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1.
Nutrients ; 13(10)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34684576

RESUMO

Numerous studies highlight that astaxanthin (ASTX) ameliorates hyperglycemic condition and hyperglycemia-associated chronic complications. While periodontitis and periodontic tissue degradation are also triggered under chronic hyperglycemia, the roles of ASTX on diabetes-associated periodontal destruction and the related mechanisms therein are not yet fully understood. Here, we explored the impacts of supplemental ASTX on periodontal destruction and systemic complications in type I diabetic mice. To induce diabetes, C57BL/6 mice received a single intraperitoneal injection of streptozotocin (STZ; 150 mg/kg), and the hyperglycemic mice were orally administered with ASTX (12.5 mg/kg) (STZ+ASTX group) or vehicle only (STZ group) daily for 60 days. Supplemental ASTX did not improve hyperglycemic condition, but ameliorated excessive water and feed consumptions and lethality in STZ-induced diabetic mice. Compared with the non-diabetic and STZ+ASTX groups, the STZ group exhibited severe periodontal destruction. Oral gavage with ASTX inhibited osteoclastic formation and the expression of receptor activator of nuclear factor (NF)-κB ligand, 8-OHdG, γ-H2AX, cyclooxygenase 2, and interleukin-1ß in the periodontium of STZ-injected mice. Supplemental ASTX not only increased the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and osteogenic transcription factors in the periodontium, but also recovered circulating lymphocytes and endogenous antioxidant enzyme activity in the blood of STZ-injected mice. Furthermore, the addition of ASTX blocked advanced glycation end products-induced oxidative stress and growth inhibition in human-derived periodontal ligament cells by upregulating the Nrf2 pathway. Together, our results suggest that ASTX does not directly improve hyperglycemia, but ameliorates hyperglycemia-triggered periodontal destruction and oxidative systemic complications in type I diabetes.


Assuntos
Antioxidantes/metabolismo , Diabetes Mellitus Experimental/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Periodontite/tratamento farmacológico , Periodontite/etiologia , Estreptozocina/administração & dosagem , Adolescente , Processo Alveolar/patologia , Animais , Glicemia/metabolismo , Catalase/sangue , Proliferação de Células , Citocinas/metabolismo , Dano ao DNA , Diabetes Mellitus Experimental/sangue , Suplementos Nutricionais , Comportamento Alimentar , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Hiperglicemia/complicações , Mediadores da Inflamação/metabolismo , Injeções , Linfócitos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Ligamento Periodontal/patologia , Periodontite/sangue , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/sangue , Regulação para Cima , Xantofilas/farmacologia , Xantofilas/uso terapêutico , Adulto Jovem
2.
Int J Mol Sci ; 22(18)2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34576288

RESUMO

This study aimed to reveal functional and morphological changes in the corticospinal tract, a pathway shown to be susceptible to diabetes. Type 1 diabetes was induced in 13-week-old male Wistar rats administered streptozotocin. Twenty-three weeks after streptozotocin injection, diabetic animals and age-matched control animals were used to demonstrate the conduction velocity of the corticospinal tract. Other animals were used for morphometric analyses of the base of the dorsal funiculus of the corticospinal tract in the spinal cord using both optical and electron microscopy. The conduction velocity of the corticospinal tract decreased in the lumbar spinal cord in the diabetic animal, although it did not decrease in the cervical spinal cord. Furthermore, atrophy of the fibers of the base of the dorsal funiculus was observed along their entire length, with an increase in the g-ratio in the lumbar spinal cord in the diabetic animal. This study indicates that the corticospinal tract fibers projecting to the lumbar spinal cord experience a decrease in conduction velocity at the lumbar spinal cord of these axons in diabetic animals, likely caused by a combination of axonal atrophy and an increased g-ratio due to thinning of the myelin sheath.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Tratos Piramidais/patologia , Tratos Piramidais/fisiopatologia , Potenciais de Ação , Animais , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangue , Masculino , Neurônios Motores/patologia , Condução Nervosa , Ratos Wistar , Medula Espinal/patologia , Estreptozocina
3.
Ann Agric Environ Med ; 28(3): 430-436, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34558266

