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1.
Life Sci ; 244: 117329, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954747

RESUMO

MicroRNAs (miRs) are small non-coding pieces of RNA that are involved in a variety of physiologic processes such as apoptosis, cell proliferation, cell differentiation, cell cycle and cell survival. These multifunctional nucleotides are also capable of preventing oxidative damages by modulating antioxidant defense systems in a variety of milieu, such as in diabetes. Although the exact molecular mechanisms by which miRs modulate the antioxidant defense elements are unclear, some evidence suggests that they may exert these effects via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This intracellular mechanism is crucial in the maintenance of the physiologic redox balance by regulating the expression and activity of various cellular antioxidative defense elements and thereby plays a pivotal role in the development of oxidative stress. Any impairment in the Nrf2 signaling pathway may result in oxidative damage-dependent complications such as various diabetic complications, neurological disorders and cancer. In the current review, we discuss the modulatory effects of miRs on the Nrf2 signaling pathway, which can potentially be novel therapeutic targets.


Assuntos
Complicações do Diabetes/prevenção & controle , Regulação da Expressão Gênica , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/prevenção & controle , Doenças do Sistema Nervoso/prevenção & controle , Estresse Oxidativo , Animais , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Transdução de Sinais
2.
Medicine (Baltimore) ; 98(47): e18067, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764838

RESUMO

Osteoporosis is a complication of type 2 diabetes mellitus (T2DM). Blockade of receptor activator of nuclear factor kappa-B ligand (RANKL) improves osteoporosis, but might also improve glucose tolerance through reduction of hepatic insulin resistance. However, the effect of denosumab (a human monoclonal antibody of RANKL) upon glycemic and metabolic parameters is controversial. We revealed the effect of denosumab upon glycemic and metabolic parameters for 52 weeks. We evaluated 20 individuals diagnosed with both osteoporosis (male and female: postmenopausal) and T2DM. We measured glycemic and metabolic parameters before and 26/52 weeks after administration of denosumab (60 mg per 26 weeks) without changing any other medication each patient was taking. All patients completed the study without complications and the T-score (lumbar spine and femoral neck) improved significantly from baseline to 52 weeks after denosumab administration (P < .001, .001, respectively). None of the glycemic parameters changed significantly from baseline to 26 weeks after denosumab administration, but levels of glycated hemoglobin and homeostasis model assessment of insulin resistance improved significantly from baseline to 52 weeks after administration (P = .019, .008, respectively). The levels of liver enzymes did not change significantly from baseline to 26 weeks after denosumab administration, but levels of aspartate transaminase and alanine aminotransferase improved significantly from baseline to 52 weeks after administration (P = .014, .004, respectively). None of the markers of lipid metabolism and body mass index changed significantly from baseline to 26/52 weeks after denosumab administration. These data demonstrated that denosumab is useful for T2DM patients with osteoporosis for glycemic control via improvement of insulin resistance. Also, the effect of denosumab might be due to improvement of hepatic function.


Assuntos
Glicemia/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/farmacologia , Denosumab/uso terapêutico , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Osteoporose/metabolismo , Idoso , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Osteoporose/etiologia , Ligante RANK/imunologia
3.
Orv Hetil ; 160(40): 1567-1573, 2019 Oct.
Artigo em Húngaro | MEDLINE | ID: mdl-31565977

