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1.
Life Sci ; 272: 119232, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33600866

RESUMO

AIMS: Diabetic retinopathy (DR) is the most common complication of type 2 diabetes mellitus, which could result in visual impairment. Accumulating studies have shown the implication of long non-coding RNAs (lncRNAs) in the pathogenesis of DR. Our aims are to investigate whether lncRNA SNHG7 plays a role during DR pathogenesis. MAIN METHODS: Human retinal microvascular endothelial cells (HRMECs) were treated with high glucose (HG) to build cell model. Relative expression of RNAs were examined using qPCR, and western blot or immunofluorescence analysis was adopted to detect the protein expression. Cell viability, migration and angiogenic capacity of HRMECs were estimated through CCK-8, transwell and tube formation experiments, respectively. Dual-luciferase reporter and RNA pull down assays were employed to verify the interplay between miR-34a-5p and SNHG7 or XBP1. Mesenchymal stem cells (MSCs) were identified by examining typical surface makers using flow cytometry and the differentiation abilities via Alizarin red, Oil red O and Alcian blue staining. MSC-derived exosomes were verified by transmission electron microscopy and western blot. KEY FINDINGS: LncRNA SNHG7 sponged to and negatively regulated miR-34a-5p. SNHG7 overexpression repressed HG induced endothelial-mesenchymal transition (EndMT) and tube formation of HRMECs, while miR-34a-5p overexpression could reverse this effect. miR-34a-5p targeted and negative regulated XBP1. Knockdown of miR-34a-5p repressed HG induced EndMT and tube formation, which were partially blocked by XBP1 inhibition. MSC-derived exosomes could transfer SNHG7 to HRMECs and modulated EndMT and tube formation. SIGNIFICANCE: The MSC-derived exosomal lncRNA SNHG7 suppresses EndMT and tube formation in HRMECs via miR-34a-5p/XBP1 axis.


Assuntos
Retinopatia Diabética/genética , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Exossomos/metabolismo , Glucose/metabolismo , Humanos , Células-Tronco Mesenquimais , MicroRNAs/genética , Retina/metabolismo , Transdução de Sinais/genética , Proteína 1 de Ligação a X-Box/metabolismo
2.
BMC Complement Med Ther ; 21(1): 66, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602182

RESUMO

BACKGROUND: High glucose (HG)-induced reactive oxygen species (ROS) overproduction impairs angiogenesis that is one pivotal factor of wound healing process. Angiogenesis impairment induces delayed wound healing, whereby it eventually leads to amputation in cases of poorly controlled diabetes with diabetic ulceration. Porcine placenta extract (PPE) is a natural waste product that comprises plenty of bioactive agents including growth factors and antioxidants. It was reported as an effective compound that prevents ROS generation. The goal of this study was to investigate the in vitro effect of PPE on HG-induced ROS-mediated angiogenesis impairment. METHODS: Primary endothelial cells (HUVECs) and endothelial cell line (EA.hy926) were treated with HG in the presence of PPE. The endothelial cells (ECs) viability, intracellular ROS generation, migration, and angiogenesis were determined by MTT assay, DCFDA reagent, wound healing assay, and tube formation assay, respectively. Additionally, the molecular mechanism of PPE on HG-induced angiogenesis impairment was investigated by Western blot. The angiogenic growth factor secretion was also investigated by the sandwich ELISA technique. RESULTS: HG in the presence of PPE significantly decreased intracellular ROS overproduction compared to HG alone. HG in the presence of PPE significantly increased ECs viability, migration, and angiogenesis compared to HG alone by showing recovery of PI3K/Akt/ERK1/2 activation. HG in the presence of PPE also decreased ECs apoptosis compared to HG alone by decreasing p53/Bax/cleaved caspase 9/cleaved caspase 3 levels and increasing Bcl 2 level. CONCLUSION: PPE attenuated HG-induced intracellular ROS overproduction that improved ECs viability, proliferation, migration, and angiogenesis by showing recovery of PI3K/Akt/ERK1/2 activation and inhibition of ECs apoptosis. This study suggests PPE ameliorated HG-induced ROS-mediated angiogenesis impairment, whereby it potentially provides an alternative treatment for diabetic wounds.