RESUMO

INTRODUCTION: Bilberry fruit is believed to be a promising factor in the treatment of diabetes mellitus. Chronic hyperglycaemia affects the function of the central nervous system, which may be manifested as changes in hypothalamic insulin signalling. MATERIAL AND METHODS: Using DPPH and ABTS assays, total phenolic content in bilberry fruit and its antioxidant activities were examined. The selected biochemical parameters of blood (glucose, fructosamine, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides), as well as the expression of insulin receptors, were studied in the hippocampal CA1 field of healthy and diabetic (streptozotocin-induced; 60 mg kg-1 body weight) Wistar rats fed with bilberry fruit (16 g kg-1 body weight per day; 6 weeks), as well as of the corresponding control groups. RESULTS: Biochemical analyses revealed ambiguous results, but a significantly (P<0.05) decrease in the level of LDL-cholesterol was observed in the group of healthy rats supplemented with bilberry pulp after 6 weeks of the treatment. There was also a difference (P<0.05) in the level of LDL-cholesterol in the mentioned healthy animals fed with bilberry, versus the healthy control group. An increased number of insulin receptors-immunoreactive neurons as well as nerve fibres in the CA1 field of diabetic rats fed with bilberry fruit was also found. CONCLUSIONS: An inclusion of bilberry fruit in the daily diet during the course of diabetes can lead to plasticity of hippocampal neurons/nerve fibres, manifested by changes in insulin receptors expression. Whether or not the observed changes had protective effects (by reducing damages caused by diabetes mellitus) on the function of the central nervous system neurons needs further study.


Assuntos
Região CA1 Hipocampal/metabolismo , Diabetes Mellitus Experimental/dietoterapia , Frutas/metabolismo , Receptor de Insulina/metabolismo , Vaccinium myrtillus/metabolismo , Animais , Glicemia/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/genética , Humanos , Masculino , Ratos , Ratos Wistar , Receptor de Insulina/genética , Triglicerídeos/sangue
4.
Cells ; 10(9)2021 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-34571886

RESUMO

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic ß-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional ß-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit ß-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of ß-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic ß-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet ß-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.


Assuntos
Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/prevenção & controle , Hipoglicemiantes/administração & dosagem , Ilhotas Pancreáticas/efeitos dos fármacos , Trombomodulina/administração & dosagem , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Injeções Intraperitoneais , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/administração & dosagem , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Estreptozocina , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
5.
Biomed Res Int ; 2021: 9920826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341763

RESUMO

Background: Abrus precatorius is used in folk medicine across Afro-Asian regions of the world. Earlier, glucose lowering and pancreato-protective effects of Abrus precatorius leaf extract (APLE) was confirmed experimentally in STZ/nicotinamide-induced diabetic rats; however, the underlying mechanism of antidiabetic effect and pancreato-protection remained unknown. Objective: This study elucidated antidiabetic mechanisms and pancreato-protective effects of APLE in diabetic rats. Materials and Methods: APLE was prepared by ethanol/Soxhlet extraction method. Total phenols and flavonoids were quantified calorimetrically after initial phytochemical screening. Diabetes mellitus (DM) was established in adult Sprague-Dawley rats (weighing 120-180 g) of both sexes by daily sequential injection of nicotinamide (48 mg/kg; ip) and Alloxan (120 mg/kg; ip) over a period of 7 days. Except control rats which had fasting blood glucose (FBG) of 4.60 mmol/L, rats having stable FBG (16-21 mmol/L) 7 days post-nicotinamide/Alloxan injection were considered diabetic and were randomly reassigned to one of the following groups (model, APLE (100, 200, and 400 mg/kg, respectively; po) and metformin (300 mg/kg; po)) and treated daily for 18 days. Bodyweight and FBG were measured every 72 hours for 18 days. On day 18, rats were sacrificed under deep anesthesia; organs (kidney, liver, pancreas, and spleen) were isolated and weighed. Blood was collected for estimation of serum insulin, glucagon, and GLP-1 using a rat-specific ELISA kit. The pancreas was processed, sectioned, and H&E-stained for histological examination. Effect of APLE on enzymatic activity of alpha (α)-amylase and α-glucosidase was assessed. Antioxidant and free radical scavenging properties of APLE were assessed using standard methods. Results: APLE dose-dependently decreased the initial FBG by 68.67%, 31.07%, and 4.39% compared to model (4.34%) and metformin (43.63%). APLE (100 mg/kg) treatment restored weight loss relative to model. APLE increased serum insulin and GLP-1 but decreased serum glucagon relative to model. APLE increased both the number and median crosssectional area (×106 µm2) of pancreatic islets compared to that of model. APLE produced concentration-dependent inhibition of α-amylase and α-glucosidase relative to acarbose. APLE concentration dependently scavenged DPPH and nitric oxide (NO) radicals and demonstrated increased ferric reducing antioxidant capacity (FRAC) relative to standards. Conclusion: Antidiabetic effect of APLE is mediated through modulation of insulin and GLP-1 inversely with glucagon, noncompetitive inhibition of α-amylase and α-glucosidase, free radical scavenging, and recovery of damaged/necro-apoptosized pancreatic ß-cells.


