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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 877-883, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33148381

RESUMO

Objective To investigate the expression levels of microRNA-186-5p (miR-186-5p) and Toll-like receptor 3 (TLR3) and their relationships with the apoptosis in high-glucose (HG)-treated AC16 cardiomyocytes. Methods Target Scan7.1 database predicted that miR-186-5p could act directly on TLR3. Diabetic cardiomyopathy model was established in cardiomyocytes stimulated by HG. The expression of miR-186-5p was detected by real-time quantitative PCR and the expression of TLR3 was detected by Western blot analysis. The expression of miR-186-5p or TLR3 was enhanced or reduced by cell transfection. The apoptosis of cardiomyocytes was detected by flow cytometry. The expression of cleaved caspase-3(c-caspase-3) was detected by Western blot analysis, and the interaction between miR-186-5p and TLR3 was analyzed by luciferase activity assay. Results The bioinformatics analysis and luciferase activity assay showed that TLR3 was a direct target gene of miR-186-5p. The expression of miR-186-5p was down-regulated in HG-treated cardiomyocytes, and the over-expression of miR-186-5p reversed HG-induced cardiomyocyte apoptosis and reduced the protein level of c-caspase-3. Down-regulation of TLR3 inhibited HG-induced apoptosis and reduced protein level of c-caspase-3 in cardiomyocytes. Over-expression of TLR3 increased HG-induced cardiomyocyte apoptosis and reversed the effect of miR-186-5p. Conclusion The miR-186-5p can inhibit the apoptosis of cardiomyocytes induced by HG via down-regulating TLR3 expression.


Assuntos
Apoptose , MicroRNAs/genética , Miócitos Cardíacos/citologia , Receptor 3 Toll-Like/genética , Caspase 3/metabolismo , Linhagem Celular , Glucose/efeitos adversos , Humanos , Miócitos Cardíacos/efeitos dos fármacos
2.
J Pharmacol Sci ; 144(4): 197-203, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070838

RESUMO

The role of cytoskeleton dynamics in the oxidative stress toward human vasculature has been unclear. The current study examined whether the cytoskeleton-disrupting agent cytochalasin B reduces oxidative stress caused by high glucose in the human arterial smooth muscle. All experiments in the human omental arteries without endothelium or the cultured human coronary artery smooth muscle cells were performed in d-glucose (5.5 mmol/L). The exposure toward d-glucose (20 mmol/L) for 60 min reduced the relaxation or hyperpolarization to an ATP sensitive K+ channel (KATP) opener levcromakalim (10-8 to 3 × 10-6 mol/L and 3 × 10-6 mol/L, respectively). Cytochalasin B and a superoxide inhibitor Tiron, restored them similarly. Cytochalasin B reduced the NADPH oxidase activity, leading to a decrease in superoxide levels of the arteries treated with high d-glucose. Also, cytochalasin B impaired the F-actin constitution and the membrane translocation of an NADPH oxidase subunit p47phox in artery smooth muscle cells treated with high d-glucose. A clinical concentration of cytochalasin B prevented human vascular smooth muscle malfunction via the oxidative stress caused by high glucose. Regulation of the cytoskeleton may be essential to keep the normal vascular function in patients with hyperglycemia.


Assuntos
Citocalasina B/farmacologia , Citoesqueleto/metabolismo , Glucose/efeitos adversos , Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adulto , Idoso , Células Cultivadas , Cromakalim/farmacologia , Feminino , Humanos , Hiperglicemia/fisiopatologia , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , NADPH Oxidases/metabolismo , Superóxidos/metabolismo
3.
Am J Chin Med ; 48(6): 1435-1454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907363

RESUMO

Endoplasmic reticulum stress (ER stress) plays a main role in pancreatic [Formula: see text]-cell dysfunction and death because of intracellular Ca[Formula: see text] turbulence and inflammation activation. Although several drugs are targeting pancreatic [Formula: see text]-cell to improve [Formula: see text]-cell function, there still lacks agents to alleviate [Formula: see text]-cell ER stress conditions. Therefore we used thapsigargin (THAP) or high glucose (HG) to induce ER stress in [Formula: see text]-cell and aimed to screen natural molecules against ER stress-induced [Formula: see text]-cell dysfunction. Through screening the Traditional Chinese drug library ([Formula: see text] molecules), luteolin was finally discovered to improve [Formula: see text]-cell function. Cellular viability results indicated luteolin reduced the THAP or HG-induced [Formula: see text]-cell death and apoptosis through MTT and flow cytometry assay. Moreover, luteolin improved [Formula: see text]-cell insulin secretion ability under ER stress conditions. Also ER stress-induced intracellular Ca[Formula: see text] turbulence and inflammation activation were inhibited by luteolin treatment. Mechanically, luteolin inhibited HNF4[Formula: see text] signaling, which was induced by ER stress. Moreover, luteolin reduced the transcriptional level of HNF4[Formula: see text] downstream gene, such as Asnk4b and HNF1[Formula: see text]. Conversely HNF4[Formula: see text] knockdown abolished the effect of luteolin on [Formula: see text]-cell using siRNA. These results suggested the protective effect of luteolin on [Formula: see text]-cell was through HNF4[Formula: see text]/Asnk4b pathway. In conclusion, our study discovered that luteolin improved [Formula: see text]-cell function and disclosed the underlying mechanism of luteolin on [Formula: see text]-cell, suggesting luteolin is a promising agent against pancreatic dysfunction.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Luteolina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tapsigargina/efeitos adversos , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Estresse do Retículo Endoplasmático/fisiologia , Glucose/efeitos adversos , Células Secretoras de Insulina/metabolismo , Luteolina/isolamento & purificação
4.
Am J Physiol Renal Physiol ; 319(2): F178-F191, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32567349