RESUMO

The relationship between the potentially developing complications of the 451 million people affected by diabetes and hyperglycaemia can be based on the enhanced generation of advanced glycation endproducts and the more intensive oxidative and carbonyl stress. Advanced glycation endproducts generated partly due to carbonyl stress play an important role in the pathogenesis of diabetic complications such as elevated arterial thickness, vascular permeability, enhanced angiogenesis or the more rigid vessels induced nephropathy, neuropathy, retinopathy. Furthermore, the elevated thrombocyte aggregation, the reduced fibrinolysis induced elevated coagulation, and the atherosclerosis or the mitochondrial dysfunction are important as well. The most potent target of both the non-oxidative and oxidative generation of advanced glycation endproducts can be the scavenging of α,ß-unsaturated aldehydes. Although, aminoguanidine, the prototype of scavenger molecules, showed protection in different animal models, it failed in the human clinical studies. Finally, the clinical studies were terminated almost 20 years ago. The endogen dipeptide L-carnosine was also expected to mitigate the complications due to carbonyl stress. However, its clinical significance was limited by the serum carnosinases and by the consequent low serum stability and bioavailability. The carnosinase resistance of the molecule can be achieved by the change of the carboxyl group of the molecule to hydroxyl group. At the same time, the biosafety and the carbonyl stress scavenging activity of the molecule could be preserved. Although clinical studies could not be performed in the last six months, on the basis of the in vitro and in vivo results, carnosinole seems to be a promising compound to mitigate and prevent the diabetic complications. Thus it is worth to the attention of the clinicians. Orv Hetil. 2019; 160(40): 1567-1573.


Assuntos
Complicações do Diabetes/fisiopatologia , Produtos Finais de Glicação Avançada/efeitos adversos , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/fisiologia , Humanos , Hiperglicemia
4.
J Diabetes Res ; 2019: 8712492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583254

RESUMO

Testicular structural and functional impairment is a serious complication in male diabetes mellitus (DM) patients that leads to impaired fertility in adulthood. In contrast to other endocrine therapies, islet transplantation (IT) can effectively prevent and even reverse diabetic nephropathy and myocardial damage. However, whether IT can alleviate diabetes-induced testicular injury remains unclear. In this study, we sought to investigate the effect of IT on diabetes-induced testicular damage. A diabetic rat model was established by streptozotocin injection. DM, IT, and insulin treatment (INS) groups were compared after 4 weeks of respective treatment. We confirmed that IT could effectively attenuate diabetes-induced testicular damage and recover sperm counts more extensively compared with INS in diabetic rats. In addition, significantly higher levels of superoxide dismutase (SOD) activity and lower contents of malondialdehyde (MDA) were detected in the testes of the IT group versus diabetic rats. Mechanism studies revealed that IT significantly activates the expression of Nrf-2, HO-1, and NQO-1 and inhibits upregulation of the NF-κB expression in response to DM, while INS only exhibit slight impact on the protein expression. Therefore, we speculate that IT may prevent the progression of testicular damage by downregulating oxidative stress and inhibiting inflammation via Nrf-2/HO-1 and NF-κB pathways.


Assuntos
Complicações do Diabetes/cirurgia , Diabetes Mellitus Experimental/cirurgia , Inflamação/metabolismo , Transplante das Ilhotas Pancreáticas , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , Doenças Testiculares/cirurgia , Testículo/metabolismo , Animais , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Heme Oxigenase (Desciclizante)/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Inflamação/patologia , Insulina/farmacologia , Insulina/uso terapêutico , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Contagem de Espermatozoides , Doenças Testiculares/tratamento farmacológico , Doenças Testiculares/metabolismo , Doenças Testiculares/patologia , Testículo/efeitos dos fármacos , Testículo/patologia
5.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575077

RESUMO

Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through a variety of mechanisms on molecular and structural levels. These changes predispose the bone to an increased fracture risk and impaired osseus healing. In a clinical practice, adequate control of diabetes mellitus is essential for preventing detrimental effects on bone health. Alternative fracture risk assessment tools may be needed to accurately determine fracture risk in patients living with diabetes mellitus. Currently, there is no conclusive model explaining the mechanism of action of diabetes mellitus on bone health, particularly in view of progenitor cells. In this review, the best available literature on the impact of diabetes mellitus on bone health in vitro and in vivo is summarised with an emphasis on future translational research opportunities in this field.


