Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.286
Filtrar
1.
Biomed Res Int ; 2021: 9924314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368359

RESUMO

Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Nicotinamida N-Metiltransferase/metabolismo , Obesidade/enzimologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético , Humanos , Redes e Vias Metabólicas , Terapia de Alvo Molecular , Obesidade/tratamento farmacológico
2.
Life Sci ; 284: 119913, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453944

RESUMO

AIM: Biliverdin reductase-A (BVR-A) other than its canonical role in the degradation pathway of heme as partner of heme oxygenase-1 (HO1), has recently drawn attention as a protein with pleiotropic functions involved in insulin-glucose homeostasis. However, whether BVR-A expression is altered in type 2 diabetes (T2D) has never been evaluated. MAIN METHODS: BVR-A protein levels were evaluated in T2D (n = 44) and non-T2D (n = 29) subjects, who underwent complete clinical workup and routine biochemistry. In parallel, levels HO1, whose expression is regulated by BVR-A as well as levels of tumor necrosis factor α (TNFα), which is a known repressor for BVR-A with pro-inflammatory properties, were also assessed. KEY FINDINGS: BVR-A levels were significantly lower in T2D subjects than in non-T2D subjects. Reduced BVR-A levels were associated with greater body mass, systolic blood pressure, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), triglycerides, transaminases and TNFα, and with lower high-density lipoprotein (HDL) levels. Lower BVR-A levels are associated with reduced HO1 protein levels and the multivariate analysis showed that BVR-A represented the main determinant of HO1 levels in T2D after adjustment. In addition, reduced BVR-A levels were able to predict the presence of T2D with AUROC = 0.69. for potential confounders. SIGNIFICANCE: Our results demonstrate for the first time that BVR-A protein levels are reduced in T2D individuals, and that this alteration strictly correlates with poor glycometabolic control and a pro-inflammatory state. Hence, these observations reinforce the hypothesis that reduced BVR-A protein levels may represent a key event in the dysregulation of intracellular pathways finally leading to metabolic disorders.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Idoso , Feminino , Heme Oxigenase-1/metabolismo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada
3.
Biomed Pharmacother ; 138: 111465, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311522

RESUMO

Acidic mammalian chitinase (CHIA) belongs to the 18-glycosidase family and is expressed in epithelial cells and certain immune cells (such as neutrophils and macrophages) in various organs. Under physiological conditions, as a hydrolase, CHIA can degrade chitin-containing pathogens, participate in Type 2 helper T (Th2)-mediated inflammation, and enhance innate and adaptive immunity to pathogen invasion. Under pathological conditions, such as rhinitis, ocular conjunctivitis, asthma, chronic atrophic gastritis, type 2 diabetes, and pulmonary interstitial fibrosis, CHIA expression is significantly changed. In addition, studies have shown that CHIA has an anti-apoptotic effect, promotes epithelial cell proliferation and maintains organ integrity, and these effects are not related to chitinase degradation. CHIA can also be used as a biomolecular marker in diseases such as chronic atrophic gastritis, dry eye, and acute kidney damage caused by sepsis. Analysis of the authoritative TCGA database shows that CHIA expression in gastric adenocarcinoma, liver cancer, renal clear cell carcinoma and other tumors is significantly downregulated compared with that in normal tissues, but the specific mechanism is unclear. This review is based on all surveys conducted to date and summarizes the expression patterns and functional diversity of CHIA in various organs. Understanding the physiological and pathophysiological relevance of CHIA in multiple organs opens new possibilities for disease treatment.


Assuntos
Encéfalo/enzimologia , Quitinases/metabolismo , Sistema Digestório/enzimologia , Olho/enzimologia , Rim/enzimologia , Sistema Respiratório/enzimologia , Animais , Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/fisiopatologia , Sistema Digestório/fisiopatologia , Olho/fisiopatologia , Humanos , Rim/fisiopatologia , Sistema Respiratório/fisiopatologia , Transdução de Sinais
4.
Biomed Pharmacother ; 138: 111532, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311531

