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1.
Clin Sci (Lond) ; 134(2): 239-259, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31943002

RESUMO

Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif-/-) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif-/- mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif-/- as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.


Assuntos
/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Albuminúria/genética , Albuminúria/metabolismo , Animais , /genética , Ciclosporina/farmacologia , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Peróxido de Hidrogênio/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , ATPases Translocadoras de Prótons/metabolismo
2.
Food Chem Toxicol ; 135: 110937, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31682932

RESUMO

Large prospective cohort studies suggested an important role of cereal insoluble fiber in the prevention and management of type 2 diabetes, which challenge the traditional view that viscosity and solubility are the main driving factors for these beneficial effects of dietary fiber. To evaluate the anti-diabetic effects of insoluble- (BIF) and soluble fibers (BSF) enzymatically isolated from barley, a conventional rat model and a type 2 diabetes rat model were used. Our results showed that 4-week treatment of BIF or BSF effectively reduced FBG in the diabetic condition, with caecal level of propionic acid and minor SCFAs increased by BIF and that of butyric acid and insulin sensitivity improved by BSF, respectively. The two treatments further ameliorated liver function, judged by the recovered serum level of ALT, albumin and total protein levels. BIF and BSF also increased HDL-C and decreased serum MDA. In normal rats, BIF and BSF showed a hypolipidaemic effect in triglycerides and LDL-C, reduced body weight and enhanced the caecal production of minor SCFAs. Furthermore, the two treatments reduced the caecal level of butyric acid while BSF increased that of propionic acid. In conclusion, BIF could exert anti-diabetic effects that might via a different mechanism from BSF.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fibras na Dieta/metabolismo , Ácidos Graxos Voláteis/metabolismo , Hordeum/química , Fígado/metabolismo , Animais , Peso Corporal/fisiologia , Ceco/metabolismo , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Ácidos Graxos Voláteis/sangue , Ratos Wistar , Solubilidade
3.
BMC Complement Altern Med ; 19(1): 326, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752797

RESUMO

BACKGROUND: It has been testified that Diabetes mellitus (DM) has a close association with chronic inflammation and Toll-like Receptors (TLRs), and DM could be prevented by mulberry leaf. Therefore, a hypothesis came into being that mulberry leaf could ameliorate proinflammation and insulin resistance (IR) through TLRs and insulin signalling pathways. METHODS: Water extracts of mulberry leaf (WEM) was given to diabetic mice by gavage for 10 weeks, and the diabetic mice was injected with low-dose streptozocin, fed with high-fat and high-sugar diet. Oral glucose tolerance tests (OGTTs) were conducted. At the same time, homeostasis model assessment of insulin (HOMA-IR) and the level of the inflammatory factor, tumour necrosis factor-α (TNF-α) was measured. The expressions of critical nodes of TLRs and insulin signalling pathway were also examined. RESULTS: WEM contributed to a significant decrease in fasting blood glucose, AUC from the investigation of OGTTs and HOMA-IR. The levels of the inflammatory factor, tumour necrosis factor-α (TNF-α) also declined. Moreover, WEM suppressed the expression of TLR2, myeloid differentiation primary-response protein 88 (MyD88), tumour-necrosis-factor receptor-associated factor 6 (TRAF6), nuclear factor kappa B (NF-κB) in the skeletal muscle. WEM could up-regulate the expression of insulin receptor (InsR) and insulin receptor substrate 1 (IRS1), and down-regulate the phosphorylation of IRS1 in adipose tissue. CONCLUSION: Through this study, a conclusion could be made that WEM mitigates hyperglycemia, IR, and inflammation through the interactions among TLR2 signalling pathway, insulin signalling pathway and TNF-α.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Morus , Extratos Vegetais/farmacologia , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Insulina/sangue , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/sangue , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
4.
Life Sci ; 238: 116971, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634462

