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1.
Comput Math Methods Med ; 2022: 8268067, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35126637

RESUMO

BACKGROUND: Tendon-to-bone healing is a difficult process in treatment of rotator cuff tear (RCT). In addition, diabetes is an important risk factor for poor tendon-to-bone healing. Therefore, we investigated the specific mechanisms through which diabetes affects tendon-to-bone healing by regulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). METHODS: Tendon-derived stem cells (TDSCs) were extracted from rats after which their proliferative capacities were evaluated by the MTT assay. The expression levels of CFTR and tendon-related markers were determined by qRT-PCR. Then, bioinformatics analyses and dual luciferase reporter gene assays were used to identify miRNAs with the ability to bind CFTR mRNA. Finally, CFTR was overexpressed in TDSCs to validate the specific mechanisms through which the high glucose microenvironment inhibits tendon-to-bone healing. RESULTS: The high glucose microenvironment downregulated mRNA expression levels of tendon-related markers and CFTR in TDSCs cultured with different glucose concentrations. Additionally, bioinformatics analyses revealed that let-7b-5p may be regulated by the high glucose microenvironment and can regulate CFTR levels. Moreover, a dual luciferase reporter gene assay was used to confirm that let-7b-5p targets and binds CFTR mRNA. Additional experiments also confirmed that overexpressed CFTR effectively reversed the negative effects of the hyperglycaemic microenvironment and upregulation of let-7b-5p on TDSC proliferation and differentiation. These findings imply that the hyperglycemic microenvironment inhibits CFTR transcription and, consequently, proliferation and differentiation of TDSCs in vitro by upregulating let-7b-5p. CONCLUSIONS: A hyperglycemic microenvironment inhibits TDSC proliferation in vitro via the let-7b-5p/CFTR pathway, and this is a potential mechanism in diabetes-induced poor tendon-to-bone healing.


Assuntos
Osso e Ossos/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Hiperglicemia/fisiopatologia , MicroRNAs/metabolismo , Tendões/fisiopatologia , Cicatrização/fisiologia , Animais , Proliferação de Células , Células Cultivadas , Biologia Computacional , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Hiperglicemia/genética , Hiperglicemia/patologia , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Lesões do Manguito Rotador/genética , Lesões do Manguito Rotador/patologia , Lesões do Manguito Rotador/fisiopatologia , Transdução de Sinais , Nicho de Células-Tronco/genética , Nicho de Células-Tronco/fisiologia , Tendões/patologia , Cicatrização/genética
2.
Artigo em Inglês | MEDLINE | ID: mdl-35151421

RESUMO

Type 2 diabetes (T2D) is a complex multifactorial disease that emerges from the combination of genetic and environmental factors, and obesity, lifestyle, and aging are the most relevant risk factors. Hyperglycemia is the main metabolic feature of T2D as a consequence of insulin resistance and ß-cell dysfunction. Among the cellular alterations induced by hyperglycemia, the overproduction of reactive oxygen species (ROS) and consequently oxidative stress, accompanied by a reduced antioxidant response and impaired DNA repair pathways, represent essential mechanisms underlying the pathophysiology of T2D and the development of late complications. Mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation are also closely correlated with insulin resistance and ß-cell dysfunction. This review focus on the mechanisms by which oxidative stress, mitochondrial dysfunction, ER stress, and inflammation are involved in the pathophysiology of T2D, highlighting the importance of the antioxidant response and DNA repair mechanisms counteracting the development of the disease. Moreover, we indicate evidence on how nutritional interventions effectively improve diabetes care. Additionally, we address key molecular characteristics and signaling pathways shared between T2D and Alzheimer's disease (AD), which might probably be implicated in the risk of T2D patients to develop AD.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Resistência à Insulina , Antioxidantes/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hiperglicemia/fisiopatologia , Inflamação , Estresse Oxidativo/efeitos dos fármacos , Fatores de Risco
3.
Invest Ophthalmol Vis Sci ; 63(2): 18, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35138346

