ; 12(1): 9713, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35690654

RESUMO

Metformin is a well-tolerated antidiabetic drug and has recently been repurposed for numerous diseases, including pain. However, a higher dose of metformin is required for effective analgesia, which can potentiate its dose-dependent gastrointestinal side effects. Curcumin is a natural polyphenol and has beneficial therapeutic effects on pain. Curcumin has been used as an analgesic adjuvant with several analgesic drugs, allowing synergistic antinociceptive effects. Nevertheless, whether curcumin can exert synergistic analgesia with metformin is still unknown. In the present study, the nature of curcumin-metformin anti-inflammatory interaction was evaluated in in vitro using lipopolysaccharide-induced RAW 264.7 macrophage and BV-2 microglia cells. In both macrophage and microglia, curcumin effectively potentiates the anti-inflammatory effects of metformin, indicating potential synergistic effects in both peripheral and central pathways of pain. The nature of the interaction between curcumin and metformin was further recapitulated using a mouse model of formalin-induced pain. Coadministration of curcumin and metformin at a 1:1 fixed ratio of their ED50 doses significantly reduced the dose required to produce a 50% effect compared to the theoretically required dose in phase II of the formalin test with a combination index value of 0.24. Besides, the synergistic interaction does not appear to involve severe CNS side effects indicated by no motor alterations, no alterations in short-term and long-term locomotive behaviors, and the general well-being of mice. Our findings suggest that curcumin exerts synergistic anti-inflammation with metformin with no potential CNS adverse effects.


Assuntos
Curcumina , Metformina , Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Humanos , Metformina/uso terapêutico , Dor/tratamento farmacológico
8.
World J Gastroenterol ; 28(19): 2148-2151, 2022 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-35664033

RESUMO

The association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) has been thoroughly investigated and reports have demonstrated that the risk of CRC is increased in DM patients. The association between DM and the survival of patients with CRC is controversial. Evidence suggests that metformin with its anti-inflammatory effects is a protective factor against the development of CRC among DM patients and that metformin therapy is associated with a better prognosis in patients with DM. In our cohort, we did not find any associations between the presence of DM or metformin and cancer specific survival or any relation to plasma levels of a panel of 40 inflammatory factors and irisin. On the other hand, we identified that the insulin-like growth factor binding protein 7 single nucleotide polymorphism rs2041437 was associated with DM in CRC patients. The dominance of the T bearing genotypes in patients with DM was statistically significant (P = 0.038), with an odds ratio of 1.66 (95% confidence interval: 1.03-2.69).


Assuntos
Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Metformina , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Suécia/epidemiologia
9.
J Transl Med ; 20(1): 263, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672854

RESUMO

BACKGROUND: Metabolic disorders are associated with increased incidence, aggressive phenotype and poor outcome of breast cancer (BC) patients. For instance, hyperinsulinemia is an independent risk factor for BC and the insulin/insulin receptor (IR) axis is involved in BC growth and metastasis. Of note, the anti-diabetic metformin may be considered in comprehensive therapeutic approaches in BC on the basis of its antiproliferative effects obtained in diverse pre-clinical and clinical studies. METHODS: Bioinformatics analysis were performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project. The naturally immortalized BC cell line, named BCAHC-1, as well as cancer-associated fibroblasts (CAFs) derived from BC patients were used as model systems. In order to identify further mechanisms that characterize the anticancer action of metformin in BC, we performed gene expression and promoter studies as well as western blotting experiments. Moreover, cell cycle analysis, colony and spheroid formation, actin cytoskeleton reorganization, cell migration and matrigel drops evasion assays were carried out to provide novel insights on the anticancer properties of metformin. RESULTS: We first assessed that elevated expression and activation of IR correlate with a worse prognostic outcome in estrogen receptor (ER)-positive BC. Thereafter, we established that metformin inhibits the insulin/IR-mediated activation of transduction pathways, gene changes and proliferative responses in BCAHC-1 cells. Then, we found that metformin interferes with the insulin-induced expression of the metastatic gene CXC chemokine receptor 4 (CXCR4), which we found to be associated with poor disease-free survival in BC patients exhibiting high levels of IR. Next, we ascertained that metformin prevents a motile phenotype of BCAHC-1 cells triggered by the paracrine liaison between tumor cells and CAFs upon insulin activated CXCL12/CXCR4 axis. CONCLUSIONS: Our findings provide novel mechanistic insights regarding the anti-proliferative and anti-migratory effects of metformin in both BC cells and important components of the tumor microenvironment like CAFs. Further investigations are warranted to corroborate the anticancer action of metformin on the tumor mass toward the assessment of more comprehensive strategies halting BC progression, in particular in patients exhibiting metabolic disorders and altered insulin/IR functions.


