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1.
Exp Cell Res ; 407(2): 112800, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34487731

RESUMO

PURPOSE: Increased permeability of retinal capillary endothelial cells is a key feature in the progression of diabetic retinopathy (DR). Precisely why and how diabetes causes dysfunction in retinal capillary endothelial cells is not well understood, making it challenging to explore more advanced therapeutics. METHODS: Cell proliferation was assessed by the Cell Counting Kit-8 assay. Ferroptosis was evaluated by measuring lipid reactive oxygen species levels by flow cytometry and determining malondialdehyde, superoxide dismutase, and glutathione peroxidase levels through biochemical assays. Western blot analysis and quantitative PCR were respectively used to check the expression of proteins and RNAs. Co-immunoprecipitation assays were used to confirm the interaction between TRIM46 and GPX4. RESULTS: High glucose (HG, 25 mM glucose) significantly suppressed cell growth, which could be reversed by the ferroptosis inhibitor, ferrostatin-1. HG treatment time-dependently induced ferroptosis in human retinal capillary endothelial cells (HRCECs) and induced TRIM46 expression. Lentiviral-mediated overexpression of TRIM46 decreased cell resistance against HG-induced ferroptosis, whereas knockdown showed the opposite effect. Administration of RSL3, a ferroptosis agonist, was able to reverse the protective effects of TRIM46 silencing. TRIM46 interacted with GPX4, an important enzyme that suppresses ferroptosis, and promoted GPX4 ubiquitination. Furthermore, lentiviral-mediated overexpression ofGPX4 ameliorated the effects of TRIM46 overexpression and conferred protection to cells against HG-induced ferroptosis. CONCLUSION: TRIM46 and GPX4 form a regulatory pathway that controls HG-induced ferroptosis of HRCECs. Inhibiting this pathway or sustaining the expression of GPX4 enables cells to resist damage caused by HG. We provide new mechanistic insight into the pathology of DR and identified TRIM46 and GPX4 as two molecular targets for the development of effective drugs for DR treatment.


Assuntos
Endotélio Vascular/patologia , Ferroptose , Glucose/efeitos adversos , Inibidores do Crescimento/efeitos adversos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Retina/patologia , Proteínas com Motivo Tripartido/metabolismo , Ubiquitinação , Morte Celular , Proliferação de Células , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Espécies Reativas de Oxigênio , Retina/efeitos dos fármacos , Retina/metabolismo , Edulcorantes/efeitos adversos
2.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360717

RESUMO

Peritoneal dialysis (PD) is an important, if underprescribed, modality for the treatment of patients with end-stage kidney disease. Among the barriers to its wider use are the deleterious effects of currently commercially available glucose-based PD solutions on the morphological integrity and function of the peritoneal membrane due to fibrosis. This is primarily driven by hyperglycaemia due to its effects, through multiple cytokine and transcription factor signalling-and their metabolic sequelae-on the synthesis of collagen and other extracellular membrane components. In this review, we outline these interactions and explore how novel PD solution formulations are aimed at utilizing this knowledge to minimise the complications associated with fibrosis, while maintaining adequate rates of ultrafiltration across the peritoneal membrane and preservation of patient urinary volumes. We discuss the development of a new generation of reduced-glucose PD solutions that employ a variety of osmotically active constituents and highlight the biochemical rationale underlying optimization of oxidative metabolism within the peritoneal membrane. They are aimed at achieving optimal clinical outcomes and improving the whole-body metabolic profile of patients, particularly those who are glucose-intolerant, insulin-resistant, or diabetic, and for whom daily exposure to high doses of glucose is contraindicated.


Assuntos
Diabetes Mellitus/terapia , Soluções para Diálise/uso terapêutico , Intolerância à Glucose/terapia , Resistência à Insulina , Falência Renal Crônica/terapia , Diálise Peritoneal , Soluções para Diálise/efeitos adversos , Glucose/efeitos adversos , Glucose/uso terapêutico , Humanos , Peritônio
3.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445501

RESUMO

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cinamatos/farmacologia , Depsídeos/farmacologia , Glucose/efeitos adversos , Lipoproteínas LDL/efeitos adversos , Macrófagos/citologia , Transportador 1 de Cassete de Ligação de ATP/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Biológicos , Proteólise/efeitos dos fármacos , Transdução de Sinais , Células THP-1
4.
Nutrients ; 13(8)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34444787