RESUMO

Purpose: To characterize the early structural and functional changes in the retinal microvasculature in response to hyperglycemia in the Ins2Akita mouse. Methods: A custom phase-contrast adaptive optics scanning light ophthalmoscope was used to image retinal capillaries of 9 Ins2Akita positive (hyperglycemic) and 9 Ins2Akita negative (euglycemic) mice from postnatal weeks 5 to 18. A 15 kHz point scan was used to image capillaries and measure red blood cell flux at biweekly intervals; measurements were performed manually. Retinal thickness and fundus photos were captured monthly using a commercial scanning laser ophthalmoscope/optical coherence tomography. Retinal thickness was calculated using a custom algorithm. Blood glucose and weight were tracked throughout the duration of the study. Results: Elevated blood glucose (>250 mg/dL) was observed at 4 to 5 weeks of age in Ins2Akita mice and remained elevated throughout the study, whereas euglycemic littermates maintained normal glucose levels. There was no significant difference in red blood cell flux, capillary anatomy, lumen diameter, or occurrence of stalled capillaries between hyperglycemic and euglycemic mice between postnatal weeks 5 and 18. Hyperglycemic mice had a thinner retina than euglycemic littermates (p < 0.001), but retinal thickness did not change with duration of hyperglycemia despite glucose levels that were more than twice times normal. Conclusions: In early stages of hyperglycemia, retinal microvasculature structure (lumen diameter, capillary anatomy) and function (red blood cell flux, capillary perfusion) were not impaired despite 3 months of chronically elevated blood glucose. These findings suggest that hyperglycemia alone for 3 months does not alter capillary structure or function in profoundly hyperglycemic mice.


Assuntos
Capilares/patologia , Retinopatia Diabética/fisiopatologia , Eritrócitos/fisiologia , Hiperglicemia/fisiopatologia , Vasos Retinianos/patologia , Animais , Velocidade do Fluxo Sanguíneo/fisiologia , Glicemia/metabolismo , Capilares/diagnóstico por imagem , Retinopatia Diabética/diagnóstico por imagem , Modelos Animais de Doenças , Contagem de Eritrócitos , Masculino , Camundongos , Oftalmoscópios , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica
4.
Microvasc Res ; 139: 104272, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34699845

RESUMO

Endothelial injury plays a vital role in vascular lesions from diabetes mellitus (DM). Therapeutic targets against endothelial damage may provide critical venues for the treatment of diabetic vascular diseases. Peroxisome proliferator-activated receptor ß (PPARß) is a crucial regulator in DM and its complications. However, the molecular signal mediating the roles of PPARß in DM-induced endothelial dysfunction is not fully understood. The impaired endothelium-dependent relaxation and destruction of the endothelium structures appeared in high glucose incubated rat aortic rings. A high glucose level significantly decreased the expression of PPARß and endothelial nitric oxide synthase (eNOS) at the mRNA and protein levels, and reduced the concentration of nitric oxide (NO), which occurred in parallel with an increase in the expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine. The effect of high glucose was inhibited by GW0742, a PPARß agonist. Both GSK0660 (PPARß antagonist) and NG-nitro-l-arginine-methyl ester (NOS inhibitor) could reverse the protective effects of GW0742. These results suggest that the activation of nitrative stress may, at least in part, mediate the down-regulation of PPARß in high glucose-impaired endothelial function in rat aorta. PPARß-nitrative stress may hold potential in treating vascular complications from DM.


Assuntos
Aorta Torácica/efeitos dos fármacos , Angiopatias Diabéticas/metabolismo , Células Endoteliais/efeitos dos fármacos , Glucose/toxicidade , Hiperglicemia/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , PPAR beta/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Hiperglicemia/genética , Hiperglicemia/patologia , Hiperglicemia/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , PPAR beta/genética , Ratos Sprague-Dawley , Transdução de Sinais , Tirosina/análogos & derivados , Tirosina/metabolismo , Vasodilatação/efeitos dos fármacos
5.
Front Endocrinol (Lausanne) ; 12: 760292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858333