Assuntos
Produtos Biológicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Glucose/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Placenta/química , Suínos , Cicatrização/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Produtos Biológicos/química , Linhagem Celular , Movimento Celular , Sobrevivência Celular , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Células Endoteliais/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
3.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33398371

RESUMO

Oxymatrine (OMT) is the primary active component of Sophora flavescens Ait., and is widely used for the treatment of diabetic complications. The present study aimed to investigate the effects of OMT on acute lung injury (ALI) in diabetic rats subjected to myocardial ischemia/reperfusion (I/R). ALI in a myocardial I/R model was established in streptozocin­induced diabetic rats. Enzyme­linked immunosorbent assays were used to evaluate the levels of creatine kinase isoenzyme MB and lactate dehydrogenase, and the inflammatory response was assessed via leukocyte counts and the levels of tumor necrosis factor (TNF)­α, interleukin (IL)­6 and IL­8 in the bronchoalveolar lavage (BAL) fluid. Hematoxylin and eosin staining was used to determine pathological changes to the lung tissue, and the autophagy­related proteins LC­3II/LC­3I, Beclin­1, autophagy protein 5 (Atg5) and p62 were detected by western blotting. Diabetic rats subjected to myocardial I/R showed increased levels of ALI with a higher lung injury score and WET/DRY ratio, and lower partial pressure of oxygen. This was accompanied by aberrant autophagy, indicated by an increased LC­3II/LC­3I ratio, decreased p62 expression levels, increased Atg5 and beclin­1 expression levels, decreased superoxide dismutase activity and increased 15­F2t­isoprostane formation in lung tissues, as well as increased levels of leukocytes, TNF­α, IL­6 and IL­8 in the BAL fluid. Administration of the autophagy inducer rapamycin significantly accelerated these alterations, while the autophagy inhibitor 3­Methyladenine exerted the opposite effects. These results indicated that diabetic lungs are more vulnerable to myocardial I/R, which was associated with aberrant autophagy. Furthermore, oxymatrine was observed to reverse and alleviate ALI in diabetic rats with myocardial I/R in a concentration­dependent manner, the mechanism of which may be associated with the inhibition of autophagy.


Assuntos
Lesão Pulmonar Aguda , Alcaloides/farmacologia , Autofagia/efeitos dos fármacos , Complicações do Diabetes , Diabetes Mellitus Experimental , Traumatismo por Reperfusão Miocárdica , Quinolizinas/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-Dawley
4.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495825

RESUMO

In diabetic animal models, high plasma/tissue levels of methylglyoxal (MG) are implicated in atherosclerosis. N­acetylcysteine (NAC) is a cysteine prodrug that replenishes intracellular glutathione (GSH) levels, which can increase the elimination of MG in diabetes mellitus (DM). The present study investigated the anti­atherosclerotic role of NAC in DM and aimed to determine whether the mechanism involved GSH­dependent MG elimination in the aorta. Apolipoprotein­E knockdown (ApoE­/­) mice injected with streptozotocin for 5 days exhibited enhanced atherosclerotic plaque size in the aortic root; notably, a high­lipid diet aggravated this alteration. NAC treatment in the drinking water for 12 weeks decreased the size of the atherosclerotic lesion, which was associated with a reduction in MG­dicarbonyl stress and oxidative stress, as indicated by decreased serum malondialdehyde levels, and increased superoxide dismutase­1 and glutathione peroxidase­1 levels in the diabetic aorta. Endothelial damage was also corrected by NAC, as indicated by an increase in the expression levels of phosphorylated (p­)Akt and p­endothelial nitric oxide synthase (eNOS) in the aorta, as well as nitric oxide (NO) in the serum. In addition, MG­treated human umbilical vein endothelial cells (HUVECs) exhibited increased reactive oxygen species and decreased antioxidant enzyme expression levels. NAC treatment corrected the alteration in HUVECs induced by MG, whereas the protective role of NAC was blocked via inhibition of GSH. These findings indicated that the diabetic aorta was more susceptible to atherosclerotic lesions compared with non­diabetic ApoE­/­ mice. Furthermore, NAC may offer protection against atherosclerotic development in DM by altering aortic and systemic responses via correcting GSH­dependent MG elimination, leading to decreased oxidative stress and restoration of the p­Akt/p­eNOS pathway in the aorta.