RESUMO

The sympathoadrenal counterregulatory response to hypoglycemia is critical for individuals with type 1 diabetes due to impaired ability to produce glucagon. Ketogenic diets (KD) are an increasingly popular diabetes management tool; however, the effects of KD on the sympathoadrenal response are largely unknown. Here, we determined the effects of KD-induced ketosis on the sympathoadrenal response to a single insulin-induced hypoglycemic challenge. We investigated how a 3 week KD feeding regimen affected the main components of the sympathoadrenal counterregulatory response: adrenal sympathetic nerve activity (ASNA), adrenal gland activity, plasma epinephrine, and brainstem glucose-responsive C1 neuronal activation in anesthetized, nondiabetic male Sprague-Dawley rats. Rats on KD had similar blood glucose (BG) levels and elevated ketone body ß-hydroxybutyrate (BHB) levels compared to the control Chow diet group. All KD rats responded to hypoglycemia with a robust increase in ASNA, which was initiated at significantly lower BG levels compared to Chow-fed rats. The delay in hypoglycemia-induced ASNA increase was concurrent with rapid disappearance of BHB from cerebral and peripheral circulation. Adrenal gland activity paralleled epinephrine and ASNA response. Overall, KD-induced ketosis was associated with initiation of the sympathoadrenal response at lower blood glucose levels; however, the magnitude of the response was not diminished.


Assuntos
Dieta Cetogênica , Hipoglicemiantes/farmacologia , Sistema Simpático-Suprarrenal , Ácido 3-Hidroxibutírico/farmacologia , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Glicemia , Modelos Animais de Doenças , Epinefrina/sangue , Glucagon , Glucose/efeitos adversos , Hipoglicemia/sangue , Hipoglicemia/terapia , Hipoglicemiantes/uso terapêutico , Insulina , Cetose , Masculino , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/efeitos dos fármacos
5.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208534

RESUMO

Endothelial cell dysfunction is considered to be one of the major causes of vascular complications in diabetes. Polyphenols are known as potent antioxidants that can contribute to the prevention of diabetes. Corn silk has been reported to contain polyphenols and has been used in folk medicine in China for the treatment of diabetes. The present study aims to investigate the potential protective role of the phenolic-rich fraction of corn silk (PRF) against injuries to vascular endothelial cells under high glucose conditions in vitro and in vivo. The protective effect of PRF from high glucose toxicity was investigated using human umbilical vein endothelial cells (HUVECs). The protective effect of PRF was subsequently evaluated by using in vivo methods in streptozotocin (STZ)-induced diabetic rats. Results showed that the PRF significantly reduced the cytotoxicity of glucose by restoring cell viability in a dose-dependent manner. PRF was also able to prevent the histological changes in the aorta of STZ-induced diabetic rats. Results suggested that PRF might have a beneficial effect on diabetic patients and may help to prevent the development and progression of diabetic complications such as diabetic nephropathy and atherosclerosis.


Assuntos
Células Endoteliais/efeitos dos fármacos , Polifenóis/farmacologia , Zea mays/metabolismo , Animais , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , China , Citoproteção/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Células Endoteliais/metabolismo , Glucose/efeitos adversos , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Extratos Vegetais/farmacologia , Polifenóis/química , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia
6.
Eur J Endocrinol ; 185(2): 313-321, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085950

RESUMO

Objectives: We aimed to investigate the clinical, biochemical, histological and radiological characteristics as well as the response to somatostatin analogs (SSA) in a large cohort of acromegaly patients with a paradoxical GH response (PR) to oral glucose tolerance test (OGTT). Design: Retrospective study. Methods: Of 110 patients with acromegaly included in our study, 30 (PR+; 27%) had a paradoxical GH increase of more than 25% relative to basal GH levels during OGTT. Results: At diagnosis, PR+ patients were older than PR- patients (52 ± 16 years vs 44 ± 14 years, P < 0.05) and had smaller pituitary tumors (40% microadenomas vs 19%, P < 0.05), which were less often invasive (17% vs 35%, P < 0.05), overall more secreting (insulin-like growth factor-1 (IGF-1)/tumoral surface: 2.35 ULN/cm2 (0.28-9.06) vs 1.08 (0.17-7.87), P = 0.011), and more often hypointense on T2-weighted MRI (92% vs 48%, P = 0.001). While the rate of remission after surgery was similar in the two groups (69%), a better response to SSA treatment was observed in PR+ patients, either before (IGF-1 reduction of > 50% after 3-6 months in 77% vs 49%, P = 0.023) or after surgery (normalization of IGF-1 in 100% vs 44%, P = 0.011). Conclusions: Our study demonstrates that in acromegaly, a paradoxical GH increase during OGTT is associated with particular features of somatotroph adenomas and with a better prognosis in terms of response to SSA.