RESUMO

Kidney injury in hypertension and diabetes entails, among in other structures, damage in a key cell of the glomerular filtration barrier, the podocyte. Podocytes are polarized and highly differentiated cells in which vesicular transport, partly driven by Rab GTPases, is a relevant process. The aim of the present study was to analyze Rab GTPases of the Rab-Rabphilin system in human immortalized podocytes and the impact of high glucose and angiotensin II. Furthermore, alterations of the system in urine cell pellets from patients with hypertension and diabetes were studied. Apoptosis was analyzed in podocytes, and mRNA level quantification, Western blot analysis, and immunofluorescence were developed to quantify podocyte-specific molecules and Rab-Rabphilin components (Rab3A, Rab27A, and Rabphilin3A). Quantitative RT-PCR was performed on urinary cell pellet from patients. The results showed that differentiated cells had reduced protein levels of the Rab-rabphillin system compared with undifferentiated cells. After glucose overload and angiotensin II treatment, apoptosis was increased and podocyte-specific proteins were reduced. Rab3A and Rab27A protein levels were increased under glucose overload, and Rabphilin3A decreased. Furthermore, this system exhibited higher levels under stress conditions in a manner of angiotensin II dose and time treatment. Immunofluorescence imaging indicated different expression patterns of podocyte markers and Rab27A under treatments. Finally, Rab3A and Rab27A were increased in patient urine pellets and showed a direct relationship with albuminuria. Collectively, these results suggest that the Rab-Rabphilin system could be involved in the alterations observed in injured podocytes and that a mechanism may be activated to reduce damage through the vesicular transport enhancement directed by this system.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Angiotensina II/farmacologia , Glucose/efeitos adversos , Podócitos/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Albuminúria/metabolismo , Apoptose/efeitos dos fármacos , Humanos , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Transporte Vesicular/metabolismo
5.
Invest Ophthalmol Vis Sci ; 61(4): 38, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32340033

RESUMO

Purpose: To test the hypothesis that hyperglycemia perturbs neurovascular\ coupling and compromises retinal vascular response during transition from dark to light in healthy subjects using optical coherence tomography angiography (OCTA). Methods: Ten eyes of 10 healthy subjects were tested, first during fasting and then after receiving a 75-g oral glucose solution. In both sessions, OCTA imaging was done in the dark-adapted state and at 50 seconds, 2 minutes, 5 minutes, and 15 minutes of ambient light. Parafoveal vessel density (VD) and adjusted flow index (AFI) were calculated for the superficial capillary plexus (SCP), middle capillary plexus (MCP), and deep capillary plexus (DCP), and vessel length density was calculated for the SCP. These measurements were compared among conditions after adjusting for age, refractive error, and OCTA scan quality. Results: Hyperglycemia leads to a complete reversal of dark/light adaptation trends in VD and AFI in all layers of the inner retina. In the dark, there is significantly decreased VD in the DCP in hyperglycemia. With a transition to light in hyperglycemia, we observed decreased VD in the SCP, increased vessel density in the MCP and DCP, and decreased AFI in all three layers. Conclusions: Our results show that hyperglycemia significantly disrupts neurovascular coupling in healthy eyes, with potential metabolic deficits affecting photoreceptor oxygen demands during dark adaptation and the inner retina during light exposure. In pathological states, such as diabetic retinopathy, where the vasculature is already attenuated, retinal neurons may be exquisitely vulnerable to intermittent hyperglycemic challenge, which should be the focus of future studies.