RESUMO

AIM: High-fat diet (HFD) intake has been associated with changes in intestinal microbiota composition, increased intestinal permeability, and onset of type 2 diabetes mellitus (T2DM). The aim of this work was twofold: 1) to investigate the structural and functional alterations of the tight junction (TJ)-mediated intestinal epithelial barrier of ileum and colon, that concentrate most of the microbiota, after exposure to a HFD for 15, 30 and 60 days, and 2) to assess the effect of in vitro exposure to free fatty acids (FFAs), one of the components of HFD, on paracellular barrier of colon-derived Caco-2 cells. METHODS/KEY FINDINGS: HFD exposure induced progressive metabolic changes in male mice that culminated in prediabetes after 60d. Morphological analysis of ileum and colon mucosa showed no signs of epithelial rupture or local inflammation but changes in the junctional content/distribution and/or cellular content of TJ-associated proteins (claudins-1, -2, -3, and occludin) in intestinal epithelia were seen mainly after a prediabetes state has been established. This impairment in TJ structure was not associated with significant changes in intestinal permeability to FITC-dextran. Exposure of Caco-2 monolayers to palmitic or linoleic acids seems to induce a reinforcement of TJ structure while treatment with oleic acid had a more diverse effect on TJ protein distribution. SIGNIFICANCE: TJ structure in distal intestinal epithelia can be specifically impaired by HFD intake at early stage of T2DM, but not by FFAs in vitro. Since the TJ change in ileum/colon was marginal, probably it does not contribute to the disease onset.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Mucosa Intestinal/patologia , Estado Pré-Diabético/patologia , Junções Íntimas/patologia , Animais , Células CACO-2 , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocludina , Estado Pré-Diabético/etiologia , Estado Pré-Diabético/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Fatores de Tempo
5.
J Agric Food Chem ; 67(45): 12472-12480, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31642672

RESUMO

Brown macroalgae are an important source of polyphenols with multiple health functions. In this work, polyphenol extracts from Lessonia trabeculate were purified and investigated for the antidiabetic activity in vitro and in vivo. The purified polyphenol extracts exhibited good antioxidant activities, α-glucosidase and lipase inhibition activities (IC50 < 0.25 mg/mL). The HPLC-DAD-ESI-MS/MS analysis indicated that the compounds in polyphenol extracts were mainly phlorotannin derivatives, phenolic acid derivatives, and gallocatechin derivatives. In vivo, C57BL/6J rats treated with polyphenol extracts for 4 weeks had lower fasting blood glucose levels, insulin levels, as well as better serum lipid profiles and antioxidant stress parameters, compared with the diabetic control (DC) group. Histopathology revealed that polyphenol extracts preserved the architecture and function of the liver. Short-chain fatty acid contents in rats' fecal samples with polyphenols administration were significantly recovered as compared with the DC group. Furthermore, the gut microflora of rats was investigated with high-throughput 16S rRNA gene sequencing and results indicated that polyphenol extracts had a positive effect on regulating the dysbiosis of the microbial ecology in diabetic rats. All of the results from the study provided a scientific reference of the potentially beneficial effects of L. trabeculate polyphenols on diabetes management.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Feófitas/química , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Alga Marinha/química , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/microbiologia , Dieta Hiperlipídica/efeitos adversos , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Ratos , Estreptozocina/efeitos adversos
6.
Endocrinology ; 160(12): 2825-2836, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31580427

RESUMO

The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1ß (ARNT/HIF1ß) plays a key role in maintaining ß-cell function and has been shown to be one of the most downregulated transcription factors in islets from patients with type 2 diabetes. We have shown a role for ARNT/HIF1ß in glucose sensing and insulin secretion in vitro and no defects in in vivo glucose homeostasis. To gain a better understanding of the role of ARNT/HIF1ß in the development of diabetes, we placed control (+/+/Cre) and ß-cell-specific ARNT/HIF1ß knockout (fl/fl/Cre) mice on a high-fat diet (HFD). Unlike the control (+/+/Cre) mice, HFD-fed fl/fl/Cre mice had no impairment in in vivo glucose tolerance. The lack of impairment in HFD-fed fl/fl/Cre mice was partly due to an improved islet glucose-stimulated NADPH/NADP+ ratio and glucose-stimulated insulin secretion. The effects of the HFD-rescued insulin secretion in fl/fl/Cre islets could be reproduced by treating low-fat diet (LFD)-fed fl/fl/Cre islets with the lipid signaling molecule 1-monoacylglcyerol. This suggests that the defects seen in LFD-fed fl/fl/Cre islet insulin secretion involve lipid signaling molecules. Overall, mice lacking ARNT/HIF1ß in ß-cells have altered lipid signaling in vivo and are resistant to an HFD's ability to induce diabetes.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Diabetes Mellitus Experimental/metabolismo , Células Secretoras de Insulina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Diabetes Mellitus Experimental/etiologia , Dieta Hiperlipídica , Diglicerídeos , Glucose/metabolismo , Homeostase , Secreção de Insulina , Masculino , Camundongos Knockout , NADP/metabolismo
7.
Int J Sports Med ; 40(14): 909-920, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639864