RESUMO

Fufang Zhenzhu Tiaozhi formula (FTZ), a preparation of Chinese herbal medicine, has various pharmacological properties, such as hypoglycemic, hypolipidemic, anticoagulant, and anti-inflammatory activities. Hepatocyte apoptosis is a marker of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. Given the multiple effects of FTZ, we investigated whether FTZ can be a therapeutic agent for NASH and its mechanism. In the present study, we observed that FTZ treatment had an obviously favorable influence on hepatic steatosis and fibrosis in the histopathologic features of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) with NASH minipigs. In addition, immunohistochemical analysis showed increased expression of the fibrotic marker α-smooth muscle actin (α-SMA), and a TUNEL assay revealed increased apoptotic positive hepatic cells in the liver tissues of the model group. Furthermore, FTZ administration reduced the increased expression of α-SMA, and FTZ inhibited apoptosis by affecting Bcl-2/Bax and cleaved caspase-3 expression. Mechanistically, our data suggested that FTZ treatment attenuated hepatic steatosis and fibrosis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. In vitro studies showed that FTZ also attenuated intracellular lipid accumulation in HepG2 cells exposed to palmitic acid (PA) and oleic acid (OA). FTZ upregulated the expression levels of P-AMPK and BCL-2 and downregulated BAX. The changes induced by FTZ were reversed by Compound C, an inhibitor of AMPK. In conclusion, FTZ attenuated NASH by ameliorating steatosis and hepatocyte apoptosis, which is attributable to the regulation of the AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Doença das Coronárias/enzimologia , Doença das Coronárias/etiologia , Doença das Coronárias/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Células Hep G2 , Humanos , Lipídeos/sangue , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/enzimologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco Miniatura
5.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067027

RESUMO

Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Inflamação/enzimologia , Inflamação/patologia , Animais , Doença Crônica , Humanos , Insulina/metabolismo , Modelos Biológicos
6.
Molecules ; 26(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066102

RESUMO

Jamaican cherry (Muntinga calabura Linn.) is tropical tree that is known to produce edible fruit with high nutritional and antioxidant properties. However, its use as functional food is still limited. Previous studies suggest that fermentation with probiotic bacteria could enhance the functional properties of non-dairy products, such as juices. In this study, we analyze the metabolite composition and activity of Jamaican cherry juice following fermentation with Lactobacillus plantarum FNCC 0027 in various substrate compositions. The metabolite profile after fermentation was analyzed using UPLC-HRMS-MS and several bioactive compounds were detected in the substrate following fermentation, including gallic acid, dihydrokaempferol, and 5,7-dihydroxyflavone. We also found that total phenolic content, antioxidant activities, and inhibition of diabetic-related enzymes were enhanced after fermentation using L. plantarum. The significance of its elevation depends on the substrate composition. Overall, our findings suggest that fermentation with L. plantarum FNCC 0027 can improve the functional activities of Jamaican cherry juice.


Assuntos
Antioxidantes/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/metabolismo , Fermentação , Sucos de Frutas e Vegetais/microbiologia , Lactobacillus plantarum/metabolismo , Malvales/metabolismo , Flavonoides/análise , Frutas/química , Frutas/metabolismo , Ácido Gálico/análise , Malvales/química , Fenóis/análise , Probióticos/metabolismo
7.
Int J Biol Macromol ; 184: 289-296, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34119546

RESUMO

Inhibiting the activity of the intestinal enzyme α-amylase that catalyzes the degradation of starch into glucose can control blood glucose and provide an essential way for the treatment of Type-II diabetes mellitus (T2DM). Here, we compared the structural information of chondroitin sulfate (CS) from different origins and the effects on activity of α-amylase and blood glucose have been investigated. The inhibitory effects of shark and porcine CSs against α-amylase activity is obvious with IC50 values of 11.97 and 14.42 mg/ml, respectively, but the bovine CS almost no effect. From the data of fluorescence spectroscopic analyses, CSs from shark and pig quench Try fluorescence intensity of the enzyme, whereas bovine CS induces an increase. In vivo, oral administration of shark and porcine CSs efficiently suppresses postprandial blood glucose levels in normal and diabetic mice. Our study found that CSs from different sources showed different biological functions even if both molecular weight and disaccharide subunit composition are almost the same, and demonstrated that the CSs from shark and pig as α-amylase inhibitors could be regarded as a novel functional food ingredient in T2DM management.