Assuntos
Adaptação Ocular/fisiologia , Adaptação à Escuridão/fisiologia , Glucose/efeitos adversos , Hiperglicemia/complicações , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adulto , Estudos de Coortes , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/fisiopatologia , Feminino , Glucose/administração & dosagem , Voluntários Saudáveis , Humanos , Modelos Lineares , Masculino , Acoplamento Neurovascular , Variações Dependentes do Observador , Estudos Prospectivos , Vasos Retinianos/patologia , Medição de Risco
6.
PLoS One ; 15(4): e0231958, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32310996

RESUMO

BACKGROUND: It is reported that postoperative nausea and vomiting, common general anesthesia complications, may be prevented by perioperative intravenous dextrose administration, but with controversial clinical effectiveness. OBJECTIVE: To evaluate perioperative intravenous dextrose for preventing postoperative nausea and vomiting through a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. DATA SOURCES: MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, clinicaltrials.gov, and the University Hospital Medical Information Network Clinical Trials Registry were searched from inception until 22 June 2019. ELIGIBILITY CRITERIA: Trials investigating intravenous dextrose effects vs. placebos on postoperative nausea and vomiting in patients who underwent general anesthesia. RESULTS: Eleven trials (1,250 patients) were included. All participants were ASA1-2. The nine trials included laparoscopic surgeries, and 92.2% of the participants were women. The timing of dextrose infusion was before, during, and after surgery in three, five, and three trials, respectively. Our results revealed intravenous dextrose administration significantly reduced postoperative nausea, but not vomiting, during early and late postoperative periods (risk ratio [95% confidence interval], early nausea: 0.76 [0.59-0.99], late nausea: 0.65 [0.48-0.89]; early vomiting: 1.00 [0.81-1.25], late vomiting: 0.96 [0.43-2.16]). Evidence quality was downgraded to low because the trial sequential analysis indicated more trials are needed for firm conclusions. CONCLUSIONS: Compared with placebos, perioperative intravenous dextrose administration may decrease postoperative nausea but not vomiting. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (registration number: UMIN000030901).


Assuntos
Glucose/administração & dosagem , Náusea e Vômito Pós-Operatórios/prevenção & controle , Administração Intravenosa , Glicemia/análise , Bases de Dados Factuais , Glucose/efeitos adversos , Humanos , Risco
7.
Biol Pharm Bull ; 43(3): 558-564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115515

RESUMO

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current therapies for DKD are insufficient. Therefore, there is an urgent need for identifying new therapies. An increasing number of micro RNAs (miRNAs) and long noncoding RNAs (lncRNAs) have been demonstrated to modulate the progression of diabetic kidney disease. Nevertheless, until now, there have been few reports evaluating the relevance of circular RNAs (circRNAs) in DKD. circRNAs have been reported to regulate the occurrence and development of multiple diseases. In this study, we intended to explore the circRNA expression profiles and determine the role of circRNA in DKD. We identified a series of dysregulated circRNAs in glucose-stressed HK-2 cells using circRNA microarray analysis. Among the candidate circRNAs, we found that circACTR2 was upregulated and may be involved in inflammation and pyroptosis. Knockdown of circACTR2 significantly decreased pyroptosis, interleukin (IL)-1ß release and collagen IV and fibronectin production, indicating the effective regulation by circACTR2 of cell death and inflammation. Overall, our study identified a new circRNA, circACTR2, that regulates high glucose-induced pyroptosis, inflammation and fibrosis in proximal tubular cells. The present study preliminarily explores the role of circRNAs in pyroptosis of tubular cells, and provides novel insight into the pathogenesis of DKD and new therapeutic strategies.


Assuntos
Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Glucose/efeitos adversos , Piroptose/genética , Piroptose/fisiologia , RNA Circular/deficiência , RNA Circular/genética , Proteína 2 Relacionada a Actina , Linhagem Celular , Colágeno/metabolismo , Células Epiteliais , Fibronectinas/metabolismo , Fibrose/genética , Fibrose/metabolismo , Expressão Gênica , Humanos , Interleucina-1beta/metabolismo , Rim/metabolismo
8.
Z Naturforsch C J Biosci ; 75(3-4): 103-112, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32187019

RESUMO

The current study aimed to evaluate the in vivo hypoglycemic potential of Myristica fragrans seed extract co-administered with glimepiride in Swiss albino mice. Computational tools were used to further verify the in vivo findings and to help compare this combination to the glimepiride-pioglitazone combination in terms of the binding affinity of the ligands to their respective target protein receptors and the relative stability of the drug-protein complexes. The effect of the combined therapy was observed both in alloxan- and glucose-induced hyperglycemic Swiss albino mice. The mean fasting blood glucose level of the test groups was measured and statistically evaluated using Student's t test. The combined therapy significantly reduced the blood glucose level in a time-dependent manner compared to glimepiride alone. The binding affinity of glimepiride was found to be -7.6 kcal/mol with sulfonylurea receptor 1 in molecular docking. Conversely, macelignan-peroxisome proliferator-activated receptor (PPAR) α and macelignan-PPAR γ complexes were stabilized with -9.2 and -8.3 kcal/mol, respectively. Molecular dynamic simulation revealed that macelignan-PPAR α and γ complexes were more stable than pioglitazone complexes. The combination shows promise in animal and computer models and requires further trials to provide evidence of its activity in humans.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Lignanas/administração & dosagem , Myristica/química , Compostos de Sulfonilureia/administração & dosagem , Aloxano/efeitos adversos , Animais , Diabetes Mellitus Tipo 2/induzido quimicamente , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Glucose/efeitos adversos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Lignanas/química , Lignanas/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pioglitazona/administração & dosagem , Pioglitazona/farmacologia , Extratos Vegetais/química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Fatores de Tempo
9.
Oxid Med Cell Longev ; 2020: 6431517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215175