RESUMO

Introduction: Type 2 diabetes (T2D) is characterized by a metabolic disorder that elevates blood glucose concentration. Chronic hyperglycemia has been associated with several complications in patients with T2D, one of which is cardiac autonomic dysfunction that can be assessed from heart rate variability (HRV) and heart rate recovery (HRR) response, both associated with many aspects of health and fitness, including severe cardiovascular outcomes. Objective: To evaluate the effects of T2D on cardiac autonomic modulation by means of HRV and HRR measurements. Materials and Methods: This study has an observational with case-control characteristic and involved ninety-three middle-aged adults stratified into two groups (control group - CG, n = 34; diabetes group - DG, n = 59). After signing the free and informed consent form, the patients were submitted to the evaluation protocols, performed biochemical tests to confirm the diagnosis of T2D, collection of R-R intervals for HRV analysis and cardiopulmonary effort test to quantify HRR. Results: At rest, the DG showed a reduction in global HRV (SDNN= 19.31 ± 11.72 vs CG 43.09 ± 12.74, p < 0.0001), lower parasympathetic modulation (RMSSD= 20.49 ± 14.68 vs 52.41 ± 19.50, PNN50 = 4.76 ± 10.53 vs 31.24 ± 19.24, 2VD%= 19.97 ± 10.30 vs 28.81 ± 9.77, p < 0.0001 for both indices) and higher HRrest when compared to CG. After interruption of physical exercise, a slowed heart rate response was observed in the DG when compared to the CG. Finally, a simple linear regression showed that fasting glycemia was able to predict cardiac autonomic involvement in volunteers with T2D. Conclusion: Patients with T2D presented lower parasympathetic modulation at rest and slowed HRR after physical exercise, which may be associated with higher cardiovascular risks. The findings show the glycemic profile as an important predictor of impaired cardiac autonomic modulation.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Glicemia/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Jejum/fisiologia , Coração/fisiopatologia , Hiperglicemia/fisiopatologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Estudos de Casos e Controles , Exercício Físico/fisiologia , Cardiopatias/fisiopatologia , Frequência Cardíaca/fisiologia , Humanos , Pessoa de Meia-Idade
6.
Int J Mol Sci ; 22(22)2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34830246

RESUMO

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA's role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been observed in animal models of experimental diabetes and in diabetic patients, too. Evidence is accumulating that advanced glycation end products (AGEs) and their precursor methylglyoxal (MGO) are associated with cognitive impairment and alterations of the dopaminergic system. Further research is needed to clarify the molecular mechanisms linking DM-associated dopaminergic dysfunction and cognitive impairment and to assess the deleterious impact of glucotoxicity.


Assuntos
Disfunção Cognitiva/metabolismo , Diabetes Mellitus/metabolismo , Dopamina/metabolismo , Glucose/toxicidade , Produtos Finais de Glicação Avançada/metabolismo , Hiperglicemia/metabolismo , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Aldeído Pirúvico/metabolismo , Transdução de Sinais
7.
PLoS One ; 16(10): e0258894, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34673829

RESUMO

INTRODUCTION: Little is known about the influence of hyperglycemia first detected in pregnancy (HFDP) on weight outcomes in exposed offspring in Africa. We investigated the influence of maternal blood glucose concentrations during pregnancy on offspring weight outcomes at birth and preschool age, in offspring exposed to HFDP, in South Africa. RESEARCH DESIGN AND METHODS: Women diagnosed with HFDP had data routinely collected during the pregnancy and at delivery, at a referral hospital, and the offspring followed up at preschool age. Maternal fasting, oral glucose tolerance test 1 and 2-hour blood glucose were measured at diagnosis of HFDP and 2-hour postprandial blood glucose during the third trimester. Offspring were classified as either those exposed to diabetes first recognized in pregnancy (DIP) or gestational diabetes (GDM). At birth, neonates were classified into macrosomia, low birth weight (LBW), large for gestational age (LGA), appropriate (AGA) and small for gestational age (SGA)groups. At preschool age, offspring had height and weight measured and Z-scores for weight, height and BMI calculated. RESULTS: Four hundred and forty-three neonates were included in the study at birth, with 165 exposed to DIP and 278 exposed to GDM. At birth, the prevalence of LGA, macrosomia and LBW were 29.6%, 12.2% and 7.5%, respectively, with a higher prevalence of LGA and macrosomia in neonates exposed to DIP. At pre-school age, the combined prevalence of overweight and obesity was 26.5%. Maternal third trimester 2-hour postprandial blood glucose was significantly associated with z-scores for weight at birth and preschool age, and both SGA and LGA at birth. CONCLUSION: In offspring exposed to HFDP, there is a high prevalence of LGA and macrosomia at birth, and overweight and obesity at preschool age, with higher prevalence in those exposed to DIP, compared to GDM. Maternal blood glucose control during the pregnancy influences offspring weight at birth and preschool age.