Assuntos
Sulfatos de Condroitina/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , alfa-Amilases/antagonistas & inibidores , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Bovinos , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/enzimologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Masculino , Camundongos , Tubarões , Especificidade da Espécie , Estreptozocina , Suínos , Resultado do Tratamento
8.
Cardiovasc Diabetol ; 20(1): 77, 2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33812377

RESUMO

BACKGROUND: Patients with type 2 diabetes (T2DM) have a prothrombotic state that needs to be fully clarified; microparticles (MPs) have emerged as mediators and markers of this condition. Thus, we investigate, in vivo, in T2DM either with good (HbA1c ≤ 7.0%; GGC) or poor (HbA1c > 7.0%; PGC) glycemic control, the circulating levels of MPs, and in vitro, the molecular pathways involved in the release of MPs from platelets (PMP) and tested their pro-inflammatory effects on THP-1 transformed macrophages. METHODS: In 59 T2DM, and 23 control subjects with normal glucose tolerance (NGT), circulating levels of CD62E+, CD62P+, CD142+, CD45+ MPs were determined by flow cytometry, while plasma levels of ICAM-1, VCAM-1, IL-6 by ELISA. In vitro, PMP release and activation of isolated platelets from GGC and PGC were investigated, along with their effect on IL-6 secretion in THP-1 transformed macrophages. RESULTS: We found that MPs CD62P+ (PMP) and CD142+ (tissue factor-bearing MP) were significantly higher in PGC T2DM than GGC T2DM and NGT. Among MPs, PMP were also correlated with HbA1c and IL-6. In vitro, we showed that acute thrombin exposure stimulated a significantly higher PMP release in PGC T2DM than GGC T2DM through a more robust activation of PAR-4 receptor than PAR-1 receptor. Treatment with PAR-4 agonist induced an increased release of PMP in PGC with a Ca2+-calpain dependent mechanism since this effect was blunted by calpain inhibitor. Finally, the uptake of PMP derived from PAR-4 treated PGC platelets into THP-1 transformed macrophages promoted a marked increase of IL-6 release compared to PMP derived from GGC through the activation of the NF-kB pathway. CONCLUSIONS: These results identify PAR-4 as a mediator of platelet activation, microparticle release, and inflammation, in poorly controlled T2DM.


Assuntos
Glicemia/metabolismo , Plaquetas/enzimologia , Cálcio/metabolismo , Calpaína/metabolismo , Micropartículas Derivadas de Células/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Macrófagos/metabolismo , Ativação Plaquetária , Receptores de Trombina/metabolismo , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Estudos de Casos e Controles , Micropartículas Derivadas de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Receptores de Trombina/agonistas , Células THP-1 , Trombina/farmacologia
9.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916292

RESUMO

Methanolic leaf extracts of four Lauraceae species endemic to Laurisilva forest (Apollonias barbujana, Laurus novocanariensis, Ocotea foetens and Persea indica) were investigated for the first time for their potential to inhibit key enzymes linked to type-2 diabetes (α-amylase, α-glucosidase, aldose reductase) and obesity (pancreatic lipase), and protein glycation. Lauraceae extracts revealed significant inhibitory activities in all assays, altough with different ability between species. In general, P. indica showed the most promissing results. In the protein glycation assay, all analysed extracts displayed a stronger effect than a reference compound: aminoguanidine (AMG). The in vitro anti-diabetic, anti-obesity and anti-glycation activities of analysed extracts showed correlation with their flavonols and flavan-3-ols (in particular, proanthocyanins) contents. These Lauraceae species have the capacity to assist in adjuvant therapy of type-2 diabetes and associated complications, through modulation of the activity of key metabolic enzymes and prevention of advanced glycation end-products (AGEs) formation.


Assuntos
Biomarcadores , Diabetes Mellitus Tipo 2/metabolismo , Glicoproteínas/metabolismo , Hipoglicemiantes/farmacologia , Lauraceae/química , Obesidade/metabolismo , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/química , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/etiologia , Florestas , Glicosilação , Hipoglicemiantes/química , Redes e Vias Metabólicas , Estrutura Molecular , Obesidade/enzimologia , Obesidade/etiologia , Fenóis/química , Extratos Vegetais/química , Ratos
10.
Cardiovasc Diabetol ; 20(1): 90, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906662