RESUMO

The aim of this study was to investigate the ameliorative effect of moderate-intensity exercise training in sole and simultaneous forms with insulin on experimental type 1 diabetes (T1D)-induced apoptosis. A total of 36 mature male Wistar rats were divided into six equally sized groups, including sedentary control (Con), moderate-intensity exercise training (E-sole), sedentary T1D-induced (D-sole), moderate-exercise-trained T1D-induced (DE), insulin-treated sedentary T1D-induced (DI) and exercise-trained, and insulin-treated T1D-induced (DEI) groups. The 6-week exercise training intervention was involved 30 min of moderate-intensity running on a treadmill once daily (5 days/week). Next, tubular differentiation (TDI) and spermiogenesis (SPI) indices were assessed. The Bcl-2, Bax and caspase-3 expressions were determined using RT-PCR, immunohistochemistry and western blot techniques. Finally, the TUNEL staining was used to analyze the apoptosis ratio. The moderate-intensity exercise training in the sole and when simultaneously considered with insulin (DEI) maintained testicular cellularity, up-regulated Bcl-2 expression, reduced Bax expression and ameliorated the diabetes-induced apoptosis. We failed to show remarkable alterations in caspase-3 mRNA and protein levels in the DE group versus D-sole animals. In conclusion, the moderate-intensity exercise training is able to potentially protect testicular cells from T1D-induced intrinsic apoptosis via up-regulating Bcl-2 and downregulating Bax expressions. Moreover, it amplifies the insulin-induced anti-apoptotic impacts.


Assuntos
Apoptose , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Condicionamento Físico Animal , Testículo/patologia , Animais , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/terapia , Regulação para Baixo , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Ratos Wistar , Espermatogênese/fisiologia , Regulação para Cima , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
8.
Life Sci ; 235: 116858, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31505195

RESUMO

AIMS: The current study was conducted to investigate the potential protective effects of hesperidin and its possible mechanisms of action on pancreatic ß-cells in diabetes. MAIN METHODS: Male Sprague Dawley rats were made diabetic using 65 mg/kg intraperitoneal injection of streptozotocin, and then administered daily with 100 mg/kg of hesperidin over 4 weeks. On conclusion of the experiment, blood and pancreatic tissue were collected to determine the function of ß-cells, apoptosis, oxidative stress, ER stress, and inflammation. KEY FINDINGS: Treatment of diabetic rats with hesperidin, significantly decreased fasting blood glucose and food intake, along with increased body weight, serum and pancreatic insulin levels, and pancreatic-duodenal homeobox-1 (PDX-1) protein expression. The beneficial roles of hesperidin on diabetic pancreatic ß-cells exhibited an increment in antioxidant SOD and GPx activities, and a decrement in nitrotyrosine as well as malondialdehyde (MDA) levels. Additionally, the elevated concentration of TNF-α and expressions of ER stress maker GRP78 and CHOP proteins in the pancreas of diabetic rats were significantly diminished by hesperidin treatment. Furthermore, hesperidin effectively modulated expressions of apoptosis-regulatory proteins in diabetic rat pancreas, as revealed by upregulating anti-apoptotic Bcl-xL; with a concomitant downregulating pro-apoptotic Bax, cleaved caspase-3, and inhibiting the activation of DNA repair protein poly (ADP-ribose) polymerase (PARP). SIGNIFICANCE: Collectively, these findings suggest that hesperidin may have the potential to protect pancreatic ß-cells and improve their function by suppressing oxidative and ER stress, along with activating its antioxidant, anti-inflammatory, and anti-apoptotic effects.


Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hesperidina/farmacologia , Células Secretoras de Insulina/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Homeodomínio/biossíntese , Inflamação , Insulina/sangue , Insulina/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Superóxido Dismutase/metabolismo , Transativadores/biossíntese , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
9.
An Acad Bras Cienc ; 91(3): e20181330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508665

RESUMO

Type 1 diabetes (T1D) is the result of the selective destruction of the pancreatic ß-cells by T cells of the immune system. Although spleen is a secondary lymphoid organ, it is also involved in the T1D pathogenesis. However, the alterations in a variety of cellular processes of this disease need to be further understood. We aimed to analyze the benefits of resveratrol, and its complexed form on diabetic complications in the spleen of rats. To this end, we investigated important enzymes of phosphoryl transfer network, and Na+, K+-ATPase activity. Wistar rats were divided into non-diabetic groups: Control, Ethanol, Resveratrol, Hydroxypropyl-ß-cyclodextrin, Resveratrol-hydroxypropyl-ß-cyclodextrin, and diabetic groups with the same treatments. Diabetes was induced by a single dose of 60 mg/kg of streptozocin intraperitoneally, and treatments by intragastric gavage once daily for 60 days. Hyperglycemia reduced creatine kinase activity, which was reversed by the administration of resveratrol. Na+, K+-ATPase activity was greatly affected, but it was reversed by resveratrol and resveratrol-hydroxypropyl-ß-cyclodextrin. This suggest an energetic imbalance in the spleen of diabetic rats, and in case this also occurs in the diabetic patients, it is possible that resveratrol supplementation could be beneficial to the better functioning of the spleen in diabetic patients.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/metabolismo , Resveratrol/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Baço/metabolismo , Animais , Antioxidantes/metabolismo , Glicemia/análise , Peso Corporal , Creatina Quinase/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Metabolismo Energético/efeitos dos fármacos , Hiperglicemia/metabolismo , Masculino , Tamanho do Órgão , Ratos , Ratos Wistar , Estreptozocina
10.
Invest Ophthalmol Vis Sci ; 60(12): 4063-4073, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31560762

RESUMO

Purpose: The balance of neuronal excitation and inhibition is important for proper retinal signaling. A previous report showed that diabetes selectively reduces light-evoked inhibition to the retinal dim light rod pathway, changing this balance. Here, changes in mechanisms of retinal inhibitory synaptic transmission after 6 weeks of diabetes are investigated. Methods: Diabetes was induced in C57BL/6J mice by three intraperitoneal injections of streptozotocin (STZ, 75 mg/kg), and confirmed by blood glucose levels more than 200 mg/dL. After 6 weeks, whole-cell voltage-clamp recordings of electrically evoked inhibitory postsynaptic currents from rod bipolar cells and light-evoked excitatory postsynaptic currents from A17-amacrine cells were made in dark-adapted retinal slices. Results: Diabetes shortened the timecourse of directly activated lateral GABAergic inhibitory amacrine cell inputs to rod bipolar cells. The timing of GABA release onto rod bipolar cells depends on a prolonged amacrine cell calcium signal that is reduced by slow calcium buffering. Therefore, the effects of calcium buffering with EGTA-acetoxymethyl ester (AM) on diabetic GABAergic signaling were tested. EGTA-AM reduced GABAergic signaling in diabetic retinas more strongly, suggesting that diabetic amacrine cells have reduced calcium signals. Additionally, the timing of release from reciprocal inhibitory inputs to diabetic rod bipolar cells was reduced, but the activation of the A17 amacrine cells responsible for this inhibition was not changed. Conclusions: These results suggest that reduced light-evoked inhibitory input to rod bipolar cells is due to reduced and shortened calcium signals in presynaptic GABAergic amacrine cells. A reduction in calcium signaling may be a common mechanism limiting inhibition in the retina.