Assuntos
Abrus/química , Diabetes Mellitus Experimental/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucagon/sangue , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Aloxano , Animais , Antioxidantes/metabolismo , Compostos de Bifenilo/química , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Flavonoides/análise , Sequestradores de Radicais Livres/farmacologia , Cobaias , Concentração Inibidora 50 , Insulina/sangue , Ferro/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Cinética , Masculino , Niacinamida , Fenóis/análise , Compostos Fitoquímicos/análise , Picratos/química , Extratos Vegetais/farmacologia , Ratos Sprague-Dawley
6.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371877

RESUMO

Pathological mechanisms underlining diabetic bone defects include oxidative damage and insulin/IGF-1 imbalance. Morin is a bioflavonoid with antioxidant and anti-diabetic effects. This study evaluates morin's protective effects against altered bone histomorphometry in diabetic rats through assessing insulin/IGF-1 pathway as a potential mechanism. Diabetic animals were administered two morin doses (15 and 30 mg/kg) for 5 weeks. Different serum hepatic and renal functions tests were assessed. Bone density and histomorphometry in cortical and trabecular tissues were evaluated histologically. The expressions of insulin, c-peptide and IGF-1 were estimated. In addition, the enzymatic activities of the major antioxidant enzymes were determined. Diabetic-associated alterations in serum glucose, aminotransferases, urea and creatinine were attenuated by morin. Diabetic bone cortical and trabecular histomorphometry were impaired with increased fibrosis, osteoclastic functions, osteoid formation and reduced mineralization, which was reversed by morin; particularly the 30 mg/kg dose. Insulin/IGF-1 levels were diminished in diabetic animals, while morin treatment enhanced their levels significantly. Diabetes also triggered systemic oxidative stress noticeably. The higher dose (30 mg/kg) of morin corrected the endogenous antioxidant enzymatic activities in diabetic rats. Findings indicate the potential value of morin supplementation against hyperglycemia-induced skeletal impairments. Activation of insulin/IGF-1 signaling could be the underlining mechanism behind these effects.


Assuntos
Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fêmur/efeitos dos fármacos , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/sangue , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Fêmur/metabolismo , Fêmur/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Estreptozocina
7.
Nutrients ; 13(8)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34444919

RESUMO

Flaxseed is an oilseed (45-50% oil on a dry-weight basis) crop. Its oil has demonstrated multiple health benefits and industrial applications. The goal of this research was to evaluate the antidiabetic and anti-inflammatory potential of the free polyphenol fraction of flax (Linum usitatissimum L.) seeds (PLU), based on their use in traditional medicine. Mice with alloxan-induced diabetes were used to study the antidiabetic activity of PLU in vivo, with an oral administration of 25 and 50 mg/kg over 28 days. Measurements of body weight and fasting blood glucose (FBG) were carried out weekly, and biochemical parameters were evaluated. An oral glucose tolerance test was also performed. Inhibitory activities of PLU on α-amylase and α-glucosidase activities were evaluated in vitro. The anti-inflammatory was evaluated in vivo in Wistar rats using the paw edema induction Test by carrageenan, and in vitro using the hemolysis ratio test. PLU administration to diabetic mice during the study period improved their body weight and FBG levels remarkably. In vitro inhibitory activity of digestive enzymes indicated that they may be involved in the proposed mode of action of PLU extract. Qualitative results of PLU revealed the presence of 18 polyphenols. These findings support daily consumption of flaxseed for people with diabetes, and suggest that polyphenols in flaxseed may serve as dietary supplements or novel phytomedicines to treat diabetes and its complications.


Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/terapia , Linho/química , Hipoglicemiantes/farmacologia , Óleos Vegetais/farmacologia , Sementes/química , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Suplementos Nutricionais , Humanos , Camundongos , Polifenóis/farmacologia , Ratos , Ratos Wistar
8.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445047