RESUMO

BACKGROUND: Diabetic and obese patients are at higher risk of severe disease and cardiac injury in corona virus 2 (SARS-CoV-2) infections. Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in normal hearts. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the human heart and whether treatment with renin-angiotensin system inhibitors or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We designed this study to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice. METHODS: Right atrial appendage biopsies were collected from 79 patients that underwent coronary artery bypass graft (CABG) surgery. We investigated the alteration in ACE2 mRNA and protein expression in heart tissue and serum. ACE2 expression was compared with clinical risk factors: diabetes, obesity and different anti-hypertensive or anti-diabetic therapies. WT or db/db mice were infused with Angiotensin II (ATII), treated with different anti-diabetic drugs (Metformin, GLP1A and SGLT2i) were also tested. RESULTS: ACE2 gene expression was increased in diabetic hearts compared to non-diabetic hearts and was positively correlated with glycosylated hemoglobin (HbA1c), body mass index (BMI), and activation of the renin angiotensin system (RAS), and negatively correlated with ejection fraction. ACE2 was not differentially expressed in patients who were on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prior to the operation. We found no correlation between plasma free ACE2 and cardiac tissue ACE2 expression. Transmembrane serine protease 2 (TMPRSS2), metalloprotease ADAM10 and ADAM17 that facilitate viral-ACE2 complex entry and degradation were increased in diabetic hearts. ACE2 expression in mice was increased with ATII infusion and attenuated following anti-diabetic drugs treatment. CONCLUSION: Patients with uncontrolled diabetes or obesity with RAS activation have higher ACE2 expressions therefore are at higher risk for severe infection. Since ACEi or ARBs show no effect on ACE2 expression in the heart further support their safety.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , Diabetes Mellitus Tipo 2/enzimologia , Cardiomiopatias Diabéticas/enzimologia , Miocárdio/enzimologia , Obesidade/enzimologia , Receptores Virais/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2/patogenicidade , Idoso , Enzima de Conversão de Angiotensina 2/genética , Animais , COVID-19/enzimologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de Risco , SARS-CoV-2/metabolismo , Regulação para Cima
11.
Toxicol Appl Pharmacol ; 421: 115533, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33848515

RESUMO

Decreased activity of AMP-activated protein kinase (AMPK) is implicated in the pathogenesis of diabetic cardiomyopathy (DCM). Recent evidence suggests a crosstalk between cinacalcet and AMPK activation. This study investigated the effects of cinacalcet on cardiac remodeling and dysfunction in type 2 diabetic rats (T2DM). High fat diet for 4 weeks combined with single intraperitoneal injection of streptozotocin (30 mg/kg) was used to induce type 2 diabetes in rats. Diabetic rats were either orally treated with vehicle, 5 or 10 mg/kg cinacalcet for 4 weeks. Control rats were fed standard chow diet and intraperitoneally injected with citrate buffer. T2DM rats showed lower body weight (BW), hyperglycemia and dyslipidemia, along with increased heart weight (HW) and HW/BW ratio. Masson's trichrome stained cardiac sections revealed massive fibrosis in T2DM rats. There were increased TGF-ß1 and hydroxyproline levels, coupled with up-regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in hearts of T2DM rats. These alterations were associated with redox imbalance and impaired cardiac functions. Decreased phosphorylation of AMPK at threonine172 residue was found in T2DM hearts. Cinacalcet for 4 weeks significantly activated AMPK and alleviated cardiac remodeling and dysfunction in a dose-dependent manner, without affecting blood glucose, serum calcium and phosphorus levels. Cinacalcet increased the mitochondrial DNA content, and expressions of PGC-1α, UCP-3, beclin-1 and LC3-II/LC3-I ratio. Cinacalcet decreased the pro-apoptotic Bax, while increased the anti-apoptotic Bcl-2 in cardiac tissue of T2DM rats. These findings might highlight cinacalcet as an alternative therapy to combat the development and progression of DCM.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Cinacalcete/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/enzimologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Fibrose , Hemodinâmica/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Estreptozocina
12.
Mol Cell Biochem ; 476(7): 2675-2684, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33666828

