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1.
Mem Inst Oswaldo Cruz ; 115: e200272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33206822

RESUMO

BACKGROUND: Metformin (MET) is a hypoglycemic drug used for the treatment of diabetes, despite interference in host immunity against microorganisms. Cutaneous infection caused by pathogens such as Leishmania braziliensis (Lb), the agent responsible for cutaneous leishmaniasis (CL) in Brazil, represents an interesting model in which to evaluate the effects associated with MET. OBJECTIVE: To evaluate the modulatory effect of MET in Lb infection. MATERIAL AND METHODS: Experimental study of Lb infection and MET treatment in BALB/c mice and Raw 264.7 macrophages. FINDINGS: MET treatment interfered with lesion kinetics, increased parasite load and reduced macrophage proliferation. Low concentrations of MET in Lb culture allow for the maintenance of stationary parasite growth phase. Lb-infected cells treated with MET exhibited increased parasite load. While both MET and Lb infection alone promoted the production of intracellular reactive oxygen species (ROS), reduced levels of ROS were seen in MET-treated Lb-infected macrophages. MAIN CONCLUSION: Experimental treatment with MET interfered with the kinetics of cutaneous ulceration, increased Lb parasite load, altered ROS production and modulated cellular proliferation. Our experimental results indicate that MET interfere with the evolution of CL.


Assuntos
Leishmania/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Metformina/farmacologia , Animais , Brasil , Leishmania braziliensis , Camundongos , Camundongos Endogâmicos BALB C
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1654-1660, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067969

RESUMO

OBJECTIVE: To investigate the effects of metformin on the proliferation of AML-MDS cells (SKM-1 cells) and its related mechanisms. METHODS: CCK-8 was used to test the cell proliferation; Flow cytometry was used to detect the cell apoptosis and cell cycle; Western blot was used to test the expression level of AMPK and cell cycle regulatory proteins. RESULTS: Metformin could inhibit the proliferation of SKM-1 cells, which may be attributed to metformin-induced cell cycle arrest in G0/G1 but not to metformin induced cell apoptosis. The expression levels of G1-related protein CyclinD1 and CDK4 were down-regulated, while the expression levels of P53, P21CIP1 and P27kIP1 were up-regulated. Moreover, the phosphorylation level of AMPK was up-regulated. CONCLUSION: Metformin inhibits the proliferation of SKM-1 cells, which may relate with AMPK-induced cell cycle arrest. However, future studies are necessary to further explore the related mechanisms.


Assuntos
Metformina , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Metformina/farmacologia
4.
Am J Chin Med ; 48(6): 1409-1433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907360

RESUMO

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut-liver-brain axis.


Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Metformina/administração & dosagem , Metformina/farmacologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/microbiologia , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo
5.
Life Sci ; 261: 118371, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32882267

RESUMO

AIMS: Metformin is a clinical drug administered to patients to treat type 2 diabetes mellitus that was found to be associated with a lower risk of occurrence of cancer and cancer-related death. The present study investigated the effects of metformin on human adipose-derived stromal cells (ADSC) - breast cancer cell line interactions. MAIN METHODS: ADSCs grown from lipoaspirates were tested for growth-stimulating and migration-controlling activity on breast cancer cell lines after pretreatment with metformin. Furthermore, secreted proteins of ADSCs, phosphorylation of intracellular proteins and the effect of metformin on adipocytic differentiation of ADSCs were assayed. KEY FINDINGS: Compared to breast cancer cell lines (4.0 ± 3.5% reduction of proliferation), 2 mM metformin significantly inhibited the proliferation of ADSC lines (19.2 ± 8.4% reduction of proliferation). This effect on ADSCs seems to be mediated by altered phosphorylation of GSK-3, CREB and PRAS40. Furthermore, treatment with metformin abolished the induction of differentiation of three ADSC lines to adipocytes. 1 and 2 mM metformin significantly impaired the migration of breast cancer cell lines MDA-MB-231 and MDA-MB-436 in scratch assays. SIGNIFICANCE: Metformin showed low direct inhibitory effects on breast cancer cell lines at physiological concentrations but exerted a significant retardation of the growth and the adipocytic differentiation of ADSCs. Thus, the anticancer activity of metformin in breast cancer at physiological drug concentrations seems to be mediated by an indirect mechanism that lowers the supportive activity of ADSCs.