Assuntos
Neoplasias da Mama , Metformina , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Insulina/farmacologia , Insulina/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Receptores CXCR4/metabolismo , Transdução de Sinais , Microambiente Tumoral
10.
Zhonghua Nei Ke Za Zhi ; 61(6): 703-707, 2022 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-35673756

RESUMO

A 22-year-old female has complained of hirsutism, acanthosis nigricans, enlarged clitoris, and menstrual disorders since puberty. Laboratory examinations revealed hyperandrogenemia. Severe insulin resistance and diabetes were found during hospitalization in our hospital. She was diagnosed with type A insulin resistance syndrome finally. After treatment with metformin, the acanthosis nigricans was significantly relieved, blood glucose was controlled satisfactorily, and the menstrual cycle was restored.


Assuntos
Acantose Nigricans , Diabetes Mellitus , Resistência à Insulina , Metformina , Síndrome do Ovário Policístico , Acantose Nigricans/diagnóstico , Adulto , Feminino , Hirsutismo , Humanos , Insulina , Metformina/uso terapêutico , Adulto Jovem
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(5): 641-648, 2022 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-35673906

RESUMO

OBJECTIVE: To investigate the effect of dihydromyricetin (DHM) on cardiac insufficiency in diabetic rats and explore the underlying mechanism. METHOD: Twenty-four male SD rats were randomized equally into normal control group, type 2 diabetes (T2DM) group fed on a high-glucose and high-fat diet for 6 weeks with low-dose streptozotocin (STZ) injection, metformin (MET) group with daily intragastric administration of MET (150 mg/kg) for 8 weeks after T2DM modeling, and dihydromyricetin (DHM) group with daily intragastric administration of DHM (250 mg/kg) for 8 weeks after modeling. The levels of fasting blood glucose, low density lipoprotein (LDL-C), triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL-C) and glycosylated hemoglobin (HbA1c) of the rats were measured, and plasma levels of insulin and high mobility group protein-1 (HMGB1) were detected with ELISA. The cardiac function of the rats was assessed using color echocardiography, ECG was measured using a biological signal acquisition system, and myocardial pathology was observed with HE staining. The protein expressions of HMGB1, nuclear factor-κB (NF-κB) p65 and phospho-NF-κB p65 (p-NF-κB p65) in the myocardial tissue were detected using Western blotting. RESULTS: Compared with the control group, the rats in T2DM group showed significant anomalies in cardiac function after modeling with significantly increased plasma HMGB1 level and expressions of HMGB1, NF-κB p65 and p-NF-κB p65 proteins in the myocardial tissue (P < 0.05 or 0.01). Treatment with DHM significantly improved the indexes of cardiac function of the diabetic rats (P < 0.05 or 0.01), decreased plasma HMGB1 level and down-regulated the protein expressions of HMGB1 and p-NF-κB p65 in the myocardial tissue (P < 0.05 or 0.01). CONCLUSION: DHM treatment can improve cardiac function in diabetic rats possibly by down-regulation of HMGB1 and phospho-NF-κB p65 expressions in the myocardium.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Proteína HMGB1 , Insuficiência Cardíaca , Metformina , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Flavonóis , Masculino , Metformina/uso terapêutico , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(5): 740-746, 2022 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-35673919