Assuntos
Acetilcisteína/farmacologia , Aorta/metabolismo , Aterosclerose , Complicações do Diabetes , Diabetes Mellitus Experimental , Glutationa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Aldeído Pirúvico/metabolismo , Animais , Aorta/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Masculino , Camundongos , Camundongos Knockout para ApoE
5.
Int J Biol Macromol ; 169: 143-152, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33338529

RESUMO

Advanced glycation endproducts (AGEs) are the final product of glycation, highly reactive in nature and contribute directly or indirectly to numerous complications related to diabetes. In this study, the antiglycation activity of glyburide was investigated using HSA as model protein, both against glucose and methylglyoxal mediated glycation. The possible mechanism of action was also deciphered using biophysical and computational tools. Approximately 70% inhibition of both early and advanced glycation end products were recorded in the presence of glyburide. Free lysine modification was reduced by glyburide treatment and improvement in biochemical markers such as free thiol groups and carbonyl content was observed. Interaction studies revealed that glyburide showed moderate to strong binding affinity towards HSA with binding constant in the order of 106 M-1. The interaction of glyburide with HSA was entropically favourable and spontaneous in nature. Molecular dynamics simulation deciphered that glyburide-HSA complex was quite stable where RMSD, RMSF, Rg, SASA, and secondary structure of HSA remained approximately same over the entire simulation period. The average binding energy of the MD simulation for glyburide-HSA complex was found to be -15.386 kJ mol-1. The findings demonstrate the antiglycation potential of glyburide and its possible mechanism of action.


Assuntos
Glibureto/química , Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Glucose/química , Glibureto/farmacologia , Glicosilação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína , Albumina Sérica/química , Albumina Sérica/metabolismo
6.
Nefrología (Madrid) ; 40(6): 585-586, nov.-dic. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-197195

RESUMO

Los métodos de diagnóstico actuales son poco sensibles para detectar las etapas iniciales de la nefropatía diabética tipo 2. En este trabajo se hace una revisión de estudios de aproximación metabolómica para la identificación de biomarcadores de esta enfermedad con potencialidad para diferenciar entre etapas tempranas, evaluar y direccionar el tratamiento y coadyuvar a ralentizar el daño renal. Utilizando bases de datos públicas (Pubmed y Google Scholar) y privadas (Scopus y Web of Knowledge), se realizó una búsqueda sistemática de la información que se ha publicado de metabolómica de la nefropatía diabética en distintos bioespecímenes (orina, suero, plasma y sangre). Posteriormente, se utilizó el programa MetaboAnalyst 4.0 para evidenciar las vías metabólicas que están asociadas con estos metabolitos. Con los datos de la literatura se identificaron grupos de metabolitos potenciales para la monitorización de la nefropatía diabética. Destacan en la orina: el óxido-3-hidroxiisovalerato, TMAO, aconitato y citrato y derivados del hidroxipropionato; en el suero: el citrato, la creatinina, la arginina y sus derivados; y en el plasma: aminoácidos como histidina, metionina y arginina. Utilizando el programa MetaboAnalyst 4.0 se detectaron las rutas metabólicas que están relacionadas con estos metabolitos. La búsqueda de biomarcadores relacionados con la progresión de la nefropatía diabética junto con estrategias analíticas para su detección y cuantificación son el punto de partida para el diseño de nuevos métodos de análisis químico-clínico. La correlación con la disfunción de vías metabólicas podría ser utilizada para la evaluación integral del tratamiento y seguimiento clínico de este padecimiento