RESUMO

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Renal tubular epithelial cell apoptosis and tubular atrophy have been recognized as indicators of the severity and progression of DKD, while the mechanism remains elusive. Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays critical roles in apoptosis. The aim of this study was to investigate the protective role TRAP1 plays in DKD and to study the potential underlying mechanisms. TRAP1 expression was decreased, and mitochondria were injured in NRK-52e cells under high-glucose (HG) conditions. The overexpression of TRAP1 ameliorated HG-induced apoptosis, increased cell viability, maintained mitochondrial morphology, adenosine triphosphate (ATP) levels, and mitochondrial membrane potential (MMP), and buffered oxidative stress, whereas TRAP1 knockdown aggravated these effects. The protective effects of TRAP1 may be exerted via the inhibition of mitochondrial permeability transition pore (mPTP) opening, and the damage caused by TRAP1 knockdown can be partially reversed by treatment with the mPTP opening inhibitor cyclosporin A (CsA). In vivo, TRAP1 expression upregulation by AAV2/9 injection prevented renal dysfunction, ameliorated histopathological changes, maintained mitochondrial morphology and function, and reduced apoptosis and reactive oxygen species (ROS) in STZ-treated DKD rats. Thus, our results suggest that TRAP1 ameliorates diabetes-induced renal injury by preventing abnormal mPTP opening and maintaining mitochondrial structure and function, which may be treated as a potential target for DKD treatment.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Glucose/efeitos adversos , Proteínas de Choque Térmico HSP90/metabolismo , Mitocôndrias/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Linhagem Celular , Sobrevivência Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Expressão Gênica , Glucose/metabolismo , Proteínas de Choque Térmico HSP90/genética , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos , Ratos Sprague-Dawley
10.
Molecules ; 25(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019168

RESUMO

Baicalein, a widely-distributed natural flavonoid, exhibits antioxidative activity in mice with type-2 diabetes. However, the underlying mechanisms remain partially elucidated. In this study, we investigated the effect of baicalein on protein kinase R-like ER kinase (PERK)/nuclear factor erythroid-2-related factor 2 (Nrf2) pathway for the alleviation of oxidative stress and apoptosis. Human liver HL-7702 cells were stimulated with 60.5 mM of glucose to induce oxidative stress and treated with baicalein. The apoptosis was determined by fluorescence microscopy and flow cytometry. The regulation of the PERK/Nrf2 pathway by baicalein was determined by immunoblotting in both HL-7702 cells and liver tissues from diabetic mice. We found that baicalein significantly alleviated the oxidative stress and apoptosis in HL-7702 cells stimulated with glucose. Mechanistic studies showed that baicalein downregulated PERK and upregulated Nrf2, two key proteins involved in endoplasmic reticulum stress, in both HL-7702 cells and liver tissues from diabetic mice receiving baicalein treatment. Furthermore, the subcellular localization of Nrf2 and the regulation of downstream proteins including heme oxygenase-1 and CCAAT-enhancer-binding protein homologous protein (CHOP) by baicalein were also investigated. Our results suggest that the regulation of the PERK/Nrf2 pathway is one of the mechanisms contributing to the bioactivities of baicalein to improve diabetes-associated complications.


Assuntos
Apoptose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavanonas/farmacologia , Glucose/efeitos adversos , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , eIF-2 Quinase/metabolismo , Animais , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Edulcorantes/efeitos adversos , eIF-2 Quinase/genética
11.
Sci Rep ; 10(1): 2961, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076013

RESUMO

Sucrose has long been regarded as the most cariogenic carbohydrate. However, why sucrose causes severer dental caries than other sugars is largely unknown. Considering that caries is a polymicrobial infection resulting from dysbiosis of oral biofilms, we hypothesized that sucrose can introduce a microbiota imbalance favoring caries to a greater degree than other sugars. To test this hypothesis, an in vitro saliva-derived multispecies biofilm model was established, and by comparing caries lesions on enamel blocks cocultured with biofilms treated with sucrose, glucose and lactose, we confirmed that this model can reproduce the in vivo finding that sucrose has the strongest cariogenic potential. In parallel, compared to a control treatment, sucrose treatment led to significant changes within the microbial structure and assembly of oral microflora, while no significant difference was detected between the lactose/glucose treatment group and the control. Specifically, sucrose supplementation disrupted the homeostasis between acid-producing and alkali-producing bacteria. Consistent with microbial dysbiosis, we observed the most significant disequilibrium between acid and alkali metabolism in sucrose-treated biofilms. Taken together, our data indicate that the cariogenicity of sugars is closely related to their ability to regulate the oral microecology. These findings advance our understanding of caries etiology from an ecological perspective.