Assuntos
Peso ao Nascer/fisiologia , Glicemia , Peso Corporal/fisiologia , Hiperglicemia/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Adulto , Pré-Escolar , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/sangue , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/fisiopatologia , África do Sul , Adulto Jovem
8.
Reprod Toxicol ; 106: 109-114, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34653594

RESUMO

Phenytoin is a known human teratogen with unknown etiology. Several mechanisms have been proposed including disturbances in folate metabolism, induction of embryonic hypoxia following phenytoin-induced bradycardia, free radical formation following re-oxygenation and phenytoin-induced maternal hyperglycemia. Using high frequency ultrasound, we demonstrated that phenytoin induced a dramatic decrease in the heart rate of embryos. This coincided with a moderate transient decrease in maternal heart rate and blood glucose levels. Embryonic heart rate had not fully recovered 24 h later in some embryos despite normal maternal physiological parameters. In a separate study, extent of hypoxia was measured using the marker pimonidazole. Phenytoin-exposed embryos did not demonstrate increased hypoxia compared to control embryos at 2, 4, 8 or 24 h dosing. Together our results show that phenytoin induces malformations as a result of a combination of insults: embryonic bradycardia, maternal bradycardia and maternal hyperglycemia. However, this does not appear to result in measurable embryonic hypoxia in our animal model.


Assuntos
Frequência Cardíaca/efeitos dos fármacos , Coração/embriologia , Fenitoína/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Feminino , Hiperglicemia/induzido quimicamente , Hiperglicemia/fisiopatologia , Hipóxia/induzido quimicamente , Gravidez , Ratos , Ratos Sprague-Dawley
9.
Nutrients ; 13(10)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34684499

RESUMO

The frequency of aerobic exercise training in reducing the increase in arterial stiffness during acute hyperglycemia, a risk factor for cardiovascular disease, is unknown. The aim of the study was to determine the aerobic exercise training frequency on arterial stiffness in a hyperglycemic state in middle-aged and elderly females. Twenty healthy elderly people were randomly assigned to a two-times-a-week (T2, n = 10) and four-times-a-week (T4, n = 10) exercise group. All participants exercised for 35 min per session, which consisted of jogging exercises with a heart rate intensity of 65%. Brachial-ankle (ba), and heart-brachial (hb) pulse wave velocity (PWV) were measured before, 4 and 8 weeks after intervention; before the oral ingestion of 75-g of glucose; and 30, 60, and 90 min after ingestion. The baPWV before and 4 weeks after the intervention increased in both groups (p < 0.05), but only increased 8 weeks after intervention in the T2 group. hbPWV was unchanged before, 4 and 8 weeks after intervention in both groups. These findings show that frequent aerobic exercise suppresses the increase in arterial stiffness following glucose intake. The results of this study can be used to support the implementation of exercise programs for middle-aged and elderly patients.


Assuntos
Exercício Físico/fisiologia , Hiperglicemia/terapia , Doença Arterial Periférica/prevenção & controle , Fatores de Tempo , Rigidez Vascular/fisiologia , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço , Glicemia/análise , Feminino , Teste de Tolerância a Glucose , Frequência Cardíaca/fisiologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Pessoa de Meia-Idade , Doença Arterial Periférica/etiologia , Análise de Onda de Pulso
10.
JAMA Netw Open ; 4(10): e2128782, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34636912

