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1.
Anticancer Res ; 40(1): 121-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892560

RESUMO

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Metformina/farmacologia , Biomarcadores , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 40(1): 153-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892563

RESUMO

BACKGROUND/AIM: In this study, we evaluated the effect of galloflavin, an inhibitor of lactate dehydrogenase, in combination with metformin, an anti-diabetic drug and inhibitor of oxidative phosphorylation, on pancreatic ductal adenocarcinoma cells. MATERIALS AND METHODS: We explored the effect of galloflavin and metformin on proliferation and cell death of murine 6606PDA and human MIA PaCa-2 cells. RESULTS: We observed that monotherapies of galloflavin and metformin both inhibit proliferation and induce cancer cell death. Moreover, the combination of both agents increased these effects on pancreatic ductal adenocarcinoma cells. The inhibition of proliferation by this combination therapy can be detected under hypoxic and normoxic conditions, leading to the assumption that this therapy might impair insufficiently supplied solid tumors as well as small clusters of cancer cells, e.g. after metastatic dissemination. CONCLUSION: Galloflavin, especially in combination with metformin, has a strong anti-cancerous effect on pancreatic ductal adenocarcinoma cells.


Assuntos
Antineoplásicos/farmacologia , Isocumarinas/farmacologia , Metformina/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/farmacologia , Ácido Láctico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo
3.
J Endod ; 46(1): 65-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753516

RESUMO

INTRODUCTION: We have previously shown that intracanal metformin ameliorates apical periodontitis, partially by modulation of osteoblast apoptosis. The action of metformin on other cell types pertinent to the development of apical periodontitis needs to be examined. In the present study, we aimed to analyze whether its effects on the expression of inducible nitric oxide synthase (iNOS) and monocyte recruitment contribute to the therapeutic effect on apical periodontitis. METHODS: Lipopolysaccharide (LPS)-induced expression of iNOS in a human monocytic cell line, Mono-Mac-6, was assessed by Western blot. The amount of nitrite in culture medium was assessed to quantify nitric oxide (NO) production. C-C motif chemokine ligand-2 (CCL-2) synthesis was measured by enzyme-linked immunosorbent assay. Experimental apical periodontitis in rats was treated with root canal debridement with or without intracanal metformin medication. Lesion progression was assessed by conventional radiography and micro-computed tomographic imaging. Cellular expression of iNOS and the number of monocytes/macrophages were assessed by immunohistochemistry. RESULTS: Metformin suppressed LPS-induced iNOS and NO production by monocytes. More importantly, metformin inhibited LPS-enhanced CCL-2 synthesis through modulation of the iNOS/NO pathway. Intracanal metformin reduced bone resorption associated with apical periodontitis and suppressed iNOS expression and monocyte recruitment. CONCLUSIONS: Our results confirmed the therapeutic efficacy of intracanal metformin for apical periodontitis. Suppression of monocyte recruitment through modulation of iNOS expression and NO production is an important mechanism underlying the beneficial effect of metformin.


Assuntos
Metformina , Óxido Nítrico Sintase Tipo II , Periodontite Periapical , Animais , Cavidade Pulpar , Humanos , Lipopolissacarídeos , Metformina/administração & dosagem , Metformina/farmacologia , Monócitos , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Periodontite Periapical/tratamento farmacológico , Periodontite Periapical/enzimologia , Ratos
4.
Adv Exp Med Biol ; 1185: 477-481, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884657

