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1.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 39(10): 726-732, 2021 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-34727651

RESUMO

Objective: To investigate the interventional effect of metformin on pulmonary inflammation and pulmonary fibrosis in silicotic rats. Methods: In April 2019, 48 Wistar male rats of SPF grade were randomly divided into negative control group, metformin control group, silicon dioxide (SiO2) model group, low, medium and high dose metformin intervention group according to the random number table method, 8 rats in each group. The SiO2 model group and the low, medium and high dose metformin intervention groups were given 1 ml 50 mg/ml of SiO2 by intratracheal instillation, the negative control group and the metformin control group were given 1 ml normal saline by intratracheal instillation. 24 hours later, the low, medium and high dose metformin intervention groups and the metformin control group were treated with 100, 200, 400 and 400 mg/kg metformin daily, the control and SiO2 model groups received normal saline daily. Then the rats were sacrificed at the 28th day after SiO2 exposure. The changes of rat body weight and pathological examination of rat lung tissue were observed, and the lung organ coefficient, the content of hydroxyproline (HYP) , the expression levels of inflammatory factors transforming growth factor beta1 (TGF-ß1) , tumor necrosis factor-alpha (TNF-α) , interleukin-1beta (IL-1ß) and the protein expression of E-cadherin (E-Cad) , Vimentin, α-SMA were detected. Results: Compared with the negative control group, SiO2 model group had a significant decrease in the body weight of rats (P<0.05) , lung organ coefficient, alveolitis and fibrosis scores, HYP content and the levels of TGF-ß1, TNF-α, IL-1ß were all significantly increased (P<0.05) . Compared with the SiO2 model group, the weights of the rats in the medium and high dose intervention group of metformin increased significantly (P<0.05) . And after intervention with different doses of metformin, the lung organ coefficient, alveolitis and fibrosis scores, HYP content and the levels of TGF-ß1, TNF-α and IL-1ß were significantly decreased (P<0.05) . Immunohistochemistry and Western blotting results showed that compared with the negative control group, the expression of E-Cad of the SiO2 model group was decreased, and the expression levels of Vimentin and α-SMA were significantly increased (P<0.05) . After metformin intervention, the expression of E-Cad was significantly increased, the expression levels of Vimentin and α-SMA were significantly decreased (P<0.05) . Conclusion: Metformin can reduce lung tissue inflammation and fibrosis in rats exposed to SiO2 dust, which may be related to reducing the expression of inflammatory factors in lung tissue and inhibiting the EMT process.


Assuntos
Metformina , Pneumonia , Fibrose Pulmonar , Animais , Pulmão , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Ratos , Ratos Wistar , Dióxido de Silício , Fator de Crescimento Transformador beta1
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(6): 644-649, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34821099