Assuntos
Tecido Adiposo/patologia , Neoplasias da Mama/patologia , Metformina/farmacologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/patologia
6.
Front Immunol ; 11: 2056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973814

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Metformina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metformina/efeitos adversos , Metformina/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
7.
Int J Nanomedicine ; 15: 5687-5700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821097

RESUMO

Background and Purpose: Sonodynamic therapy (SDT) has been widely used for the noninvasive treatment of solid tumors, but the hypoxic tumor microenvironment limits its therapeutic effect. The current methods of reoxygenation to enhance SDT have limitations, prompting reconsideration of the design of therapeutic approaches. Here, we developed a tumor microenvironment-responsive nanoplatform by reducing oxygen consumption to overcome hypoxia-induced resistance to cancer therapy. Methods: A pH-responsive drug-loaded liposome (MI-PEOz-lip) was prepared and used to reduce oxygen consumption, attenuating hypoxia-induced resistance to SDT and thereby improving therapeutic efficiency. Photoacoustic imaging (PAI) and fluorescence imaging (FI) of MI-PEOz-lip were evaluated in vitro and in breast xenograft tumor models. The pH-sensitive functionality of MI-PEOz-lip was applied for pH-triggered cargo release, and its capacity was evaluated. The MI-PEOz-lip-mediated SDT effect was compared with other treatments in vivo. Results: MI-PEOz-lip was demonstrated to specifically accumulate in tumors. Metformin molecules in liposomes selectively accumulate in tumors by pH-responsive drug release to inhibit the mitochondrial respiratory chain while releasing IR780 to the tumor area. These pH-responsive liposomes demonstrated PAI and FI imaging capabilities in vitro and in vivo, providing potential for treatment guidance and monitoring. In particular, the prepared MI-PEOz-lip combined with ultrasound irradiation effectively inhibited breast tumors by producing toxic reactive singlet oxygen species (ROS), while the introduction of metformin inhibited mitochondrial respiration and reduced tumor oxygen consumption, resulting in excellent sonodynamic therapy performance compared with other treatments. Conclusion: In this study, we present a novel strategy to achieve high therapeutic efficacy of SDT by the rational design of multifunctional nanoplatforms. This work provides a new strategy that can solve the current problems of inefficient oxygen delivery strategies and weaken resistance to various oxygen-dependent therapies.


Assuntos
Mitocôndrias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Hipóxia Tumoral , Terapia por Ultrassom , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Metformina/farmacologia , Camundongos , Oxigênio/metabolismo , Técnicas Fotoacústicas , Distribuição Tecidual/efeitos dos fármacos , Microambiente Tumoral
8.
Int J Nanomedicine ; 15: 5203-5215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801686