Assuntos
Osso e Ossos/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Diástase Óssea/etiologia , Diástase Óssea/metabolismo , Animais , Biomarcadores , Densidade Óssea , Remodelação Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Epigênese Genética , Humanos , Células-Tronco Mesenquimais/metabolismo , Transdução de Sinais
6.
Mater Sci Eng C Mater Biol Appl ; 105: 110083, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546466

RESUMO

Cutaneous wounds, especially chronic wounds, remain clinical challenges, and this is partially due to the complex healing process composed of four overlapping but distinct stages including hemostasis, inflammation, proliferation and remodeling. Therefore, wound dressings with spatially designed structures which can temporally regulate certain bioactive components to function at specific healing stages might be able to accelerate the healing process. In this study, nanobioglass incorporated chitosan-PVA (polyvinyl alcohol) trilayer nanofibrous membrane (nBG-TFM) was fabricated via sequential electrospinning. This membrane exhibited excellent biocompatibility, antibacterial activity and regeneration promotion effect. Furthermore, spatially designed structure optimized functions of each component and provided more suitable microenvironment as compared with uniform membrane. Rat full-thickness skin defects model and mice diabetic chronic wound model showed that nBG-TFM could achieve significantly accelerated and enhanced healing, in terms of complete re-epithelialization, improved collagen alignment and formation of skin appendages. It was revealed that nBG-TFM functioned through upregulating growth factors including VEGF and TGF-ß. Meanwhile inflammatory cytokines such as TNF-α and IL-1ß were downregulated. The technology presented in this study shed new light on designing functional wound dressings which can promote healing of chronic wounds.


Assuntos
Bandagens , Cerâmica , Quitosana , Membranas Artificiais , Nanofibras , Álcool de Polivinil , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões , Animais , Linhagem Celular , Cerâmica/química , Cerâmica/farmacologia , Quitosana/química , Quitosana/farmacologia , Doença Crônica , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Complicações do Diabetes/terapia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Masculino , Camundongos , Nanofibras/química , Nanofibras/uso terapêutico , Álcool de Polivinil/química , Álcool de Polivinil/farmacologia , Ratos , Ratos Sprague-Dawley , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia , Ferimentos e Lesões/terapia
7.
Food Funct ; 10(9): 5350-5360, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393485

RESUMO

Diabetic osteoporosis (DOP) is a systemic endocrine-metabolic osteopathy which has the characteristics of bone mineral density (BMD) reduction and bone microstructural destruction. Although anthocyanin-rich extract from black rice (AEBR) was reported to have a beneficial effect on diabetic rats, no studies have been performed on whether black rice anthocyanins are beneficial for diabetic osteoporosis. Therefore, in this study, a streptozotocin-induced diabetic rat model was established to investigate the protective effect of AEBR on diabetes-induced osteoporosis and its possible mechanism. AEBR at three doses (0.5, 1.0, and 2.0 g kg-1 d-1) were administered by oral gavage to diabetic rats for 8 weeks. The blood glucose, BMD, bone histomorphometry parameters, serum bone turnover biomarkers, bone marrow adipocyte numbers, as well as osteoprotegerin (OPG), runt-related transcription factor 2 (RUNX 2), and receptor activator of nuclear factor-κ B ligand (RANKL) protein expression in bone and serum were detected. The results indicated that AEBR dose-dependently decreased the blood glucose, increased the BMD, and decreased the serum bone turnover markers. The bone microstructure and osteoclast numbers in bone tissues returned to normal in the high AEBR dosage group; at the same time, the AEBR dose-dependently suppressed bone marrow adipogenesis. The RUNX 2 as well as the OPG/RANKL ratio in diabetic rats' bone tissues increased significantly in the AEBR treatment group. Our results indicate that AEBR administration can ameliorate bone loss caused by diabetes; this is mainly attributed to its inhibition of bone turnover, suppression of bone marrow adipogenesis, and up-regulation of RUNX 2 and the OPG/RANKL expression ratio.