Assuntos
Sinalização do Cálcio/fisiologia , Retinopatia Diabética/metabolismo , Células Bipolares da Retina/metabolismo , Células Amácrinas/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Estimulação Luminosa , Estreptozocina , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
11.
Reprod Domest Anim ; 54 Suppl 3: 4-11, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31512318

RESUMO

In a diabetic pregnancy, an altered maternal metabolism led to increased formation of reactive α-dicarbonyls such as glyoxal (GO) and methylglyoxal (MGO) in the reproductive organs and embryos. The enzyme glyoxalase (GLO) 1 detoxifies reactive α-dicarbonyls thus protecting cells against malfunction or modifications of proteins by advanced glycated end products (AGEs). The aim of this study was to analyse the influence of a maternal insulin-dependent diabetes mellitus (IDD) on GLO1 expression and activity in preimplantation embryos in vivo and human trophoblast cells (Ac-1M88) in vitro. Maternal diabetes was induced in female rabbits by alloxan before conception and maintained during the preimplantation period. GLO1 expression and activity were investigated in 6-day-old blastocysts from healthy and diabetic rabbits. Furthermore, blastocysts and human trophoblast cells were exposed in vitro to hyperglycaemia, GO and MGO and analysed for GLO1 expression and activity. During gastrulation, GLO1 was expressed in all compartments of the rabbit blastocyst. Maternal diabetes decreased embryonic GLO1 protein amount by approx. 30 per cent whereas the enzymatic activity remained unchanged, indicating that the specific GLO1 activity increases along with metabolic changes. In in vitro cultured embryos, neither hyperglycaemia nor MGO and GO had an effect on GLO1 protein amount. In human trophoblast cells, a stimulating effect on the GLO1 expression was shown in the highest GO concentration, only. Our data show that maternal diabetes mellitus affects the specific activity of GLO1, indicating that GLO1 was post-translationally modified due to changes in metabolic processes in the preimplantation embryos.


Assuntos
Blastocisto/metabolismo , Diabetes Mellitus Experimental/metabolismo , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Animais , Blastocisto/enzimologia , Linhagem Celular , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/genética , Feminino , Glioxal/farmacologia , Humanos , Hiperglicemia/metabolismo , Gravidez , Aldeído Pirúvico/farmacologia , Coelhos , Trofoblastos
12.
Invest Ophthalmol Vis Sci ; 60(12): 3943-3951, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31546260

RESUMO

Purpose: Diabetes causes dysfunction in the retinal mitochondria and increases base mismatches in their DNA (mtDNA). The enzyme responsible for repairing the base mismatches, MutL homolog 1 (Mlh1), is compromised. Diabetes also favors many epigenetic modifications and activates DNA methylation machinery, and Mlh1 has a CpG-rich promoter. Our aim is to identify the molecular mechanism responsible for impaired mtDNA mismatch repair in the pathogenesis of diabetic retinopathy. Methods: Human retinal endothelial cells, incubated in 20 mM glucose, were analyzed for mitochondrial localization of Mlh1 by an immunofluorescence technique, Mlh1 promoter DNA methylation by the methylated DNA capture method, and the binding of Dnmt1 and transcriptional factor Sp1 by chromatin immunoprecipitation. The results were confirmed in retinal microvessels from streptozotocin-induced diabetic mice, with or without Dnmt inhibitors, and from human donors with diabetic retinopathy. Results: Compared with cells in 5 mM glucose, high glucose decreased Mlh1 mitochondrial localization, and its promoter DNA was hypermethylated with increased Dnmt-1 binding and decreased Sp1 binding. Dnmt inhibitors attenuated Mlh1 promoter hypermethylation and prevented a decrease in its gene transcripts and an increase in mtDNA mismatches. The administration of Dnmt inhibitors in mice ameliorated a diabetes-induced increase in Mlh1 promoter hypermethylation and a decrease in its gene transcripts. Similar decreases in Mlh1 gene transcripts and its promoter DNA hypermethylation were observed in human donors. Conclusions: Thus, as a result of the epigenetic modifications of the Mlh1 promoter, its transcription is decreased, and decreased mitochondrial accumulation fails to repair mtDNA mismatches. Therapies targeted to halt DNA methylation have the potential to prevent/halt mtDNA damage and the development of diabetic retinopathy.


