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1.
J Agric Food Chem ; 68(1): 147-159, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31826616

RESUMO

This study was aimed at investigating the hypoglycemic and hypolipidemic effects of a polysaccharide (RTFP) isolated from Rosa roxburghii Tratt fruit on type-2 diabetic db/db mice. The results indicated that the oral administration of RTFP could significantly decrease the body weight, fat, and liver hypertrophy and the levels of fasting blood glucose, serum insulin, and serum lipids of the db/db mice. Histopathological observation showed that RTFP could effectively protect the pancreas, liver, and epididymal fat against damage and dysfunction. Real-time quantitative polymerase chain reaction analysis confirmed that the gene expression levels of peroxisome proliferator-activated receptors-γ (PPAR-γ), sterol regulatory element-binding protein-1 (SREBP-1c), acetyl-CoA carboxylase-1 (ACC-1), fatty acid synthase (FAS), and glucose-6-phosphatase (G6 Pase) were significantly down-regulated in the liver of db/db mice after treatment with RTFP. Moreover, RTFP treatment reversed gut dysbiosis by lowering the Firmicutes-to-Bacteroidetes ratio and enhancing the relative abundances of beneficial bacteria including Bacteroidaceae, Bacteroidaceae S24-7 group, and Lactobacillaceae. These findings suggest that RTFP can be used as a promising functional supplement for the prevention and treatment of type-2 diabetes mellitus.


Assuntos
Colo/microbiologia , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Extratos Vegetais/administração & dosagem , Polissacarídeos/administração & dosagem , Rosa/química , Animais , Colo/metabolismo , Modelos Animais de Doenças , Frutas/química , Microbioma Gastrointestinal , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/microbiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Triglicerídeos/metabolismo
2.
J Agric Food Chem ; 68(3): 742-750, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31880937

RESUMO

Superhongmi is a new rice variety, which was developed for the enrichment of bioactive compounds through cross-breeding three varieties of rice breeds in Korea. The high-performance liquid chromatography coupled with a photodiode array detector quadrupole and tandem time-of-flight mass spectrometry (HPLC/PDA/QTOF-MS) analysis has revealed that superhongmi bran extract contained four taxifolin derivatives as well as cyanidin 3-glucoside. The high-performance countercurrent chromatography (CCC) and reversed-phase HPLC led to the isolation of aforementioned five compounds, and spectroscopic analysis identified cyanidin 3-glucoside (1), along with (2R,3R)-taxifolin 3-O-ß-d-glucopyranoside (2), (2R,3R)-4'-O-methyltaxifolin 3-O-ß-d-glucopyranoside (a novel compound) (3), (2R,3R)-taxifolin (4), and (2R,3R)-4'-O-methyltaxifolin (5). Compound 2 had the highest rat small intestinal sucrase inhibitory activity (0.54 mM) relevant for potentially managing postprandial hyperglycemia, followed by compound 1 (0.97 mM) and compound 4 (1.74 mM, IC50). The anti-hyperglycemic effect of compound 4 (taxifolin), a main peak in HPLC analysis was investigated using a Sprague-Dawley (SD) rat model. Compared to a control, taxifolin treatment (p < 0.001) reduced significantly after sucrose loading the observed postprandial blood glucose and the maximum blood glucose (Cmax) by 15% (203.60 ± 15.86 to 172.30 ± 12.74). These results indicate that taxifolin derivatives that inhibit the activity of carbohydrate-hydrolyzing enzymes resulting in reduced dietary carbohydrate absorption can potentially be used as a strategy to manage diabetes.