RESUMO

OBJECTIVE: To investigate the effect of metformin on the proliferation and apoptosis of HER-2-positive breast cancer cell line SKBR3 and explore the possible mechanism of its action. METHODS: SKBR3 cells were treated with different concentrations (20-120 µmol/L) of metformin, and the changes in cell proliferation and colony formation ability were assessed using CCK-8 assay and crystal violet staining, respectively. Flow cytometry was performed to analyze cell apoptosis and cell cycle changes. Real-time fluorescent quantitative PCR (qRT-PCR) was used to detect mRNA expressions of YAP, TAZ, EGFR, CTGF, CYR61, E-cadherin, N-cadherin, vimentin and fibronectin in the treated cells, and the protein expressions of YAP and TAZ were detected using Western blotting; immunofluorescence assay was used to observe YAP/TAZ nuclear translocation in the cells. RESULTS: Metformin treatment significantly inhibited the proliferation of SKBR3 cells (P < 0.05) in a concentration- and time-dependent manner. The results of flow cytometry showed that metformin significantly promoted apoptosis and caused cell cycle arrest at G1 phase in SKBR3 cells. Metformin treatment significantly down-regulated the mRNA expressions of YAP, TAZ, EGFR, CTGF and CYR61, N-cadherin, vimentin and fibronectin (P < 0.05) and up-regulated the expression of E-cadherin (P < 0.05); Western blotting results showed that YAP and TAZ protein expressions were significantly down-regulated in the cells after metformin treatment (P < 0.05). Immunofluorescence assay revealed that metformin treatment caused the concentration of YAP and TAZ in the cytoplasm, and significantly reduced their amount in the cell nucleus. CONCLUSION: Metformin can inhibit proliferation and promote apoptosis and epithelal-mesenchymal transition of HER-2 positive breast cancer cells possibly by that inhibing YAP and TAZ expression and their nuclear localization.


Assuntos
Metformina , Neoplasias , Apoptose , Caderinas , Proliferação de Células , Receptores ErbB , Fibronectinas , Metformina/farmacologia , RNA Mensageiro , Fatores de Transcrição/metabolismo , Vimentina
13.
Cardiovasc Diabetol ; 21(1): 92, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35658864

RESUMO

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have proven cardiovascular benefits in patients with type 2 diabetes (T2D). This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits. METHODS: T2D patients with metformin and/or SGLT2i prescriptions between 2015 and 2020 were identified from the Hong Kong population. Study outcomes were composite cardiovascular diseases (CVD), coronary heart disease (CHD), hospitalisation for heart failure (HHF), stroke, and erythrocytosis. Risk periods were patient-time divided into four mutually exclusive windows: (i) 'baseline period' of metformin use without SGLT2i; (ii) pre-SGLT2i period; (iii) exposure to SGLT2i without metformin; and (iv) exposure to the drug combination. Another SCCS model was applied to evaluate the association between erythrocytosis and cardiovascular outcomes regarding SGLT2i exposure. Four mutually exclusive risk periods included (i) SGLT2i exposure with erythrocytosis; (ii) SGLT2i exposure without erythrocytosis; (iii) absence of SGLT2i exposure with erythrocytosis; and (iv) absence of SGLT2i exposure without erythrocytosis. Incidence rate ratios (IRR) of events at different risk periods were estimated using conditional Poisson regression model. RESULTS: Among 20,861 patients with metformin and/or SGLT2i prescriptions, 2575 and 1700 patients with events of composite CVD and erythrocytosis were identified, respectively. Compared to metformin use without SGLT2i, SGLT2i initiation was associated with lower risks of composite CVD, CHD, and HHF-regardless of the presence (CVD: IRR = 0.43, 95% CI 0.37-0.51; CHD: IRR = 0.44, 95% CI 0.37-0.53; HHF: IRR = 0.29, 95% CI 0.22-0.40; all p < 0.001) and absence of concomitant metformin (CVD: IRR = 0.31, 95% CI 0.20-0.48; CHD: IRR = 0.38, 95% CI 0.25-0.59; HHF: IRR = 0.17, 95% CI 0.09-0.31; all p < 0.001); while SGLT2i was neutral on stroke risk. Compared to metformin-SGLT2i combination, exposure to SGLT2i alone was associated with comparable risks of all cardiovascular outcomes (all p > 0.05). Incidence rates of erythrocytosis at baseline, SGLT2i without and with metformin use periods were 0.75, 3.06 and 3.27 per 100 person-years, respectively. SGLT2i users who developed erythrocytosis had lower risk of HHF (IRR = 0.38, 95% CI 0.14-0.99, p = 0.049) than those who did not. CONCLUSIONS: Our real-world data suggested that SGLT2i-associated cardiovascular benefits were not attenuated by metformin use. Further studies will delineate the role of erythrocytosis as a surrogate marker of SGLT2i-associated cardiovascular benefit in reducing HHF.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Metformina , Policitemia , Inibidores do Transportador 2 de Sódio-Glicose , Acidente Vascular Cerebral , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Insuficiência Cardíaca/epidemiologia , Humanos , Metformina/efeitos adversos , Policitemia/induzido quimicamente , Policitemia/diagnóstico , Policitemia/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente
14.
Biomed Pharmacother ; 152: 113223, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35709650

