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1.
Medicine (Baltimore) ; 99(37): e21663, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925713

RESUMO

BACKGROUND: The incidence of heart failure with normal ejection fraction (HFNEF) is increasing yearly, accounting for approximately half of all heart failure cases. Even after standardized treatment, the patient's prognosis is not good. Therefore, it is necessary to explore new treatment methods for HFNEF. Yangyin Shuxin Decoction, a traditional Chinese medicine prescription from our clinical experience in the treatment of HFNEF, has a potential cardioprotective effect. Preliminary clinical trials have shown that this prescription can improve the quality of life of HFNEF. This prompted us to use more objective indicators to further evaluate whether Yangyin Shuxin Decoction can improve the exercise capacity in HENEF patients. METHODS: This is a single-center parallel randomized controlled trial. The 64 patients who met the inclusion criteria were from the Cardiovascular Clinic. They will be randomly assigned to the treatment group (Yangying Shuxin Decoction combined with standard treatment) or the control group (standard treatment) according to the ratio of 1:1. The course of treatment will be 2 weeks. Both groups were interviewed at the following time points: of at enrollment (V1), and week 2 (V2), week 4 (V3), week 8 (V4), and week 12 (V5) after enrollment. The primary indicator is the peak oxygen consumption (Peak VO2) of the cardiopulmonary exercise test (CPET). Secondary indicators include CPET indicators such as anaerobic threshold oxygen consumption, carbon dioxide ventilation equivalent slope, echocardiographic indicators such as the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity(E/e'), left atrial volume index (LAVI), left ventricular mass index (LVMI), the peak velocity of tricuspid regurgitation (TR), B-type natriuretic peptide (BNP), New York Heart Association (NYHA) cardiac function grading, and so on. These indicators will be used to evaluate the effect of Yangyin Shuxin Decoction on exercise capacity in patients with HFNEF. DISCUSSION: At present, it is unclear whether the exercise capacity can be maintained after long-term use of Yangyin Shuxin Decoction. In this study, we will evaluate whether Yangyin Shuxin Decoction can improve the exercise capacity and quality of life of patients with HFNEF. This will provide an objective basis for the therapeutic effect of traditional Chinese medicine on HFNEF. TRIAL REGISTRATION: This study protocol has been listed in the Chinese Clinical Trial Registry (registration number: ChiCTR-IOR-17014206, http://www.chictr.org.cn/showproj.aspx?proj=24304) on December 28, 2017.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/fisiologia , Adulto , Idoso , Ecocardiografia , Teste de Esforço , Tolerância ao Exercício , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome , Resultado do Tratamento
2.
Aquat Toxicol ; 226: 105563, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32673887

RESUMO

Climate warming and nitrate pollution are pervasive aquatic stressors that endanger the persistence of fishes prevailing in anthropogenically disturbed habitats. Individually, elevated nitrate and temperature can influence fish energy homeostasis by increasing maintenance costs and impairing oxygen transport capacity. However, it remains unknown how fish respond to simultaneous exposure to elevated temperature and nitrate pollution. Hence, we examined the combined effects of nitrate and elevated temperatures on aerobic scope (AS, maximum-standard metabolic rates) and cardiorespiratory attributes (haemoglobin HB, haematocrit HCT, relative ventricle mass RVM, and somatic spleen index SSI) in a freshwater salmonid, Thymallus thymallus. A 3 × 2 factorial design was used, where fish were exposed to one of three ecologically relevant levels of nitrate (0, 50, or 200 mg NO3- l-1) and one of two temperatures (18 °C or 22 °C) for 6 weeks. Elevated temperature increased AS by 36 % and the improvement was stronger when coupled with nitrate exposure, indicating a positive synergistic interaction. HB was reduced by nitrate exposure, while HCT was independent of nitrate pollution and temperature. Stressor exposure induced remodeling of key elements of the cardiorespiratory system. RVM was 39 % higher in fish exposed to 22 °C compared to 18 °C but was independent of nitrate exposure. SSI was independent of temperature but was 85 % and 57 % higher in fish exposed to 50 and 200 mg NO3- l-1, respectively. Taken together, these results highlight that simultaneous exposure to elevated temperatures and nitrate pollution offers cross-tolerance benefits, which may be underscored by cardiorespiratory remodeling.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Água Doce/química , Temperatura Alta , Nitratos/toxicidade , Salmonidae/metabolismo , Poluentes Químicos da Água/toxicidade , Aclimatação/efeitos dos fármacos , Animais , Ecossistema , Eutrofização , Hematócrito , Consumo de Oxigênio/efeitos dos fármacos , Salmonidae/sangue
3.
Anesthesiology ; 133(2): 304-317, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32482999