Assuntos
Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Oryza/química , Extratos Vegetais/administração & dosagem , Quercetina/análogos & derivados , Animais , Glicemia/metabolismo , Cromatografia Líquida de Alta Pressão , Cor , Humanos , Hiperglicemia/metabolismo , Hipoglicemiantes/química , Masculino , Extratos Vegetais/química , Período Pós-Prandial/efeitos dos fármacos , Quercetina/administração & dosagem , Quercetina/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
3.
Eur J Histochem ; 63(4)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31833328

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by interleukin (IL)-6 and IL-10 that generate nearly opposing responses. The suppressor of cytokine signaling 3 (SOCS3) is the negative regulator of STAT3 and plays an important role in the negative regulation of the inflammatory process. Evidence has shown the importance of STAT3 and SOCS3 during implantation and normal pregnancy. However, little is known about the relationship of both factors under hyperglycemic condition. The aim of this study was to evaluate the placenta regions exhibiting immunopositivity for STAT3 and SOCS3 in hyperglycemic rats, as well as correlate these proteins with IL-10 and IL-6 levels. It was observed increased expression of STAT3 at the labyrinth (approximately 47% of increase compared to control) and junctional zone (approximately 32% of increase compared to control) from hyperglycemic placentas. Similar results were observed to SOCS3 (approximately 71% -labyrinth- and 53% -junctional zone- of increase compared to control). The levels of IL-10 were augmented at hyperglycemic placentas (approximately 1.5 fold of increase) and they were positively correlated with the increase of STAT3 at the labyrinth and SOCS at junctional zone. Therefore, under hyperglycemic conditions, the relation between STAT3 and SOCS3 was changed, leading to unbalance of the cytokine profile.


Assuntos
Hiperglicemia/metabolismo , Placenta/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Anticorpos/imunologia , Feminino , Cabras , Hiperglicemia/patologia , Imuno-Histoquímica , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Placenta/patologia , Gravidez , Coelhos , Ratos Wistar , Fator de Transcrição STAT3/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia
4.
Nat Med ; 25(11): 1733-1738, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700171

RESUMO

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Hiperfagia/genética , Obesidade/genética , Adolescente , Adulto , Criança , Metabolismo Energético/genética , Feminino , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperfagia/complicações , Hiperfagia/metabolismo , Hiperfagia/patologia , Hipertensão/complicações , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Fatores de Risco , Adulto Jovem
5.
BMC Complement Altern Med ; 19(1): 309, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718632

RESUMO

BACKGROUND: Sheng Mai San (SMS) has been proven to exhibit cardio-protective effects. This study aimed to explore the molecular mechanisms of SMS on hyperglycaemia (HG)-induced apoptosis in H9C2 cells. METHODS: HG-induced H9C2 cells were established as the experimental model, and then treated with SMS at 25, 50, and 100 µg/mL. H9C2 cell viability and apoptosis were quantified using MTT and Annexin V-FITC assays, respectively. Furthermore, Bcl-2/Bax signalling pathway protein expression and Fas and FasL gene expression levels were quantified using western blotting and RT-PCR, respectively. RESULTS: SMS treatments at 25, 50, 100 µg/mL significantly improved H9C2 cell viability and inhibited H9C2 cell apoptosis (p < 0.05). Compared to the HG group, SMS treatment at 25, 50, and 100 µg/mL significantly downregulated p53 and Bax expression and upregulated Bcl-2 expression (p < 0.05). Moreover, SMS treatment at 100 µg/mL significantly downregulated Fas and FasL expression level (p < 0.05) when compared to the HG group. CONCLUSION: SMS protects H9C2 cells from HG-induced apoptosis probably by downregulating p53 expression and upregulating the Bcl-2/Bax ratio. It may also be associated with the inhibition of the Fas/FasL signalling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hiperglicemia/fisiopatologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
6.
BMC Complement Altern Med ; 19(1): 278, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640743