RESUMO

Inhibition of succinate dehydrogenase (SDH) by Dimethyl Malonate (DiMal) reduces cardiac ischemia-reperfusion (IR) injury. We investigated the cardioprotective effect of DiMal in a rat model during advancing type 2 diabetes. Zucker Diabetic Fatty rats and lean controls were investigated corresponding to prediabetes, onset and mature diabetes. Hearts were mounted in an isolated perfused model, and subjected to IR for investigation of infarct size (IS) and mitochondrial respiratory control ratio (RCR). DiMal was administered for 10 min before ischemia. Compared with age-matched non-diabetic rats, prediabetic rats had larger IS (49 ± 4% vs. 36 ± 2%, p = 0.007), rats with onset diabetes smaller IS (51 ± 3% vs. 62 ± 3%, p = 0.05) and rats with mature diabetes had larger IS (79 ± 3% vs. 69 ± 2%, p = 0.06). At the prediabetic stage DiMal did not alter IS. At onset of diabetes DiMal 0.6 mM increased IS in diabetic but not in non-diabetic control rats (72 ± 4% vs. 51 ± 3%, p = 0.003). At mature diabetes DiMal 0.1 and 0.6 mM reduced IS (68 ± 3% vs. 79 ± 3% and 64 ± 5% vs. 79 ± 3%, p = 0.1 and p = 0.01), respectively. DiMal 0.1 mM alone reduced IS in age-matched non-diabetic animals (55 ± 3% vs. 69 ± 2% p = 0.01). RCR was reduced at mature diabetes but not modulated by DiMal. Modulation of SDH activity results in variable infarct size reduction depending on presence and the stage of diabetes. Modulation of SDH activity may be an unpredictable cardioprotective approach.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Traumatismo por Reperfusão Miocárdica , Miocárdio , Succinato Desidrogenase , Animais , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/enzimologia , Miocárdio/patologia , Ratos , Ratos Zucker , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo
13.
Int J Mol Sci ; 22(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668109

RESUMO

Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50-80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky's seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Animais , Diabetes Mellitus Tipo 2/enzimologia , Humanos
14.
Adv Protein Chem Struct Biol ; 124: 47-85, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33632470

RESUMO

Diabetes mellitus has emerged as a severe burden on the medical health system across the globe. Presently, around 422 million people are suffering from diabetes which is speculated to be expanded to about 600 million by 2035. Patients with type 2 diabetes are at increased risk of developing detrimental metabolic and cardiovascular complications. The scientific understanding of this chronic disease and its underlying root cause is not yet fully unraveled. Protein kinases are well known to regulate almost every cellular process through phosphorylation of target protein in diverse signaling pathways. The important role of several protein kinases including AMP-activated protein kinase, IκB kinase and protein kinase C have been well demonstrated in various animal models. They modulate glucose tolerance, inflammation and insulin resistance in the cells via acting on diverse downstream targets and signaling pathways. Thus, modulating the activity of potential human kinases which are significantly involved in diabetes by targeting with small molecule inhibitors could be an attractive therapeutic strategy to tackle diabetes. In this chapter, we have discussed the potential role of protein kinases in glucose metabolism and insulin sensitivity, and in the pathogenesis of diabetes mellitus. Furthermore, the small molecules reported in the literature that can be potentially used for the treatment of diabetes have been discussed in detail.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Animais , Glucose , Intolerância à Glucose , Humanos , Resistência à Insulina , Transdução de Sinais
15.
High Blood Press Cardiovasc Prev ; 28(2): 129-139, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33635533

RESUMO

Ever since its outbreak, Corona Virus Disease 2019(COVID-19) caused by SARS-CoV-2 has affected more than 26 million individuals in more than 200 countries. Although the mortality rate of COVID-19 is low, but several clinical studies showed, patients with diabetes mellitus (DM) or other major complication at high risk of COVID-19 and reported more severe disease and increased fatality. The angiotensin-converting-enzyme 2 (ACE2), a component of renin-angiotensin-system (RAS); acts on ACE/Ang-II/AT1recptor axis, and regulates pathological processes like hypertension, cardiac dysfunction, Acute Respiratory Distress Syndrome (ARDS) etc. The progression of T2DM and hypertension show decreased expression and activity of ACE2. There are several treatment strategies for controlling diabetes, hypertension, etc; like ACE2 gene therapies, endogenous ACE2 activators, human recombinant ACE2 (hrACE2), Angiotensin-II receptor blockers (ARBs) and ACE inhibitors (ACEi) medications. ACE2, the receptors for SARS-CoV2, facilitates virus entry inside host cell. Clinicians are using two classes of medications for the treatment of COVID-19; one targets the SARS-CoV-2-ACE2 interaction, while other targets human immune system. The aim of this review is to discuss the role of ACE2 in diabetes and in COVID-19 and to provide an analysis of data proposing harm and benefit of RAS inhibitor treatment in COVID-19 infection as well as showing no association whatsoever. This review also highlights some candidate vaccines which are undergoing clinical trials.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Animais , Anti-Hipertensivos/uso terapêutico , Antivirais/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , COVID-19/enzimologia , COVID-19/virologia , Vacinas contra COVID-19/uso terapêutico , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/fisiopatologia , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Segurança do Paciente , Medição de Risco , Fatores de Risco , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
16.
Biomed Pharmacother ; 135: 111176, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33401224