RESUMO

Introduction: Metformin is an ideal candidate to treat the liver tumor with insulin resistance because of its good performance in the treatment of type 2 diabetes and the advantage in cancer therapy. We aim to develop a delivery system with higher efficiency than free drug. Methods: Metformin-bovine serum albumin (met-BSA) nanoparticles (NPs) were prepared using the anti-solvent precipitation method with a stabilizer of BSA for particle growth. The therapeutic effect of the drug was tested by the insulin-resistant HepG2 cells and C57BL/6J mice at a glucose starvation condition. The interaction mechanism of the drug and the protein during the formation of the NPs was tested using a series of spectroscopy. Results: Metformin and BSA formed nonporous and spherical particles of about 200 nm with proper lognormal distribution and thermostability. The cellular uptake, as well as the anti-liver cancer activities of met-BSA, was enhanced dramatically compared with the free drug. The thermodynamic studies suggested that the weak binding of metformin to BSA was governed by hydrogen bonds and van der Waals forces. Moreover, the results of synchronous, circular dichroism (CD) and three-dimensional fluorescence demonstrated that the BSA skeleton and chromophore microenvironments were changed in the presence of metformin. Conclusion: Therefore, met-BSA has been proved as a simple yet effective therapeutic agent for cancer with insulin resistance, promising for future clinic translations in cancer treatment.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Resistência à Insulina , Metformina/farmacologia , Nanopartículas/administração & dosagem , Soroalbumina Bovina/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Dicroísmo Circular , Diabetes Mellitus Tipo 2 , Células Hep G2 , Humanos , Ligação de Hidrogênio , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Metformina/administração & dosagem , Metformina/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Soroalbumina Bovina/química , Termodinâmica , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Medicine (Baltimore) ; 99(30): e21409, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791755

RESUMO

BACKGROUND: This study aim at evaluating the efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes mellitus (T2DM). METHOD: PubMed, Cochrane library, Embase, CNKI and Wanfang databases were searched up to 31 December 2019. Randomized controlled trials (RCTs) applicable in dapagliflozin plus saxagliptin vs monotherapy as added to metformin in the treatment of T2DM were included. The outcomes included changes in HbA1c, FPG, body weight, SBP, DBP and adverse reactions. Fixed or random effects model were used to assess these outcomes. RESULTS: In this study, 8 RCTs involved 7346 patients were included. Compared with dapagliflozin plus metformin(DM) group, patients treated with dapagliflozin plus saxagliptin add on to metformin(DSM) could significantly increase the adjusted mean change levels of HbA1c, FPG, SBP and DBP(P < .00001, SMD = -4.88, 95%CI = -6.93∼-2.83; P < .00001, SMD = -6.50, 95%CI = -8.55∼-4.45; P < .00001, SMD = -0.97, 95%CI = -1.15∼-0.78; P < .00001, SMD = -2.00, 95%CI = -2.20∼-1.80), but no major difference in body weight loss showed(P = .12, SMD = 0.92, 95%CI = -0.22∼2.06). Furthermore, DSM therapy displayed better effects than saxagliptin plus metformin(SM) in the adjusted mean change levels of HbA1c, FPG, body weight and SBP(P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P = .04, SMD = -3.40, 95%CI = -6.64∼-0.17; P = .04, SMD = -7.75, 95%CI = -8.84∼-6.66), whereas no obvious difference in lowering DBP(P = .18, SMD = -16.35, 95%CI = -40.12∼7.41). Additionally, compared with DM and SM groups, there were no remarkable difference in the incidence of nausea, influenza, headache, diarrhea, urinary tract infection and renal failure for patients taking DSM, but the incidence of genital infection and hypoglycemia were higher in DSM group. CONCLUSIONS: Patients taking the DSM therapy had better effects in reducing the level of HbA1c, FPG, body weight, SBP and DBP than the DM and SM therapy. However, patients treated with DSM therapy are more likely to have hypoglycemia and genital infection. Dapagliflozin plus saxagliptin may be a suitable therapy strategy for patients with T2DM inadequately controlled with metformin, and this will provide a clinical reference for the treatment of T2DM.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Quimioterapia Combinada , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
10.
PLoS One ; 15(8): e0237400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780768

RESUMO

Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c ≥ 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log2FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.