RESUMO

Evidence suggests that metabolic dysregulation plays an important role in disease etiology of retinal degenerations. Several studies suggest that preserving the retinal metabolic ecosystem may be protective against retinal degenerations. We investigated whether activation of 5' adenosine monophosphate protein kinase (AMPK) is protective to the retina in several preclinical mouse models of retinal degeneration and found that metformin-induced activation of AMPK was able to delay or prevent retinal degeneration in the rd10 model of retinitis pigmentosa, the NaIO3 model of RPE and retinal injury, and the light damage model of retinal degeneration. This protection was associated with increased mitochondrial DNA copy number, increased levels of ATP, and a reduction in oxidative stress and oxidative DNA damage. We propose that AMPK plays an important role in regulation of the retinal metabolic ecosystem and that activation of AMPK may promote metabolic processes to prevent retinal degeneration.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Retina/enzimologia , Degeneração Retiniana/prevenção & controle , Animais , Dano ao DNA , DNA Mitocondrial/genética , Modelos Animais de Doenças , Dosagem de Genes , Metformina/farmacologia , Camundongos , Estresse Oxidativo , Retinite Pigmentosa/enzimologia , Retinite Pigmentosa/prevenção & controle
5.
Life Sci ; 236: 116906, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614147

RESUMO

AIMS: The anti-hyperglycemic action of metformin on skeletal muscles is presently unclear. Long noncoding RNAs (lncRNAs) are implicated in multiple cellular functions. This study aims to explore the role of lncRNAs in the glucometabolic action of metformin on skeletal muscle cells. MAIN METHODS: Metformin accumulation was assessed using [14C]-metformin. A lncRNA array was used to investigate metformin-regulated lncRNAs in C2C12 skeletal muscle cells. Knockdown studies were applied to evaluate the function of lncRNA Dreh. A colorimetric assay was used for the measurement of medium glucose concentration; glucose transport was assessed using [3H]-2-deoxyglucose; real-time PCR was used for RNA expression analysis, and western blotting was used to assess protein expression in myotubes. A Dreh overexpression plasmid was transfected into the cells. KEY FINDINGS: Metformin accumulated in C2C12 myotubes. Metformin reduced medium glucose concentration and repressed lncRNA Dreh expression in the myotubes. Knockdown of Dreh in the myotubes resulted in reduced glucose concentration in the culture medium, increased glucose transport, and increased levels of GLUT4 protein in the plasma membrane. Overexpression of Dreh attenuated the glucose-lowering effect of metformin in myotubes. SIGNIFICANCE: The glucoregulatory actions of metformin are mediated in part by a lncRNA, Dreh, in the skeletal muscle cells. Dreh is a novel regulator for glucose transport and could be a therapeutic target for diabetes.


Assuntos
Glucose/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , RNA Longo não Codificante/genética , Animais , Transporte Biológico , Linhagem Celular , Regulação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos
6.
Nat Neurosci ; 22(11): 1806-1819, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636448

RESUMO

Prediabetes and Alzheimer's disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates CDK5 and interferes with the GSK3ß-induced degradation of ß-catenin. CDK5 contributes to neuronal cell death while ß-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer's disease are described.


Assuntos
Envelhecimento/fisiologia , Ciclo Celular/fisiologia , Senescência Celular/fisiologia , Hiperinsulinismo/fisiopatologia , Resistência à Insulina/fisiologia , Neurônios/fisiologia , Animais , Morte Celular/fisiologia , Senescência Celular/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Hiperinsulinismo/líquido cefalorraquidiano , Potenciais Pós-Sinápticos Inibidores/fisiologia , Insulina/farmacologia , Liraglutida/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Metformina/farmacologia , Camundongos , Neurônios/metabolismo , Fosfotransferases/metabolismo , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitinação/fisiologia , beta Catenina/metabolismo
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1387-1394, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607288