Assuntos
Biofilmes/efeitos dos fármacos , Cárie Dentária/microbiologia , Disbiose/induzido quimicamente , Microbiota/efeitos dos fármacos , Sacarose/efeitos adversos , Adulto , Contagem de Colônia Microbiana , Esmalte Dentário/microbiologia , Glucose/efeitos adversos , Humanos , Concentração de Íons de Hidrogênio , Lactose/efeitos adversos , Saliva/microbiologia
12.
Trials ; 21(1): 62, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924234

RESUMO

BACKGROUND: Organ preservation before transplantation is still a challenge. Both the University of Wisconsin and Bretschneider's histidine-tryptophan-ketoglutarate (HTK; Custodiol®) solution are standard for liver, kidney and pancreas preservation. Organ preservation with both solutions is comparable; recently, however, Custodiol® solution has been modified to Custodiol-N according to the needs of today. Thus, our study was defined to study its effect in clinical transplantation. METHODS: Patients undergoing kidney transplantation (n = 412) (including approximately 30 combined kidney-pancreas) or liver transplantation (n = 202) receive grafts that have been cold stored in either Custodiol® or Custodiol-N to demonstrate noninferiority of Custodiol-N regarding both graft function and graft injury after transplantation. DISCUSSION: Preclinical data have clearly shown that Custodiol-N is superior to Custodiol® in cold static organ preservation via mechanisms including inhibition of hypoxic cell injury, cold-induced cell injury and avoidance of adverse effects during warm exposure to the solution. Further clinical safety data on Custodiol-N for cardioplegia are available. Thus, this study was designed to compare Custodiol® with Custodiol-N for the first time in a prospective, randomized, single-blinded, multicentre, phase III clinical transplantation trial. TRIAL REGISTRATION: Eudra-CT, 2017-002198-20. Registered on 28 November 2018.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Rim , Transplante de Fígado , Soluções para Preservação de Órgãos/uso terapêutico , Preservação de Órgãos , Transplante de Pâncreas , Coleta de Tecidos e Órgãos , Áustria , Ensaios Clínicos Fase III como Assunto , Glucose/efeitos adversos , Glucose/uso terapêutico , Humanos , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Manitol/efeitos adversos , Manitol/uso terapêutico , Estudos Multicêntricos como Assunto , Preservação de Órgãos/efeitos adversos , Soluções para Preservação de Órgãos/efeitos adversos , Transplante de Pâncreas/efeitos adversos , Cloreto de Potássio/efeitos adversos , Cloreto de Potássio/uso terapêutico , Procaína/efeitos adversos , Procaína/uso terapêutico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Fatores de Tempo , Coleta de Tecidos e Órgãos/efeitos adversos , Resultado do Tratamento
13.
Phytomedicine ; 66: 153107, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790903

RESUMO

BACKGROUND: Gomisin A is a lignan isolated from the hexane of Schisandra chinensis fruit extract with antioxidant properties. Oxidative stress mediated by high glucose is one of the major complications of diabetes mellitus. PURPOSE: This study investigates the role of gomisin A in osteoblast differentiation under high glucose-induced oxidative stress in MC3T3 E1 cells and determines its relationship with heme oxygenase-1 (HO-1) and mitochondrial biogenesis. METHODS: MC3T3 E1 cells were treated by gomisin A following induced by high glucose levels and glucose oxidase to investigate the inhibitory effect of gomisin A against high glucose oxidative stress. Western blot analysis, alizarin red staining, alkaline phosphatase (ALP) activity, analysis of reactive oxygen species (ROS) and confocal microscopy were used to determine mitochondrial biogenesis, oxidative stress, osteoblast differentiation and mineralization. To analyze the role of HO-1, the MC3T3 E1 cells were treated with the HO-1 inhibitor zinc protoporphyrin IX (ZnPP). RESULTS: Gomisin A enhanced the expression of HO-1, increased mitochondrial biogenesis factors (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A), antioxidant enzymes (copper-zinc superoxide dismutases and manganese superoxide dismutase), osteoblast differentiation molecules (bone morphogenic protein-2/7, osteoprotegerin and Runt-related transcription factor-2) and mineralization by upregulation of ALP and alizarin red staining, which were decreased by ZnPP and high glucose oxidative stress. Similarly, gomisin A inhibited ROS which was increased by ZnPP and the high glucose-mediated oxidative stress. CONCLUSIONS: The findings demonstrated the antioxidative effects of gomisin A, and its role in mitochondrial biogenesis and osteoblast differentiation. It potentially regulated osteoblast differentiation under high glucose-induced oxidative stress via upregulation of HO-1 and maintenance of mitochondrial homeostasis. Thus, gomisin A may represent a potential therapeutic agent for prevention of bone fragility fractures and implant failure triggered by diabetes.