Assuntos
Antocianinas/administração & dosagem , Complicações do Diabetes/tratamento farmacológico , Oryza/química , Osteoporose/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Antocianinas/análise , Glicemia/metabolismo , Densidade Óssea/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Feminino , Humanos , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/fisiopatologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Diabetes Metab Syndr ; 13(2): 1303-1307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336482

RESUMO

AIM: Alteration in the metabolism of magnesium have an influence on different metabolic and signaling pathways involved in development of diabetes and its progression. Reduced magnesium level was associated with diabetes related complications. The aim of this study is to determine the serum levels of magnesium in diabetic patients having different complications and the association of magnesium with status of glycemic control. MATERIALS AND METHODS: This study was conducted among 88 type 2 diabetic patients, subdivided into two groups according to diabetic complications (with complications n = 55; without complications n = 33) and biochemical variables were measured. RESULTS: The serum magnesium level was decreased in diabetic patients having any complications (P = 0.039) or independent complication (nephropathy, P = 0.437; retinopathy, P = 0.038; neuropathy, P = 0.012 and macrovascular complication, P = 0.039), also decrease with increase in number of diabetic complications. Serum magnesium showed an inverse relation with glycemic parameters (HbA1c (r = -0.323; P = 0.002) and fasting blood glucose (r = - 0.321; P = 0.002)). CONCLUSION: The low levels of magnesium in diabetic complications, indicates the poor glycemic control in diabetic patients. Hence, maintaining the sufficient level of magnesium can control glycemia, thereby prevent the development of diabetic complications.


Assuntos
Biomarcadores/metabolismo , Complicações do Diabetes/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Magnésio/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Complicações do Diabetes/etiologia , Complicações do Diabetes/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
9.
Diabetes Metab Syndr ; 13(2): 1511-1516, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336514

RESUMO

AIMS: The present study aimed to compare the clinical characteristics of patients with fibrocalculous pancreatic diabetes (FCPD) and those with type 2 diabetes mellitus (T2DM) to identify the characteristics distinctive of FCPD. METHODS: A total of 133 patients with FCPD were compared with 665 patients with T2DM matched for duration of diabetes. Biochemical parameters and microvascular and macrovascular complications were assessed in all patients. Multivariate regression analyses were performed to study the determinants of microvascular and macrovascular complications in both groups. RESULTS: The mean duration of diabetes was 4.42 ±â€¯5.65 years in the FCPD group and 4.51 ±â€¯3.88 years in the T2DM group. FCPD participants were significantly younger at diagnosis and leaner than patients with T2DM. The FCPD group had higher fasting and postprandial glucose and HbA1c levels than the T2DM group. The FCPD group had significantly lower triglyceride, total cholesterol, low-density lipoprotein cholesterol, serum total calcium, hemoglobin, and serum creatinine values than the T2DM group. The prevalence of coronary artery disease, stroke, and retinopathy was significantly higher in the T2DM patients while the prevalence of distal symmetric polyneuropathy was significantly lower. On multivariate logistic regression analysis, duration of diabetes and HbA1c (OR = 1.17, P = 0 0.04) in FCPD patients and age (OR = 1.04, P < 0 0.001), duration of diabetes (OR = 1.17, P < 0 0.001) and HbA1c (OR = 1.28, P < 0.001) in T2DM patients were associated with microvascular complications. CONCLUSIONS: There are several differences in the phenotype, biochemical parameters, and prevalence of diabetic complications between patients with FCPD and T2DM. Timely diagnosis may have implications in the follow-up and management of patients.


Assuntos
Biomarcadores/análise , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/epidemiologia , Pancreatopatias/fisiopatologia , Idoso , Glicemia/análise , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/metabolismo , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Pancreatopatias/metabolismo , Prevalência , Prognóstico
10.
Life Sci ; 232: 116582, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220525