RESUMO

BACKGROUND: Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the effects of phenylephrine and ephedrine on cerebral blood flow and cerebral metabolic rate of oxygen in brain tumor patients. The authors hypothesized that phenylephrine reduces cerebral metabolic rate of oxygen in selected brain regions compared with ephedrine. METHODS: In this double-blinded, randomized clinical trial, 24 anesthetized patients with brain tumors were randomly assigned to ephedrine or phenylephrine treatment. Positron emission tomography measurements of cerebral blood flow and cerebral metabolic rate of oxygen in peritumoral and normal contralateral regions were performed before and during vasopressor infusion. The primary endpoint was between-group difference in cerebral metabolic rate of oxygen. Secondary endpoints included changes in cerebral blood flow, oxygen extraction fraction, and regional cerebral oxygen saturation. RESULTS: Peritumoral mean ± SD cerebral metabolic rate of oxygen values before and after vasopressor (ephedrine, 67.0 ± 11.3 and 67.8 ± 25.7 µmol · 100 g · min; phenylephrine, 68.2 ± 15.2 and 67.6 ± 18.0 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 1.5 [-13.3 to 16.3] µmol · 100 g · min [P = 0.839]). Corresponding contralateral hemisphere cerebral metabolic rate of oxygen values (ephedrine, 90.8 ± 15.9 and 94.6 ± 16.9 µmol · 100 g · min; phenylephrine, 100.8 ± 20.7 and 96.4 ± 17.7 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 8.2 [-2.0 to 18.5] µmol · 100 g · min [P = 0.118]). Ephedrine significantly increased cerebral blood flow (difference [95% CI], 3.9 [0.7 to 7.0] ml · 100 g · min [P = 0.019]) and regional cerebral oxygen saturation (difference [95% CI], 4 [1 to 8]% [P = 0.024]) in the contralateral hemisphere compared to phenylephrine. The change in oxygen extraction fraction in both regions (peritumoral difference [95% CI], -0.6 [-14.7 to 13.6]% [P = 0.934]; contralateral hemisphere difference [95% CI], -0.1 [- 12.1 to 12.0]% [P = 0.989]) were comparable between groups. CONCLUSIONS: The cerebral metabolic rate of oxygen changes in peritumoral and normal contralateral regions were similar between ephedrine- and phenylephrine-treated patients. In the normal contralateral region, ephedrine was associated with an increase in cerebral blood flow and regional cerebral oxygen saturation compared with phenylephrine.


Assuntos
Anestesia/tendências , Neoplasias Encefálicas/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Efedrina/uso terapêutico , Consumo de Oxigênio/efeitos dos fármacos , Fenilefrina/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Circulação Cerebrovascular/fisiologia , Método Duplo-Cego , Efedrina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Fenilefrina/farmacologia , Estudos Prospectivos , Resultado do Tratamento , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico
5.
PLoS One ; 15(5): e0232759, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453737