Assuntos
Análise Química do Sangue , Perfilação da Expressão Gênica , Metformina/farmacologia , Idoso , Colesterol/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Masculino , Pessoa de Meia-Idade
11.
Int J Nanomedicine ; 15: 4471-4481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606689

RESUMO

Background: Ineffective integration has been recognized as one of the major causes of early orthopedic failure of titanium-based implants. One strategy to address this problem is to develop modified titanium surfaces that promote osteoblast differentiation. This study explored titanium surfaces modified with TiO2 nanotubes (TiO2 NTs) capable of localized drug delivery into bone and enhanced osteoblast cell differentiation. Materials and Methods: Briefly, TiO2 NTs were subjected to anodic oxidation and loaded with Metformin, a widely used diabetes drug. To create surfaces with sustainable drug-eluting characteristics, TiO2 NTs were spin coated with a thin layer of chitosan. The surfaces were characterized via scanning electron microscopy, atomic force microscopy, and contact angle measurements. The surfaces were then exposed to mesenchymal bone marrow stem cells (MSCs) to evaluate cell adhesion, growth, differentiation, and morphology on the modified surfaces. Results: A noticeable increase in drug release time (3 days vs 20 days) and a decrease in burst release characteristics (85% to 7%) was observed in coated samples as compared to uncoated samples, respectively. Chitosan-coated TiO2 NTs exhibited a considerable enhancement in cell adhesion, proliferation, and genetic expression of type I collagen, and alkaline phosphatase activity as compared to uncoated TiO2 NTs. Conclusion: TiO2 NT surfaces with a chitosan coating are capable of delivering Metformin to a bone site over a sustained period of time with the potential to enhance MSCs cell attachment, proliferation, and differentiation.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Quitosana/química , Liberação Controlada de Fármacos , Metformina/farmacologia , Nanotubos/química , Osteoblastos/citologia , Titânio/química , Fosfatase Alcalina/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Nanotubos/ultraestrutura , Osteoblastos/efeitos dos fármacos , Osteoblastos/ultraestrutura , Osteogênese/efeitos dos fármacos , Ratos Wistar , Molhabilidade
12.
Proc Natl Acad Sci U S A ; 117(31): 18591-18599, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690681

RESUMO

Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and G4C2 expansion RNAs activate PKR, which leads to increased levels of multiple RAN proteins. Blocking PKR using PKR-K296R, the TAR RNA binding protein or PKR-KO cells, reduces RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD human and mouse brains, and inhibiting PKR in C9orf72 BAC transgenic mice using AAV-PKR-K296R or the Food and Drug Administration (FDA)-approved drug metformin, decreases RAN proteins, and improves behavior and pathology. In summary, targeting PKR, including by use of metformin, is a promising therapeutic approach for C9orf72 ALS/FTD and other expansion diseases.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Proteína C9orf72 , Metformina/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , eIF-2 Quinase , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Modelos Animais de Doenças , Demência Frontotemporal/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Repetições de Microssatélites/genética , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
13.
PLoS One ; 15(7): e0236603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706828

RESUMO

BACKGROUND AND OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-ß). However, whether HOMA-ß is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-ß and proinsulin-to-insulin ratio (PIR). METHODS: We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-ß or PIR during study periods were calculated for pairwise comparisons. RESULTS: Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-ß and PIR, respectively. HOMA-ß and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-ß showed no significant differences between DPP-4 inhibitors and the two other agents. CONCLUSION: DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-ß or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-ß and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.


Assuntos
Biomarcadores/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Proinsulina/metabolismo , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
14.
Life Sci ; 257: 118066, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652135

RESUMO

AIMS: Understanding the underlying molecular mechanisms involved in epileptogenesis is necessary to target the best therapeutic interventions in epilepsy. Recently, it has been postulated that metformin, an old antidiabetic oral drug, has anti-seizure properties mostly due to its antioxidant activities. This study was designed to evaluate the ameliorative effects of metformin on the progression of epilepsy in the temporal lobe epilepsy model in rats. MAIN METHODS: Temporal lobe Epilepsy was induced by intracerebroventricular microinjection of kainic acid. Metformin was orally administered for two weeks before induction of epilepsy. Anti-epileptogenic activity of metformin was evaluated by intracranial electroencepholography (IEEG) recording to detect spontaneous seizures, mossy fiber sprouting by Timm staining, neurogenesis by BrdU staining. KEY FINDINGS: Oral administration of metformin prior to kainite-induced status epilepticus blocked the variant characterizations of epileptogenesis like neuronal cell death, aberrant neurogenesis, mossy fiber sprouting, and spontaneous seizures. SIGNIFICANCE: These findings indicate that metformin has potential anti-epileptogenic properties in temporal lobe epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Metformina/farmacologia , Administração Oral , Animais , Anticonvulsivantes/administração & dosagem , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/fisiopatologia , Ácido Caínico/toxicidade , Masculino , Metformina/administração & dosagem , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar
15.
Arch Oral Biol ; 116: 104763, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32480011