Assuntos
Acromegalia/diagnóstico , Acromegalia/terapia , Glucose/administração & dosagem , Hormônio do Crescimento Humano/sangue , Acromegalia/sangue , Administração Oral , Adulto , Idoso , Feminino , Seguimentos , Glucose/efeitos adversos , Teste de Tolerância a Glucose , Hormônio do Crescimento Humano/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos
7.
Eur J Endocrinol ; 185(2): 289-297, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081617

RESUMO

Objective: High insulin-like growth factor 1 (IGF-1) and unsuppressed growth hormone (GH) levels after glucose load confirm the diagnosis of acromegaly. Management of patients with conflicting results could be challenging. Our aim was to evaluate the clinical and hormonal evolution over a long follow-up in patients with high IGF-1 but normal GH nadir (GHn < 0.4 µg/L according to the latest guidelines). Design: Retrospective cohort study. Methods: We enrolled 53 patients presenting high IGF-1 and GHn < 0.4 µg/L, assessed because of clinical suspicion of acromegaly or in other endocrinological contexts (e.g. pituitary incidentaloma). Clinical and hormonal data collected at the first and last visit were analyzed. Results: At the first evaluation, the mean age was 54.1 ± 15.4 years, 34/53 were females, median IGF-1 and GHn were +3.1 SDS and 0.06 µg/L, respectively. In the whole group, over a median time of 6 years, IGF-1 and GHn levels did not significantly change (IGF-1 mean of differences: -0.58, P = 0.15; GHn +0.03, P = 0.29). In patients with clinical features of acromegaly, the prevalence of acromegalic comorbidities was higher than in the others (median of 3 vs 1 comorbidities per patient, P = 0.005), especially malignancies (36% vs 6%, P = 0.03), and the clinical worsening overtime was more pronounced (4 vs 1 comorbidities at the last visit). Conclusions: In patients presenting high IGF-1 but GHn < 0.4 µg/L, a hormonal progression is improbable, likely excluding classical acromegaly in its early stage. However, despite persistently low GH nadir values, patients with acromegalic features present more acromegalic comorbidities whose rate increases over time. Close clinical surveillance of this group is advised.


Assuntos
Acromegalia/diagnóstico , Glucose/administração & dosagem , Hormônio do Crescimento Humano/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Acromegalia/sangue , Acromegalia/metabolismo , Administração Oral , Adulto , Idoso , Estudos de Coortes , Técnicas de Diagnóstico Endócrino , Regulação para Baixo/efeitos dos fármacos , Feminino , Seguimentos , Glucose/efeitos adversos , Teste de Tolerância a Glucose , Hormônios/sangue , Hormônios/metabolismo , Hormônio do Crescimento Humano/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
J Physiol Biochem ; 77(3): 443-450, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34129225

RESUMO

Metformin has been successfully used as an anti-aging agent but exact molecular mechanisms of metformin in anti-aging remain unknown. Hyperglycemia during skin aging not only causes oxidative damage to cellular macromolecules, like dermal collagen, but also modulates the activation of transcription factor nuclear factor kappa B (NF-kB). We aimed to investigate in vitro effects of high glucose (HG) and metformin treatment on proliferation and apoptosis of human primary dermal fibroblasts (HDFs), and the expression of COL1A1, COL3A1, and RELA/p65 genes. Effects of normal glucose (5.5 mM) and HG concentration (50 mM HG) on HDFs, with two doses of metformin (50 µM and 500 µM), were investigated by immunostaining. Apoptotic levels were analyzed by flow cytometry. Expression of COL1A1, COL3A1, and RELA/p65 genes was measured by quantitative real-time PCR. The proliferation of HDFs was decreased significantly (P < 0.01) and expression of COL1A1 was downregulated by HG without metformin, whereas proliferation was elevated and expression was upregulated with 500 µM metformin + HG compared to 5.5 mM glucose (P < 0.05). The expression of COL3A1 and RELA/p65 were upregulated (P < 0.01 for COL3A1), and percentage of late apoptotic cells increased significantly by HG without metformin (P < 0.001) while it decreased in two concentrations of metformin dramatically compared with 5.5 mM glucose (P < 0.01 for expressions and < 0.001 for apoptosis). Metformin not only significantly downregulated RELA/p65 expression, but also inhibited the apoptosis of HDFs from aged human skin at toxic glucose concentrations which could be inversely mediated via COL1A1 and COL3A1 expression.