RESUMO

SUMMARY: Reprogramming autologous adult cells to pluripotent cells allows for relatively safe cell replacement therapy. This can be achieved by nuclear transfer, cell fusion, or induced pluripotent stem cell technology However, the epigenetic memory of the cell is considered as a great challenge facing the complete reprograming of cells by these methods. Introducing oocyte-specific factors into differentiated cells may present a promising approach by mimicking cellular reprogramming during fertilization. METHODS: Human bone marrow mesenchymal stromal cells (hBM-MSCs) were cultured with different concentrations of human metaphase II (M II) oocyte extract (0.1, 1, 5, 10, 30 ng/µl). Reprogramming was assessed at various exposure times (1, 4, 7 days). Cells were tested for their proliferation rate, morphological changes, expression of pluripotency markers, expression of mesenchymal to epithelial transition markers, and mitochondrial rejuvenation. (mitochondrial localization, morphological changes, bioenergetics, transmembrane potential, and levels of reactive oxygen species, ROS). RESULTS: Treatment of human BM-MSCs with 10 ng/µl oocyte extract resulted in increased cell proliferation, which was associated with the upregulation of the pluripotency genes OCT-4, NANOG, and SOX-2 and a concomitant downregulation of mesenchymal-specific genes. MSCs exhibited small, immature round mitochondria with few swollen cristae localized proximal to the cell nucleus. This was accompanied by morphological cell changes, a metabolic shift towards oxidative phosphorylation, a high mitochondrial membrane potential, and increased ROS production. CONCLUSION: These data show that treatment with 10 ng/µl human MII-phase oocyte extract induced genetic and mitochondrial reprogramming of human BM-MSCs to a more embryonic phenotype.


Assuntos
Extratos Celulares/farmacologia , Reprogramação Celular/genética , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias/metabolismo , Oócitos/metabolismo , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Células Cultivadas , Reprogramação Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Potenciais da Membrana/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Oócitos/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fatores de Tempo
6.
J Vasc Res ; 57(4): 178-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32434183

RESUMO

BACKGROUND: Lysophosphatidic acid (LPA) is a small phospholipid-signaling molecule, which can alter responses to stress in the central nervous system. OBJECTIVE: We hypothesized that exogenous LPA would increase the size of infarct and reduce microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. METHODS: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without LPA (1 mg/kg, at 30, 60, and 90 min after reperfusion). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small-vessel (20-60 µm in diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. RESULTS: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O2 saturation (43 of 80 veins with O2 saturation below 50%). LPA did not significantly alter cerebral blood flow, but it did significantly increase O2 extraction and consumption of the ischemic-reperfused region. It also significantly increased the number of small veins with low O2 saturations in the reperfused region (76 of 80 veins with O2 saturation below 50%). This was associated with a significantly increased cortical infarct size after LPA administration (11.4 ± 0.5% control vs. 16.4 ± 0.6% LPA). CONCLUSION: This suggests that LPA reduces cell survival and that it is associated with an increase in the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.


Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Lisofosfolipídeos/toxicidade , Microcirculação/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/sangue , Traumatismo por Reperfusão/patologia , Animais , Morte Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Veias Cerebrais/efeitos dos fármacos , Veias Cerebrais/patologia , Veias Cerebrais/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/fisiopatologia
7.
Diabetes Metab Syndr ; 14(4): 405-406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32335366

RESUMO

It has been reported that frequent occurrence of COVID-19 infection in these patients is associated with low cytosolic pH. During virus infection, serum lactate dehydrogenase (LDH) level excessively rises. LDH is a cytosolic enzyme and the serum level increases as the cell break down. When anaerobic conditions develop, lactate formation increases from pyruvate. Cell pH is regulated by very complex mechanisms. When lactate increases in the extracellular area, this symporter carries lactate and H+ ion into the cell, and the intracellular pH quickly becomes acidic. Paradoxically, Na+/H+ exchanger activation takes place. While H+ ion is thrown out of the cell, Na+ and Ca+2 enter the cell. When Na+ and Ca+2 increase in the cell, the cells swell and die. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor. Dapagliflozin has been reported to reduce lactate levels by various mechanisms. Also, it reduces oxygen consumption in tissues and causes the use of glucose in the aerobic pathway, thereby reducing lactate production. A lactate decrease in the environment reduces the activation of lactate/H+ symporter. Thus, the H ion pumping into the cell by this symporter is reduced and the cytosolic pH is maintained. Dapagliflozin also directly inhibits NHE. Thus, Na+ and Ca+2 flow to the cell are inhibited. Dapagliflozin provides the continuation of the structure and functions of the cells. Dapagliflozin can prevent the severe course of COVID-19 infection by preventing the lowering of cytosolic pH and reducing the viral load.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Diabetes Mellitus/tratamento farmacológico , Glucosídeos/uso terapêutico , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Comorbidade , Infecções por Coronavirus/epidemiologia , Desidratação/prevenção & controle , Diabetes Mellitus/epidemiologia , Humanos , Insulina/uso terapêutico , Ácido Láctico/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Pneumonia Viral/epidemiologia
8.
Metabolism ; 107: 154227, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32275974