Assuntos
Antioxidantes/farmacologia , Ciclo-Octanos/farmacologia , Diabetes Mellitus/tratamento farmacológico , Dioxóis/farmacologia , Glucose/efeitos adversos , Lignanas/farmacologia , Osteogênese/efeitos dos fármacos , Schisandra/química , Animais , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Heme Oxigenase-1/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Biogênese de Organelas , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Protoporfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
14.
Mol Cell Endocrinol ; 500: 110641, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31711985

RESUMO

Endothelial cells (ECs) primarily rely on glycolysis for their energy metabolism, and the final product of glycolysis-lactate-is transferred out of cells via monocarboxylate transporter 4 (MCT4). We previously showed that MCT4 downregulation is involved in diabetic endothelial injury. However, the underlying regulatory mechanisms of MCT4 in diabetes remain unclear. This study showed that miR-425-5p was significantly upregulated in diabetic patients and human umbilical vein endothelial cells (HUVECs) treated with high glucose (HG) and interleukin-1ß (IL-1ß). MCT4 was shown to be a direct target gene of miR-425-5p, and miR-425-5p expression led to MCT4 downregulation, lactate accumulation and increased apoptosis in HUVECs. Furthermore, the results indicated that NF-κB signaling activation increased miR-425-5p levels and induced MCT4 downregulation, lactate accumulation and apoptosis in HUVECs. In conclusion, NF-κB/miR-425-5p/MCT4 axis activation plays a crucial role in the EC injury induced by HG and IL-1ß.


Assuntos
Diabetes Mellitus/genética , Células Endoteliais da Veia Umbilical Humana/citologia , MicroRNAs/genética , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , NF-kappa B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Regulação para Baixo , Glucose/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-1beta/efeitos adversos , Ácido Láctico/metabolismo , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos
15.
Curr Med Sci ; 39(6): 938-946, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31845225

RESUMO

Diabetic cardiomyopathy (DCM) is one of the major heart complications of diabetic patients. Hydrogen sulfide (H2S) is now recognized as an important signaling molecule and has been shown to attenuate the development of diabetic cardiomyopathy. However, the underlying mechanisms linking H2S and the development of DCM have not been fully elucidated. In the present study, we therefore sought to explore the role and mechanism of H2S in the pathogenesis of DCM by establishing high glucose-induced injury model in neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Using cystathionine gamma-lyase (CSE) overexpression and CSE interference vectors transfection, the cell viability, cell apoptosis. and oxidative stress were determined and compared between the treatment of high glucose induction and exgenous NaHS administration. Meanwhile, the relationship between the CSE/H2S system and Wnt/beta-catenin pathway was analyzed and discussed in the high glucose-induced cardiomyocytes. Our results indicated that H2S played an important protective role in high glucose-induced apoptosis and oxidative stress in cardiomyocytes, as shown by the decreased reactive oxygen species and malondialdehyde levels, and the increased activities of superoxide dismutase, catalase and glutathione peroxidase. Moreover, H2S could attenuate the Wnt/ß-catenin signalling pathway and up-regulate the expression of haem oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the diabetic myocardium cells. Together, these results demonstrated that H2S could attenuate high glucose-induced myocardial injury in rat cardiomyocytes by suppressing Wnt/ß-catenin pathway.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Glucose/efeitos adversos , Sulfeto de Hidrogênio/administração & dosagem , Miócitos Cardíacos/citologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Cardiomiopatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Sulfeto de Hidrogênio/farmacologia , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos
16.
Mediators Inflamm ; 2019: 5648051, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885497