RESUMO

Sargassum fusiforme alginate (SF-Alg) possess many pharmacological activities, including hypoglycemic and hypolipidemic. However, the hypoglycemic mechanisms of SF-Alg remain unclear due to its low bioavailability. In this study, we evaluated the therapeutic effect of SF-Alg on high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes (T2D) mice. SF-Alg intervention was found to significantly reduce fasting blood glucose (FBG), triglycerides (TG), and total cholesterol (TC), while increasing high-density lipoprotein cholesterol (HDL-c) and improving glucose tolerance. In addition, administrating SF-Alg to diabetic mice moderately attenuated pathological changes in adipose, hepatic, and heart tissues as well as skeletal muscle, and diminished oxidative stress. To probe the underlying mechanisms, we further analyzed the gut microbiota using 16S rRNA amplicon sequencing, as well as metabolites by non-targeted metabolomics. Here, SF-Alg significantly increased some benign bacteria (Lactobacillus, Bacteroides, Akkermansia Alloprevotella, Weissella and Enterorhabdus), and significantly decreased harmful bacteria (Turicibacter and Helicobacter). Meanwhile, SF-Alg dramatically decreased branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in the colon of T2D mice, suggesting a positive benefit of SF-Alg as an adjvant agent for T2D.


Assuntos
Alginatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Sargassum/química , Animais , Glicemia/efeitos dos fármacos , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/etiologia , Camundongos , Estreptozocina , Triglicerídeos/sangue
9.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443451

RESUMO

Diabetes mellitus is characterized by tissue oxidative damage and impaired microcirculation, as well as worsened erythrocyte properties. Measurements of erythrocyte deformability together with determination of nitric oxide (NO) production and osmotic resistance were used for the characterization of erythrocyte functionality in lean (control) and obese Zucker diabetic fatty (ZDF) rats of two age categories. Obese ZDF rats correspond to prediabetic (younger) and diabetic (older) animals. As antioxidants were suggested to protect erythrocytes, we also investigated the potential effect of quercetin (20 mg/kg/day for 6 weeks). Erythrocyte deformability was determined by the filtration method and NO production using DAF-2DA fluorescence. For erythrocyte osmotic resistance, we used hemolytic assay. Erythrocyte deformability and NO production deteriorated during aging-both were lower in older ZDF rats than in younger ones. Three-way ANOVA indicates improved erythrocyte deformability after quercetin treatment in older obese ZDF rats only, as it was not modified or deteriorated in both (lean and obese) younger and older lean animals. NO production by erythrocytes increased post treatment in all experimental groups. Our study indicates the potential benefit of quercetin treatment on erythrocyte properties in condition of diabetes mellitus. In addition, our results suggest potential age-dependency of quercetin effects in diabetes that deserve additional research.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Eritrócitos/metabolismo , Quercetina/uso terapêutico , Animais , Antioxidantes , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Deformação Eritrocítica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Osmose , Estresse Oxidativo , Quercetina/farmacologia , Ratos Zucker
10.
Sci Rep ; 11(1): 16983, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417511

RESUMO

Obesity (Ob) poses a significant risk factor for the onset of metabolic syndrome with associated complications, wherein the Mesenchymal Stem Cell (MSC) therapy shows pre-clinical success. Here, we explore the therapeutic applications of human Placental MSCs (P-MSCs) to address Ob-associated Insulin Resistance (IR) and its complications. In the present study, we show that intramuscular injection of P-MSCs homed more towards the visceral site, restored HOMA-IR and glucose homeostasis in the WNIN/GR-Ob (Ob-T2D) rats. P-MSC therapy was effective in re-establishing the dysregulated cytokines. We report that the P-MSCs activates PI3K-Akt signaling and regulates the Glut4-dependant glucose uptake and its utilization in WNIN/GR-Ob (Ob-T2D) rats compared to its control. Our data reinstates P-MSC treatment's potent application to alleviate IR and restores peripheral blood glucose clearance evidenced in stromal vascular fraction (SVF) derived from white adipose tissue (WAT) of the WNIN/GR-Ob rats. Gaining insights, we show the activation of the PI3K-Akt pathway by P-MSCs both in vivo and in vitro (palmitate primed 3T3-L1 cells) to restore the insulin sensitivity dysregulated adipocytes. Our findings suggest a potent application of P-MSCs in  pre-clinical/Ob-T2D management.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Experimental/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Modelos Biológicos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Diabetes Mellitus Tipo 2/terapia , Feminino , Transportador de Glucose Tipo 4/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Macrófagos/metabolismo , Obesidade/complicações , Fosfatidilinositol 3-Quinases/metabolismo , Placenta/citologia , Gravidez , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais
11.
Transplantation ; 105(9): 1980-1988, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34416751