Assuntos
DNA Mitocondrial/genética , Retinopatia Diabética/genética , Epigênese Genética , Adulto , Idoso , Animais , Western Blotting , Células Cultivadas , Dano ao DNA , Metilação de DNA/genética , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Plasmídeos , Controle de Qualidade , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Estreptozocina
13.
Invest Ophthalmol Vis Sci ; 60(12): 3842-3853, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31529081

RESUMO

Purpose: Outer blood retinal barrier breakdown is a neglected feature of diabetic retinopathy (DR). We demonstrated that the agonism of the δ opioid receptor (DOR) by epicatechin preserves the tight junction proteins in ARPE-19 cells under diabetic conditions. Presently, we aimed to evaluate the possible role of the DOR on the maintenance of tight junction of RPE layer and on the early markers of experimental DR. Methods: DR markers and external retinal tight junction proteins were evaluated in CL57B diabetic mice submitted to intravitreous injection of short hairpin RNA (shRNA)-DOR (108 transducing units [TU]/mL) treated or not with DOR agonist (0.05 g/animal/d of epicatechin in drinking water) for 16 weeks. The presence of DOR in human retina from postmortem eyes from diabetic and nondiabetic donors were also performed. Results: DOR is present in RPE layer and in neuro retina. The treatment with DOR agonist prevented the upregulation of the early markers of retinopathy (glial fibrillary acidic protein, VEGF) and the downregulation of pigment epithelium-derived factor, occludin, claudin-1, and zonula occludens-1 tight junction expressions. The silencing of DOR in retina of diabetic mice partially abolished the protective effects of epicatechin. In human retina specimens, DOR is present throughout the retina, similarly in nondiabetic and diabetic donors. Conclusions: This set of experiments strongly indicates that the DOR agonism preserves RPE tight junctions and reduces the early markers of retinopathy in model of diabetes. These novel findings designate DOR as a potential therapeutic tool to treat DR with preservation of the RPE tight junction proteins.


Assuntos
Catequina/farmacologia , Diabetes Mellitus Experimental/prevenção & controle , Retinopatia Diabética/prevenção & controle , Receptores Opioides delta/agonistas , Epitélio Pigmentado da Retina/metabolismo , Junções Íntimas/metabolismo , Idoso , Animais , Glicemia/metabolismo , Western Blotting , Claudina-1/metabolismo , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Impedância Elétrica , Proteínas do Olho/metabolismo , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fatores de Crescimento Neural/metabolismo , Ocludina/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Receptores Opioides delta/metabolismo , Serpinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
14.
Drug Deliv ; 26(1): 849-859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524015

RESUMO

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus whose expand process is linked with the fibrosis, renal hypertrophy and inflammation. The current study was to formulate and optimize the nano-formulation of crocetin (CT-PLGA-NPs) against Streptozotocin-induced renal nephropathy in rats. Double emulsion evaporation technique was used for the preparation of CT-PLGA-NPs. CT-PLGA-NPs were scrutinized for polydispersity index, size, gastric stability, entrapment, drug-loading capacity and in-vitro drug release and in vivo preclinical study. Single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) and rats were divided into different group. Renal function and metabolic parameters of urine and serum were estimated. Fibrotic protein, renal pro-inflammatory cytokines and degree of renal damage expression were also determined. We also estimated the fibronectin, type IV collagen and transforming growth factor-ß1 for a possible mechanism of action. Crocetin supplement (10 mg/kg) and CT-PLGA-NPs exhibited the accumulation of the drug in kidney and liver of diabetic rats. Crocetin reduced the BGL and enhanced plasma insulin and body weight. Dose dependent treatment of crocetin significantly (p < .001) down-regulated the expression of renal tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin (IL)-1ß (IL-1ß) and Monocyte Chemoattractant Protein-1 (MCP-1). Crocetin significantly (p < .001) altered the expression of fibronectin, type IV collagen, and transforming growth factor-ß1 (TGF-1ß). Crocetin significantly (p < .001) down-regulated the protein kinase C activity and the expression of nuclear factor κB (NF-κB) p65 activity and protein production in renal tissue. On the basis of the available result, we can conclude that nano-formulation of crocetin could attenuate the diabetic nephropathy via antifibrotic and anti-inflammatory effect.