RESUMO

Background: Single-dose cardioplegia is preferred in minimal invasive mitral valve surgery to maintain the adjustment of the operative site without change of preset visualization. The aim of our study was to compare two widely used crystalloid cardioplegias Bretschneider (Custodiol®) versus St. Thomas 2 in patients who underwent mitral valve repair via small anterolateral right thoracotomy. Material and Methods: From May 2012 until February 2019, 184 isolated mitral valve procedures for mitral valve repair via anterolateral right thoracotomy were performed using Bretschneider (Custodiol®) cardioplegia (n = 123) or St. Thomas (n = 61). Primary efficacy endpoint was peak postoperative high-sensitivity cardiac troponin (hs-cTnT) during hospitalization. Secondary endpoints were peak creatine kinase-muscle brain type (CK-MB) and creatine kinase (CK) as well as safety outcomes. We used inverse probability of treatment weighting (IPTW) in order to adjust for confounding by indication. Results: Peak hs-cTnT was higher after use of Bretschneider (Custodiol®) (geometric mean 716 mg/L, 95% confidence interval (CI) 605-847 mg/L) vs. St. Thomas 2 (561 mg/L, CI 467-674 mg/L, p = 0.047). Peak CK-MB (geometric mean after Bretschneider (Custodiol®): 40 µg/L, CI 35-46, St. Thomas 2: 33 µg/L, CI 27-41, p = 0.295) and CK (geometric mean after Bretschneider (Custodiol®): 1370 U/L, CI 1222-1536, St. Thomas 2: 1152 U/L, CI 972-1366, p = 0.037) showed the same pattern. We did not see any difference with respect to postoperative complications between treatment groups after IPTW. Conclusion: Use of St. Thomas 2 cardioplegia was associated with lower postoperative peak levels of all cardiac markers that reflect cardiac ischemia such as hs-cTnT, CK, and CK-MB as compared to Bretschneider (Custodiol®) in propensity-weighted treatment groups.


Assuntos
Soluções Cardioplégicas/uso terapêutico , Valva Mitral/efeitos dos fármacos , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Soluções Cardioplégicas/efeitos adversos , Intervalos de Confiança , Feminino , Glucose/efeitos adversos , Glucose/uso terapêutico , Coração/efeitos dos fármacos , Humanos , Masculino , Manitol/efeitos adversos , Manitol/uso terapêutico , Pessoa de Meia-Idade , Valva Mitral/metabolismo , Valva Mitral/cirurgia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/prevenção & controle , Miocárdio/metabolismo , Cloreto de Potássio/efeitos adversos , Cloreto de Potássio/uso terapêutico , Procaína/efeitos adversos , Procaína/uso terapêutico , Toracotomia/métodos
17.
Artif Cells Nanomed Biotechnol ; 47(1): 4172-4181, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713440

RESUMO

Diabetic cardiomyopathy (DCM) is an important cardiac disorder in patients with diabetes. High glucose (HG) levels lead to inflammation of cardiomyocytes, oxidative stress, and long-term activation of autophagy, resulting in myocardial fibrosis and remodelling. Astragaloside-IV (AS-IV) has a wide range of pharmacological effects. This study aimed to investigate the effects of AS-IV on injury induced by HG in rat cardiomyocytes (H9C2(2-1)) and the involvement of the miR-34a-mediated autophagy pathway. An AS-IV concentration of 100 µM was selected based on H9C2(2-1) cell viability using the cell counting kit-8 (CCK-8). We found that 33 mM HG induced a morphologic change in cells and caused excessive oxidative stress, whereas AS-IV inhibited lipid peroxidation and increased superoxide dismutase activity. In terms of mRNA expression, HG increased miR-34a and inhibited Bcl2 and Sirt1, whereas AS-IV and miR-34a-inhibitor reversed the above effects. Further, LC3-GFP adenovirus infection and western blotting showed that HG increased autophagy, which was reversed synergistically by AS-IV and miR-34a-inhibitor. Bcl2 and pAKT/AKT protein expressions in the HG group was significantly lower than that in controls, but AS-IV and miR-34a-inhibitor antagonized the process. Thus, AS-IV inhibits HG-induced oxidative stress and autophagy and protects cardiomyocytes from injury via the miR-34a/Bcl2/(LC3II/LC3I) and pAKT/Bcl2/(LC3II/LC3I) pathways.


Assuntos
Autofagia/efeitos dos fármacos , Autofagia/genética , Glucose/efeitos adversos , MicroRNAs/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Relação Dose-Resposta a Droga , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos
18.
Mol Med Rep ; 20(6): 5125-5133, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702814