Assuntos
Metformina/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Apoptose , Células Cultivadas , Regulação para Baixo , Feminino , Fibroblastos/efeitos dos fármacos , Glucose/efeitos adversos , Humanos , Pessoa de Meia-Idade , Cultura Primária de Células , Pele/citologia
9.
J Cell Mol Med ; 25(11): 5316-5325, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33942489

RESUMO

Type 2 diabetes mellitus (T2DM) leads to monocyte dysfunction associated with atherogenesis and defective arteriogenesis. Transforming growth factor (TGF)-ß1, placenta growth factor (PlGF)-1 and vascular endothelial growth factor (VEGF)A play important roles in atherogenesis and arteriogenesis. VEGF-receptor (VEGFR)-mediated monocyte migration is inhibited in T2DM (VEGFA resistance), while TGF-ß1-induced monocyte migration is fully functional. Therefore, we hypothesize that TGF-ß antagonises the VEGFA responses in human monocytes. We demonstrate that monocytes from T2DM patients have an increased migratory response towards low concentrations of TGF-ß1, while PlGF-1/VEGFA responses are mitigated. Mechanistically, this is due to increased expression of type II TGF-ß receptor in monocytes under high-glucose conditions and increased expression of soluble (s)VEGFR1, which is known to interfere with VEGFA signalling. VEGFA resistance in monocytes from T2DM patients can be rescued by either experimental down-regulation of TGF-ß receptor expression in vitro or by functional blocking of TGF-ß signalling using either a TGF-ß receptor kinase inhibitor or a TGF-ß neutralizing antibody. Our data demonstrate that both T2DM and high-glucose potentiate the TGF-ß pathway. TGF-ß signalling impairs VEGFR-mediated responses in T2DM monocytes and in this way contributes to mononuclear cell dysfunction, provide novel insights into T2DM vascular dysfunction.


Assuntos
Diabetes Mellitus Tipo 2/patologia , Glucose/efeitos adversos , Monócitos/patologia , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais , Edulcorantes/efeitos adversos , Fator de Crescimento Transformador beta1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Cochrane Database Syst Rev ; 5: CD012152, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33998668

RESUMO

BACKGROUND: Neonatal hypoglycaemia is a common condition that can be associated with brain injury. Current practice usually includes early identification of at-risk infants (e.g. infants of diabetic mothers; preterm, small- or large-for-gestational-age infants), and prophylactic measures are advised. However, these measures usually involve use of formula milk or admission to the neonatal unit. Dextrose gel is non-invasive, inexpensive and effective for treatment of neonatal hypoglycaemia. Prophylactic dextrose gel can reduce the incidence of neonatal hypoglycaemia, thus potentially reducing separation of mother and baby and supporting breastfeeding, as well as preventing brain injury.  This is an update of a previous Cochrane Review published in 2017.  OBJECTIVES: To assess the effectiveness and safety of oral dextrose gel given to newborn infants at risk of hypoglycaemia in preventing hypoglycaemia and reducing long-term neurodevelopmental impairment. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 10) in the Cochrane Library; and Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) on 19 October 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing oral dextrose gel versus placebo, no intervention, or other therapies for the prevention of neonatal hypoglycaemia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We contacted investigators to obtain additional information. We used fixed-effect meta-analyses. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included two studies conducted in high-income countries comparing oral dextrose gel versus placebo in 2548 infants at risk of neonatal hypoglycaemia. Of these, one study was included in the previous version of this review. We judged these two studies to be at low risk of bias, and that the evidence for most outcomes was of moderate certainty. Meta-analysis of the two studies showed that oral dextrose gel reduces the risk of hypoglycaemia (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.79 to 0.95; risk difference (RD) -0.06, 95% CI -0.10 to -0.02; 2548 infants; high certainty evidence). One study reported that oral dextrose gel probably reduces the risk of major neurological disability at two years' corrected age (RR 0.21, 95% CI 0.05 to 0.78; RD -0.05, 95% CI -0.09 to 0.00; 360 infants; moderate certainty evidence). Meta-analysis of the two studies showed that oral dextrose gel probably reduces the risk of receipt of treatment for hypoglycaemia during initial hospital stay (RR 0.89, 95% CI 0.79 to 1.00; 2548 infants; moderate certainty evidence) but makes little or no difference to the risk of receipt of intravenous treatment for hypoglycaemia (RR 1.01, 0.68 to 1.49; 2548 infants; moderate certainty evidence). Oral dextrose gel may have little or no effect on the risk of separation from the mother for treatment of hypoglycaemia (RR 1.12, 95% CI 0.81 to 1.55; two studies, 2548 infants; low certainty evidence). There is probably little or no difference in the risk of adverse events in infants who receive oral dextrose gel compared to placebo gel (RR 1.22, 95% CI 0.64 to 2.33; two studies, 2510 infants; moderate certainty evidence), but there are no studies comparing oral dextrose with other comparators such as no treatment, standard care or other therapies. No data were available on exclusive breastfeeding after discharge. AUTHORS' CONCLUSIONS: Oral dextrose gel reduces the risk of neonatal hypoglycaemia in at-risk infants and probably reduces the risk of major neurological disability at two years of age or greater without increasing the risk of adverse events compared to placebo gel. Additional large follow-up studies at two years of age or older are required. Future research should also be undertaken in low- and middle-income countries, preterm infants, using other dextrose gel preparations, and using comparators other than placebo gel. There are three studies awaiting classification and one ongoing study which may alter the conclusions of the review when published.