RESUMO

OBJECTIVE: To investigate the effect of metformin on the proliferation, apoptosis and energy metabolism of acute myeloid leukemia (AML) K562 cells and the possible mechanism. METHODS: Different doses (0, 5, 10, 20 and 30 mmol/L) of metformin was added into the K562 cells, which were cultivated for 24 h, 48 h and 72 h. The inverted optical microscope was used to observe the cell growth, CCK 8 was used to detect the cell vitality. The appropriate metformin doses (0, 10, 20 and 30 mmol/L) and the best time (48 h) were selected for subsequent experiments. The flow cytometer with Annexin V-FITC /PI doulde staining was used to detect apoptosis; the glucose detection kit and lactate detection kit were used to detect glucose consumption and lactate production; fluorescence quantitative PCR was used to detect glycolysis-related gene expression, and Western blot was used to detect protein expression. RESULTS: Metformin inhibited the proliferation of K562 cells in a dose-dependent manner (r=0.92), and the relative survival in the 30 mmol/L group was as low as 19.84% at 72 h. When treated with metformin for 48 h, the apoptosis rates of 0, 10, 20 and 30 mmol/L groups were 5.14%, 12.19%, 26.29% and 35.5%, respectively. Compared with the control group, the glucose consumption and lactate secretion of K562 cells treated with metformin were significantly reduced (P<0.05), and showed a dose-dependent effect(r=0.94,r=0.93,respectively). Metformin inhibited the expression of GLUT1, LDHA, ALDOA, PDK1, and PGK1 genes of K562 cells (P<0.05) showing a dose-dependent manner(r=0.83,r=0.80,r=0.72,r=0.76,r=0.73,respectively). Metformin inhibited the expression of P-Akt, P-S6, GLUT1, LDHA proteins of K562 cells(P<0.05), showing a dose-dependent relationship(r=0.80,r=0.92,r=0.83,r=0.92,respectively). CONCLUSION: Metformin can inhibit the growth and proliferation of K562 cells and promote the apoptosis of K562 cells by inhibiting glycolysis energy metabolism. PI3K/Akt/mTOR signaling pathway may be one of the molecular mechanisms of metformin on k562 cells.


Assuntos
Metformina/farmacologia , Apoptose , Proliferação de Células , Glicólise , Humanos , Células K562 , Fosfatidilinositol 3-Quinases
8.
Rev Assoc Med Bras (1992) ; 65(9): 1144-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618328

RESUMO

OBJECTIVE: In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS: A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS: The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION: The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.


Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Muco do Colo Uterino/efeitos dos fármacos , Clomifeno/farmacologia , Quimioterapia Combinada , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto Jovem
9.
Anticancer Res ; 39(9): 4699-4709, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519569

RESUMO

BACKGROUND/AIM: Metformin, a drug for type 2 diabetes, also exerts anticancer effects. This study addressed the immunological effects of metformin on peritoneal dissemination. MATERIALS AND METHODS: We developed a mouse model of peritoneal dissemination via intraperitoneal injection of RLmale1, an X-ray-induced leukemia cell line, into BALB/c mice. Cell-surface markers, cytokine production, and myeloid-derived suppressor cells (MDSCs) were examined in cells from spleen and peritoneal lavage fluid. RESULTS: Metformin-treated mice exhibited suppressed intraperitoneal tumor growth and extended survival, and these effects were lost in mice with severe combined immunodeficiency. MDSCs induction was inhibited in metformin-treated mice. Although MDSC mobilization into the peritoneal cavity was correlated with suppression of interferon-γ production by tumor-infiltrating lymphocytes, the T-helper 1 ability of these lymphocytes was preserved in metformin-treated mice. CONCLUSION: Our findings demonstrate the action of metformin on both intraperitoneal tumors and immune-suppressive cells and might contribute to the development of immunotherapy against peritoneal dissemination.


Assuntos
Imunomodulação/efeitos dos fármacos , Metformina/farmacologia , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Masculino , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Metástase Neoplásica , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/mortalidade , Modelos de Riscos Proporcionais , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Commun ; 10(1): 4303, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541100