RESUMO

Diabetic retinopathy is a major complication of diabetes. Increasing evidence has indicated that microRNAs (miRs) serves an important role in diabetic retinopathy. However, the expression and mechanism of miR­217 in high glucose­induced human retinal pigment epithelial cells ARPE­19 is still unclear. Therefore, the aim of this study was to investigate the role of miR­217 in high glucose­induced retinal epithelial cell damage, and further to explore the molecular mechanisms. In our study, we found that compared with control group, miR­217 was upregulated in high glucose­induced ARPE­19 cells. In addition, TargetScan and a dual­luciferase reporter gene assay showed that Sirtuin 1 (SIRT1) was a direct target of miR­217. Then, we performed reverse transcription­quantitative polymerase chain reaction assay and western blot assay to explore the expression of SIRT1 in high glucose­induced ARPE­19 cells. Our results demonstrated that SIRT1 was downregulated at the mRNA and protein levels in high glucose­induced ARPE­19 cells. Then, ARPE­19 cells were transfected with inhibitor control, miR­217 inhibitor or miR­217 inhibitor + SIRT1­small interfering RNA for 6 h, and then the cells were treated with 50 mM D­glucose for 24 h. We then investigated the effects of miR­217 inhibitor on ARPE­19 cell viability and apoptosis. An MTT assay revealed that miR­217 inhibitor significantly increased the viability and decreased the apoptosis of high glucose­induced ARPE­19 cells. ELISA indicated that miR­217 inhibitor significantly reduced the expression of inflammatory factors, such as interleukin (IL)­1ß, tumor necrosis factor­α, and IL­6 in high glucose­treated ARPE­19 cells. Additionally, a western blot assay demonstrated that miR­217 inhibitor suppressed the expression of p­p65. The effects of miR­217 inhibitor on high glucose­treated ARPE­19 cells were significantly reversed by the silencing the SIRT1 gene. Therefore, our findings suggested that miR­217 inhibitor protected against retinal epithelial cell damage caused by high glucose via targeting SIRT1, thereby playing a protective role in diabetic retinopathy. Targeting miR­217 may have therapeutic potential in the treatment of diabetic retinopathy.


Assuntos
Apoptose/efeitos dos fármacos , Glucose/efeitos adversos , Inflamação/metabolismo , MicroRNAs/metabolismo , MicroRNAs/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Retinopatia Diabética/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Nutrients ; 11(11)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31684006

RESUMO

Aralia elata (Miq.) Seem (AS) is widely been for treating many diseases, enhancing energy, and boosting immunity; however, its protective effects against high-glucose (HG)-triggered endothelial dysfunction and the potential underlying mechanisms have not been investigated. In this study, we determined the effect of AS on senescence in human umbilical vein endothelial cells (HUVECs) and elucidated the mechanisms underlying its anti-aging effects. The senescence model of endothelial cells (ECs) was established by culturing HUVECs in media containing HG (30 mM). We found that the proportion of senescent (senescence-associated ß-galactosidase+) cells in the HG group was significantly higher than that in the control group; however, this increase was suppressed by AS treatment. Moreover, cell cycle analysis revealed that AS (20 µg/mL) significantly recovered HG-induced cell cycle arrest in ECs, and Western blot revealed that AS prevented HG-induced decreases in silent information regulator 1 (SIRT1) level and endothelial nitric oxide synthase (eNOS) phosphorylation. These results show that AS delayed HG-induced senescence in ECs by modulation of the SIRT1/5' AMP-activated protein kinase and AKT/eNOS pathways.


Assuntos
Aralia/química , Senescência Celular/efeitos dos fármacos , Glucose/efeitos adversos , Extratos Vegetais/farmacologia , Sirtuína 1/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos
20.
Can J Physiol Pharmacol ; 97(12): 1141-1151, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638409

RESUMO

Diabetes induces vascular endothelial damage and this study investigated high-glucose-induced inflammation "metabolic memory" of human retinal vascular endothelial cells (HRVECs), the effects of resveratrol on HRVECs, and the underlying signaling. HRVECs were grown under various conditions and assayed for levels of sirtuin 1 (SIRT1); acetylated nuclear factor κB (Ac-NF-κB); NOD-like receptor family, pyrin domain containing 3 (NLRP3); and other inflammatory cytokines; and cell viability. A high glucose concentration induced HRVEC inflammation metabolic memory by decreasing SIRT1 and increasing Ac-NF-κB, NLRP3, caspase 1, interleukin-1ß, inducible nitric oxide synthase, and tumor necrosis factor α, whereas exposure of HRVECs to a high glucose medium for 4 days, followed by a normal glucose concentration for an additional 4 days, failed to reverse these changes. A high glucose concentration also significantly reduced HRVEC viability. In contrast, resveratrol, a selective SIRT1 activator, markedly enhanced HRVEC viability and reduced the inflammatory cytokines expressions. In addition, high glucose reduced AMP-activated protein kinase (AMPK) phosphorylation and retained during the 4 days of the reversal period of culture. The effects of resveratrol were abrogated after co-treatment with the SIRT1 inhibitor nicotinamide and the AMPK inhibitor compound C. In conclusion, resveratrol was able to reverse high-glucose-induced inflammation "metabolic memory" of HRVECs by activation of the SIRT1/AMPK/NF-κB pathway.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucose/efeitos adversos , Resveratrol/farmacologia , Retina/citologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais/patologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia
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