RESUMO

Importance: Despite rising costs and public scrutiny devoted to insulin, less is known regarding recent trends in its ambulatory use in the United States. Objective: To characterize trends in ambulatory insulin use, overall and based on insulin characteristics, among adults with type 2 diabetes in the United States from January 1, 2016, through December 31, 2020. Design, Setting, and Participants: This serial cross-sectional study included patients whose data were collected in IQVIA's National Disease and Therapeutic Index (NDTI), a 2-stage, all-payer, nationally representative audit of outpatient care. Approximately 4800 physicians each calendar quarter completed a form for 2 consecutive days regarding visits for each of their patients, including diagnoses, treatments, and demographic information. Data were collected from January 2016 through December 2020. Exposures: Ambulatory use of insulin. Main Outcomes and Measures: Nationally representative projections for ambulatory use of insulin (ie, treatment visits), overall and aggregated by insulin molecule (insulins regular, neutral protamine Hagedorn [NPH], lispro, glulisine, glargine, detemir, degludec, and aspart), delivery devices (vials/syringes or pens), therapeutic class (short-acting, rapid-acting, long-acting, intermediate-acting, and premixed insulin), insulin type (human, analog, and biosimilar), and date of approval (newer: before 2010; and older: after 2010). Results: There were 27 860 691 insulin treatment visits between 2016 and 2020. Among all patient encounters that indicated use of insulin in 2020, 1 989 154 (43.9%) were among those aged 60 to 74 years; 2 372 629 (52.4%) among men; 2 646 247 (58.4%) among White patients; 811 639 (17.9%) among Black patients; and 701 912 (15.5%) among Hispanic patients. Insulin glargine was the most frequently used insulin from 2016 to 2020, accounting for approximately half of treatment visits (eg, 2020: 2.6 of 4.9 million visits; 95% CI, 2.1-3.1 million). Among insulin classes, long-acting insulin accounted for approximately two-thirds of treatment visits during this period (eg, 2020: 3.7 million visits; 95% CI, 3.0-4.4 million). Treatment visits for insulin pens increased from 36.1% in 2016 (2.2 of 6.0 million visits; 95% CI, 1.7-2.7 million) to 58.7% in 2020 (2.9 million visits; 95% CI, 2.3-3.5 million), while use of insulin vials/syringes declined in parallel. Analog insulin use predominated and accounted for more than 80% of total treatment visits across all years (eg, 2020: 4.3 million visits; 95% CI, 3.4-5.1 million). Newer insulins were increasingly used, from 18.1% of total treatment visits in 2016 (1.1 million visits; 95% CI, 0.8-1.4 million) to 40.9% in 2020 (2.0 million visits; 95% CI, 1.5-2.5 million). The use of biosimilar insulin, which was first approved in 2015, increased from 2.6% in 2017 (0.1 of 5.3 million visits; 95% CI, 0.04-0.2 million) to 8.2% in 2020 (0.4 million visits; 95% CI, 0.2-0.6 million) of total insulin treatment visits. The total number of insulin treatment visits declined from a peak of 6.0 million visits in 2016 to a nadir of 4.9 million visits in 2020 (approximately 18% decline). Conclusions and Relevance: In this study, ambulatory insulin use in the United States during the past 5 years remained dominated by the use of insulin analogs and insulin pen delivery devices, with increasing uptake of newer products as they have been brought to market.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Utilização de Equipamentos e Suprimentos/tendências , Insulina/classificação , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/psicologia , Feminino , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/fisiopatologia , Hipoglicemiantes/classificação , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estados Unidos
11.
Int J Mol Sci ; 22(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34639171

RESUMO

Diabetes is a major risk factor for cardiovascular diseases, especially cardiomyopathy, a condition in which the smooth muscles of the heart become thick and rigid, affecting the functioning of cardiomyocytes, the contractile cells of the heart. Uncontrolled elevated glucose levels over time can result in oxidative stress, which could lead to inflammation and altered epigenetic mechanisms. In the current study, we investigated whether hyperglycemia can modify cardiac function by directly affecting these changes in cardiomyocytes. To evaluate the adverse effect of high glucose, we measured the levels of gap junction protein, connexin 43, which is responsible for modulating cardiac electric activities and Troponin I, a part of the troponin complex in the heart muscles, commonly used as cardiac markers of ischemic heart disease. AC16 human cardiomyocyte cells were used in this study. Under hyperglycemic conditions, these cells demonstrated altered levels of connexin 43 and Troponin-I after 24 h of exposure. We also examined hyperglycemia induced changes in epigenetic markers: H3K9me1, Sirtuin-1 (SIRT1), and histone deacetylase (HDAC)-2 as well as in inflammatory and stress-related mediators, such as heat shock protein (HSP)-60, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1 and CXC chemokine receptor (CXCR)-4. Cardiomyocytes exposed to 25mM glucose resulted in the downregulation of HSP60 and SIRT1 after 48 h. We further examined that hyperglycemia mediated the decrease in the gap junction protein CX43, as well as CXC chemokine receptor CXCR4 which may affect the physiological functions of the cardiomyocytes when exposed to high glucose for 24 and 48 h. Upregulated expression of DNA-binding nuclear protein HMGB1, along with changes in histone methylation marker H3K9me1 have demonstrated hyperglycemia-induced damage to cardiomyocyte at 24 h of exposure. Our study established that 24 to 48 h of hyperglycemic exposure could stimulate stress-mediated inflammatory mediators in cardiomyocytes in vitro. These stress-related changes in hyperglycemia-induced cardiomyocytes may further initiate an increase in injury markers which eventually could alter the epigenetic processes. Therefore, epigenetic and inflammatory mechanisms in conjunction with alterations in a downstream signaling pathway could have a direct effect on the functionality of the cardiomyocytes exposed to high glucose during short and long-term exposures.