RESUMO

OBJECTIVES: To investigate the underlying mechanism between diabetic periodontitis and NLR family pyrin domain containing 3 (NLRP3) inflammasome associated pyroptosis. DESIGN: Experimental models of diabetes-associated periodontitis were implemented in db/db mice. We detected NLRP3 inflammasome related cytokines and gasdermin D (GSDMD) both in vitro and in vivo. We performed bioinformatics predictions based on microarray analysis using bone marrow derived macrophages (BMDMs). RESULTS: Diabetes-associated periodontitis mice exhibited the worst fasting glucose and alveolar bone destruction. GSDMD positive cells and NLRP3 inflammasome expression were augmented in gingival tissue, which were partly reversed by metformin. In vitro data suggested NLRP3 inflammasomes stimuli induced cell pyroptotic death and deletion of NLRP3 decreased GSDMD expression. We found a profile of differential lncRNAs expression and three co-expressed lncRNAs of nlrp3 and gsdmd in BMDMs. CONCLUSIONS: Our data show that NLRP3 mediated pyroptosis has a significant role in diabetes-associated periodontitis. The pyroptotic cell death may be the pivot reason of the deteriorated inflammation in this disease, which is ameliorated by metformin treatment. Moreover, the role of both NLRP3 and GSDMD may be regulated by lncRNA_1810058I24Rik, lncRNA_Gm12474 and lncRNA_Gm41514.


Assuntos
Complicações do Diabetes , Diabetes Mellitus , Metformina , Periodontite , Animais , Inflamassomos , Metformina/farmacologia , Camundongos , Quinases Relacionadas a NIMA/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Periodontite/tratamento farmacológico , Periodontite/etiologia , Piroptose
16.
Life Sci ; 256: 117923, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522567

RESUMO

AIMS: Liver kinase B1 (LKB1) deficiency is associated with reduced expression of programmed death ligand 1 (PD-L1) and inferior clinical outcomes of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC). This study aimed to investigate the mechanism by which LKB1 regulates PD-L1 expression and its role in programmed death 1 (PD-1) blockade therapy in NSCLC. MAIN METHODS: The impact of LKB1 on PD-L1 was assessed by western blot, qRT-PCR and immunohistochemistry in NSCLC. Activators/inhibitors of AMPK and NRF2 were applied to explore the mechanisms underlying the regulation of PD-L1 by LKB1. Efficiency of combined application of metformin and PD-1 blockade was evaluated in immunocompetent C57BL/6 mice. KEY FINDINGS: A remarkable positive correlation between LKB1 and PD-L1 expression was demonstrated in NSCLC tissues. Knockdown of LKB1 decreased PD-L1 in TC-1 cells, whereas overexpression of LKB1 increased PD-L1 in A549 cells. We further characterized that AMPK mediated the upregulation of PD-L1 by LKB1. Inhibition of AMPK or NRF2 markedly reduced PD-L1 in LKB1-intact NSCLC cells. In contrast, activation of AMPK or NRF2 reversed PD-L1 expression in LKB1-deficient NSCLC cells. Combined administration of metformin and anti-PD-1 antibody efficiently inhibited the growth of LKB1-intact tumors, whereas no obvious suppression was observed in LKB1-deficient tumors. SIGNIFICANCE: These findings demonstrated that LKB1 upregulates PD-L1 expression in NSCLC by activating the AMPK and KEAP1/NRF2 signaling. Activation of LKB1-AMPK with metformin improves the therapeutic effect of PD-1 blockade in NSCLC with wild-type LKB1.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Metformina/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metformina/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais , Ativação Transcricional , Regulação para Cima
17.
Maturitas ; 137: 1-6, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32498930