RESUMO

Objective: To investigate the effects of metformin and sitagliptin on the function of islet ß cells in insulin resistance pre-diabetic KKay mice. Methods: Thirty 6-week-old KKAy mice were randomly divided into two groups: normal diet fed group (NC group, n=10) and high-fat diet fed group (n=20). At 8 weeks, KKAy mice were randomly divided into two groups: metformin intervention group (met group, n=10) and sitagliptin intervention group (SP group, n=10), which were treated by gavage for 8 weeks. Glucose tolerance was measured by oral glucose tolerance test (OGTT), serum insulin level and plasma lipid level were measured by tail blood sampling, and HOMA-ß and HOMA-IR were calculated. The mice were killed after blood collection, and the pancreas of KKAy mice was taken. The ß cell volume of each group was compared by immunofluorescence staining of insulin and glucagon, respectively. The proliferation and apoptosis of ß cell were analyzed by Ki67/INS. The expressions of pancreatic transcription factors PDX-1 and MafA were detected by Western blot. Results: ① The OGTT results indicated that blood glucose of KKAy mice at fast, 30, 60 and 120 min after oral administration of glucose in the Met and SP groups were decreased significantly compared with the NC group, and the area under the blood glucose time curve (AUC) was significantly reduced (P<0.01, P<0.01). There was no significant difference between the Met group and the SP group in blood glucose level at 30 and 60 min after oral administration of glucose. Compared with the SP group, the blood glucose of Met group at 120 min was decreased significantly (P<0.05). There was no significant difference in AUC between the two groups. ② The results of the insulin tolerance test (ITT) indicated that, compared with NC, the fasting blood glucose and the blood glucose at 30, 60 and 90 min after insulin injection in KKAy mice in the Met and SP groups were decreased significantly, and the area under the ITT blood glucose curve (AUC) was increased significantly (P<0.01), while there was no significant difference between the Met and SP groups. ③ In the NC group, the brightness of the areas of the islet ß cells was low and the edges were scattered. After treated with metformin, the areas and brightness of the ß cells were increased. After treatment with sitagliptin, the area and brightness of the ß cells were increased significantly. In the NC group, the α cells were disordered in the islet distribution and the brightness was large. After the administration of metformin, the α cell area and the brightness were decreased, and distributed to the edge of the islet to a certain extent. After the administration of sitagliptin, there was a significant decrease in the area of the α cells, with a significant decrease in the brightness and distribution at the edge of the islet. ④ Compared with the NC group, the expression levels of pancreatic MafA in the Met group and SP group were increased significantly, which were 1.63 times and 1.58 times, respectively (P<0.01, P<0.01). There was no significant difference in the expression of pancreatic PDX-1 between the groups. Conclusion: In pre-diabetes mellitus KKAy mice with insulin resistance, metformin can maintain the function and morphology of pancreatic islets, and sitagliptin may promote the proliferation of islet ßcells, improve the expression level of insulin transcription factor MafA, and prevent the occurrence and development of diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Ilhotas Pancreáticas , Metformina , Estado Pré-Diabético , Animais , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina , Metformina/farmacologia , Camundongos , Fosfato de Sitagliptina/farmacologia
3.
Nutrients ; 13(10)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684608

RESUMO

Anti-obesity activity has been reported for beta-carotene (BC) supplementation at high doses and metformin (MET). We studied whether BC treatment at a closer to dietary dose and MET treatment at a lower than therapeutic dose are effective in ameliorating unwanted effects of an obesogenic diet and whether their combination is advantageous. Obesity-prone mice were challenged with a high-fat diet (HFD, 45% energy as fat) for 4 weeks while receiving a placebo or being treated orally with BC (3 mg/kg/day), MET (100 mg/kg/day), or their combination (BC+MET); a fifth group received a placebo and was kept on a normal-fat diet (10% energy as fat). HFD-induced increases in body weight gain and inguinal white adipose tissue (WAT) adipocyte size were attenuated maximally or selectively in the BC+MET group, in which a redistribution towards smaller adipocytes was noted. Cumulative energy intake was unaffected, yet results suggested increased systemic energy expenditure and brown adipose tissue activation in the treated groups. Unwanted effects of HFD on glucose control and insulin sensitivity were attenuated in the treated groups, especially BC and BC+MET, in which hepatic lipid content was also decreased. Transcriptional analyses suggested effects on skeletal muscle and WAT metabolism could contribute to better responses to the HFD, especially in the MET and BC+MET groups. The results support the benefits of the BC+MET cotreatment.