RESUMO

Glucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting. The regulatory factors that are involved in fasting glucagon response are not well understood. Here we report a role of p52, a key activator of the noncanonical nuclear factor-kappaB signaling, in hepatic glucagon response. We show that p52 is activated in livers of HFD-fed and glucagon-challenged mice. Knockdown of p52 lowers glucagon-stimulated hyperglycemia, while p52 overexpression augments glucagon response. Mechanistically, p52 binds to phosphodiesterase 4B promoter to inhibit its transcription and promotes cAMP accumulation, thus augmenting the glucagon response through cAMP/PKA signaling. The anti-diabetic drug metformin and ginsenoside Rb1 lower blood glucose at least in part by inhibiting p52 activation. Our findings reveal that p52 mediates glucagon-triggered hepatic gluconeogenesis and suggests that pharmacological intervention to prevent p52 processing is a potential therapeutic strategy for diabetes.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Glucagon/metabolismo , Fígado/metabolismo , Subunidade p52 de NF-kappa B/metabolismo , Animais , Glicemia , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Jejum/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Ginsenosídeos , Gluconeogênese , Glucose/metabolismo , Células Hep G2 , Humanos , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p52 de NF-kappa B/antagonistas & inibidores , Subunidade p52 de NF-kappa B/genética , Regiões Promotoras Genéticas , Transdução de Sinais
11.
Nat Commun ; 10(1): 4146, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515476

RESUMO

In vitro gut microbiome models could provide timely and cost-efficient solutions to study microbiome responses to drugs. For this purpose, in vitro models that maintain the functional and compositional profiles of in vivo gut microbiomes would be extremely valuable. Here, we present a 96-deep well plate-based culturing model (MiPro) that maintains the functional and compositional profiles of individual gut microbiomes, as assessed by metaproteomics, while allowing a four-fold increase in viable bacteria counts. Comparison of taxon-specific functions between pre- and post-culture microbiomes shows a Pearson's correlation coefficient r of 0.83 ± 0.03. In addition, we show a high degree of correlation between gut microbiome responses to metformin in the MiPro model and those in mice fed a high-fat diet. We propose MiPro as an in vitro gut microbiome model for scalable investigation of drug-microbiome interactions such as during high-throughput drug screening.


Assuntos
Microbioma Gastrointestinal , Modelos Biológicos , Filogenia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Contagem de Colônia Microbiana , Microbioma Gastrointestinal/efeitos dos fármacos , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Viabilidade Microbiana/efeitos dos fármacos
12.
Adv Gerontol ; 32(3): 431-438, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512431

RESUMO

In recent years, the effectiveness of high-dose metformin (MF) to treat the endocrine and oncological diseases has been shown. However, the use of high-dose MF may be associated with the lactic acidosis and the liver dysfunctions. The aim of the work was to study the effect of long-term (10 days) oral administration of a relatively high dose of MF (600 mg/kg per day) into yellow C57Bl/6J (Ay/a) Agouti line mice with the melanocortin type obesity on the liver function, which was evaluated by the morphology of hepatocytes and the severity of steatosis, the expression of the inflammatory and apoptotic factors of and the activity of aminotransferases, as well as on the plasma lactate level in the animals. In Agouti line mice, MF (600 mg/kg per day) caused a decrease in the body and fat weight, led to the reduced hyperglycemia, hyperinsulinemia and hyperleptinemia, and restored the sensitivity to glucose and insulin. At the same time, in the liver of Agouti line mice treated with MF, the small-drop and large-drop fatty degeneration and the hydropic degeneration were attenuated, and the expression of pro-inflammatory IL-1ß and pro-apoptotic Bax protein and the Bax/Bcl-2 ratio did not differ from the control C57Bl/6J (a/a) mice. In the blood of Agouti line mice treated with MF, the activity of alanine aminotransferase was normalized, and the lactate levels was increased, but to a moderate degree. It was concluded that the high-dose MF did not induce the lactic acidosis in Agouti line mice, and at the same time it restored the liver functions impaired in the melanocortin obesity. This allows us to consider the use of the high doses of MF as one of the possible ways to treat obesity and metabolic disorders that are associated with the hepatic steatosis.