RESUMO

BACKGROUND: Type 1 diabetes (T1DM) is a chronic autoimmune disease characterized by T-cell-mediated destruction of insulin-producing beta cells. Evidence shows that patients with T1DM and mice used in specific diabetic models both exhibit changes in their intestinal microbiota and dysregulated microbiota contributes to the pathogenesis of T1DM. Islet transplantation (Tx) is poised to play an important role in the treatment of T1DM. However, whether treatment of T1DM with islet Tx can rescue dysregulated microbiota remains unclear. METHODS: In this study, we induced diabetic C57BL/6 mice with streptozotocin. Then treatment with either insulin administration, or homogenic or allogenic islet Tx was performed to the diabetic mice. Total DNA was isolated from fecal pellets and high-throughput 16S rRNA sequencing was used to investigate intestinal microbiota composition. RESULTS: The overall microbial diversity was comparable between control (nonstreptozotocin treated) and diabetic mice. Our results showed the ratio of the Bacteroidetes: Firmicutes between nondiabetic and diabetic mice was significant different. Treatment with islet Tx or insulin partially corrects the dysregulated bacterial composition. At the genus level, Bacteroides, Odoribacter, and Alistipes were associated with the progression and treatment efficacy of the disease, which may be used as a biomarker to predict curative effect of treatment for patients with T1DM. CONCLUSIONS: Collectively, our results indicate that diabetic mice show changed microbiota composition and that treatment with insulin and islet Tx can partially correct the dysregulated microbiota.


Assuntos
Bactérias/crescimento & desenvolvimento , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Microbioma Gastrointestinal , Controle Glicêmico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/microbiologia , Disbiose , Fezes/microbiologia , Transplante das Ilhotas Pancreáticas , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ribotipagem , Estreptozocina , Técnicas de Cultura de Tecidos
12.
J Steroid Biochem Mol Biol ; 212: 105948, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34224859

RESUMO

Oxidative stress injury is an important link in the pathogenesis of diabetes, and reducing oxidative stress damage caused by long-term hyperglycemia is an important diabetic treatment strategy. Melatonin has been proved to be a free radical scavenger with strong antioxidant activity, and its protective effect on diabetes and the complications has been confirmed. However, the role and potential mechanism of melatonin in oxidative stress injury of diabetic aorta have not been reported. Besides, Notch signaling pathway plays an important role in vascular growth, differentiation, and apoptosis. We speculated that melatonin could improve oxidative stress injury of diabetic aorta through Notch1/Hes1 signaling pathway. STZ-induced diabetic rats and vascular smooth muscle cells (VSMCs) cultured with high glucose were treated with or without melatonin, melatonin receptor antagonist Luzindole, γ-secretase inhibitor DAPT respectively. We found that melatonin could improve the oxidative stress injury of diabetic aorta and reduce the apoptosis of VSMCs. Interestingly, melatonin could activate Notch1 signaling pathway, play an antioxidant role, and reduce the expression of apoptosis-related proteins. However, these protective effects could be largely eliminated by Luzindole or DAPT. We concluded that the repression of Notch1 signaling pathway would inhibit the repair of oxidative stress injury in diabetes. Melatonin could ameliorate oxidative stress injury and apoptosis of diabetic aorta by activating Notch1/Hes1 signaling pathway.


Assuntos
Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Melatonina/uso terapêutico , Animais , Antioxidantes/farmacologia , Aorta Torácica/citologia , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Melatonina/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição HES-1/metabolismo
13.
Methods Mol Biol ; 2312: 35-57, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228283

RESUMO

Diabetes mellitus is a complex metabolic disease characterized by chronically deregulated blood-glucose levels. To restore glucose homeostasis, therapeutic strategies allowing well-controlled production and release of insulinogenic hormones into the blood circulation are required. In this chapter, we describe how mammalian cells can be engineered for applications in diabetes treatment. While closed-loop control systems provide automated and self-sufficient synchronization of glucose sensing and drug production, drug production in open-loop control systems is engineered to depend on exogenous user-defined trigger signals. Rational, robust, and reliable manufacture practices for mammalian cell engineering are essential for industrial-scale mass-production in view of clinical and commercial applications.


Assuntos
Técnicas Biossensoriais , Glicemia/metabolismo , Engenharia Celular , Diabetes Mellitus Experimental/terapia , Terapia Genética , Peptídeo 1 Semelhante ao Glucagon/genética , Células Secretoras de Insulina/transplante , Insulina/genética , Biologia Sintética , Animais , Biomarcadores/sangue , Encapsulamento de Células , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Homeostase , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transfecção
14.
Methods Mol Biol ; 2312: 141-158, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228289