Assuntos
Dieta Hiperlipídica , Metformina/farmacologia , Substâncias Protetoras/farmacologia , beta Caroteno/farmacologia , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Adiposidade , Animais , Glicemia/metabolismo , Tamanho Celular , Metabolismo Energético/genética , Ácidos Graxos/sangue , Regulação da Expressão Gênica , Insulina/sangue , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ganho de Peso
4.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638899

RESUMO

This study examined the effect of combination treatment with the poly (ADP-ribose) polymerase inhibitor olaparib and metformin on homologous recombination (HR)-proficient epithelial ovarian cancer (EOC). Ovarian cancer cell lines (OV-90 and SKOV-3) were treated with olaparib, metformin, or a combination of both. Cell viability was assessed by MTT and colony formation assays. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential were examined using the specific fluorescence probes, DCFH2-DA (2',7'-dichloro-dihydrofluorescein diacetate) and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine). Apoptotic and necrotic changes were measured by double staining with Hoechst 33258 and propidium iodide, orange acridine and ethidium bromide staining, phosphatidylserine externalization, TUNEL assay, caspase 3/7 activity, and cytochrome c and p53 expression. Compared with single-drug treatment, the combination of olaparib and metformin significantly inhibited cell proliferation and colony formation in HR-proficient ovarian cancer cells. ROS production preceded a decrease in mitochondrial membrane potential. The changes in ROS levels suggested their involvement in inducing apoptosis in response to combination treatment. The present results indicate a shift towards synergism in cells with mutant or null p53, treated with olaparib combined with metformin, providing a new approach to the treatment of gynecologic cancers. Taken together, the results support the use of metformin to sensitize EOC to olaparib therapy.


Assuntos
Apoptose/efeitos dos fármacos , Metformina/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Sinergismo Farmacológico , Feminino , Humanos , Hipoglicemiantes/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fosfatidilserinas/metabolismo
5.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623325

RESUMO

Mitochondrial electron transport chain complex I (ETCC1) is the essential core of cancer metabolism, yet potent ETCC1 inhibitors capable of safely suppressing tumor growth and metastasis in vivo are limited. From a plant extract screening, we identified petasin (PT) as a highly potent ETCC1 inhibitor with a chemical structure distinct from conventional inhibitors. PT had at least 1700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. PT administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo. Despite its higher potency, it showed no apparent toxicity toward nontumor cells and normal organs. Also, treatment with PT attenuated cellular motility and focal adhesion in vitro as well as lung metastasis in vivo. Metabolome and proteome analyses revealed that PT severely depleted the level of aspartate, disrupted tumor-associated metabolism of nucleotide synthesis and glycosylation, and downregulated major oncoproteins associated with proliferation and metastasis. These findings indicate the promising potential of PT as a potent ETCC1 inhibitor to target the metabolic vulnerability of tumor cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Sesquiterpenos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Complexo I de Transporte de Elétrons/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metaboloma/efeitos dos fármacos , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Neoplasias Experimentais/patologia , Petasites/química , Fenformin/farmacologia , Sesquiterpenos/química , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Front Immunol ; 12: 718136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646263

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is a receptor for the spike protein of SARS-COV-2 that allows viral binding and entry and is expressed on the surface of several pulmonary and non-pulmonary cell types, with induction of a "cytokine storm" upon binding. Other cell types present the receptor and can be infected, including cardiac, renal, intestinal, and endothelial cells. High ACE2 levels protect from inflammation. Despite the relevance of ACE2 levels in COVID-19 pathogenesis, experimental studies to comprehensively address the question of ACE2 regulations are still limited. A relevant observation from the clinic is that, besides the pro-inflammatory cytokines, such as IL-6 and IL-1ß, the anti-inflammatory cytokine IL-10 is also elevated in worse prognosis patients. This could represent somehow a "danger signal", an alarmin from the host organism, given the immuno-regulatory properties of the cytokine. Here, we investigated whether IL-10 could increase ACE2 expression in the lung-derived Calu-3 cell line. We provided preliminary evidence of ACE2 mRNA increase in cells of lung origin in vitro, following IL-10 treatment. Endothelial cell infection by SARS-COV-2 is associated with vasculitis, thromboembolism, and disseminated intravascular coagulation. We confirmed ACE2 expression enhancement by IL-10 treatment also on endothelial cells. The sartans (olmesartan and losartan) showed non-statistically significant ACE2 modulation in Calu-3 and endothelial cells, as compared to untreated control cells. We observed that the antidiabetic biguanide metformin, a putative anti-inflammatory agent, also upregulates ACE2 expression in Calu-3 and endothelial cells. We hypothesized that IL-10 could be a danger signal, and its elevation could possibly represent a feedback mechanism fighting inflammation. Although further confirmatory studies are required, inducing IL-10 upregulation could be clinically relevant in COVID-19-associated acute respiratory distress syndrome (ARDS) and vasculitis, by reinforcing ACE2 levels.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anti-Inflamatórios/farmacologia , COVID-19/enzimologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Interleucina-10/farmacologia , Pulmão/efeitos dos fármacos , RNA Mensageiro/metabolismo , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , COVID-19/imunologia , Linhagem Celular , Interações Hospedeiro-Patógeno , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Pulmão/enzimologia , Pulmão/imunologia , Metformina/farmacologia , RNA Mensageiro/genética , SARS-CoV-2/imunologia , Regulação para Cima
7.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34638615