Assuntos
Fígado , Melanocortinas , Metformina , Obesidade , Animais , Dasyproctidae , Fígado/efeitos dos fármacos , Melanocortinas/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia
13.
Inflammopharmacology ; 27(5): 941-948, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31482259

RESUMO

Metformin (MET), a biguanide oral hypoglycaemic agent, recently has been shown to be effective in various conditions other than type-2 diabetes including cancer, stroke, weight reduction, and polycystic ovarian syndrome, to name a few. MET has also possessed antioxidant and antiinflammatory properties by activation of AMPK . This study was aimed at evaluating the effects of MET on lipopolysaccharide (LPS)-induced systemic and neuroinflammation, oxidative stress, and behavioural changes. The study consisted of six groups, where three selected doses of MET (100, 200, and 300 mg/kg) were employed in male Swiss albino mice, with one group of imipramine (IMI), saline, and LPS each. Systemic inflammation was induced by injecting LPS (1.5 mg/kg) by intraperitoneal route. A battery of behavioural tests including open field, forced swim, and tail suspension tests were employed to assess the impact of systemic inflammation on exploratory behaviour and learned helplessness. LPS induced significant immobility with profound symptoms of sickness behaviour. Furthermore, LPS led to significant increase in serum and brain proinflammatory cytokines TNF-α and IL-6; and also increased lipid peroxidation with reduced glutathione levels. Pretreatment of the animals with 100 and 200 mg/kg of MET significantly reduced both systemic and central inflammatory markers along with protecting against LPS-induced oxidative stress. The higher dose, 300 mg/kg of MET was not effective against most of LPS-induced biochemical changes. Our preliminary results from this study suggest the antiinflammatory and neuroprotective effects of MET in LPS-induced model of sickness behaviour and neuroinflammation.


Assuntos
Encéfalo/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Metformina/farmacologia , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
14.
Acta Crystallogr C Struct Chem ; 75(Pt 9): 1250-1258, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484813

RESUMO

A drug-drug anhydrous pharmaceutical salt containing tolbutamide {systematic name: 3-butyl-1-[(4-methylbenzene)sulfonyl]urea, TOL, C12H18N2O3S} and metformin (systematic name: 1-carbamimidamido-N,N-dimethylmethanimidamide, MET, C4H11N5) was created based on antidiabetic drug combinations to overcome the poor pharmaceutical properties of the parent drugs. Proton transfer and the proportion of the two components were confirmed by 1H NMR spectroscopy and single-crystal X-ray diffraction analysis. Comprehensive characterization of the new pharmaceutical salt crystal, 2-[(dimethylamino)(iminiumyl)methyl]guanidine (butylcarbamoyl)[(4-methylbenzene)sulfonyl]azanide, C4H12N5+·C12H17N2O3S-, was performed and showed enhancement of the pharmaceutical properties, such as lower hygroscopicity and greater accelerated stability than the parent drug MET, and higher solubility and dissolution rate than TOL. The property alterations were correlated with the crystal packing features and potential hydrogen-bonding sites through observed changes in the crystal structures.


Assuntos
Hipoglicemiantes/farmacologia , Metformina/farmacologia , Tolbutamida/farmacologia , Cristalografia por Raios X , Combinação de Medicamentos , Ligações de Hidrogênio , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Metformina/síntese química , Metformina/química , Estrutura Molecular , Solubilidade , Tolbutamida/síntese química , Tolbutamida/química
15.
Mol Carcinog ; 58(11): 2008-2016, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31385375