Assuntos
Glucose/administração & dosagem , Hipoglicemia/prevenção & controle , Edulcorantes/administração & dosagem , Administração Oral , Géis , Glucose/efeitos adversos , Humanos , Hipoglicemia/complicações , Lactente , Recém-Nascido , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Edulcorantes/efeitos adversos
11.
Am J Med Genet A ; 185(6): 1854-1857, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33686767

RESUMO

The COVID-19 pandemic has affected the health and healthcare of individuals of all ages worldwide. There have been multiple reports and reviews documenting a milder effect and decreased morbidity and mortality in the pediatric population, but there have only been a small number of reports discussing the SARS-CoV-2 infection in the setting of an inborn error of metabolism (IEM). Here, we report two patients with underlying metabolic disorders, propionic acidemia and glutaric aciduria type 1, and discuss their clinical presentation, as well as their infectious and metabolic management. Our report demonstrates that individuals with an underlying IEM are at risk of metabolic decompensation in the setting of a COVID-19 infection. The SARS-CoV-2 virus does not appear to cause a more severe metabolic deterioration than is typical.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Encefalopatias Metabólicas/complicações , COVID-19/complicações , Glutaril-CoA Desidrogenase/deficiência , Acidemia Propiônica/complicações , SARS-CoV-2 , Acidose/etiologia , Acidose/terapia , Acidose Láctica/etiologia , Transfusão de Componentes Sanguíneos , COVID-19/diagnóstico , Teste de Ácido Nucleico para COVID-19 , Terapia Combinada , Proteínas na Dieta/administração & dosagem , Gerenciamento Clínico , Suscetibilidade a Doenças , Ingestão de Energia , Nutrição Enteral , Feminino , Hidratação , Glucose/administração & dosagem , Glucose/efeitos adversos , Humanos , Hiperamonemia/etiologia , Hiperamonemia/terapia , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Lactente , Insulina/uso terapêutico , Unidades de Terapia Intensiva Pediátrica , Oxigenoterapia , Pancitopenia/etiologia , Pancitopenia/terapia , Diálise Renal , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico
12.
Mol Cell Endocrinol ; 528: 111224, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33675865

RESUMO

Intermedin(IMD) is a novel member of the calcitonin/calcitonin gene-related peptide (CT/CGRP) family that has anti-inflammatory, antioxidant and anti-apoptosis properties. This study aimed to evaluate the renoprotective effects of IMD on podocyte apoptotic loss and slit diaphragm protein deficiency the kidneys of rats with in streptozotocin (STZ) induced diabetes in high glucose-exposed podocytes. Our results showed that IMD significantly attenuated proteinuria, and alleviated the abnormal alterations in glomerular ultrastructure in vivo. IMD also improved the induction of slit diaphragm proteins, and restored the decreased Bcl-2 expression and suppressed Bax and caspase-3 induction in the diabetic glomeruli. In addition, IMD attenuated podocyte apoptosis and filamentous actin (F-actin) rearrangement in high glucose-exposed podocytes. Exposure to high glucose elevated the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress in renal podocytes, and IMD treatment blocked such ER stress responses pertinent to podocyte apoptosis and reduced synthesis of slit diaphragm proteins in vivo and in vitro. These observations demonstrate that targeting ER stress is an underlying mechanism of IMD-mediated amelioration of diabetes-associated podocyte injury and dysfunction.


Assuntos
Adrenomedulina/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Podócitos/citologia , Adrenomedulina/farmacologia , Animais , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glucose/efeitos adversos , Masculino , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória , Ratos , Estreptozocina , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
13.
Int J Mol Med ; 47(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33786607