RESUMO

With the development of mobile communication technology, smartphones have been used in point-of-care technologies (POCTs) as an important part of telemedicine. Using a multidisciplinary design principle coupling electrical engineering, software development, synthetic biology, and optogenetics, the investigators developed a smartphone-controlled semiautomatic theranostic system that regulates blood glucose homeostasis in diabetic mice in an ultraremote-control manner. The present chapter describes how the investigators tailor-designed the implant architecture "HydrogeLED," which is capable of coharboring a designer-cell-carrying alginate hydrogel and wirelessly powered far-red light LEDs. Using diabetes mellitus as a model disease, the in vivo expression of insulin or human glucagon-like peptide 1 (shGLP-1) from HydrogeLED implants could be controlled not only by pre-set ECNU-TeleMed programs, but also by a custom-engineered Bluetooth-active glucometer in a semiautomatic and glycemia-dependent manner. As a result, blood glucose homeostasis was semiautomatically maintained in diabetic mice through the smartphone-controlled semiautomatic theranostic system. By combining digital signals with optogenetically engineered cells, the present study provides a new method for the integrated diagnosis and treatment of diseases.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Experimental/terapia , Controle Glicêmico/instrumentação , Optogenética/instrumentação , Smartphone , Telemedicina/instrumentação , Nanomedicina Teranóstica/instrumentação , Tecnologia sem Fio/instrumentação , Alginatos/química , Animais , Biomarcadores/sangue , Automonitorização da Glicemia/instrumentação , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/genética , Regulação da Expressão Gênica/efeitos da radiação , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Homeostase , Humanos , Hidrogéis , Insulina/genética , Insulina/metabolismo , Luz , Masculino , Camundongos Endogâmicos C57BL , Aplicativos Móveis
15.
Anticancer Res ; 41(8): 4053-4059, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281874

RESUMO

BACKGROUND/AIM: Diabetes is a risk factor for dementia. However, no radical preventive method for diabetes-associated dementia has yet been developed. Our previous study revealed that oral administration of lipopolysaccharide (LPS) prevents high-fat diet-induced cognitive impairment. Therefore, we investigated here whether oral administration of LPS (OAL) could also prevent diabetes-associated dementia. MATERIALS AND METHODS: Diabetic mice were produced by intraperitoneal administration of streptozotocin (STZ), and then mice were orally administered LPS. Cognitive ability was evaluated using the Morris water maze, and gene expression was analyzed in isolated microglia. RESULTS: OAL prevented STZ-induced diabetic cognitive impairment, but did not affect blood glucose levels. Moreover, OAL promoted the expression of neuroprotective genes in microglia, such as heat shock protein family 40 (HSP40) and chemokine CCL7. CONCLUSION: OAL prevents diabetes-associated dementia, potentially via promotion of HSP40 and CCL7 expression in microglia.


Assuntos
Disfunção Cognitiva/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Quimiocina CCL7/genética , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Proteínas de Choque Térmico HSP40/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia
16.
Nutrients ; 13(7)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206641

RESUMO

Previous studies have reported the therapeutic effects of oleuropein (OP) consumption on the early stage of type 2 diabetes. However, the efficacy of OP on the advanced stage of type 2 diabetes has not been investigated, and the relationship between OP and intestinal flora has not been studied. Therefore, in this study, to explore the relieving effects of OP intake on the advanced stage of type 2 diabetes and the regulatory effects of OP on intestinal microbes, diabetic db/db mice (17-week-old) were treated with OP at the dose of 200 mg/kg for 15 weeks. We found that OP has a significant effect in decreasing fasting blood glucose levels, improving glucose tolerance, lowering the homeostasis model assessment-insulin resistance index, restoring histopathological features of tissues, and promoting hepatic protein kinase B activation in db/db mice. Notably, OP modulates gut microbiota at phylum level, increases the relative abundance of Verrucomicrobia and Deferribacteres, and decreases the relative abundance of Bacteroidetes. OP treatment increases the relative abundance of Akkermansia, as well as decreases the relative abundance of Prevotella, Odoribacter, Ruminococcus, and Parabacteroides at genus level. In conclusion, OP may ameliorate the advanced stage of type 2 diabetes through modulating the composition and function of gut microbiota. Our findings provide a promising therapeutic approach for the treatment of advanced stage type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Glucosídeos Iridoides/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Jejum/sangue , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos
17.
PLoS One ; 16(7): e0254718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270619