RESUMO

Treatment of acute myeloid leukemia (AML) is still a challenge because of common relapses or resistance to treatment. Therefore, the development of new therapeutic approaches is necessary. Various studies have shown that certain cancers, including some chemoresistant AML subsets, have upregulated oxidative phosphorylation. In this study, we aimed to assess treatment-resistant AML patients' cell modulation using oxidative phosphorylation inhibitors metformin and atovaquone alone and in various combinations with cytosine analog cytarabine and apoptosis inducer venetoclax. Metabolic activity analysis using Agilent Seahorse XF Extracellular Flux Analyzer revealed that peripheral blood mononuclear cells' metabolic state was different among treatment-resistant AML patients. We demonstrated that metformin decreased therapy-resistant-AML cell oxidative phosphorylation ex vivo, cotreatment with cytarabine and venetoclax slightly increased the effect. However, treatment with atovaquone did not have a marked effect in our experiment. Cell treatment had a slight effect on cell proliferation inhibition; combination of metformin, cytarabine, and venetoclax had the strongest effect. Moreover, a slightly higher effect on cell proliferation and cell cycle regulation was demonstrated in the cells with higher initial oxidative phosphorylation rate as demonstrated by gene expression analysis using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Proteomic analysis by liquid chromatography-mass spectrometry demonstrated that chemoresistant AML cell treatment with metformin modulated metabolic pathways, while metformin combination with cytarabine and venetoclax boosted the effect. We suggest that oxidative phosphorylation inhibition is effective but not sufficient for chemoresistant AML treatment. Indeed, it causes anticancerous changes that might have an important additive role in combinatory treatment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Metformina/farmacologia , Proteômica , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Proteínas de Neoplasias/genética , Fosforilação Oxidativa/efeitos dos fármacos
16.
Mediators Inflamm ; 2019: 1868170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396016

RESUMO

Myeloid angiogenic cells (MAC) derive from hematopoietic stem/progenitor cells (HSPCs) that are mobilized from the bone marrow. They home to sites of neovascularization and contribute to angiogenesis by production of paracrine factors. The number and function of proangiogenic cells are impaired in patients with diabetes or cardiovascular diseases. Both conditions can be accompanied by decreased levels of heme oxygenase-1 (HMOX1), cytoprotective, heme-degrading enzyme. Our study is aimed at investigating whether precursors of myeloid angiogenic cells (PACs) treated with known pharmaceuticals would produce media with better proangiogenic activity in vitro and if such media can be used to stimulate blood vessel growth in vivo. We used G-CSF-mobilized CD34+ HSPCs, FACS-sorted from healthy donor peripheral blood mononuclear cells (PBMCs). Sorted cells were predominantly CD133+. CD34+ cells after six days in culture were stimulated with atorvastatin (AT), acetylsalicylic acid (ASA), sulforaphane (SR), resveratrol (RV), or metformin (Met) for 48 h. Conditioned media from such cells were then used to stimulate human aortic endothelial cells (HAoECs) to enhance tube-like structure formation in a Matrigel assay. The only stimulant that enhanced PAC paracrine angiogenic activity was atorvastatin, which also had ability to stabilize endothelial tubes in vitro. On the other hand, the only one that induced heme oxygenase-1 expression was sulforaphane, a known activator of a HMOX1 inducer-NRF2. None of the stimulants changed significantly the levels of 30 cytokines and growth factors tested with the multiplex test. Then, we used atorvastatin-stimulated cells or conditioned media from them in the Matrigel plug in vivo angiogenic assay. Neither AT alone in control media nor conditioned media nor AT-stimulated cells affected numbers of endothelial cells in the plug or plug's vascularization. Concluding, high concentrations of atorvastatin stabilize tubes and enhance the paracrine angiogenic activity of human PAC cells in vitro. However, the effect was not observed in vivo. Therefore, the use of conditioned media from atorvastatin-treated PAC is not a promising therapeutic strategy to enhance angiogenesis.


Assuntos
Atorvastatina/farmacologia , Meios de Cultivo Condicionados/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Antígeno AC133/metabolismo , Antígenos CD34/metabolismo , Aspirina/farmacologia , Células Cultivadas , Heme Oxigenase-1/metabolismo , Humanos , Imunoensaio , Isotiocianatos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Metformina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Fenótipo , Resveratrol/farmacologia
17.
Adv Exp Med Biol ; 1155: 87-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468388