Current diagnostic methods are not very sensitive to detect the initial stages diabetic nephropathy of type 2. In this work, a review of metabolomic approximation studies for the identification of biomarkers of this disease with potential to differentiate between early stages, evaluate and direct treatment and help slow kidney damage. Using public (Pubmed and Google Scholar) and private (Scopus and Web of Knowledge) databases, a systematic search of the information published related to metabolomics of diabetic nephropathy in different biospecimens (urine, serum, plasma and blood) was made. Later, the MetaboAnalyst 4.0 software was used to identify the metabolic pathways associated with these metabolites. Groups of potential metabolites were identified for monitoring diabetic nephropathy with the available literature data. In the urine, oxide-3-hydroxyisovalerate, TMAO, aconite and citrate and hydroxypropionate derivatives are highlighted; meanwhile, in the serum: citrate, creatinine, arginine and its derivatives; and in the plasma: amino acids such as histidine, methionine and arginine has a potential contribution. Using MetaboAnalyst 4.0 the metabolic pathways related to these metabolites were related. The search for biomarkers to measure the progression of diabetic nephropathy, together with analytical strategies for their detection and quantification, are the starting point for designing new methods of clinical chemistry analysis. The association between the metabolic pathway dysfunction could be useful for the overall assessment of the treatment and clinical follow-up of this disease


Assuntos
Humanos , Nefropatias Diabéticas/metabolismo , Metabolômica/métodos , Progressão da Doença , Biomarcadores/metabolismo , Insuficiência Renal Crônica , Complicações do Diabetes/metabolismo , Biomarcadores/análise
7.
Elife ; 92020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32930095

RESUMO

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.


Assuntos
Infecções por Coronavirus/microbiologia , Diabetes Mellitus/microbiologia , Obesidade/microbiologia , Pneumonia Viral/microbiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/virologia , Animais , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/microbiologia , Complicações do Diabetes/virologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/virologia , Regulação para Baixo , Interações entre Hospedeiro e Microrganismos , Humanos , Interações Microbianas , Obesidade/metabolismo , Obesidade/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Carga Viral
8.
Acta Diabetol ; 57(11): 1275-1285, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32865671

RESUMO

The COronaVirus DISease 19 (COVID-19) is a pandemic infectious disease caused by the novel coronavirus Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Older age and presence of comorbidities, including diabetes, were shown to be associated with a more severe course and a higher fatality rate. Studies from the most affected countries, including China, United States and Italy, seem to indicate that prevalence of diabetes among patients affected by COVID-19 is not higher than that observed in the general population, thus suggesting that diabetes is not a risk factor for SARS-CoV-2 infection. However, a large body of evidence demonstrate that diabetes is a risk factor for disease progression towards critical illness, development of acute respiratory distress syndrome, need for mechanical ventilation or admission to intensive care unit, and ultimately death. The mechanisms underlying the relationship between COVID-19 and diabetes remain to be elucidated. In particular, it is still unresolved whether is diabetes per se, especially if poorly controlled, or rather the various comorbidities/complications associated with it that predispose patients with COVID-19 to a worse prognosis. In fact, conditions that cluster with diabetes in the context of the metabolic syndrome, such as obesity and hypertension, or complicate chronic hyperglycemia, such as cardiovascular disease and chronic kidney disease, have also been associated with poor prognosis in these individuals and the available studies have not consistently shown that diabetes predict disease severity independently of them.