RESUMO

The health crisis caused by the new coronavirus SARS-CoV-2 highlights the need to identify new treatment strategies for this viral infection. During the past year, over 400 coronavirus disease (COVID-19) treatment patents have been registered; nevertheless, the presence of new virus variants has triggered more severe disease presentations and reduced treatment effectiveness, highlighting the need for new treatment options for the COVID-19. This study evaluates the Metformin Glycinate (MG) effect on the SARS-CoV-2 in vitro and in vivo viral load. The in vitro study was conducted in a model of Vero E6 cells, while the in vivo study was an adaptive, two-armed, randomized, prospective, longitudinal, double-blind, multicentric, and phase IIb clinical trial. Our in vitro results revealed that MG effectively inhibits viral replication after 48 h of exposure to the drug, with no cytotoxic effect in doses up to 100 µM. The effect of the MG was also tested against three variants of interest (alpha, delta, and epsilon), showing increased survival rates in cells treated with MG. These results are aligned with our clinical data, which indicates that MG treatment reduces SARS-CoV2-infected patients´ viral load in just 3.3 days and supplementary oxygen requirements compared with the control group. We expect our results can guide efforts to position MG as a therapeutic option for COVID-19 patients.


Assuntos
COVID-19 , Metformina , COVID-19/tratamento farmacológico , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Estudos Prospectivos , RNA Viral , SARS-CoV-2 , Carga Viral
15.
Int Immunopharmacol ; 109: 108889, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35679661

RESUMO

Hyperinsulinemia, hyperglycemia, and chronic inflammation may play a role in hepatocellular carcinoma (HCC). Treatment of HCC patients with the antidiabetic medication metformin corrected the pathological changes of HCC by affecting proliferation, apoptosis, and angiogenesis. On the other hand, our review aims to uncover new pathways underlying metformin's anti-tumor action in the liver, focusing on immunological mediators and immune archetypes. In this review, we discuss the effect of metformin on restructuring the HCC immune microenvironment, such as dendritic cells, T cells, Tregs, macrophages, neutrophils, and myeloid-derived suppressors cells (MDSCs). Furthermore, Metformin also changes the expression pattern of immune mediators in HCC immune microenvironment, including programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), transforming growth factor-beta (TGF-ß), Interleukin 12 (IL-12), indoleamine 2,3 dioxygenase (IDO), forkhead box protein P3 (FOXP3), and interferon-gamma (IFN-γ). This review summarizes a state-of-the-art understanding of the molecular mechanisms underlining novel anticarcinogenic approaches of metformin through modulation of liver cancer immune microenvironment both on the cellular and molecular scales, which aids in regaining immune fitness and thus better prognosis. The changes in tumor immune architecture and mediators induced by metformin make it a robust antineoplastic agent with multiple mechanisms of action, especially for people with diabetes and HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Metformina , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Microambiente Tumoral
16.
Theriogenology ; 188: 79-89, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35688042

RESUMO

ATP is essential for mammalian sperm to maintain fertilizing capacity. Metformin (Met) can activate 5'-AMP-activated protein kinase (AMPK) to maintain energy homeostasis. Thus, the aim of the present study was to investigate whether Met can improve testis function, semen quality, antioxidant and autophagy capacity through AMPK mediation of energy metabolism in goats. Twelve adult goats were randomly divided into three dietary treatments. All goats were fed a basal diet for 3 weeks and then assigned to a Met supplementation diet containing 0, 150, or 300 mg/kg for 8 weeks. The results showed that sperm viability, sperm membranal functional integrity, and acrosome integrity increased (P < 0.05) relative to the other treatments in the 300 mg/kg Met group. Growth hormone (GH) and insulin-like growth factor (IGF-1) in the 300 mg/kg Met group significantly decreased (P < 0.05) relative to the control group. Estrogen levels (E2) in the 300 mg/kg Met group remarkably improved (P < 0.05) compared with the control group. The activities of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GSH-px), and superoxide dismutase (SOD) significantly increased (P < 0.05) in the 300 mg/kg Met group relative to the control group. A significant increase in AMPK and p-AMPK protein expression in the 300 mg/kg Met group was observed relative to the control group (P < 0.05). Belicin-1 and LC3II/I protein expression was significantly increased by adding Met to the diet (P < 0.05) and reached a maximum in the 300 mg/kg Met group. In addition, differentially expressed genes (DEGs) of goat testis were confirmed by RNA-seq. GO enrichment analysis revealed that DEGs were enriched in testicular metabolism and sperm development-related functional pathways. Overall, the results indicate that Met may play an important role in the regulation of testis function, semen quality, antioxidant, and autophagy capacity. These findings will help elucidate the role of Met in goat testis development.