Assuntos
Biomarcadores/metabolismo , Carotenoides/administração & dosagem , Carotenoides/química , Nefropatias Diabéticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
15.
J Biol Regul Homeost Agents ; 33(5): 1327-1335, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31487982

RESUMO

The glucose transporter 4 (GLUT4) translocation is a vital link of insulin-induced glucose uptake in adipose tissue and skeletal muscle. It is an important topic in anti-diabetic research to explore novel agents to facilitate the role of insulin. The aim of this study was to verify the hypothesis that neuropeptide galanin may enhance insulin-induced GLUT4 translocation to increase glucose uptake in adipose tissue of type 2 diabetic models. Insulin and/or galanin were injected respectively or cooperatively into type 2 diabetic rats once a day for fifteen days. The results showed that administration of galanin significantly enhanced insulin-induced GLUT4 and vesicle-associated membrane protein 2 (VAMP2) translocation, Akt phosphorylation and glucose uptake, but not GLUT4 mRNA and protein expression levels in adipose cells. The beneficial roles of galanin on insulin-induced events may be blocked by MK-2206, an Akt inhibitor, indicating that the Akt phosphorylation is essential for promoting impact of galanin on the insulin-induced events. These results suggest that galanin may benefit insulin-induced GLUT4 and VAMP2 translocation, and subsequent glucose uptake via the activated Akt-VAMP2-GLUT4 pathway in adipose cells. These findings deepen our understanding of the anti-diabetic effect of galanin and its mechanism.


Assuntos
Adipócitos/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Galanina/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Insulina/farmacologia , Animais , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Proteína 2 Associada à Membrana da Vesícula/metabolismo
16.
Life Sci ; 236: 116836, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493479

RESUMO

AIMS: The present experiment was conceptualised to explore the therapeutic response of tetramethylpyrazine (TMP), a major active constituent of Ligusticum chuanxiong, a Chinese traditional medicinal plant, in high-fat diet (HFD)-streptozotocin (STZ)-induced diabetes in rats and to identify the possible mechanism of action. MAIN METHODS: Dose-reliant effect of oral treatment of TMP (100, 150 and 200 mg/kg/day) for 28 days was evaluated by calculating the alteration in body weight, level of fasting blood glucose (FBG), plasma insulin, homeostasis model assessment (HOMA), serum lipids, oral glucose & intraperitoneal insulin tolerance and glycosylated haemoglobin in HFD-STZ-induced type-2 diabetic (T2D) rats and underlying molecular mechanisms of TMP was also studied. KEY FINDINGS: TMP treatment prominently reduced the level of FBG, glycosylated haemoglobin and revived body weight gain and level of serum insulin dose-dependently in diabetic rats. TMP treatment considerably improved insulin resistance, as observed in oral glucose tolerance and insulin tolerance tests. Moreover, dose-dependent reduction in the level of pro-inflammatory cytokines, C-reactive protein (CRP) and interleukin-6 (IL-6) was observed and their level was found to be significantly reduced in highest dose TMP (200 mg/kg) treated diabetic rats, pointing towards TMP mediated recovery of insulin signalling and a decrease in insulin resistance. The expressions of p-PI3K-p85/p-Akt/GLUT-4 were also significantly up-regulated by TMP (200 mg/kg), suggesting the connection of the PI3K/Akt signal pathway in the anti-hyperglycemic action of TMP. SIGNIFICANCE: These findings suggest that TMP may be used as a potential agent for type-2 diabetes treatment.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/farmacologia , Animais , Glicemia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Transportador de Glucose Tipo 4/genética , Masculino , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Wistar , Transdução de Sinais , Vasodilatadores/farmacologia
17.
Pestic Biochem Physiol ; 159: 127-135, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400774