RESUMO

BACKGROUND: Recent epidemiological and experimental studies suggest that cadmium and diabetes-related hyperglycemia may act synergistically to worsen metabolic regulation. The present study aims to evaluate the potential effects of Enhydra fluctuans extract in diabetes and dyslipidemia in cadmium (CdCl2) induced- normal and type 2 diabetic model rats. METHOD: Forty-eight Long-Evans rats were divided equally into the following six groups: Normal Control (N-C), Normal treated with CdCl2 (N-Cd), Normal treated with plant extract (N-P), Normal treated with both plant extract and CdCl2 (N-PCd), Diabetic treated with plant extract (DM-P) and Diabetic treated with both plant extract and CdCl2 (DM-PCd). Blood glucose and other biochemical parameters were estimated by the enzymatic colorimetric method. Histological analysis of liver and heart was done by the hematoxylin-eosin (H & E) method. RESULTS: Twenty-one days treatment of E. fluctuans extracts at a dose of 200 mg/kg significantly reduced blood glucose level in N-PCd and DM-PCd (p < 0.05), and DM-P (p < 0.01) group. The plant extract had no direct effects on total blood lipids but, it had beneficial effects on TG/HDL-C ratio in N-P and DM-PCd groups (p < 0.05). Cd induction significantly reduced body weight [(N-Cd, N-PCd, DM-PCd) (p < 0.01)], and induced liver [N-Cd (p < 0.05), N-PCd, p < 0.001] and renal impairment [N-Cd (p < 0.05)]. In bi-variate association, a significant positive correlation between serum glucose and SGPT (p < 0.05) as well as SGPT and TG/HDL ratio (p = 0.019) was found in DM-P and in the merged group. The histology of liver and heart showed severe damages including inflammation, nuclear pyknosis, loss of myocardial fibers, necrosis and fibrosis in the Cd treated groups compared to plant treated groups. CONCLUSION: E. fluctuans seems to have potent antihyperglycemic effects in diabetes and Cd toxicity along with partial antidyslipidemic properties in euglycemic and diabetic rats. Our study suggests a novel oral antihyperglycemic agent in the present environmental context.


Assuntos
Asteraceae/química , Cádmio/toxicidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Glicemia/metabolismo , Cádmio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Ratos , Ratos Long-Evans
7.
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
8.
Nature ; 574(7776): 63-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554967

RESUMO

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.


Assuntos
Receptor gp130 de Citocina/metabolismo , Citocinas/síntese química , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ligação Competitiva , Citocinas/química , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Drogas , Fígado Gorduroso/prevenção & controle , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Incretinas/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Pâncreas/metabolismo , Fosfoproteínas/metabolismo , Engenharia de Proteínas , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Fatores de Transcrição , Ganho de Peso/efeitos dos fármacos
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.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(8): 949-952, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31537217

RESUMO

OBJECTIVE: To explore the effect of intensive insulin therapy (IIT) on high mobility group box-1/nuclear factor-ΚB (HMGB1/NF-ΚB) signaling pathway in severe traumatic brain injury (sTBI) patient with stress hyperglycemia. METHODS: Sixty-one sTBI patients with stress hyperglycemia [Glasgow coma scale (GCS) ≤ 8, three times of random blood glucose levels > 11.1 mmoL/L, glycosylated hemoglobin (HbA1c) < 0.065] admitted to the Affiliated Huaian No.1 People's Hospital of Nanjing Medical University from July 2015 to October 2017 were enrolled. Patients were divided into IIT group (29 cases, keeping blood glucose at 4.4-7.8 mmol/L) and conventional glycemic therapy (CGT) group (32 cases, keeping blood glucose at 7.8-12.2 mmo/L) according to the random number table method. Before treatment and 1, 7 and 14 days after treatment, the levels of plasma HMGB1 and tumor necrosis factor-α (TNF-α) were measured by enzyme linked immunosorbent assay (ELISA); C-reactive protein (CRP) was determined by automatic biochemical analyzer, and NF-ΚB p65 gene expression in peripheral blood mononuclear cells was detected by real-time quantitative polymerase chain reaction (PCR). RESULTS: Nine patients were withdrawn from the observation because the 4 consecutive blood glucose monitoring did not reach the target value, combined with severe infection, or abandoned the treatment with serious brain damage. Finally, 52 patients were enrolled in the analysis, including 28 in CGT group and 24 in IIT group. The levels of plasma HMGB1, TNF-α, CRP and the expression of NF-ΚB gene in monocytes of the two groups at 1 day after treatment were significantly higher than those before treatment, and reached the peak value, then gradually decreased. After 7 days of treatment, they were significantly lower than 1 day. The levels of plasma CRP and TNF-α in the IIT group were significantly lower than those in the CGT group [CRP (mg/L): 36.7±4.4 vs. 45.1±6.1, TNF-α (ng/L): 42.4±9.7 vs. 53.2±9.1, both P < 0.05], the level of HMGB1 in plasma and the expression of NF-ΚB p65 in monocytes were significantly lower than those in the CGT group after 14 days of treatment [HMGB1 (µg/L): 60.1±8.7 vs. 80.5±9.1, NF-ΚB p65 (ΔCt): 35.8±8.5 vs. 53.5±7.3, both P < 0.05]. CONCLUSIONS: IIT inhibits the inflammatory response in sTBI patients with stress hyperglycemia through HMGB1/NF-ΚB pathway.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Proteína HMGB1/metabolismo , Hiperglicemia/metabolismo , Insulina/uso terapêutico , NF-kappa B/metabolismo , Glicemia , Automonitorização da Glicemia , Humanos , Leucócitos Mononucleares , Fator de Necrose Tumoral alfa
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.
Biol Pharm Bull ; 42(9): 1562-1568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474716