Assuntos
Metformina , Análise do Sêmen , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/metabolismo , Autofagia , Suplementos Nutricionais , Cabras/fisiologia , Masculino , Metformina/farmacologia , Análise do Sêmen/veterinária , Espermatozoides/fisiologia , Testículo/metabolismo
17.
Acta Biochim Pol ; 69(2): 321-326, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35704903

RESUMO

BACKGROUND: Gastric cancer is one of the most common cancers worldwide. The disease has a poor prognosis, especially when the tumor becomes inoperable. The present study investigated the potential synergistic effects of oxaliplatin and metformin in gastric cancer cells. METHODS: The effect of oxaliplatin and metformin on cell proliferation was assessed with CCK-8 assay in human gastric cancer cell lines SGC7901 and SNU-16, where , the IC50 and (combination index) CI values were determined. RT-PCR and Western blotting were used to determine mRNA and protein expression levels of cell cycle- and apoptosis-related genes. The apoptotic rate was detected with flow cytometry in SGC7901 and SNU-16 cells. RESULTS: The CCK-8 assay showed inhibited proliferation of SGC7901 and SNU-16 cells upon oxaliplatin or metformin treatment and an increase in inhibitory potency when the drugs were administered in combination. Similarly, cell apoptosis was increased in both cell lines in the combination group compared to the metformin and oxaliplatin groups. Both metformin and oxaliplatin reduced Bcl-2 and increased Bax and caspase-3 expression in SGC7901 and SNU-16; and these effects were enhanced when the drugs were used in combination. CONCLUSION: The combination of metformin and oxaliplatin inhibited proliferation and induced apoptosis in gastric cancer cells. The underlying mechanisms may be related to the suppression of cyclin D1, Bcl-2 and the increase of expression of Bax and caspase-3.


Assuntos
Metformina , Neoplasias Gástricas , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Metformina/farmacologia , Oxaliplatina/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sincalida/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
18.
Int Immunopharmacol ; 109: 108903, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35709590

RESUMO

With the widespread use of volatile anesthetic agents in the prolonged sedation for COVID-19 pneumonia and ARDS, there is an urgent need to investigate the effects and treatments of lengthy low-concentration inhaled anesthetics exposure on cognitive function in adults. Previous studies showed that general anesthetics dose- and exposure length-dependently induced neuroinflammatory response and cognitive decline in neonatal and aging animals. The anti-diabetes drug metformin has anti-neuroinflammation effects by modulating microglial polarization and inhibiting astrocyte activation. In this study, we demonstrated that the inhalation of 1.3% isoflurane (a sub-minimal alveolar concentration, sub-MAC) for 6 h impaired recognition of novel objects from Day 1 to Day3 in adult mice. Prolonged sub-MAC isoflurane exposure also triggered typically reactive microglia and A1-like astrocytes in the hippocampus of adult mice on Day 3 after anesthesia. In addition, prolonged isoflurane inhalation switched microglia into a proinflammatory M1 phenotype characterized by elevated CD68 and iNOS as well as decreased arginase-1 and IL-10. Metformin pretreatment before anesthesia enhanced cognitive performance in the novel object test. The positive cellular modifications promoted by metformin pretreatment included the inhibition of reactive microglia and A1-like astrocytes and the polarization of microglia into M2 phenotype in the hippocampus of adult mice. In conclusion, prolonged sub-MAC isoflurane exposure triggered significant hippocampal neuroinflammation and cognitive decline in adult mice which can be alleviated by metformin pretreatment via inhibiting reactive microglia and A1-like astrocytes and promoting microglia polarization toward anti-inflammatory phenotype in the hippocampus.