RESUMO

Pesticides cardiotoxicity in case of diabetic-induced cardiac complications is unidentified. The probable amelioration role of propolis is gauged against the cardiotoxic effects of chlorpyrifos in the diabetic rats through paraoxonase-1 (PON1) and xanthine oxidase (XO) genes dysregulation. Fifty-six male rats were distributed (n = 7) into eight groups. The first one saved as control whereas the 2nd, 3rd, and 4th were kept for propolis aqueous extract (100 mg/kg), diabetes (60 mg/kg streptozotocin) and chlorpyrifos (2.5 mg/kg), respectively. The 5th was diabetes/chlorpyrifos combination, while 6th, 7th, and 8th were intubated with propolis for four weeks after diabetic induction, chlorpyrifos intoxication, and their combination, respectively. The plasma glucose, lipid profiles, cardiac enzymes and interleukin-6 (IL-6) significantly elevated, while insulin decreased in the diabetic and combination groups. Although the cardiac acetylcholinesterase, total thiols, and PON1 significantly reduced after diabetic and/or chlorpyrifos gavage, the protein carbonyl, superoxide dismutase, catalase, and XO significantly elevated. The mRNA genes expression of PON1 and XO have also confirmed the enzymatic activities. Interestingly, propolis significantly restored the hyperglycemia, hypoinsulinemia, hyperlipidemia, IL-6 elevations, and antioxidant defense system disorder. These records revealed that the immunomodulatory, anti-diabetic and antioxidant tasks are fine pointers for the cardiovascular defender of propolis especially during diabetes and/or pesticides exposure.


Assuntos
Arildialquilfosfatase/metabolismo , Clorpirifos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Própole/uso terapêutico , Xantina Oxidase/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Inseticidas/uso terapêutico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos
18.
Phytother Res ; 33(10): 2765-2774, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385371

RESUMO

The purpose of this study was to evaluate the pancreatic beta cell protective and glucose uptake enhancing effect of the water extract of Tinospora cordifolia stem (TCSE) by using rat insulinoma (RIN)-m5F cells and 3 T3-L1 adipocytes. RIN-m5F cells were stimulated with interleukin-1ß and interferon-γ, and the effect of TCSE on insulin secretion and cytokine-induced toxicity was measured by ELISA and MTT assay, respectively. The glucose uptake and protein expression were measured by fluorometry and western blotting. Antidiabetic effect of TCSE was measured using streptozotocin-induced diabetic rats. TCSE dose dependently increased cell viability and insulin secretion in RIN-m5F cells. In addition, TCSE increased both the glucose uptake and glucose transporter 4 translocation in 3 T3-L1 adipocytes via PI3K pathway. Finally, TCSE significantly lowered blood glucose and diet intake and increased body weight in streptozotocin-induced diabetic rats. The level of serum insulin and hepatic glycogen was increased, whereas the level of serum triglyceride, total cholesterol, dipeptidyl peptidase-4, and thiobarbituric acid reactive substances was decreased in TCSE-administered rats. TCSE also increased glucose transporter 4 protein expression in the adipose tissue and liver of TCSE-fed diabetic rats. Our results suggested that TCSE preserved RIN-m5F cells from cytokine-induced toxicity and enhanced glucose uptake in 3 T3-L1 adipocytes, which may regulate glucose metabolism in diabetic rats.


Assuntos
Adipócitos/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tinospora , Adipócitos/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Estreptozocina
19.
J Diabetes Res ; 2019: 2813489, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467926

RESUMO

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to ß-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect ß-cell mass against glucotoxicity and to increase ß-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-ß cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on ß-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of ß-cell mass after new-onset T1D.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glucosídeos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Compostos Benzidrílicos/administração & dosagem , Glicemia/metabolismo , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Esquema de Medicação , Quimioterapia Combinada , Intervenção Médica Precoce , Teste de Tolerância a Glucose , Glucosídeos/administração & dosagem , Injeções Intraperitoneais , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/fisiologia , Masculino , Camundongos , Estreptozocina , Fatores de Tempo , Ácido gama-Aminobutírico/administração & dosagem
20.
J Diabetes Res ; 2019: 5451038, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467927

RESUMO

Aims: Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods: We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results: GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion: Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.


Assuntos
Metabolismo dos Carboidratos/genética , Proteínas de Ligação a DNA/fisiologia , Glucose/metabolismo , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/fisiologia , Histona Desmetilases com o Domínio Jumonji/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Homeostase/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Estreptozocina
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