RESUMO

Artificial pancreas system (APS) is an emerging new treatment for type 1 diabetes mellitus. The aim of this study was to develop a rat APS as a research tool and demonstrate its application. We established a rat APS using Medtronic Minimed Pump 722, Medtronic Enlite sensor, and the open artificial pancreas system as a controller. We tested different dilutions of Humalog (100 units/ml) in saline ranged from 1:3 to 1:20 and determined that 1:7 dilution works well for rats with ~500g bodyweight. Blood glucose levels (BGL) of diabetic rats fed with chow diet (58% carbohydrate) whose BGL was managed by the closed-loop APS for the total duration of 207h were in euglycemic range (70-180 mg/dl) for 94.5% of the time with 2.1% and 3.4% for hyperglycemia (>180mg/dl) and hypoglycemia (<70 mg/dl), respectively. Diabetic rats fed with Sucrose pellets (94.8% carbohydrate) for the experimental duration of 175h were in euglycemic range for 61% of the time with 35% and 4% for hyperglycemia and hypoglycemia, respectively. Heathy rats fed with chow diet showed almost a straight line of BGL ~ 95 mg/dl (average 94.8 mg/dl) during the entire experimental period (281h), which was minimally altered by food intake. In the healthy rats, feeding sucrose pellets caused greater range of BGL in high and low levels but still within euglycemic range (99.9%). Next, to study how healthy and diabetic rats handle supra-physiological concentrations of glucose, we intraperitoneally injected various amounts of 50% dextrose (2, 3, 4g/kg) and monitored BGL. Duration of hyperglycemia after injection of 50% dextrose at all three different concentrations was significantly greater for healthy rats than diabetic rats, suggesting that insulin infusion by APS was superior in reducing BGL as compared to natural insulin released from pancreatic ß-cells. Ex vivo studies showed that islets isolated from diabetic rats were almost completely devoid of pancreatic ß-cells but with intact α-cells as expected. Lipid droplet deposition in the liver of diabetic rats was significantly lower with higher levels of triacylglyceride in the blood as compared to those of healthy rats, suggesting lipid metabolism was altered in diabetic rats. However, glycogen storage in the liver determined by Periodic acid-Schiff staining was not altered in diabetic rats as compared to healthy rats. A rat APS may be used as a powerful tool not only to study alterations of glucose and insulin homeostasis in real-time caused by diet, exercise, hormones, or antidiabetic agents, but also to test mathematical and engineering models of blood glucose prediction or new algorithms for closed-loop APS.


Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Insulina/administração & dosagem , Pâncreas Artificial , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/diagnóstico , Hemoglobina A Glicada/análise , Humanos , Infusões Intravenosas/instrumentação , Infusões Intravenosas/métodos , Masculino , Ratos , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade
18.
J Oleo Sci ; 70(7): 965-977, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34121030

RESUMO

Due to the growing demand of n-3 polyunsaturated fatty acids (PUFA) as supplements and pharmaceutical products worldwide, there are concerns about the exhaustion of n-3 PUFA supply sources. We have successfully prepared high-quality scallop oil (SCO), containing high eicosapentaenoic acid and phospholipids contents, from the internal organs of the Japanese giant scallop (Patinopecten yessoensis), which is the largest unutilized marine resource in Japan. This study compared the cholesterol-lowering effect of SCO with fish oil (menhaden oil, MO) and krill oil (KO) in obese type II diabetic KK-A y mice. Four-week-old male KK-A y mice were divided into four groups; the control group was fed the AIN93G-modified high-fat (3 wt% soybean oil + 17 wt% lard) diet, and the other three groups (SCO, MO, and KO groups) were fed a high-fat diet, in which 7 wt% of the lard in the control diet was replaced with SCO, MO, or KO, respectively. After the mice were fed the experimental diet for 42 days, their serum, liver, and fecal lipid contents as well as their liver mRNA expression levels were evaluated. The SCO group had significantly decreased cholesterol levels in the serum and liver; this decrease was not observed in the MO and KO groups. The cholesterol-lowering effect of SCO was partly mediated by the enhancement of fecal total sterol excretion and expression of liver cholesterol 7α-hydroxylase, a rate-limiting enzyme for bile acid synthesis. These results indicate that dietary SCO exhibits serum and liver cholesterol-lowering effects that are not found in dietary MO and KO and can help prevent lifestyle-related diseases.