Assuntos
Biomarcadores/metabolismo , Epigênese Genética , Hiperglicemia/fisiopatologia , Mediadores da Inflamação/metabolismo , Miócitos Cardíacos/patologia , Estresse Fisiológico , Chaperonina 60/genética , Chaperonina 60/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
12.
Cell Mol Biol Lett ; 26(1): 40, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479471

RESUMO

BACKGROUND: Endothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms. METHODS: We conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry. RESULTS: High glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors. CONCLUSIONS: These findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease.


Assuntos
Hiperglicemia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/fisiopatologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Estresse Oxidativo/fisiologia , Lesões do Sistema Vascular/patologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperglicemia/metabolismo , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Histona Desmetilases com o Domínio Jumonji/genética , Transdução de Sinais , Lesões do Sistema Vascular/metabolismo
13.
Commun Biol ; 4(1): 1036, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480097

RESUMO

Diabetes mellitus is a metabolic disease associated with dysregulated glucose and insulin levels and an increased risk of developing Alzheimer's disease (AD) later in life. It is thought that chronic hyperglycemia leads to neuroinflammation and tau hyperphosphorylation in the hippocampus leading to cognitive decline, but effects on hippocampal network activity are unknown. A sustained hyperglycemic state was induced in otherwise healthy animals and subjects were then tested on a spatial delayed alternation task while recording from the hippocampus and anterior cingulate cortex (ACC). Hyperglycemic animals performed worse on long delay trials and had multiple electrophysiological differences throughout the task. We found increased delta power and decreased theta power in the hippocampus, which led to altered theta/delta ratios at the end of the delay period. Cross frequency coupling was significantly higher in multiple bands and delay period hippocampus-ACC theta coherence was elevated, revealing hypersynchrony. The highest coherence values appeared long delays on error trials for STZ animals, the opposite of what was observed in controls, where lower delay period coherence was associated with errors. Consistent with previous investigations, we found increases in phosphorylated tau in STZ animals' hippocampus and cortex, which might account for the observed oscillatory and cognitive changes.


Assuntos
Doença de Alzheimer/fisiopatologia , Giro do Cíngulo/fisiopatologia , Hipocampo/fisiopatologia , Hiperglicemia/fisiopatologia , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo , Ritmo Teta , Doença de Alzheimer/etiologia , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Long-Evans , Fatores de Risco
14.
Cancer Res ; 81(21): 5506-5522, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34535458

RESUMO

High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.


Assuntos
Plaquetas/patologia , Fibrossarcoma/patologia , Glucose/toxicidade , Hiperglicemia/fisiopatologia , Neoplasias Pulmonares/secundário , Megacariócitos/patologia , Melanoma Experimental/patologia , Animais , Apoptose , Plaquetas/metabolismo , Proliferação de Células , Fibrossarcoma/etiologia , Fibrossarcoma/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Hiperglicemia/induzido quimicamente , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Masculino , Melanoma Experimental/etiologia , Melanoma Experimental/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Edulcorantes/toxicidade , Células Tumorais Cultivadas
15.
Toxicol Ind Health ; 37(9): 555-563, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34452584