RESUMO

Chronopharmacology is the study of the varying responses of drugs to changes in biological timing and endogenous periodicities. The dipeptidyl peptidase-4 inhibitor sitagliptin is a globally prescribed anti-hyperglycemic drug. Although dipeptidyl peptidase-4 inhibitors are usually administered once, the specific intake time is generally not mentioned. Therefore, this study aimed at investigating the diurnal effects of sitagliptin-induced anti-hyperglycemia in high-fat diet (HFD)-induced obesity in mice. Five-week-old male C57BL/6J mice were fed normal (control) diet or HFD for 10 weeks. During the last 2 weeks, the mice were administered saline or sitagliptin (10 mg/kg, per os) in the light or dark phase, respectively. At the end of the experiment, the mice were euthanized after an 18 h fasting period, and plasma and tissue samples (liver, kidney, and epididymal white adipose tissues) were collected, or the oral glucose tolerance test was performed. Sitagliptin administration in the light phase significantly decreased plasma glucose levels, insulin levels, hepatic steatosis, and restored the glucose tolerance compared with the HFD group. In contrast, these parameters remained unchanged in the dark phase-treated mice. Our data therefore suggests that sitagliptin portrays definite chronopharmacology, which may provide valuable information on the importance of drug administration timing for maximum pharmacological effects.


Assuntos
Cronoterapia Farmacológica , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Fosfato de Sitagliptina/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Glicemia/análise , Dieta Hiperlipídica , Modelos Animais de Doenças , Glucose/metabolismo , Hiperglicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/sangue , Tamanho do Órgão/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico
13.
J Sci Food Agric ; 99(15): 6981-6988, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31414473

RESUMO

BACKGROUND: Diabetes mellitus is a serious chronic disease, characterized by hyperglycemia. This study administered either ß-mannanase-treated yeast cell autolysis supernatant (YCS) or yeast cell-wall residues after autolysis (YCR) to investigate their influence on the alleviation of diabetes in a diabetic mouse model. RESULTS: Application of either YCS or YCR led to body weight gain, blood glucose reduction, and an improvement in lipid composition in the diabetic mice. Administration of YCS was more effective in inhibiting oxidative stress than YCR. The expression of PPARα and CPT1α was enhanced, improving lipid biosynthesis, and Trx1 and HIF-1-α genes were downregulated due to the activation of thioredoxin following the interventions, indicating that the processes of lipid metabolism and oxidative stress were heavily involved in the reduction of diabetic characteristics following the interventions. The current study revealed that consumption of YCR also led to a reduction in hyperglycemia, this being associated with its richness in mineral elements, such as chromium and selenium. CONCLUSION: This study may highlight the potential of both YCS and YCR as functional ingredients in dietary formula for improving diabetic syndromes. © 2019 Society of Chemical Industry.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Saccharomyces cerevisiae/química , beta-Manosidase/química , Animais , Biocatálise , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Suplementos Nutricionais/análise , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Minerais/análise , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo
14.
Invest Ophthalmol Vis Sci ; 60(10): 3547-3555, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415078