RESUMO

Diabetic osteoporosis is a serious complication of diabetes affecting human bones. Uncarboxylated osteocalcin (GluOC), a small molecular protein specifically synthesized and secreted from osteoblasts, is of importance in regulating energy metabolism. In previous studies, the authors demonstrated that high glucose inhibited osteoblastic differentiation, but promoted adipocytic differentiation. GluOC promoted osteogenic and inhibited adipogenic differentiation under high glucose conditions. However, the corresponding receptors and signaling pathways through which GluOC exerts its effects on MC3T3E1 cells remain elusive. Thus, in the present study, Cell Counting kit­8 assays and western blot analysis were performed to assess the proliferation of MC3T3E1 cells. Alizarin Red S or Oil Red O staining, as well as reverse transcription­quantitative PCR analysis were performed to examine osteogenic and adipogenic differentiation. The cells were transfected with short interfering RNA or inhibitors to investigate the possible signaling pathways involved. The results revealed that G­protein coupled receptor, class C, group 6, subtype A (GPRC6A) receptor expression was markedly increased following the addition of GluOC to the MC3T3E1 cells. GPRC6A silencing decreased osteogenic gene expression, while it increased adipogenic gene expression. Furthermore, GluOC promoted osteoblast differentiation via the subsequent activation of the cyclic AMP (cAMP)/protein kinase A(PKA)/AMP­activated protein kinase (AMPK) signaling pathway in MC3T3E1 cells. On the whole, the results of the present study suggest that GluOC reverses the high glucose­induced inhibition of osteogenic differentiation via the GPRC6A/cAMP/PKA/AMPK signaling pathway in MC3T3E1 cells, and thus may prove to be beneficial in the treatment of diabetic osteoporosis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Complicações do Diabetes/prevenção & controle , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glucose/efeitos adversos , Camundongos , Osteogênese/fisiologia , Receptores Acoplados a Proteínas G/metabolismo
14.
Lab Invest ; 101(5): 588-599, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33526807

RESUMO

NOD-like receptor protein 3 (NLRP3) promotes the inflammatory response during progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). This study aimed to further delineate the role of NLRP3 in NASH development by abolishing its expression in mice. A high-fat and calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) was used to establish NASH in both wild-type (WT) and NLRP3 knock-out (KO) mice. Hepatocellular injury, hepatic steatosis and fibrosis, as well as inflammatory response and insulin resistance in the liver and epidydimal white adipose tissue (eWAT) were determined. Elevated body weight, liver weight and serum alanine transaminase level, increased hepatic triglyceride accumulation and collagen deposition, and worsened systemic insulin resistance were observed in Nlrp3-/- mice compared to WT mice under HFCD-HF/G feeding. Upregulated hepatic transcription of tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), and enhanced infiltration of inducible nitric oxide synthase-positive (iNOS+) M1 macrophages were also documented in HFCD-HF/G-fed Nlrp3-/- mice in comparison to HFCD-HF/G-fed WT mice. Moreover, transcription of TNF-α and MCP-1 and infiltration of iNOS+ M1 macrophages were increased in the liver of Nlrp3-/- mice under control diet. NLRP3 deficiency did not attenuate, but instead aggravated NASH development under HFCD-HF/G feeding. The worsened extent of NASH might be attributed to enhanced hepatic MCP-1 expression and M1 macrophage infiltration in Nlrp3-/- mice. Our study points to additional caution when NLRP3 blockade is considered as a therapeutic strategy in the treatment of human NASH.


Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Colágeno/metabolismo , Dieta Hiperlipídica/efeitos adversos , Frutose/efeitos adversos , Glucose/efeitos adversos , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado/imunologia , Fígado/metabolismo , Masculino , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Nutrients ; 13(2)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33562540

RESUMO

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. It is a heterogeneous condition characterized by reproductive, endocrine, metabolic, and psychiatric abnormalities. More than one pathogenic mechanism is involved in its development. On the other hand, the hypothalamus plays a crucial role in many important functions of the body, including weight balance, food intake, and reproduction. A high-fat diet with a large amount of long-chain saturated fatty acids can induce inflammation in the hypothalamus. Hypothalamic neurons can sense extracellular glucose concentrations and participate, with a feedback mechanism, in the regulation of whole-body glucose homeostasis. When consumed nutrients are rich in fat and sugar, and these regulatory mechanisms can trigger inflammatory pathways resulting in hypothalamic inflammation. The latter has been correlated with metabolic diseases, obesity, and depression. In this review, we explore whether the pattern and the expansion of hypothalamic inflammation, as a result of a high-fat and -sugar diet, may contribute to the heterogeneity of the clinical, hormonal, and metabolic presentation in PCOS via pathophysiologic mechanisms affecting specific areas of the hypothalamus. These mechanisms could be potential targets for the development of effective therapies for the treatment of PCOS.