RESUMO

We intended to examine the molecular mechanism of action of isorhamnetin (IHN) to regulate the pathway of insulin signaling. Molecular analysis, immunofluorescence, and histopathological examination were used to assess the anti-hyperglycemic and insulin resistance lowering effects of IHN in streptozotocin /high fat diet-induced type 2 diabetes using Wistar rats. At the microscopic level, treatment with IHN resulted in the restoration of myofibrils uniform arrangement and adipose tissue normal architecture. At the molecular level, treatment with IHN at three different doses showed a significant decrease in m-TOR, IGF1-R & LncRNA-RP11-773H22.4. expression and it up-regulated the expression of AKT2 mRNA, miR-1, and miR-3163 in both skeletal muscle and adipose tissue. At the protein level, IHN treated group showed a discrete spread with a moderate faint expression of m-TOR in skeletal muscles as well as adipose tissues. We concluded that IHN could be used in the in ameliorating insulin resistance associated with type 2 diabetes mellitus.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Resistência à Insulina , Insulina/sangue , Miofibrilas/efeitos dos fármacos , Quercetina/análogos & derivados , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Miofibrilas/metabolismo , Miofibrilas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/farmacologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos Wistar , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
17.
J Sci Food Agric ; 101(6): 2294-2303, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33006384

RESUMO

BACKGROUND: Obesity and type 2 diabetes mellitus are the most extended current chronic diseases and also Alzheimer pathology which is a progressive degenerative neurological disorder. Therefore, finding effective enzyme inhibitors responsible for the development of these diseases are essential. Therefore, the aim of this study was to investigate the impact of fruit purée (Cydonia oblonga, Ziziphus jujube and Malus domestica) and pomegranate juice cultivar ('Mollar de Elche' and 'Wonderful') of dried pomegranate sheets (DS) on the inhibition of enzymes associated with metabolic (α-amylase, α-glucosidase, and pancreatic lipase activity), and neurological disorder (acetylcholinesterase and butyrylcholinesterase activity). Quality properties (colour coordinates, texture properties and sensory characteristics) of DS were also studied. In addition, it was researched the effect of storage conditions (4 months at 4 and 20 °C) on phenolic content. RESULTS: DS from jujube had the highest antioxidant capacity and were characterized by the highest storage stability with respect to phenolic compounds. The α-amylase and α-glucosidase half maximal inhibitory concentration (IC50 , in mg mL-1 ) inhibition of DS ranged from 107 to 216 and from 55.2 to values indicating no effect, respectively. The inhibition toward pancreatic lipase (IC50 < 5 mg mL-1 ), acetylcholinesterase (ranged 9.15-22.2%) and butyrylcholinesterase (ranged 20.6-48.6%) was increased with the presence of total flavonoids and hydroxycinnamic acids content (identifying mainly in DS from quinces). It is noteworthy that none of the samples presented off-flavour notes, supporting the high quality of the products. CONCLUSION: DS can be an innovative supplement to a diet as a snack used in the prevention of neurological changes and disorders of carbohydrate and lipid metabolism. © 2020 Society of Chemical Industry.


Assuntos
Doença de Alzheimer/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/química , Sucos de Frutas e Vegetais/análise , Frutas/química , Preparações de Plantas/química , Romã (Fruta)/química , Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Humanos , Lipase/antagonistas & inibidores , Lipase/química , Malus/química , Rosaceae/química , Ziziphus/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química
18.
Med Chem ; 17(3): 264-272, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32851964

RESUMO

BACKGROUND: α-Glucosidase is a hydrolyzing enzyme that plays a crucial role in the degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in carbohydrate mediated diseases such as diabetes mellitus. OBJECTIVE: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. METHODS: These compounds were obtained from the reaction between 4-(bromomethyl)-7- methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence of potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, a docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). RESULTS: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 µM) in comparison to acarbose as a standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, the secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound competes with a substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Moreover, a molecular docking study predicted that this compound interacted with the α-glucosidase active site pocket. CONCLUSION: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for designing potent α-glucosidase inhibitors for the treatment of type 2 diabetes.