RESUMO

Metformin is the first-line antidiabetic drug that is widely used in the treatment of type 2 diabetes mellitus (T2DM). Even though the various therapeutic potential of metformin treatment has been reported, as well as the improvement of insulin sensitivity and glucose homeostasis, the mechanisms underlying those benefits are still not fully understood. In order to explain the beneficial effects on metformin treatment, various metabolomics analyses have been applied to investigate the metabolic alterations in response to metformin treatment, and significant systemic metabolome changes were observed in biofluid, tissues, and cells. In this review, we compare the latest metabolomic research including clinical trials, animal models, and in vitro studies comprehensively to understand the overall changes of metabolome on metformin treatment.


Assuntos
Hipoglicemiantes/farmacologia , Metaboloma/efeitos dos fármacos , Metformina/farmacologia , Animais , Biomarcadores/sangue , Biomarcadores/urina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/química , Resistência à Insulina , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Metformina/química
8.
Expert Opin Drug Metab Toxicol ; 17(10): 1199-1210, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34632898

RESUMO

INTRODUCTION: As the global population ages at an unprecedented rate, the burden of neurodegenerative diseases is expected to grow. Given the profound impact illness like dementia exert on individuals and society writ large, researchers, physicians, and scientific organizations have called for increased investigation into their treatment and prevention. Both metformin and aspirin have been associated with improved cognitive outcomes. These agents are related in their ability to stimulate AMP kinase (AMPK). Momordica charantia, another AMPK activator, is a component of traditional medicines and a novel agent for the treatment of cancer. It is also being evaluated as a nootropic agent. AREAS COVERED: This article is a comprehensive review which examines the role of AMPK activation in neuroprotection and the role that AMPK activators may have in the management of dementia and cognitive impairment. It evaluates the interaction of metformin, aspirin, and Momordica charantia, with AMPK, and reviews the literature characterizing these agents' impact on neurodegeneration. EXPERT OPINION: We suggest that AMPK activators should be considered for the treatment and prevention of neurodegenerative diseases. We identify multiple areas of future investigation which may have a profound impact on patients worldwide.


Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aspirina/farmacologia , Ativadores de Enzimas/farmacologia , Humanos , Metformina/farmacologia , Momordica charantia/química , Doenças Neurodegenerativas/fisiopatologia
9.
Adv Clin Exp Med ; 30(11): 1185-1193, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34595852