Assuntos
Infecções por Coronavirus , Complicações do Diabetes , Diabetes Mellitus , Pandemias , Pneumonia Viral , Betacoronavirus , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/metabolismo , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Progressão da Doença , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença
9.
PLoS One ; 15(8): e0237004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756589

RESUMO

Dysregulated expression of MicroRNAs (miRNAs) plays substantial role in the initiation and progression of both diabetes and periodontitis. The aim of the present study was to validate four miRNAs in saliva as potential predictive biomarkers of periodontal disease among patients with and without diabetes mellitus (DM). MiRNAs were extracted from the saliva of 24 adult subjects with DM and 29 healthy controls. Each group was subdivided into periodontally healthy or having periodontitis. In silico analysis identified 4 miRNAs (miRNA 155, 146 a/b and 203) as immune modulators. The expression of miRNAs-146a/b, 155, and 203 was tested using quantitative PCR. The expression levels in the study groups were compared to explore the effect of diabetes on periodontal status and vice versa. In our cohort, the four miRNAs expression were higher in patients with periodontitis and/or diabetes. miRNA-155 was the most reliable predictors of periodontitis among non-diabetics with an optimum cut-off value of < 8.97 with accuracy = 82.6%. MiRNA 146a, on the other hand, was the only reliable predictor of periodontitis among subjects with diabetes with optimum cut-off value of ≥11.04 with accuracy = 86.1%. The results of the present study concluded that MiRNA-146a and miRNA155 in saliva provide reliable, non-invasive, diagnostic and prognostic biomarkers that can be used to monitor periodontal health status among diabetic and non-diabetic patients.


Assuntos
Diabetes Mellitus/diagnóstico , MicroRNAs/metabolismo , Periodontite/diagnóstico , Adolescente , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Análise Discriminante , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Periodontite/genética , Periodontite/metabolismo , Projetos Piloto , Saliva/metabolismo , Regulação para Cima , Adulto Jovem
10.
Diab Vasc Dis Res ; 17(7): 1479164120942119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32744067

RESUMO

Type 2 diabetes mellitus is a type of metabolic disorder characterized by hyperglycaemia with multiple serious complications, such as diabetic neuropathies, diabetic nephropathy, diabetic retinopathy, and diabetic foot. Platelet-derived growth factors are growth factors that regulate cell growth and division, playing a critical role in diabetes and its harmful complications. This review focused on the cellular mechanism of platelet-derived growth factors and their receptors on diabetes development. Furthermore, we raise some proper therapeutic molecular targets for the treatment of diabetes and its complications.


Assuntos
Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/uso terapêutico , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Transdução de Sinais
11.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697943

RESUMO

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Assuntos
Betacoronavirus/fisiologia , Glicemia/metabolismo , Infecções por Coronavirus/complicações , Complicações do Diabetes/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Monócitos/metabolismo , Pneumonia Viral/complicações , Adulto , Linhagem Celular , Infecções por Coronavirus/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Feminino , Glicólise , Humanos , Inflamação/complicações , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Pandemias , Pneumonia Viral/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
12.
PLoS One ; 15(6): e0234362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520973

RESUMO

BACKGROUND: Patients with diabetes mellitus are at an increased risk for adverse clinical events following percutaneous coronary interventions (PCI). However, the clinical impact of diabetes mellitus (DM) on second-generation drug-eluting stent (DES) implantation is not well-known. The aim of the current analysis was to examine the clinical impact of DM on clinical outcomes and the time sequence of associated risks in patients treated with second-generation DES. METHODS: Using patient-level data from two stent-specific, all-comer, prospective DES registries, we evaluated 1,913 patients who underwent PCI with second-generation DES between Feb 2009 and Dec 2013. The primary outcomes assessed were two-year major cardiac adverse events (MACE), composite endpoints of death from any cause, myocardial infarction (MI), and any repeat revascularization. We classified 0-1 year as the early period and 1-2 years as the late period. Landmark analyses were performed according to diabetes mellitus status. RESULTS: There were 1,913 patients with 2,614 lesions included in the pooled dataset. The median duration of clinical follow-up in the overall population was 2.0 years (interquartile range 1.9-2.1). Patients with DM had more cardiovascular risk factors than patients without DM. In multivariate analyses, the presence of DM and renal failure were strong predictors of MACE and target-vessel revascularization (TVR). After inverse probability of treatment weighting (IPTW) analyses, patients with DM had significantly increased rates of 2-year MACE (HR 2.07, 95% CI; 1.50-2.86; P <0.001). In landmark analyses, patients with DM had significantly higher rates of MACE in the early period (0-1 year) (HR 3.04, 95% CI; 1.97-4.68; P < 0.001) after IPTW adjustment, but these findings or trends were not observed in the late period (1-2 year) (HR 1.24, 95% CI; 0.74-2.07; P = 0.41). CONCLUSIONS: In the second-generation DES era, the clinical impact of DM significantly increased the 2-year event rate of MACE, mainly caused by clinical events in the early period (0-1 year). Careful observation of patients with DM is advised in the early period following PCI with second-generation DES.