Assuntos
Cumarínicos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Tiocarbamatos/química , Tiocarbamatos/farmacologia , alfa-Glucosidases/metabolismo , Simulação por Computador , Diabetes Mellitus Tipo 2/enzimologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Cinética , Simulação de Acoplamento Molecular , Conformação Proteica , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/metabolismo , alfa-Glucosidases/química
19.
Arterioscler Thromb Vasc Biol ; 41(1): e46-e62, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33176446

RESUMO

OBJECTIVE: Diabetic retinopathy, one of retinal vasculopathy, is characterized by retinal inflammation, vascular leakage, blood-retinal barrier breakdown, and neovascularization. However, the molecular mechanisms that contribute to diabetic retinopathy progression remain unclear. Approach and Results: Tpl2 (tumor progression locus 2) is a protein kinase implicated in inflammation and pathological vascular angiogenesis. Nε-carboxymethyllysine (CML) and inflammatory cytokines levels in human sera and in several diabetic murine models were detected by ELISA, whereas liquid chromatography-tandem mass spectrometry analysis was used for whole eye tissues. The CML and p-Tpl2 expressions on the human retinal pigment epithelium (RPE) cells were determined by immunofluorescence. Intravitreal injection of pharmacological inhibitor or NA (neutralizing antibody) was used in a diabetic rat model. Retinal leukostasis, optical coherence tomography, and H&E staining were used to observe pathological features. Sera of diabetic retinopathy patients had significantly increased CML levels that positively correlated with diabetic retinopathy severity and foveal thickness. CML and p-Tpl2 expressions also significantly increased in the RPE of both T1DM and T2DM diabetes animal models. Mechanistic studies on RPE revealed that CML-induced Tpl2 activation and NADPH oxidase, and inflammasome complex activation were all effectively attenuated by Tpl2 inhibition. Tpl2 inhibition by NA also effectively reduced inflammatory/angiogenic factors, retinal leukostasis in streptozotocin-induced diabetic rats, and RPE secretion of inflammatory cytokines. The attenuated release of angiogenic factors led to inhibited vascular abnormalities in the diabetic animal model. CONCLUSIONS: The inhibition of Tpl2 can block the inflammasome signaling pathway in RPE and has potential clinical and therapeutic implications in diabetes-associated retinal microvascular dysfunction.


Assuntos
Inibidores da Angiogênese/farmacologia , Retinopatia Diabética/prevenção & controle , Inflamassomos/antagonistas & inibidores , MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Neovascularização Retiniana/prevenção & controle , Epitélio Pigmentado da Retina/efeitos dos fármacos , Idoso , Animais , Células Cultivadas , Estudos Transversais , Bases de Dados Factuais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/enzimologia , Retinopatia Diabética/enzimologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Feminino , Humanos , Inflamassomos/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Gravidez , Estudos Prospectivos , Proteínas Proto-Oncogênicas/metabolismo , Neovascularização Retiniana/enzimologia , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/patologia , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais
20.
Biomolecules ; 10(11)2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33143193

RESUMO

Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. Ceramide is a heterogeneous lipid entity determined by the length of the fatty acyl chain linked to its carbon backbone sphingosine, which can be generated either by de novo synthesis from serine and palmitoyl-CoA in the endoplasmic reticulum or via sphingomyelin (SM) hydrolysis by sphingomyelinases (SMases). Unlike de novo synthesis, SMase-induced SM hydrolysis represents a rapid and transient mechanism of ceramide generation in specific intracellular sites that accounts for the diverse biological effects of ceramide. Several SMases have been described at the molecular level, which exhibit different pH requirements for activity: neutral, acid or alkaline. Among the SMases, the neutral (NSMase) and acid (ASMase) are the best characterized for their contribution to signaling pathways and role in diverse pathologies, including liver diseases. As part of a Special Issue (Phospholipases: From Structure to Biological Function), the present invited review summarizes the physiological functions of NSMase and ASMase and their role in chronic and metabolic liver diseases, of which the most relevant is nonalcoholic steatohepatitis and its progression to hepatocellular carcinoma, due to the association with the obesity and type 2 diabetes epidemic. A better understanding of the regulation and role of SMases in liver pathology may offer the opportunity for novel treatments of liver diseases.


Assuntos
Diabetes Mellitus Tipo 2/genética , Hepatopatias/genética , Esfingomielina Fosfodiesterase/genética , Esfingomielinas/metabolismo , Ceramidas/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/enzimologia , Hepatopatias/patologia , Transdução de Sinais/genética , Esfingolipídeos/genética , Esfingolipídeos/metabolismo , Esfingomielinas/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...