RESUMO

BACKGROUND: Lithium is widely used in the treatment of bipolar disorders and may lead to nephrogenic diabetes insipidus (NDI), following long-term treatment. Metformin is considered the preferred initial therapy for patients with type 2 diabetes mellitus (T2D). OBJECTIVES: To investigate the protective effect of metformin on the kidney damage caused by lithium administration. MATERIAL AND METHODS: Using an animal model of chronic lithium-induced NDI, rats were divided into 4 groups: sham, metformin, lithium, and lithium + metformin. The effects of these treatments were examined using serum electrolytes, blood and tissue total antioxidant status, total oxidant status, the oxidative stress index, urine and blood osmolality, and tissue aquaporin-2 (AQP2) levels. Additionally, histopathological changes, including congestion, hydropic swelling, tubular necrosis, tubular atrophy, and Bowman's capsule dilatation, were evaluated. The total histopathological score was obtained by summing the scores for each pathological finding. RESULTS: In the lithium group, biochemical variables indicating NDI, including sodium, chloride and blood osmolality, increased, and urine osmolality decreased, compared to the sham group. With metformin treatment, the blood osmolality decreased from 328.17 mOsm/kg to 306.33 mOsm/kg, and urine osmolality increased from 349.67 mOsm/kg to 754.50 mOsm/kg (p = 0.004 and p = 0.001, respectively). Tissue AQP2 levels decreased with lithium administration but stabilized with metformin treatment. Additionally, in comparison to the lithium group, the total histopathological score in the metformin group declined from 8.0 to 2.0 (p = 0.002). CONCLUSIONS: Metformin may help protect the kidneys from lithium-induced NDI through the AQP2 regulating effect and a reduction in oxidative stress.


Assuntos
Diabetes Insípido Nefrogênico , Diabetes Mellitus Tipo 2 , Metformina , Animais , Aquaporina 2 , Diabetes Insípido Nefrogênico/induzido quimicamente , Diabetes Insípido Nefrogênico/prevenção & controle , Humanos , Lítio , Metformina/farmacologia , Ratos
10.
Nutrients ; 13(10)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34684418

RESUMO

Maternal high-fat (HF) diet is associated with offspring metabolic disorder. This study intended to determine whether maternal metformin (MT) administration during gestation and lactation prevents the effect of maternal HF diet on offspring's skeletal muscle (SM) development and metabolism. Pregnant Sprague-Dawley rats were divided into four groups according to maternal diet {CHOW (11.8% fat) or HF (60% fat)} and MT administration {control (CT) or MT (300 mg/kg/day)} during gestation and lactation: CH-CT, CH-MT, HF-CT, HF-MT. All offspring were weaned on CHOW diet. SM was collected at weaning and 18 weeks in offspring. Maternal metformin reduced plasma insulin, leptin, triglyceride and cholesterol levels in male and female offspring. Maternal metformin increased MyoD expression but decreased Ppargc1a, Drp1 and Mfn2 expression in SM of adult male and female offspring. Decreased MRF4 expression in SM, muscle dysfunction and mitochondrial vacuolization were observed in weaned HF-CT males, while maternal metformin normalized them. Maternal metformin increased AMPK phosphorylation and decreased 4E-BP1 phosphorylation in SM of male and female offspring. Our data demonstrate that maternal metformin during gestation and lactation can potentially overcome the negative effects of perinatal exposure to HF diet in offspring, by altering their myogenesis, mitochondrial biogenesis and dynamics through AMPK/mTOR pathways in SM.


Assuntos
Lactação/efeitos dos fármacos , Exposição Materna , Metformina/farmacologia , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Peso Corporal , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Idade Gestacional , Lactação/metabolismo , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Desenvolvimento Muscular/genética , Fenótipo , Gravidez , Ratos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
11.
Biomed Pharmacother ; 144: 112230, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34628168

RESUMO

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Imunidade Celular/efeitos dos fármacos , Metformina/uso terapêutico , Índice de Gravidade de Doença , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Imunidade Celular/fisiologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Metformina/farmacologia , Mortalidade/tendências , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/imunologia , Serina-Treonina Quinases TOR/metabolismo
12.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502314