Assuntos
Complicações do Diabetes/metabolismo , Stents Farmacológicos/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Idoso , Doença da Artéria Coronariana/complicações , Complicações do Diabetes/terapia , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Sistema de Registros , República da Coreia/epidemiologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
14.
Sci Rep ; 10(1): 7238, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350374

RESUMO

Acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI) and diabetes mellitus (DM) is an independent risk factor of AKI. Recent clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in patients with DM. We recently reported that canagliflozin normalized susceptibility of diabetic rats to AKI after acute MI via ß-hydroxybutyrate-mediated suppression of NOX expression. Here we examined whether the same renoprotective effect is shared by empagliflozin. Serum creatinine levels were not changed by MI induced by coronary artery occlusion in LETO, non-diabetic control rats, and OLETF, obese type 2 diabetic rats. However, immunohistochemistry revealed that MI increased renal expression of NGAL and KIM-1, early markers of tubular injury, by 3.2-fold and 2.6-fold, respectively, in OLETF. These increases in injury markers were not observed in LETO. Pretreatment with empagliflozin of OLETF for 2 weeks improved hyperglycemia, increased blood ß-hydroxybutyrate level, and suppressed MI-induced expression of NGAL and KIM-1. Empagliflozin suppressed upregulation of NOX2 and NOX4 in the kidney of OLETF. Taken together with the results of our previous study, it was concluded that treatment with the SGLT2 inhibitor protects the diabetic kidney from MI-induced AKI.


Assuntos
Lesão Renal Aguda , Compostos Benzidrílicos/farmacologia , Complicações do Diabetes , Diabetes Mellitus Experimental , Glucosídeos/farmacologia , Rim , Infarto do Miocárdio , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , 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 , Rim/metabolismo , Rim/patologia , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Ratos
16.
Cell Prolif ; 53(6): e12834, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32468637

RESUMO

OBJECTIVES: Advanced glycation end products (AGEs) are considered a cause of diabetic osteoporosis. Although adipose-derived stem cells (ASCs) are widely used in the research of bone regeneration, the mechanisms of the osteogenic differentiation of ASCs from diabetic osteoporosis model remain unclear. This work aimed to investigate the influence and the molecular mechanisms of AGEs on the osteogenic potential of ASCs. MATERIALS AND METHODS: Enzyme-linked immunosorbent assay was used to measure the change of AGEs in diabetic osteoporotic and control C57BL/6 mice. ASCs were obtained from the inguinal fat of C57BL/6 mice. AGEs, 5-aza2'-deoxycytidine (5-aza-dC) and DKK-1 were used to treat ASCs. Real-time cell analysis and cell counting kit-8 were used to monitor the proliferation of ASCs within and without AGEs. Real-time PCR, Western blot and Immunofluorescence were used to analyse the genes and proteins expression of osteogenic factors, DNA methylation factors and Wnt/ß-catenin signalling pathway among the different groups. RESULTS: The AGEs and DNA methylation were increased in the adipose and bone tissue of the diabetic osteoporosis group. Untreated ASCs had higher cell proliferation activity than AGEs-treatment group. The expression levels of osteogenic genes, Opn and Runx2, were lower, and mineralized nodules were less in AGEs-treatment group. Meanwhile, DNA methylation was increased, and the Wnt signalling pathway markers, including ß-Catenin, Lef1 and P-GSK-3ß, were inhibited. After treatment with 5-aza-dC, the osteogenic differentiation capacity of ASCs in the AGEs environment was restored and the Wnt signalling pathway was activated during this process. CONCLUSIONS: Advanced glycation end products inhibit the osteogenic differentiation ability of ASCs by activating DNA methylation and inhibiting Wnt/ß-catenin pathway in vitro. Therefore, DNA methylation may be promising targets for the bone regeneration of ASCs with diabetic osteoporosis.