RESUMO

Purpose: Current treatments for diabetic retinopathy (DR) have considerable limitations, underpinning the need for new therapeutic options. In this article, the ability of an engineered angiopoietin-1 variant (COMP-Ang1) to ameliorate the injurious effects of hyperglycemia on barrier integrity in a human retinal microvascular endothelial cell (HRMvEC) model is comprehensively investigated. Methods: Confluent HRMvECs were treated (0-72 hours) with d-glucose (5 or 30 mM) in the absence and presence of COMP-Ang1 (10-200 ng/mL). l-glucose (30 mM) was used as osmotic control. Posttreatment, intact cell monolayers were monitored for permeability to FITC-dextran 40 kDa. Cells were also harvested for analysis of interendothelial junction targets by RT-qPCR and Western blotting. The impact of receptor tyrosine kinase Tie2 gene silencing on COMP-Ang1 efficacy was also evaluated. Results: Treatment with 30 mM d-glucose (but not l-glucose) demonstrated a time-dependent elevation in the mean rate of FITC-dextran diffusion across intact HRMvEC monolayers, in parallel with significant reductions in mRNA/protein levels of occludin, claudin-5, ZO-1, and VE-Cadherin. These effects were all attenuated by COMP-Ang1 in a concentration-dependent fashion, with 200 ng/mL recovering barrier function by ∼88%, and recovering reduced interendothelial junction protein levels by more than 50%. Finally, Tie2 knockdown by small interfering RNA silencing blocked the ability of COMP-Ang1 to mitigate against hyperglycemia-induced permeabilization of HRMvECs and depletion of junctional expression levels. Conclusions: In summary, this article presents a reproducible in vitro cell study that quantifies the concentration-dependent efficacy of COMP-Ang1 to mitigate the injurious effects of hyperglycemic challenge on HRMvEC barrier properties via Tie2-mediated signaling.


Assuntos
Barreira Hematorretiniana/fisiologia , Células Endoteliais/efeitos dos fármacos , Hiperglicemia/prevenção & controle , Proteínas Recombinantes de Fusão/farmacologia , Vasos Retinianos/efeitos dos fármacos , Antígenos CD/genética , Western Blotting , Caderinas/genética , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Claudina-5/genética , Dextranos/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Inativação Gênica/fisiologia , Glucose/farmacologia , Humanos , Hiperglicemia/metabolismo , Ocludina/genética , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor TIE-2/genética , Vasos Retinianos/metabolismo
15.
Postgrad Med ; 131(7): 423-437, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31382796

RESUMO

Hyperglycemia on hospital admission is a common phenomenon in acute ischemic stroke patients and represents an independent predictor of poor clinical outcome with or without acute recanalization therapies (systemic thrombolysis or mechanical thrombectomy). Effective restoration of normoglycemia is considered to be beneficial, but conclusive evidence from randomized controlled clinical trials and specific recommendations are lacking. In addition, aggressive glucose control can be complicated by hypoglycemia leading to early neurological deterioration. We conducted a systematic literature review with the aim of addressing several questions: timing of glucose control, target range, type of insulin delivery, duration and practicability of glucose-lowering protocols. Special issues regarding mechanical thrombectomy and glycemic variability can then be investigated in future trials which are also being considered.


Assuntos
Isquemia Encefálica/terapia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Acidente Vascular Cerebral/terapia , Glicemia/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Hospitalização , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hipoglicemia/induzido quimicamente , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismo , Trombectomia , Terapia Trombolítica
16.
Sensors (Basel) ; 19(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366169

RESUMO

Diabetes is a very complex condition affecting millions of people around the world. Its occurrence, always accompanied by sustained hyperglycemia, leads to many medical complications that can be greatly mitigated when the disease is treated in its earliest stage. In this paper, a novel sensing approach for the early non-invasive detection and monitoring of sustained hyperglycemia is presented. The sensing principle is based on millimeter-wave transmission spectroscopy through the skin and subsequent statistical analysis of the amplitude data. A classifier based on functional principal components for sustained hyperglycemia prediction was validated on a sample of twelve mice, correctly classifying the condition in diabetic mice. Using the same classifier, sixteen mice with drug-induced diabetes were studied for two weeks. The proposed sensing approach was capable of assessing the glycemic states at different stages of induced diabetes, providing a clear transition from normoglycemia to hyperglycemia typically associated with diabetes. This is believed to be the first presentation of such evolution studies using non-invasive sensing. The results obtained indicate that gradual glycemic changes associated with diabetes can be accurately detected by non-invasively sensing the metabolism using a millimeter-wave spectral sensor, with an observed temporal resolution of around four days. This unprecedented detection speed and its non-invasive character could open new opportunities for the continuous control and monitoring of diabetics and the evaluation of response to treatments (including new therapies), enabling a much more appropriate control of the condition.