RESUMO

The present study has investigated the effect of adding taurine (TAU) to a treatment of diabetes with metformin (MET), a hypoglycemic, and lovastatin (LOV), an antihyperlipidemic. To this end, male Sprague-Dawley rats, agent, 250-275 g in weight, were made diabetic with a single 60 mg/kg intraperitoneal (i.p.) dose of streptozocin (STZ) in 10 mM citrate buffer pH 4.5, and, after 14 days, treated daily with oral doses of MET (2.4 mM/kg), LOV (0.075 mM/kg) or TAU (2.4 mM/kg), and with binary and ternary combinations of these agents. Rats receiving only 10 mM citrate buffer pH 4.5 or only STZ served as negative and positive controls, respectively. In addition, rats receiving insulin (INS, 4 units/kg) by the subcutaneous route served as a reference treatment. All the rats were sacrificed on day 57 and their bloods collected into heparinized tubes. The corresponding plasma samples were analyzed for their glucose (GLC), insulin (INS), glycated hemoglobin (HbA1c), cholesterol (CHOL) and triglycerides (TG) contents. In comparison to normal rats, diabetic ones showed marked increases in GLC (+313%), HbA1c (+207%), CHOL (+66%) and TG (+188) and a profound decrease of INS levels (-76%) (p < 0.001 vs. control values). Among the various treatments, one with INS produced the greatest lowering effect on the plasm a GLC (+23%, p < 0.05), INS (+23%, p < 0.05) and TG (+3%), with the remaining changes being similar to those seen with MET. A treatment with MET reduced all the diabetic changes by at least threefold; and one with LOV had a significant (p < 0.001) lowering effect on the plasma CHOL and TG but was without an effect on the plasma GLC, INS and HbA1c. In common with LOV, TAU reduced the diabetic levels of both CHOL and TG and, in addition, reduced the diabetic plasma GLC and raised the corresponding INS level. Among binary combinations, one with LOV-MET provided a greater effect than MET alone only in terms of the plasma CHOL and TG; and one with LOV-TAU was only significantly better than TAU alone in lowering the TG levels. However, a treatment with LOV-MET-TAU led to reductions in all the plasma parameters examined that were much greater than those achieved with any of the individual agents or with their binary combinations (at p ≤ 0.05).


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Lovastatina/farmacologia , Metformina/farmacologia , Taurina/farmacologia , Animais , Glicemia , Carboidratos/sangue , Hipolipemiantes/farmacologia , Insulina , Lipídeos/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina
18.
Nutrients ; 11(8)2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374931

RESUMO

To examine the effects of the alpha-amylase inhibitor isoform 1 called phaseolamin, a standardized extract from white kidney beans (Phaseolus vulgaris L) was tested against the hallmarks of metabolic syndrome. The efficacy of a per os repeated treatment with P. vulgaris extract (500 mg/kg) was compared with metformin (100 mg/kg) and atorvastatin (10 mg/kg) in a model of metabolic syndrome evoked by prolonged high fat diet (HFD; week 1 to week 19) in C57BL/6 mice. Bean extract and compounds administration started after metabolic syndrome establishment (week 11). P. vulgaris extract reduced the body weight overtime, as well as effectively lowered glycaemia, triglycerides, and cholesterol. On week 19, bean extract normalized the HFD-evoked tolerance to glucose and insulin. According to the phytochemical characterization, it inhibited the alpha-amylase activity. Animals treated with the extract were rescued from motor impairments and nociceptive threshold alterations induced by HFD. Specific organs analysis revealed that P. vulgaris extract decreased hepatic steatosis and lipid peroxidation in liver. It protected the heart from HFD oxidative alterations increasing the expression of the detoxifying enzymes catalase and glutathione reductase, and normalizing NADH dehydrogenase level. The histological analysis of aorta showed a protection about the development of fatty streaks in the muscular layers. In conclusion, a prolonged treatment with the standardized extract of P. vulgaris significantly reduced several pathological features related to a metabolic syndrome-like condition; a multifactorial approach that candidates this vegetal product as a possible therapeutic option against metabolic syndrome.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Síndrome Metabólica/tratamento farmacológico , Phaseolus/química , Extratos Vegetais/farmacologia , Lectinas de Plantas/farmacologia , Sementes/química , Animais , Atorvastatina/farmacologia , Comportamento Animal/efeitos dos fármacos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Resistência à Insulina , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/enzimologia , Síndrome Metabólica/patologia , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Lectinas de Plantas/isolamento & purificação , Fatores de Tempo
19.
Mol Carcinog ; 58(11): 1946-1959, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31338907