Assuntos
Anticolesterolemiantes/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Óleos de Peixe/uso terapêutico , Hipercolesterolemia/dietoterapia , Pectinidae/química , Animais , Colesterol/sangue , Colesterol 7-alfa-Hidroxilase/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Euphausiacea/química , Ácidos Graxos/análise , Ácidos Graxos/química , Fezes/química , Peixes , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Fígado/química , Masculino , Camundongos , RNA Mensageiro/metabolismo , Triglicerídeos/sangue , Triglicerídeos/química
19.
Life Sci ; 284: 119664, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34090859

RESUMO

AIM: Present study focuses on the effect of daidzein in an experimental model of diabetic cardiomyopathy in rats. MATERIALS AND METHODS: Diabetes was induced in male Sprague Dawley rats by a single intraperitoneal injection of STZ at dose 55 mg/kg. Daidzein treatment was started after six weeks of diabetes induction. Animals received daidzein at a dose of 25, 50, and 100 mg/kg orally for the next four weeks. KEY FINDINGS: Diabetic control animals showed significant prolongation in QT interval, PR interval, and R wave amplitude as compared to normal control animals. Treatment with daidzein at dose 100 mg/kg significantly normalized the QT interval, PR interval, and R wave amplitude. A significant reduction in QRS duration was observed in diabetic animals. Treatment with daidzein significantly improved the QRS duration after treatment. Hemodynamic parameters like systolic pressure (SBP), diastolic pressure (DBP) and mean atrial pressure (MAP) were found to be significantly decreased in diabetic animals. Treatment with daidzein at dose 100 mg/kg significantly improved the SBP, DBP, and MAP. Daidzein treatment prevented the loss of cardiac marker enzyme from heart tissue and also increased the level of AMPK and SIRT1 in plasma. Protein expression of NOX-4 and RAC-1 was also found to be reduced in cardiac tissue of daidzein treated animals. Daidzein treatment improved oxidative defense mechanism and reduced cardiac tissue necrosis and fibrosis. SIGNIFICANCE: From the results, it can be concluded that daidzein mitigates the progression of diabetic cardiomyopathy by inhibiting NOX-4 induced oxidative stress in cardiac tissue.


Assuntos
Diabetes Mellitus Experimental/patologia , Isoflavonas/farmacologia , Miocárdio/patologia , Adenilato Quinase/metabolismo , Animais , Antioxidantes/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Cardiomegalia/sangue , Cardiomegalia/complicações , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/diagnóstico por imagem , Diabetes Mellitus Experimental/fisiopatologia , Eletrocardiografia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Isoflavonas/química , Lipídeos/sangue , Masculino , Miocárdio/enzimologia , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Sirtuína 1/metabolismo , Troponina I/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
20.
Front Immunol ; 12: 653088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122410

RESUMO

Allogeneic islet transplantation is a promising cell-based therapy for Type 1 Diabetes (T1D). The long-term efficacy of this approach, however, is impaired by allorejection. Current clinical practice relies on long-term systemic immunosuppression, leading to severe adverse events. To avoid these detrimental effects, poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) were engineered for the localized and controlled release of immunomodulatory TGF-ß1. The in vitro co-incubation of TGF-ß1 releasing PLGA MPs with naïve CD4+ T cells resulted in the efficient generation of both polyclonal and antigen-specific induced regulatory T cells (iTregs) with robust immunosuppressive function. The co-transplantation of TGF-ß1 releasing PLGA MPs and Balb/c mouse islets within the extrahepatic epididymal fat pad (EFP) of diabetic C57BL/6J mice resulted in the prompt engraftment of the allogenic implants, supporting the compatibility of PLGA MPs and local TGF-ß1 release. The presence of the TGF-ß1-PLGA MPs, however, did not confer significant graft protection when compared to untreated controls, despite measurement of preserved insulin expression, reduced intra-islet CD3+ cells invasion, and elevated CD3+Foxp3+ T cells at the peri-transplantation site in long-term functioning grafts. Examination of the broader impacts of TGF-ß1/PLGA MPs on the host immune system implicated a localized nature of the immunomodulation with no observed systemic impacts. In summary, this approach establishes the feasibility of a local and modular microparticle delivery system for the immunomodulation of an extrahepatic implant site. This approach can be easily adapted to deliver larger doses or other agents, as well as multi-drug approaches, within the local graft microenvironment to prevent transplant rejection.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Portadores de Fármacos/química , Rejeição de Enxerto/prevenção & controle , Fatores Imunológicos/administração & dosagem , Transplante das Ilhotas Pancreáticas/efeitos adversos , Fator de Crescimento Transformador beta1/administração & dosagem , Animais , Glicemia/análise , Técnicas de Cocultura , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Liberação Controlada de Fármacos , Estudos de Viabilidade , Teste de Tolerância a Glucose , Rejeição de Enxerto/imunologia , Humanos , Imunomodulação , Transplante das Ilhotas Pancreáticas/métodos , Masculino , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Cultura Primária de Células , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/farmacocinética , Transplante Homólogo/efeitos adversos
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