Assuntos
Tecido Adiposo/citologia , Metilação de DNA , Complicações do Diabetes/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Células-Tronco/metabolismo , Tecido Adiposo/metabolismo , Animais , Osso e Ossos/metabolismo , Proliferação de Células , Células Cultivadas , Decitabina/farmacologia , Complicações do Diabetes/patologia , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Camundongos Endogâmicos C57BL , Osteoporose/patologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Via de Sinalização Wnt
17.
Diabetes Metab Syndr ; 14(4): 319-323, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298984

RESUMO

INTRODUCTION: and aims: To prevent the spread of coronavirus disease (COVID19) total lockdown is in place in India from March 24, 2020 for 21 days. In this study, we aim to assess the impact of the duration of the lockdown on glycaemic control and diabetes-related complications. MATERIALS AND METHODS: A systematic search was conducted using Cochrane library. A simulation model was created using glycemic data from previous disasters (taken as similar in impact to current lockdown) taking baseline HBA1c and diabetes-related complications data from India-specific database. A multivariate regression analysis was conducted to analyse the relationship between the duration of lockdown and glycaemic targets & diabetes-related complications. RESULTS: The predictive model was extremely robust (R2 = 0.99) and predicted outcomes for period of lockdown up to 90 days. The predicted increment in HBA1c from baseline at the end of 30 days and 45 days lockdown was projected as 2.26% & 3.68% respectively. Similarly, the annual predicted percentage increase in complication rates at the end of 30-day lockdown was 2.8% for non-proliferative diabetic retinopathy, 2.9% for proliferative diabetic retinopathy, 1.5% for retinal photocoagulation, 9.3% for microalbuminuria, 14.2% for proteinuria, 2.9% for peripheral neuropathy, 10.5% for lower extremity amputation, 0.9% for myocardial infarction, 0.5% for stroke and 0.5% for infections. CONCLUSION: The duration of lockdown is directly proportional to the worsening of glycaemic control and diabetes-related complications. Such increase in diabetes-related complications will put additional load on overburdened healthcare system, and also increase COVID19 infections in patients with such uncontrolled glycemia.


Assuntos
Betacoronavirus/isolamento & purificação , Simulação por Computador , Infecções por Coronavirus/complicações , Complicações do Diabetes/patologia , Diabetes Mellitus/fisiopatologia , Hemoglobina A Glicada/análise , Modelos Estatísticos , Pneumonia Viral/complicações , Glicemia/metabolismo , Infecções por Coronavirus/virologia , Complicações do Diabetes/etiologia , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/virologia , Humanos , Metanálise como Assunto , Pandemias , Pneumonia Viral/virologia , Análise de Regressão
18.
Med Hypotheses ; 140: 109759, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32344305