Assuntos
Hipotálamo/fisiopatologia , Encefalite Límbica/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , Animais , Dieta Hiperlipídica/efeitos adversos , Doenças do Sistema Endócrino/etiologia , Ácidos Graxos/administração & dosagem , Ácidos Graxos/efeitos adversos , Retroalimentação Fisiológica , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Feminino , Glucose/efeitos adversos , Glucose/metabolismo , Humanos , Hiperuricemia/complicações , Hipotálamo/anatomia & histologia , Hipotálamo/metabolismo , Encefalite Límbica/etiologia , Encefalite Límbica/metabolismo , Transtornos Mentais/etiologia , Doenças Metabólicas/etiologia , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/terapia , Ratos , Estresse Fisiológico/fisiologia
16.
Asian Cardiovasc Thorac Ann ; 29(2): 77-83, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33530706

RESUMO

BACKGROUND: Despite the increasing popularity of single-dose cardioplegia techniques in coronary artery bypass grafting, the time window for successful reperfusion remains unclear. This study aimed to compare different cardioplegic techniques based on early and 30-day clinical outcomes via thorough monitoring. METHODS: This prospective cohort study included high-risk patients undergoing coronary artery bypass grafting and receiving 3 different types of cardioplegia between January 2017 and June 2019. Group 1 (n = 101) had a single dose of del Nido cardioplegia, group 2 (n = 92) had a single dose of histidine-tryptophane-ketoglutarate, and group 3 (n = 119) had cold blood cardioplegia. Patients were examined perioperatively by memory loop recording and auto-triggered memory loop recording for 30 days, with documentation of predefined events. RESULTS: Interleukin-6 and cardiac troponin levels in group 1 were significantly higher than those in groups 2 and 3. The incidence of predefined events as markers of inadequate myocardial protection was significantly higher group 1, with more frequent atrial fibrillation attacks and more hospital readmissions. The readmission rate was 17.6% in group 1, 9% in group 2, and 8% in group 3. CONCLUSIONS: Our data demonstrate the long-term efficacy of cardioplegic techniques, which may become more crucial in high-risk patients who genuinely have a chance to benefit from adjunct myocardial protection. Patients given del Nido cardioplegia had a significantly more prominent inflammatory response and higher troponin levels after cardiopulmonary bypass. This group had issues in the longer term with significantly more cardiac events and a higher rehospitalization rate.


Assuntos
Temperatura Baixa , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Eletrólitos/uso terapêutico , Parada Cardíaca Induzida , Lidocaína/uso terapêutico , Sulfato de Magnésio/uso terapêutico , Manitol/uso terapêutico , Cloreto de Potássio/uso terapêutico , Bicarbonato de Sódio/uso terapêutico , Soluções/uso terapêutico , Idoso , Biomarcadores/sangue , Temperatura Baixa/efeitos adversos , Ponte de Artéria Coronária/efeitos adversos , Eletrólitos/efeitos adversos , Feminino , Glucose/efeitos adversos , Glucose/uso terapêutico , Parada Cardíaca Induzida/efeitos adversos , Humanos , Interleucina-6/sangue , Lidocaína/efeitos adversos , Sulfato de Magnésio/efeitos adversos , Masculino , Manitol/efeitos adversos , Pessoa de Meia-Idade , Readmissão do Paciente , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/terapia , Cloreto de Potássio/efeitos adversos , Procaína/efeitos adversos , Procaína/uso terapêutico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Bicarbonato de Sódio/efeitos adversos , Soluções/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Troponina/sangue
17.
J Tradit Chin Med ; 41(1): 44-50, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33522196

RESUMO

OBJECTIVE: To investigate the efficacy of Xiaokeping (XKP)-containing serum on the proliferation of high-glucose-induced mesangial cells (MCs) and the potential underlying mechanism. METHODS: XKP-containing serum was prepared by the intragastric administration of XKP in rats. HBZY-1 cells were cultured with normal glucose (NC group), high glucose (HG group), and high glucose with different XKP concentrations. Cell proliferation was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the cell cycle distribution was detected by flow cytometry. The expression of p38 mitogen-activated protein kinase (p38MAPK) pathway components in MCs was detected by Western blotting and quantitative real-time polymerase chain reaction. RESULTS: The MC proliferation level in the high-glucose group was significantly higher than that in the normal control group, and XKP suppressed the HG-induced proliferation of MCs dose dependently. Moreover, flow cytometry revealed that XKP blocked cell cycle progression by inducing cell cycle arrest in G1 phase and inhibiting S phase entry. XKP down-regulated the protein and mRNA expression of p38MAPK in MCs (P < 0.05 vs HG). CONCLUSION: The present study demonstrated that XKP-containing serum inhibits high-glucoseinduced proliferation of MCs by causing cell cycle arrest at G1 phase and inhibiting S phase entry. The underlying mechanism involves the down-regulation of the p38MAPK signaling pathway, providing a theoretical basis for the use of XKP to treat diabetic kidney disease.