Assuntos
Glicemia/isolamento & purificação , Diabetes Mellitus Experimental/diagnóstico , Hiperglicemia/diagnóstico , Análise Espectral/métodos , Animais , Diabetes Mellitus Experimental/metabolismo , Humanos , Hiperglicemia/metabolismo , Camundongos
17.
Nat Commun ; 10(1): 3545, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391467

RESUMO

Tens of millions suffer from insulin deficiency (ID); a defect leading to severe metabolic imbalance and death. The only means for management of ID is insulin therapy; yet, this approach is sub-optimal and causes life-threatening hypoglycemia. Hence, ID represents a great medical and societal challenge. Here we report that S100A9, also known as Calgranulin B or Myeloid-Related Protein 14 (MRP14), is a leptin-induced circulating cue exerting beneficial anti-diabetic action. In murine models of ID, enhanced expression of S100A9 alone (i.e. without administered insulin and/or leptin) slightly improves hyperglycemia, and normalizes key metabolic defects (e.g. hyperketonemia, hypertriglyceridemia, and increased hepatic fatty acid oxidation; FAO), and extends lifespan by at least a factor of two. Mechanistically, we report that Toll-Like Receptor 4 (TLR4) is required, at least in part, for the metabolic-improving and pro-survival effects of S100A9. Thus, our data identify the S100A9/TLR4 axis as a putative target for ID care.


Assuntos
Calgranulina B/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hiperglicemia/metabolismo , Longevidade/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Toxina Diftérica/toxicidade , Ácidos Graxos/metabolismo , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Insulina/deficiência , Leptina/administração & dosagem , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Oxirredução , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estreptozocina/toxicidade , Receptor 4 Toll-Like/genética
18.
Int J Mol Sci ; 20(15)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382355

RESUMO

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/fisiopatologia , Hiperglicemia/fisiopatologia , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
J Exp Clin Cancer Res ; 38(1): 327, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337431

RESUMO

Malignant tumors are often multifactorial. Epidemiological studies have shown that hyperglycemia raises the prevalence and mortality of certain malignancies, like breast, liver, bladder, pancreatic, colorectal, endometrial cancers. Hyperglycemia can promote the proliferation, invasion and migration, induce the apoptotic resistance and enhance the chemoresistance of tumor cells. This review focuses on the new findings in the relationship between hyperglycemia and tumor development.


Assuntos
Progressão da Doença , Hiperglicemia/metabolismo , Neoplasias/metabolismo , Apoptose/genética , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/patologia , Neoplasias/complicações , Neoplasias/genética , Neoplasias/patologia
20.
Drug Discov Ther ; 13(3): 133-136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31327788

RESUMO

Using a silkworm evaluation system, we previously evaluated various substances that suppress postprandial hyperglycemia. Enterococcus faecalis YM0831, a lactic acid bacterium that inhibits glucose uptake by the human intestinal Caco-2 cell line, exhibited hyperglycemia-suppressing effects in the silkworm system. In the present study, we found that Kothala himbutu (Salacia reticulata) extract, a traditional medicine containing α-glucosidase inhibitors, suppressed sucrose-induced hyperglycemia in the silkworm system. Moreover, combined oral administration of lactic acid bacteria YM0831 with Kothala himbutu extract had stronger suppressive effects on sucrose-induced hyperglycemia than single administration of either component. These findings suggest that the silkworm system provides a simple way to evaluate the effects of supplements on the suppression of blood glucose level induced by sucrose ingestion.


Assuntos
Enterococcus faecalis/fisiologia , Hiperglicemia/terapia , Extratos Vegetais/administração & dosagem , Salacia/química , Animais , Glicemia/metabolismo , Bombyx , Terapia Combinada , Modelos Animais de Doenças , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Extratos Vegetais/uso terapêutico , Sacarose/efeitos adversos , Resultado do Tratamento
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