RESUMO

Diabetes is a major risk factor for the development of cardiovascular disease with a higher incidence of myocardial infarction. This study explores the role of metformin, a first-line antihyperglycemic agent, in postinfarction fibrotic and inflammatory remodeling in mice. Three-month-old C57BI/6J mice were submitted to 30 min cardiac ischemia followed by reperfusion for 14 days. Intraperitoneal treatment with metformin (5 mg/kg) was initiated 15 min after the onset of reperfusion and maintained for 14 days. Real-time PCR was used to determine the levels of COL3A1, αSMA, CD68, TNF-α and IL-6. Increased collagen deposition and infiltration of macrophages in heart tissues are associated with upregulation of the inflammation-associated genes in mice after 14 days of reperfusion. Metformin treatment markedly reduced postinfarction fibrotic remodeling and CD68-positive cell population in mice. Moreover, metformin resulted in reduced expression of COL3A1, αSMA and CD68 after 14 days of reperfusion. Taken together, these results open new perspectives for the use of metformin as a drug that counteracts adverse myocardial fibroticand inflammatory remodeling after MI.


Assuntos
Fibrose/tratamento farmacológico , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Metformina/farmacologia , Infarto do Miocárdio/complicações , Miocárdio/patologia , Animais , Fibrose/etiologia , Fibrose/patologia , Inflamação/etiologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Remodelação Ventricular
13.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502402

RESUMO

Microglial functioning depends on Ca2+ signaling. By using Ca2+ sensitive fluorescence dye, we studied how inhibition of mitochondrial respiration changed spontaneous Ca2+ signals in soma of microglial cells from 5-7-day-old rats grown under normoxic and mild-hypoxic conditions. In microglia under normoxic conditions, metformin or rotenone elevated the rate and the amplitude of Ca2+ signals 10-15 min after drug application. Addition of cyclosporin A, a blocker of mitochondrial permeability transition pore (mPTP), antioxidant trolox, or inositol 1,4,5-trisphosphate receptor (IP3R) blocker caffeine in the presence of rotenone reduced the elevated rate and the amplitude of the signals implying sensitivity to reactive oxygen species (ROS), and involvement of mitochondrial mPTP together with IP3R. Microglial cells exposed to mild hypoxic conditions for 24 h showed elevated rate and increased amplitude of Ca2+ signals. Application of metformin or rotenone but not phenformin before mild hypoxia reduced this elevated rate. Thus, metformin and rotenone had the opposing fast action in normoxia after 10-15 min and the slow action during 24 h mild-hypoxia implying activation of different signaling pathways. The slow action of metformin through inhibition of complex I could stabilize Ca2+ homeostasis after mild hypoxia and could be important for reduction of ischemia-induced microglial activation.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Metformina/farmacologia , Animais , Cafeína/farmacologia , Sinalização do Cálcio/fisiologia , Cromanos/farmacologia , Ciclosporina/farmacologia , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Hipóxia/genética , Hipóxia/metabolismo , Masculino , Metformina/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Neurônios/metabolismo , Cultura Primária de Células , Ratos , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologia
14.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576111

RESUMO

Mitochondrial functional abnormalities or quantitative decreases are considered to be one of the most plausible pathogenic mechanisms of Parkinson's disease (PD). Thus, mitochondrial complex inhibitors are often used for the development of experimental PD. In this study, we used rotenone to create in vitro cell models of PD, then used these models to investigate the effects of 1,5-anhydro-D-fructose (1,5-AF), a monosaccharide with protective effects against a range of cytotoxic substances. Subsequently, we investigated the possible mechanisms of these protective effects in PC12 cells. The protection of 1,5-AF against rotenone-induced cytotoxicity was confirmed by increased cell viability and longer dendritic lengths in PC12 and primary neuronal cells. Furthermore, in rotenone-treated PC12 cells, 1,5-AF upregulated peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) expression and enhanced its deacetylation, while increasing AMP-activated protein kinase (AMPK) phosphorylation. 1,5-AF treatment also increased mitochondrial activity in these cells. Moreover, PGC-1α silencing inhibited the cytoprotective and mitochondrial biogenic effects of 1,5-AF in PC12 cells. Therefore, 1,5-AF may activate PGC-1α through AMPK activation, thus leading to mitochondrial biogenic and cytoprotective effects. Together, our results suggest that 1,5-AF has therapeutic potential for development as a treatment for PD.