Assuntos
Proliferação de Células/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Medicamentos de Ervas Chinesas/administração & dosagem , Glucose/efeitos adversos , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Glucose/metabolismo , Humanos , Masculino , Células Mesangiais/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Mol Med ; 27(1): 13, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568044

RESUMO

BACKGROUND: Gestational diabetes mellitus is a risk factor for congenital heart defects. The article aimed to investigate the expression and roles of MST1, YAP1, Last1/2 and Survivin in modulating HG-induced cardiomyocyte apoptosis and maternal diabetes-induced heart abnormality. METHODS: Diabetes mellitus was induced in rats using streptozotocin. The protein expression and phosphorylation analysis in fetal heart tissue was assessed by western blot and immunohistochemical staining. Hoechst 33342 staining assay was performed to explore H9C2 apoptosis. The gene and protein expression in H9C2 cells was assessed by quantitative PCR and western blot. Knockdown of gene expression was assessed by RNA interference. RESULTS: Our results revealed that increased MST1 protein levels in the heart tissues of the offspring of diabetic rats in vivo and in H9C2 cardiomyocytes under HG treatment in vitro, respectively. Knockdown and overexpression experiments showed that MST1 played a key role in mediating HG-induced apoptosis in cardiomyocytes. Downregulation of YAP1 was associated with HG-induced, MST1-mediated cardiomyocyte apoptosis. Further study showed that MST1 downregulated the protein level of YAP1 through mediation of YAP1 phosphorylation on Ser127 and Ser397; this process also required LATS1/2 participation. MST1 overexpression increased the phosphorylation levels of LATS1/2, which were also shown to be increased in the heart tissues of diabetic offspring. We also found that YAP1 mediated the expression of Survivin during HG-induced apoptosis, and the Survivin-inhibitor YM155 partially inhibited the role of YAP1 in suppressing apoptosis induced by HG in cardiomyocytes. CONCLUSION: These findings reveal a regulatory mechanism of MST1/YAP1/Survivin signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Glucose/efeitos adversos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miócitos Cardíacos/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Survivina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Regulação para Baixo , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Naftoquinonas/farmacologia , Fosforilação , Ratos , Estreptozocina
19.
Mol Syst Biol ; 17(1): e9684, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417276

RESUMO

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/genética , Glucose/efeitos adversos , Resistência à Insulina/genética , MAP Quinase Quinase 6/genética , Proteínas Nucleares/genética , Animais , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Variação Genética , Lipidômica , Masculino , Camundongos , Fosfatidilcolinas/metabolismo , Triglicerídeos/metabolismo
20.
Mol Nutr Food Res ; 65(6): e2000777, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33481349

RESUMO

SCOPE: Pro-inflammatory stimuli such as hyperglycemia and cytokines have been shown to negatively affect endothelial cell functions. The aim of this study is to assess the potential of quercetin and its human metabolites to overcome the deleterious effects of hyperglycemic or inflammatory conditions on the vascular endothelium by modulating endothelial cell metabolism. METHODS AND RESULTS: A metabolomics approach enabled identification and quantification of 27 human umbilical vein endothelial cell (HUVEC) metabolites. Treatment of HUVECs with high-glucose concentrations causes significant increases in lactate and glutamate concentrations. Quercetin inhibits glucose-induced increases in lactate and adenosine 5'-triphosphate (ATP) and also increased inosine concentrations. Tumor necrosis factor α-treatment (TNFα) of HUVECs causes increases in asparagine and decreases in aspartate concentrations. Co-treatment with quercetin reduces pyruvate concentrations compared to TNFα-only treated controls. Subsequently, it was shown that quercetin and its HUVEC phase-2 conjugates inhibit adenosine deaminase, xanthine oxidase and 5'nucleotidase (CD73) but not ectonucleoside triphosphate diphosphohydrolase-1 (CD39) or purine nucleoside phosphorylase activities. CONCLUSION: Quercetin was shown to alter the balance of HUVEC metabolites towards a less inflamed phenotype, both alone and in the presence of pro-inflammatory stimuli. These changes are consistent with the inhibition of particular enzymes involved in purine metabolism by quercetin and its HUVEC metabolites.


Assuntos
Citocinas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glucose/efeitos adversos , Quercetina/farmacologia , 5'-Nucleotidase/metabolismo , Adenosina Desaminase/metabolismo , Apirase/metabolismo , Endotélio Vascular/citologia , Metabolismo Energético/efeitos dos fármacos , Proteínas Ligadas por GPI/metabolismo , Glucose/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/metabolismo , Purina-Núcleosídeo Fosforilase/metabolismo , Purinas/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Xantina Oxidase/metabolismo
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