RESUMO

Current research suggests that cadmium (Cd) exposure may be associated with the progression of diabetic nephropathy; however, the details of this relationship are insufficiently understood. The present study investigated the effects of elevated glucose on Cd-induced toxicity to glomerular cells using in vitro and in vivo models, and it demonstrated that Cd exposure and the hyperglycemia of diabetes acting together increased the risk of developing glomerular nephrosis. In vitro, human podocytes were exposed to a DMEM low-glucose media without (control), or with Cd (as CdCl2), or a high-glucose media plus Cd. The CCK-8, ROS, apoptosis, and mitochondrial transmembrane potential (ΔΨm) assays showed that human podocytes exposed to Cd in a high-glucose media had greater degrees of injury compared with cells treated with Cd at low (euglycemic)-glucose levels. In vivo, diabetic hyperglycemia was induced by streptozotocin in 8-week-old male C57BL/6 mice to which either CdCl2 or saline (control) was intraperitoneally injected twice weekly for 24 weeks. Compared with euglycemic saline-treated controls, the diabetic mice exposed to Cd demonstrated decreased body weight and increased blood urea nitrogen levels along with histopathological renal architecture changes including collagen fiber accumulation. The results of this study supported the hypothesis that hyperglycemia plus Cd exposure increases the risk of damage to glomerular podocytes compared with Cd exposure in euglycemia.


Assuntos
Glicemia/metabolismo , Cádmio/farmacologia , Rim/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Peso Corporal , Linhagem Celular , Diabetes Mellitus Experimental , Humanos , Hiperglicemia/fisiopatologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina/farmacologia
16.
Cancer Chemother Pharmacol ; 88(5): 857-865, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34350479

RESUMO

PURPOSE: Cytotoxic chemotherapy-induced lung injury is a fatal complication in patients with lung cancer and interstitial lung disease (ILD). We aimed to evaluate the association between hyperglycemia and this form of lung injury in patients with lung cancer concomitant with ILD. METHODS: From 1147 patients with advanced lung cancer, we retrospectively enrolled 98 patients with ILD whose hemoglobin A1c (HbA1c) levels were measured, and investigated the association between HbA1c levels and cytotoxic chemotherapy-induced lung injury. In 73 patients whose serum samples were retained, we measured serum levels of advanced glycation end products (AGE) and assessed the association of AGE levels with HbA1c levels and cytotoxic chemotherapy-induced lung injury. RESULTS: The incidence of cytotoxic chemotherapy-induced lung injury was significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8%, but not in those with HbA1c levels ≥ 6.5% than in those with HbA1c levels < 6.5%. The multivariate logistic regression model revealed that HbA1c level ≥ 5.8% was a significant risk factor for this complication [odds ratio 3.178 (95% confidence interval 1.057-9.556), P = 0.040]. In addition, serum AGE levels were significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8% [median (interquartile range); 0.129 (0.023-0.290) and 0.474 (0.213-1.109) µg/mL, P = 0.001]. CONCLUSION: Glucose intolerance (e.g., HbA1c level ≥ 5.8%) may be a risk factor of cytotoxic chemotherapy-induced lung injury, which might be associated with elevated AGE production due to hyperglycemia.


Assuntos
Antineoplásicos/efeitos adversos , Intolerância à Glucose/induzido quimicamente , Doenças Pulmonares Intersticiais/tratamento farmacológico , Lesão Pulmonar/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Feminino , Hemoglobina A Glicada/análise , Produtos Finais de Glicação Avançada/sangue , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/fisiopatologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/fisiopatologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Estudos Retrospectivos , Capacidade Vital
17.
J Bioenerg Biomembr ; 53(5): 553-560, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34427826

RESUMO

The current therapeutic strategy for hyperglycemia is reasonable diet and appropriate exercise with drugs, whose outcome is unsatisfied. Therefore, we aimed to explore the new candidate drug 7-Ethoxyrosmanol (7ERM) on hyperglycemia-induced endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) were treated with different doses of 7ERM in the presence of 33 mM high glucose to measure cell injury, inflammation, and reactive oxygen species (ROS) production. Then F-box/LRR-repeat protein 7 (FBXL7) knockdown by siRNA or overexpressed by plasmid in HUVECs was assessed its effect in the protective role on hyperglycemia-induced endothelial dysfunction. 7ERM time-dependently increased high glucose-induced cell injury, the secretions of pro-inflammatory cytokines and ROS production in HUVECs. Moreover, high glucose time-dependently increased the FBXL7 expressions, which could be gradually inhibited by 7ERM. FBXL7 knockdown ameliorated high glucose-induced cell injury. On the contrary, FBXL7 over-expression inhibited the protective effect of 7ERM on cell injury. In conclusion, 7ERM effectively attenuates high glucose-induced endothelial dysfunction in HUVECs by regulating FBXL7 expression, indicating its potential as a therapeutic drug to treat hyperglycemia.