RESUMO

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased in recent decades due to human papillomavirus (HPV)-mediated oncogenesis. Unfortunately, a growing number of HPV-positive (+) OPSCC survivors are living with the irreversible side effects of treatment. The novel, well-tolerated chemotherapeutics with improved side effect profiles are, therefore, in high demand. Metformin is one such drug, widely used as a first-line oral agent in the treatment of type 2 diabetes mellitus. Curcumin is another well-tolerated agent quickly gaining attention for its medicinal properties. Both metformin and curcumin have been shown to display anticancer properties. This study aimed to determine the antitumor effects of these agents, individually and combined, in HPV+​​​​ ​​​and HPV-negative (-) head and neck squamous cell carcinoma (HNSCC) cell lines. This was achieved by assessing the efficacy of varying drug concentrations on the overall cell viability, proliferation, and expression of common HNSCC biomarkers. The results from protein and RNA expression data are highly variable, as expected, with multiple pathways being affected in cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and immunofluorescence microscopy suggest that both agents are capable of slowing proliferation and inducing apoptosis. We conclude that curcumin and metformin display effective antitumor effects in both HPV+ and HPV- HNSCC cell lines. The curcumin effects appear more pronounced in the HPV- cell lines. Metformin appears to be more effective at reducing the overall cell numbers in HPV+ cell lines. Metformin and curcumin combined did not appear to have synergistic effects on the proliferation or apoptosis of the treated cell lines.


Assuntos
Curcumina/farmacologia , Metformina/farmacologia , Infecções por Papillomavirus/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Antígeno Ki-67/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
20.
Mol Immunol ; 114: 72-80, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31344551

RESUMO

Scleroderma is an inflammatory autoimmune disease characterized by extensive tissue fibrosis. The imbalance of effector T (Teff) and regulatory T (Treg) cells and the production of autoantibodies contribute to the pathogenesis of this disease. Metformin (MET) has anti-inflammatory and anti-fibrotic effects, but its effect on the in vivo pathogenesis of scleroderma remains unknown. Therefore, we investigated the potential therapeutic effects of MET treatment of mice with bleomycin (BLM)-induced scleroderma. Scleroderma was induced in female C57BL mice by daily subcutaneous injections of BLM for 28 days. After each 2 h BLM injection, mice received MET (200, 100 or 50 mg/kg) or saline (control) by intraperitoneal injection. At the end of the fourth week, spleen mononuclear cells were collected for flow cytometry analysis. Skin samples were harvested for immunohistochemistry and quantification of other biological parameters.Our results showed that BLM increased dermal thickness, collagen deposition, and hydroxyproline level, and MET markedly mitigated these effects. MET also restored the Treg/Teff cell balance. Accordingly, the level of IL-17A and RORγt (related to Th17 cells) decreased, but Foxp3 (related to Treg function) increased in a dose-dependent manner. In addition, MET treatment inhibited spleen germinal center formation. These results indicate that the immunomodulatory and anti-fibrosis effects of MET on BLM-induced scleroderma are mediated by the upregulation of Treg cell differentiation, inhibition of Teff cell differentiation, and suppression of spleen germinal center formation. These results suggest that MET may be a potential therapeutic for scleroderma.


Assuntos
Bleomicina/farmacologia , Centro Germinativo/efeitos dos fármacos , Metformina/farmacologia , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológico , Baço/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Centro Germinativo/metabolismo , Hidroxiprolina/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Dermatopatias/metabolismo , Baço/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
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