RESUMO

AIMS: Vascular calcification/aging can cause different kind of serious diabetic vascular complications. High glucose could induce vascular smooth muscle cells (VSMCs) calcification/aging and then lead to diabetes-related vascular calcification/aging. In this study, we investigated how information in the blood is transmitted to VSMCs and the mechanisms of VSMCs calcification/aging under hyperglycaemic conditions. MATERIALS AND METHODS: Transmission electron microscopy and molecular size analysis were used to assess the morphology and size of exosomes. Alizarin Red S staining and senescence-associated ß galactosidase (SA-ß-gal) staining were carried out to detect calcification and senescence in VSMCs, respectively. Proteomics analysis was carried out to detect the different expression of exosomal proteins. Protein levels were measured by western blot analysis. KEY FINDINGS: The results show that exosomes isolated from high glucose stimulated human umbilical vein endothelial cell (HG-HUVEC-Exo) exhibited a bilayer structure morphology with a mean diameter of 63.63 ±â€¯2.96 nm. The presence of exosome markers including CD9, CD63 and TSG101 were also detected in HG-HUVEC-Exo. High glucose could induce VSMCs calcification/aging by increasing the expression of osteocalcin (OC) and p21 as well as the formation of mineralised nodules and SA-ß-gal positive cells. Fluorescence microscopy verified that the exosomes were taken up by VSMCs and Notch3 protein was enriched in HG-HUVEC-Exo. Most importantly, mTOR signalling was closely related to Notch3 protein and was involved in regulating HG-HUVEC-Exo-induced VSMCs calcification/aging. SIGNIFICANCE: The data demonstrate that Notch3 is required for HG-HUVEC-Exo promoted VSMCs calcification/aging and regulates VSMCs calcification/aging through the mTOR signalling pathway.


Assuntos
Músculo Liso Vascular/metabolismo , Receptor Notch3/fisiologia , Calcificação Vascular/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Senescência Celular/fisiologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Exossomos/metabolismo , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiperglicemia/metabolismo , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/metabolismo , Osteocalcina/metabolismo , Receptor Notch3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Calcificação Vascular/fisiopatologia
11.
Diabetes Metab Syndr ; 13(3): 1923-1927, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235116

RESUMO

Adipokines are cytokines produced by adipocytes that may mediate inflammatory processes, whilst adipocyte-derived proteins may have the converse effect. C1q/TNF-related protein-3 or CTRP3 is a novel adipokine that is expressed and released by most types of human tissues including adipose tissue. This adipokine, considered as an adiponectin, can normalize blood glucose by several mechanisms. In addition, it can modulate the expression/secretion of other cytokine and adipokines leading to lower insulin resistance in peripheral tissues. Beneficial effects of CTRP3 against hyperglycemia-induced complications in the kidney and eye have been reported. In this review, we have presented the latest findings on the in vitro and in vivo hypoglycemic effects of CTRP3, followed by the findings on the preventive/therapeutic effects of CTRP3 adipokines against diabetes related complications.


Assuntos
Complicações do Diabetes/prevenção & controle , Homeostase , Hiperglicemia/prevenção & controle , Fatores de Necrose Tumoral/metabolismo , Glicemia/análise , Complicações do Diabetes/etiologia , Complicações do Diabetes/metabolismo , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Resistência à Insulina
12.
J Neuroinflammation ; 16(1): 121, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174550

RESUMO

The NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome is a member of the NLR family of innate immune cell sensors. These are crucial regulators of cytokine secretions, which promote ischemic cell death and insulin resistance. This review summarizes recent progress regarding the NLRP3 inflammasome as a potential treatment for ischemic stroke in patients with diabetes, two complicated diseases that often occur together. Stroke worsens glucose metabolism abnormalities, and the outcomes after stroke are more serious for diabetic patients compared with those without diabetes. Inflammation contributes to organ injury after ischemic stroke and diabetes. Recent research has focused on inhibiting the activation of inflammasomes and thus reducing the maturation of proinflammatory cytokines such as interleukin (IL)-1ß and IL-18. Studies suggest that inhibition of NLRP3 prevents or alleviates both ischemic stroke and diabetes. Targeting against the assembly and activity of the NLRP3 inflammasome is a potential and novel therapy for inflammasome-associated diseases, including ischemic stroke concomitant with diabetes.