Assuntos
Diterpenos/farmacologia , Endotélio Vascular/metabolismo , Proteínas F-Box/biossíntese , Hiperglicemia/tratamento farmacológico , Endotélio Vascular/fisiopatologia , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/fisiopatologia , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Cells ; 10(8)2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34440883

RESUMO

Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.


Assuntos
Disfunção Cognitiva/fisiopatologia , Hiperglicemia/fisiopatologia , Idoso , Disfunção Cognitiva/tratamento farmacológico , Células Endoteliais/metabolismo , Idoso Fragilizado , Humanos , Hiperglicemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Metformina/uso terapêutico , Pessoa de Meia-Idade , Fatores de Risco
19.
Int J Obes (Lond) ; 45(12): 2675-2678, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34321614

RESUMO

Insulin resistance of glucose utilization is fully restored following BMI normalization after bariatric surgery. We investigated if this also pertains to insulin-induced effects on fatty acid handling. Forty-three women with obesity (OB) were investigated before and 2 years after Roux-en-Y gastric by-pass when BMI was <30 kg/m2 (PO) and compared with 26 never obese women (NO). The Adipo-IR index was used as measure of insulin antilipolytic sensitivity. Changes (delta) in circulating glycerol and fatty acid levels during hyperinsulinemic euglycemic clamp represented the insulin maximum antilipolytic effect. Overall fatty acid utilization was reflected by delta fatty acids minus 3 × delta glycerol. Adipo-IR was higher in OB than in NO and PO (p < 0.0001), the latter two groups having similar values. Insulin lowered glycerol levels by about 70% in all groups, but delta glycerol was 30% larger in PO than in NO (p = 0.04). Delta adds and adds utilization were similar in all groups. We conclude that women with obesity, whose BMI is normalized after bariatric surgery, have improved maximum in vivo antilipolytic effect of insulin above expected in absolute but not relative terms as regards glycerol changes, while the handling of circulating fatty acids is changed to the normal state.


Assuntos
Cirurgia Bariátrica/efeitos adversos , Insulina/efeitos adversos , Lipólise/efeitos dos fármacos , Adulto , Cirurgia Bariátrica/estatística & dados numéricos , Glicemia/análise , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Feminino , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/fisiopatologia , Insulina/uso terapêutico , Lipólise/fisiologia , Estudos Longitudinais , Pessoa de Meia-Idade
20.
Hum Cell ; 34(6): 1617-1628, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34324139

RESUMO

Emergent studies reveal the roles of inflammatory cells and cytokines in the development of diabetic retinopathy (DR), which is gradually portrayed as a chronic inflammatory disease accompanied by metabolic disorder. Through the pathogenesis of DR, macrophages or microglia play a critical role in the inflammation, neovascularization, and neurodegeneration of the retina. Conventionally, macrophages are generally divided into M1 and M2 phenotypes which mainly rely on glycolysis and oxidative phosphorylation, respectively. Recently, studies have found that nutrients (including glucose and lipids) and metabolites (such as lactate), can not only provide energy for cells, but also act as signaling molecules to regulate the function and fate of cells. In this review, we discussed the intrinsic correlations among the metabolic status, polarization, and function of macrophage/microglia in DR. Hyperglycemia and hyperlipidemia could induce M1-like and M2-like macrophages polarization in different phases of DR. Targeting the regulation of microglial metabolic profile might be a promising therapeutic strategy to modulate the polarization and function of macrophages/microglia, thus attenuating the progression of DR.


Assuntos
Retinopatia Diabética/etiologia , Macrófagos/fisiologia , Microglia/fisiologia , Polaridade Celular , Retinopatia Diabética/imunologia , Retinopatia Diabética/patologia , Glicólise , Humanos , Hiperglicemia/patologia , Hiperglicemia/fisiopatologia , Hiperlipidemias/patologia , Hiperlipidemias/fisiopatologia , Inflamação , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Microglia/metabolismo , Nutrientes/farmacologia , Fosforilação Oxidativa , Retina/patologia
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