RESUMO

BACKGROUND: With the significant improvement of the cure rate and survival rate of cancer patients, the survivors face quality-of-life problems, such as a significant decline in reproductive system development, ovarian reserves and function, and even fertility loss and early menopause. These problems are often highly associated with chemotherapy-induced ovarian damage in cancer treatment. However, there are no ideal treatment strategies at present. In our attempt to develop reagents and approaches for delaying ovarian aging and protecting chemotherapy-induced ovarian injury, we recently found that metformin may be the most promising drug to protect female malignant tumor patients from chemotherapy-induced ovarian injury. This trial aims to test whether administration of metformin during chemotherapy can protect the normal ovarian function of patients with early breast cancer. METHODS: This study is prospective, randomized, double-blind and placebo-controlled. Female patients with early breast cancer (N = 314) will be randomly assigned to two groups (placebo, metformin 2000 mg). Metformin will be administered during and after chemotherapy for patients with stage I-IIIa breast cancer. The primary outcome will be the menstruation recovery rate 12 months after chemotherapy, defined as recovery of menstruation twice in a row within 1 year. Patients will be followed up for 5 years to observe long-term ovarian function and prognosis, such as overall survival (OS), objective response rate (ORR), and disease-free survival (DFS). Quality of life and safety will also be assessed. DISCUSSION: Our research will provide a new treatment strategy for fertility protection, and clinical treatment guidance for cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Menstruação/efeitos dos fármacos , Metformina/uso terapêutico , Ovário/efeitos dos fármacos , Adolescente , Adulto , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Pessoa de Meia-Idade , Testes de Função Ovariana , Ovário/patologia , Ovário/fisiopatologia , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica/efeitos dos fármacos , Taxa de Sobrevida , Adulto Jovem
18.
Clin Sci (Lond) ; 134(12): 1537-1553, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32556103

RESUMO

Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.


Assuntos
Adipócitos/patologia , Tecido Adiposo Bege/patologia , Tecido Adiposo Branco/patologia , Ácidos Graxos não Esterificados/sangue , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Resistência à Insulina , Metformina/uso terapêutico , Células 3T3-L1 , Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Adulto , Animais , Ativação Enzimática , Feminino , Humanos , Hipertrofia , Leptina/metabolismo , Lipogênese , Lipólise , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais , Triglicerídeos/metabolismo , Ácido Úrico/sangue
19.
Cell Prolif ; 53(7): e12809, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32557964

RESUMO

OBJECTIVES: Arecoline is the main bioactive substance extracted from Areca catechu L, which has cell, neural and genetic toxicity. The function of arecoline in reproductive system has not been well explored. MATERIALS AND METHODS: To investigate the toxic effects of arecoline on oocyte development, immunofluorescence staining, qPCR, Western blotting, sperm binding assays and in vitro fertilization were performed to evaluate oocyte meiosis competence and embryo development. RESULTS: Our data revealed that arecoline exposure disrupts actin filament dynamics, spindle assembly and kinetochore-microtubule attachment stability in mouse oocytes, leading to aneuploidy and oocyte meiosis arrest. In addition, arecoline treatment disturbs the distribution of mitochondria, reduces ATP production and increases the level of oxidative stress, which ultimately induces oocyte apoptosis. Supplementation with metformin, a medicine for type 2 diabetes in the clinic, partially alleviates these damages. CONCLUSIONS: Metformin has a protective effect on arecoline-induced mouse oocytes apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Arecolina/farmacologia , Metformina/farmacologia , Oócitos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Meiose/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
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