RESUMO

COVID-19, the disease caused by the novel SARS-CoV-2, a betacoronavirus structurally similar to SARS-CoV. Based on both structural and syndromic similarities with SARS-CoV, a hypothesis is formed on SARS-CoV-2 potential to affect the host's metabolism as part of its lifecycle. This hypothesis is evaluated by (a) exploratory analysis of SARS-CoV/human transcriptomic interaction data and gene set enrichment analysis (b) a confirmatory, focused review of the literature based on the findings by (a). A STRING Viruses (available search for human - SARS-CoV (NCBI taxonomy Id: 9606 vs. NCBI taxonomy Id: 694009) genomic interactions reveals ten human proteins, interacting with SARS-CoV: SGTA, FGL2, SPECC1, STAT3, PHB, BCL2L1, PPP1CA, CAV1, JUN, XPO1. Gene set enrichment analyses (GSEA) with STRING on this network revealed their role as a putative protein - protein interaction network (PPI; Enrichment p-value = 0.0296) mediating, viral parasitism, interleukin as well as insulin signaling, diabetes and triglyceride catabolism. In the literature, SARS-CoV has been known to cause de novo diabetes by ACE2-dependent uptake on pancreatic isle cells, and furthermore dysregulate lipid autophagy in favor of the viral lifecycle. Conversely, currently there are only non-causative, observational evidence of worse outcomes for COVID-19 patients with comorbid diabetes or hyperglycemia. No study has reported on the lipid profiles of COVID-19 patients; however, lipid-targeting molecules have been proposed as agents against SARS-CoV-2. Future studies, reporting on lipid and glucose metabolism of COVID-19 patients could help elucidate the disease's seculae and aid drug design.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Epigênese Genética , Pneumonia Viral/genética , Autofagia , Simulação por Computador , Infecções por Coronavirus/virologia , Complicações do Diabetes/metabolismo , Desenho de Fármacos , Humanos , Hiperglicemia/complicações , Lipídeos/química , Pandemias , Pneumonia Viral/virologia , Ligação Proteica , Proteômica , Transdução de Sinais , Transcriptoma
19.
Circ Res ; 126(10): 1456-1474, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32264791

RESUMO

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.


Assuntos
Betacoronavirus/fisiologia , Doenças Cardiovasculares , Infecções por Coronavirus , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral , Sistema Renina-Angiotensina/fisiologia , Proteína ADAM17/fisiologia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Humanos , Terapia de Alvo Molecular , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Receptores Virais/fisiologia , Ligação Viral
20.
Gene ; 738: 144476, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061761

RESUMO

BACKGROUND: Metabolic syndrome (MetS) contributes to increased risk of morbidity and mortality. The United Arab Emirates (UAE) has a high prevalence of MetS which may be linked to modifiable and genetic risk factors in the local population. The association between MetS as a phenotype and key genetic variants in the UAE has not been investigated. This study reports on the clinical, biochemical and genetic associations of MetS and its risk factors to improve individualized medicine outcomes. METHODS: There were 471 subjects included in this cross-sectional study, 367 with MetS and 104 without MetS. Along with clinical and laboratory parameters, multiple risk genetic variants were tested for their association with MetS, which include 49 variants that have previously been shown to be linked with MetS development as a phenotype, 116 variants for association with waist-hip ratio (WHR), 398 variants with body-mass index (BMI), 213 variants with T2DM and insulin resistance, 307 variants with different lipid traits, 308 variants with blood pressure traits, and 64 variants with coronary and cerebrovascular accidents. RESULTS: Patients with MetS had higher rates of type 2 diabetes mellitus (T2DM), hypertension and dyslipidemia (p < 0.0001). Waist circumference and T2DM were identified as the key risk factors for MetS development. Individuals with MetS were also found to have a higher rate of clinical complications than those without MetS (76% vs. 52%). Several gene variants including those of the FTO gene were found to be associated with a predisposition to developing MetS or some of its components (PFTO ~0.005-0.009). CONCLUSIONS: This study showed associations between MetS as well as clinical factors contributing to MetS and specific genetic and metabolic risk factors, providing an insight into the metabolic and genetic links to disease development. Knowledge with respect to population specific risk markers including at risk genotypes will help in early identification of individuals with increased susceptibility to MetS in the UAE and provide the opportunity for timely intervention to prevent or delay the onset of MetS.


Assuntos
Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Adulto , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos Transversais , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Prevalência , Fatores de Risco , Emirados Árabes Unidos/epidemiologia , Circunferência da Cintura , Relação Cintura-Quadril
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