Assuntos
Anestésicos , COVID-19 , Disfunção Cognitiva , Isoflurano , Metformina , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Isoflurano/farmacologia , Isoflurano/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Microglia
19.
J Natl Compr Canc Netw ; 20(6): 674-682.e15, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35714677

RESUMO

BACKGROUND: The aim of this study was to compare the risks of new-onset prostate cancer between metformin and sulfonylurea users with type 2 diabetes mellitus (T2DM). METHODS: This population-based retrospective cohort study included male patients with T2DM presenting to public hospitals/clinics in Hong Kong between January 1, 2000, and December 31, 2009. We only included patients prescribed either, but not both, metformin or sulfonylurea. All patients were followed up until December 31, 2019. The primary outcome was new-onset prostate cancer and the secondary outcome was all-cause mortality. One-to-one propensity score matching was performed between metformin and sulfonylurea users based on demographics, comorbidities, antidiabetic and cardiovascular medications, fasting blood glucose level, and hemoglobin A1c level. Subgroup analyses based on age and use of androgen deprivation therapy were performed. RESULTS: The final study cohort consisted of 25,695 metformin users (mean [SD] age, 65.2 [11.8] years) and 25,695 matched sulfonylurea users (mean [SD] age, 65.3 [11.8] years) with a median follow-up duration of 119.6 months (interquartile range, 91.7-139.6 months) after 1:1 propensity score matching of 66,411 patients. Metformin users had lower risks of new-onset prostate cancer (hazard ratio, 0.80; 95% CI, 0.69-0.93; P=.0031) and all-cause mortality (hazard ratio, 0.89; 95% CI, 0.86-0.92; P<.0001) than sulfonylurea users. Metformin use was more protective against prostate cancer but less protective against all-cause mortality in patients aged <65 years (P for trend <.0001 for both) compared with patients aged ≥65 years. Metformin users had lower risk of all-cause mortality than sulfonylurea users, regardless of the use of androgen deprivation therapy (P for trend <.0001) among patients who developed prostate cancer. CONCLUSIONS: Metformin use was associated with significantly lower risks of new-onset prostate cancer and all-cause mortality than sulfonylurea use in male patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Neoplasias da Próstata , Idoso , Antagonistas de Androgênios/uso terapêutico , Androgênios/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Masculino , Metformina/efeitos adversos , Pontuação de Propensão , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etiologia , Estudos Retrospectivos , Compostos de Sulfonilureia/efeitos adversos
20.
Oxid Med Cell Longev ; 2022: 9144644, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693700

RESUMO

Ovarian damage induced by platinum-based chemotherapy seriously affects young women with cancer, manifesting as infertility, early menopause, and premature ovarian insufficiency. However, effective prevention strategies for such damage are lacking. Senescent cells may be induced by chemotherapeutic agents. We hypothesized that cisplatin can lead to senescence in ovarian cells during the therapeutic process, and senolytic drugs can protect animals against cisplatin-induced ovarian injury. Here, we demonstrated the existence of senescent cells in cisplatin-treated ovaries, identified the senescence-associated secretory phenotype, and observed significant improvement of ovarian function by treatment with metformin or dasatinib and quercetin (DQ) independently or in combination. These senotherapies improved both oocyte quality and fertility, increased the ovarian reserve, and enhanced hormone secretion in cisplatin-exposed mice. Additionally, attenuated fibrosis, reorganized subcellular structure, and mitigated DNA damage were observed in the ovaries of senotherapeutic mice. Moreover, RNA sequencing analysis revealed upregulation of the proliferation-related genes Ki, Prrx2, Sfrp4, and Megfl0; and the antioxidative gene H2-Q10 after metformin plus DQ treatment. Gene ontology analysis further revealed that combining senotherapies enhanced ovarian cell differentiation, development, and communication. In this study, we demonstrated that metformin plus DQ recovered ovarian function to a greater extent compared to metformin or DQ independently, with more follicular reserve, increased pups per litter, and reduced DNA damage. Collectively, our work indicates that senotherapies might prevent cisplatin-induced ovarian injury by removing senescent cells and reducing DNA damage, which represent a promising therapeutic avenue to prevent chemotherapy-induced ovarian damage.


Assuntos
Cisplatino , Metformina , Animais , Apoptose , Senescência Celular , Dano ao DNA , Feminino , Proteínas de Homeodomínio/farmacologia , Humanos , Metformina/farmacologia , Camundongos
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