Assuntos
Isquemia Encefálica/metabolismo , Complicações do Diabetes/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/imunologia , Complicações do Diabetes/imunologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/imunologia
13.
Mol Cell Biochem ; 459(1-2): 61-71, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102033

RESUMO

Hyperglycemia in diabetes causes protein glycation that leads to oxidative stress, release of cytokines, and establishment of secondary complications such as neuropathy, retinopathy, and nephropathy. Several other metabolic disorders, stress, and inflammation generate free radicals and oxidative stress. It is essential to study whether oxidative stress independently enhances protein glycation leading to rapid establishment of secondary complications. Oxidative stress was experimentally induced using rotenone and Fenton reagent for in vivo and in vitro studies, respectively. Results showed significant increase in the rate of modification of BSA in the form of fructosamine and protein-bound carbonyls in the presence of fenton reagent. Circular dichroism studies revealed gross structural changes in the reduction of alpha helix structure and decreased protein surface charge was confirmed by zeta potential studies. Use of rotenone demonstrated enhanced AGE formation, ROS generation, and liver and kidney tissue glycation through fluorescence measurement. Similar findings were also observed in cell culture studies. Use of aminoguanidine, a protein glycation inhibitor, demonstrated reduction in these changes; however, a combination of aminoguanidine along with vitamin E demonstrated better amelioration. Thus, oxidative stress accelerates the process of protein glycation causing gross structural changes and tissue glycation in insulin-independent tissues. Use of antioxidants and protein glycation inhibitors in combination are more effective in preventing such changes and could be an effective therapeutic option for preventing establishment of secondary complications of diabetes.


Assuntos
Antioxidantes/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Guanidinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Rotenona/farmacologia , Animais , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Complicações do Diabetes/prevenção & controle , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
14.
Cell Mol Life Sci ; 76(22): 4551-4568, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31073745

RESUMO

The gene CNDP1 was associated with the development of diabetic nephropathy. Its enzyme carnosinase 1 (CN1) primarily hydrolyzes the histidine-containing dipeptide carnosine but other organ and metabolic functions are mainly unknown. In our study we generated CNDP1 knockout zebrafish, which showed strongly decreased CN1 activity and increased intracellular carnosine levels. Vasculature and kidneys of CNDP1-/- zebrafish were not affected, except for a transient glomerular alteration. Amino acid profiling showed a decrease of certain amino acids in CNDP1-/- zebrafish, suggesting a specific function for CN1 in the amino acid metabolisms. Indeed, we identified a CN1 activity for Ala-His and Ser-His. Under diabetic conditions increased carnosine levels in CNDP1-/- embryos could not protect from respective organ alterations. Although, weight gain through overfeeding was restrained by CNDP1 loss. Together, zebrafish exhibits CN1 functions, while CNDP1 knockout alters the amino acid metabolism, attenuates weight gain but cannot protect organs from diabetic complications.


Assuntos
Aminoácidos/metabolismo , Complicações do Diabetes/metabolismo , Dipeptidases/metabolismo , Ganho de Peso/fisiologia , Animais , Carnosina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Técnicas de Inativação de Genes/métodos , Rim/metabolismo , Peixe-Zebra
15.
J Diabetes Res ; 2019: 9489826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089475

RESUMO

Ischemic heart disease (IHD) has several risk factors, among which diabetes mellitus represents one of the most important. In diabetic patients, the pathophysiology of myocardial ischemia remains unclear yet: some have atherosclerotic plaque which obstructs coronary blood flow, others show myocardial ischemia due to coronary microvascular dysfunction in the absence of plaques in epicardial vessels. In the cross-talk between myocardial metabolism and coronary blood flow (CBF), ion channels have a main role, and, in diabetic patients, they are involved in the pathophysiology of IHD. The exposition to the different cardiovascular risk factors and the ischemic condition determine an imbalance of the redox state, defined as oxidative stress, which shows itself with oxidant accumulation and antioxidant deficiency. In particular, several products of myocardial metabolism, belonging to oxidative stress, may influence ion channel function, altering their capacity to modulate CBF, in response to myocardial metabolism, and predisposing to myocardial ischemia. For this reason, considering the role of oxidative and ion channels in the pathophysiology of myocardial ischemia, it is allowed to consider new therapeutic perspectives in the treatment of IHD.