Assuntos
Frutose/análogos & derivados , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Biogênese de Organelas , Rotenona/toxicidade , Adenilato Quinase/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Frutose/química , Frutose/farmacologia , Inativação Gênica/efeitos dos fármacos , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Células PC12 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação/efeitos dos fármacos , Ratos
15.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576192

RESUMO

The Warburg effect is important for cancer cell proliferation. This phenomenon can be flexible by interaction between glycolysis and mitochondrial oxidation for energy production. We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of DCA and metformin were evaluated in HCC murine model. The results showed that metformin and DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A combination treatment of metformin and DCA significantly suppressed the tumor growth of liver cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with advanced liver cancer.


Assuntos
Carcinoma Hepatocelular/metabolismo , Ácido Dicloroacético/farmacologia , Neoplasias Hepáticas/metabolismo , Metformina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Células Hep G2 , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo
16.
Dent Med Probl ; 58(3): 343-349, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34491005

RESUMO

BACKGROUND: Considering the complications associated with autogenous bone grafting, the use of freezedried bone allograft (FDBA) granules may be considered as an alternative treatment plan. OBJECTIVES: The aim of this study was to evaluate the effect of metformin on both the proliferation and osteogenic capability of dental pulp stem cells (DPSCs) cultured on FDBA granules. MATERIAL AND METHODS: First, a pilot study was conducted only on DPSCs to confirm cellular viability and the osteoinducing effect of 100 µmol/L metformin. Next, the cells were loaded on FDBA granules and treated with and without metformin. Finally, the following analyses were performed: scanning electron microscopy (SEM) (cell attachment); the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (proliferation); and alkaline phosphatase (ALP) activity analysis (osteogenic differentiation). RESULTS: The SEM images revealed that metformin enhanced the adhesion of DPSCs on FDBA granules. In addition, metformin was shown to increase cell proliferation/viability from day 1 to day 7. Compared to the control, a significant difference was observed after 7 days of treatment. Metformin enhanced the osteogenic capability of FDBA in both standard and osteoinducing conditions. An increase in ALP activity was significant after 7 days of treatment. The positive effect of metformin on differentiation was significant in osteoinducing conditions. CONCLUSIONS: Metformin can be applied as an additional osteoinductive factor in bone regeneration treatment. Moreover, scaffolds with controlled release of metformin can be considered a proper osteoinductive bone substitute that may lessen the complications related to applying allograft scaffolds alone.


Assuntos
Polpa Dentária , Metformina , Aloenxertos , Transplante Ósseo , Células Cultivadas , Metformina/farmacologia , Osteogênese , Projetos Piloto , Células-Tronco
17.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502073

RESUMO

Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is associated with skeletal muscle wasting and fatigue. The purpose of this study was to assess muscle function in situ following DOX administration in mice. Furthermore, pre-treatments with exercise (EX) or metformin (MET) were used in an attempt to preserve muscle function following DOX. Mice were assigned to the following groups: control, DOX, DOX + EX, or DOX + MET, and were given a single injection of DOX (15 mg/kg) or saline 3 days prior to sacrifice. Preceding the DOX injection, DOX + EX mice performed 60 min/day of running for 5 days, while DOX + MET mice received 5 daily oral doses of 500 mg/kg MET. Gastrocnemius-plantaris-soleus complex function was assessed in situ via direct stimulation of the sciatic nerve. DOX treatment increased time to half-relaxation following contractions, indicating impaired recovery (p < 0.05). Interestingly, EX prevented any increase in half-relaxation time, while MET did not. An impaired relaxation rate was associated with a reduction in SERCA1 protein content (p = 0.07) and AMPK phosphorylation (p < 0.05). There were no differences between groups in force production or mitochondrial respiration. These results suggest that EX, but not MET may be an effective strategy for the prevention of muscle fatigue following DOX administration in mice.