Assuntos
Complicações do Diabetes/metabolismo , Diabetes Mellitus/patologia , Coração/fisiologia , Isquemia Miocárdica/metabolismo , Estresse Oxidativo , Antioxidantes/metabolismo , Circulação Coronária , Diabetes Mellitus/metabolismo , Coração/fisiopatologia , Humanos , Canais Iônicos/metabolismo , Íons/metabolismo , MicroRNAs/metabolismo , Isquemia Miocárdica/complicações , Oxirredução , Ácido Peroxinitroso/metabolismo , Fatores de Risco
16.
Probl Endokrinol (Mosk) ; 65(1): 57-65, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091052

RESUMO

Despite the well-studied effect of insulin in peripheral tissues, its role in functioning of the central nervous system is much less understood. The effects of insulin in the brain are extremely diverse: insulin plays an important role in neuron growth and differentiation, affects higher cognitive functions (in particular, the formation of long-term memory), and also has a neuroprotective effect. Both peripheral and central insulin resistance as well as absolute insulin deficiency impairs the functional activity of neurons and neurogenesis. Several studies have investigated intranasal administration of insulin as a potential way for correction of these disorders. The review presents data on abnormalities of the insulin signaling system in the brain in diabetes mellitus, which is accompanied by cognitive dysfunction of varying severity and is associated with the development of neurodegenerative disorders, including Alzheimer's disease. We analyzed the results of studies on the use of intranasal insulin in animal models with diabetes mellitus, healthy volunteers, and patients with cognitive impairments.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Insulina/uso terapêutico , Administração Intranasal , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/complicações , Disfunção Cognitiva/metabolismo , Complicações do Diabetes/metabolismo , Humanos , Insulina/administração & dosagem , Insulina/metabolismo , Transdução de Sinais
17.
Pancreas ; 48(5): 636-643, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091209

RESUMO

OBJECTIVES: We have investigated the efficacy of mono- and combined therapy with green tea extract (GTE) in mobilizing redox iron, scavenging reactive oxygen species (ROS), and improving insulin production in iron-loaded pancreatic cells. METHODS: Rat insulinoma pancreatic ß-cells were iron-loaded using culture medium supplemented with either fetal bovine serum or ferric ammonium citrate and treated with various doses of GTE for epigallocatechin-3-gallate (EGCG) equivalence and in combination with iron chelators. Cellular iron, ROS, and secretory insulin were measured. RESULTS: The rat insulinoma pancreatic cells took up iron from fetal bovine serum more rapidly than ferric ammonium citrate. After treatment with GTE (0.23-2.29 µg EGCG equivalent), cellular levels of iron and ROS were dose dependently decreased. Importantly, secretory insulin levels were increased nearly 2.5-fold with 2.29 µg of EGCG equivalent GTE, indicating a recovery in insulin production. CONCLUSIONS: Green tea EGCG ameliorated oxidative damage of iron-loaded ß-cells by removing redox iron and free radicals and attenuating insulin production. The impact can result in the restoration of pancreatic functions and an increase in insulin production. Green tea extract exerts iron-chelating, free-radical scavenging, and pancreato-protective effects in the restoration of ß-cell functions, all of which we believe can increase insulin production in diabetic ß-thalassemia patients.


Assuntos
Catequina/análogos & derivados , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ferro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Chá/química , Animais , Catequina/farmacologia , Linhagem Celular Tumoral , Complicações do Diabetes/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Ratos , Talassemia beta/complicações , Talassemia beta/metabolismo
18.
Chem Biol Interact ; 310: 108665, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125535

RESUMO

Diabetes mellitus (DM) is metabolism related problems that share the phenotype of hyperglycemia, which is triggered by a complicated interaction of hereditary and environmental elements. It is the main reason for end-stage renal disease (ESRD), amputations of the traumatic lower extremity, and grown-up visual impairment. It additionally inclines to neurodegenerative and cardiovascular sicknesses. With an expanding rate around the world, DM may be the main motive of morbidity and mortality within the foreseeable future. The objective of treatment for DM is to inhibit mortality and difficulties through normalizing blood glucose stage. Genistein, a naturally available soy isoflavone, is accounted for to have various medical advantages credited to numerous natural capacities. In the course of recent years, various examinations have shown that genistein has hostile to diabetic impacts, specifically, direct consequences for ß-cell expansion, glucose-triggered insulin discharge, and safety towards apoptosis, unbiased of its functions as an estrogen receptor agonist, cancer prevention agent, or tyrosine kinase inhibitor. The present evaluation emphases on the promising molecular and biochemical paths associated with DM complications and, specifically, the multi-target method of genistein in diminishing diabetic neuropathy, nephropathy, and retinopathy.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Genisteína/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Genisteína/farmacologia , Humanos
19.
J Zhejiang Univ Sci B ; 20(5): 437-448, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31090269

RESUMO

O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification occurring on myriad proteins in the cell nucleus, cytoplasm, and mitochondria. The donor sugar for O-GlcNAcylation, uridine-diphosphate N-acetylglucosamine (UDP-GlcNAc), is synthesized from glucose through the hexosamine biosynthetic pathway (HBP). The recycling of O-GlcNAc on proteins is mediated by two enzymes in cells-O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and removal of O-GlcNAc, respectively. O-GlcNAcylation is involved in a number of important cell processes including transcription, translation, metabolism, signal transduction, and apoptosis. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, neurodegenerative diseases, and cardiovascular diseases. A better understanding of the roles of O-GlcNAcylation in physiopathological processes would help to uncover novel avenues for therapeutic intervention. The aim of this review is to discuss the recent updates on the mechanisms and impacts of O-GlcNAcylation on these diseases, and its potential as a new clinical target.


Assuntos
Acetilglucosamina/química , Doenças Cardiovasculares/metabolismo , Doenças Neurodegenerativas/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Apoptose , Catálise , Núcleo Celular/metabolismo , Proliferação de Células , Citoplasma/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hexosaminas/química , Humanos , Insulina , Mitocôndrias/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Neoplasias/metabolismo , Fosforilação , Transdução de Sinais , beta-N-Acetil-Hexosaminidases/metabolismo
20.
Vasc Med ; 24(5): 383-394, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31090495

RESUMO

Diabetes mellitus (DM) and chronic kidney disease (CKD) separately are known to facilitate the progression of medial arterial calcification (MAC) in patients with symptomatic peripheral artery disease (PAD), but their combined effect on MAC and associated mediators of calcification is not well studied. The association of MAC and calcification inducer bone morphogenetic protein (BMP-2) and inhibitor fetuin-A, with PAD, is well known. Our aim was to investigate the association of MAC with alterations in BMP-2 and fetuin-A protein expression in patients with PAD with DM and/or CKD. Peripheral artery plaques (50) collected during directional atherectomy from symptomatic patients with PAD were evaluated, grouped into no-DM/no-CKD (n = 14), DM alone (n = 10), CKD alone (n = 12), and DM+CKD (n = 14). MAC density was evaluated using hematoxylin and eosin, and alizarin red stain. Analysis of inflammation, neovascularization, BMP-2 and fetuin-A protein density was performed by immunohistochemistry. MAC density, inflammation grade and neovessel content were significantly higher in DM+CKD versus no-DM/no-CKD and CKD (p < 0.01). BMP-2 protein density was significantly higher in DM+CKD versus all other groups (p < 0.01), whereas fetuin-A protein density was significantly lower in DM+CKD versus all other groups (p < 0.001). The combined presence of DM+CKD may be associated with MAC severity in PAD plaques more so than DM or CKD alone, as illustrated in this study, where levels of calcification mediators BMP-2 and fetuin-A protein were related most robustly to DM+CKD. Further understanding of mechanisms involved in mediating calcification and their association with DM and CKD may be useful in improving management and developing therapeutic interventions.


Assuntos
Proteína Morfogenética Óssea 2/análise , Complicações do Diabetes/etiologia , Artéria Femoral/química , Doença Arterial Periférica/etiologia , Insuficiência Renal Crônica/complicações , Calcificação Vascular/etiologia , alfa-2-Glicoproteína-HS/análise , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Estudos Transversais , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/metabolismo , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Medição de Risco , Fatores de Risco , Calcificação Vascular/diagnóstico , Calcificação Vascular/metabolismo
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