Assuntos
Metformina/farmacologia , Fadiga Muscular , Músculo Esquelético/fisiologia , Corrida , Animais , Doxorrubicina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Quinases/metabolismo
18.
Theriogenology ; 175: 7-22, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34481229

RESUMO

Metformin is a commonly used for treating type 2 diabetes and it acts on a variety of organs including the male reproductive system. 17ß-estradiol plays an important role in Sertoli cell (SC) proliferation which determines the germ cell development and spermatogenesis. The aim of this study is to investigate the effect of metformin on immature chicken SC proliferation and the potential mechanisms by which 17ß-estradiol regulate this process. Results showed that metformin significantly inhibited SC proliferation, whereas 17ß-estradiol weakened the inhibitory effects of metformin on SC viability, cell growth, and cell cycle progression. SC proliferation-inhibiting effect of metformin exposure was regulated by decreasing adenosine triphosphate level and respiratory enzyme activity in the mitochondria; this process was possibly mediated by the adenosine monophosphate-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR) signaling pathway, which was regulated by the down-expressed miR-1764 and by the decreased antioxidant enzyme activity and excessive reactive oxygen species generation. In addition, SCs transfected with the miR-1764 agomir led to an improvement of proliferation capacity through down-regulating AMPKα2 level, which further decreased TSC2 expression and induced mTOR activation. However, the anti-proliferative effect of miR-1764 antagomir can be alleviated by 17ß-estradiol treatment via the up-expression of miR-1764 in transfected SCs. Our findings suggest appropriate dose of exogenous 17ß-estradiol treatment can ameliorate the inhibitory effect of metformin on SC proliferation via the regulation of AMPK/TSC2/mTOR signaling pathway, this might reduce the risk of poor male fertility caused by the abuse of anti-diabetic agents.


Assuntos
Estradiol , Metformina , Células de Sertoli/efeitos dos fármacos , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proliferação de Células , Galinhas , Estradiol/farmacologia , Masculino , Metformina/farmacologia , Células de Sertoli/citologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa
19.
Elife ; 102021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34544550

RESUMO

Aging is associated with central fat redistribution and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived stromal cells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25 years) or older women (>60 years). Increased cell passages of young-donor ASCs (in vitro aging) resulted in senescence but not oxidative stress. ASC-derived adipocytes presented impaired adipogenesis but no early mitochondrial dysfunction. Conversely, aged-donor ASCs at early passages displayed oxidative stress and mild senescence. ASC-derived adipocytes exhibited oxidative stress, and early mitochondrial dysfunction but adipogenesis was preserved. In vitro aging of aged-donor ASCs resulted in further increased senescence, mitochondrial dysfunction, oxidative stress, and severe adipocyte dysfunction. When in vitro aged young-donor ASCs were treated with metformin, no alteration was alleviated. Conversely, metformin treatment of aged-donor ASCs decreased oxidative stress and mitochondrial dysfunction resulting in decreased senescence. Metformin's prevention of oxidative stress and of the resulting senescence improved the cells' adipogenic capacity and insulin sensitivity. This effect was mediated by the activation of AMP-activated protein kinase as revealed by its specific inhibition and activation. Overall, aging ASC-derived adipocytes presented impaired adipogenesis and insulin sensitivity. Targeting stress-induced senescence of ASCs with metformin may improve age-related adipose tissue dysfunction.


Assuntos
Adipócitos/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Metformina/farmacologia , Proteínas Quinases Ativadas por AMP , Adipócitos/metabolismo , Adipócitos/patologia , Envelhecimento/patologia , Células Cultivadas , Feminino , Humanos , Resistência à Insulina , Pessoa de Meia-Idade , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Adulto Jovem
20.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
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