RESUMO

OBJECTIVE: L5, a highly electronegative subtype of low-density lipoprotein (LDL), is likely associated with the development of atherosclerosis and cardiovascular diseases. Normal LDL is composed mainly of apolipoprotein (Apo) B, but L5 has additional proteins such as ApoE. We previously demonstrated that L5 induces endothelial cell senescence by increasing mitochondrial reactive oxygen species. In the present study, we examined the effect of L5 on mitochondrial function in cardiomyocytes. METHODS: We used the Seahorse XF24 extracellular flux analyzer to examine the effect of L5 and its components on mitochondrial energy production. The effects of L5 on mitochondrial morphology were examined by immunofluorescence using MitoTracker Green FM and the corresponding probes in H9c2 cardiomyoblasts. Mitochondrial permeability was assessed by using a calcium-induced swelling assay with a voltage-dependent anion-selective channel (VDAC) inhibitor to determine VDAC-dependence both in vitro and in vivo. L5 without ApoE, referred to as △L5, was used to clarify the role of ApoE in L5-induced mitochondrial dysfunction. RESULTS: L5 not only significantly decreased basal (P < 0.05) and maximal respiration (P < 0.01) but also reduced spare respiratory capacity (P < 0.01) in H9c2 cells. Additionally, L5 caused phosphorylation of Drp1 and mitochondrial fission. Recombinant ApoE mimicked the mitochondrial effects of L5, but △L5 did not cause similar effects. After entering cells, ApoE on L5 colocalized with mitochondrial VDAC and caused mitochondria swelling both in vitro and in vivo. This effect was also seen with recombinant ApoE but not △L5. CONCLUSIONS: ApoE may play an important role in electronegative LDL-induced mitochondrial dysfunction through the opening of the mitochondrial permeability transition pore via the interaction of ApoE and VDAC.


Assuntos
Apolipoproteínas E/metabolismo , Lipoproteínas LDL/farmacologia , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Humanos , Técnicas In Vitro , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Espécies Reativas de Oxigênio
9.
Metabolism ; 107: 154228, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32289346

RESUMO

OBJECTIVE: Mangiferin (MF), a xanthonoid derived from Mangifera indica, has shown therapeutic effects on various human diseases including cancer, diabetes, and obesity. Nonetheless, the influence of MF on non-shivering thermogenesis and its underlying mechanism in browning remains unclear. Here, our aim was to investigate the effects of MF on browning and its molecular mechanisms in murine C3H10T1/2 mesenchymal stem cells (MSCs). MATERIALS/METHODS: To determine the function of MF on browning, murine C3H10T1/2 MSCs were treated with MF in an adipogenic differentiation cocktail and the thermogenic and correlated metabolic responses were assessed using MF-mediated signalling. Human adipose-derived MSCs were differentiated and treated with MF to confirm its role in thermogenic induction. RESULTS: MF treatment induced the expression of a brown-fat signature, UCP1, and reduced triglyceride (TG) in C3H10T1/2 MSCs. MF also induced the expression of major thermogenesis regulators: PGC1α, PRDM16, and PPARγ and up-regulated the expression of beiging markers CD137, HSPB7, TBX1, and COX2 in both murine C3H10T1/2 MSCs and human adipose-derived mesenchymal stem cells (hADMSC). We also observed that MF treatment increased the mitochondrial DNA and improved mitochondrial homeostasis by regulating mitofission-fusion plasticity via suppressing PINK1-PRKN-mediated mitophagy. Furthermore, MF treatment improved mitochondrial respiratory function by increasing mitochondrial oxygen consumption and expression of oxidative-phosphorylation (OXPHOS)-related proteins. Chemical-inhibition and gene knockdown experiments revealed that ß3-AR-dependent PKA-p38 MAPK-CREB signalling is crucial for MF-mediated brown-fat formation via suppression of mitophagy in C3H10T1/2 MSCs. CONCLUSIONS: MF promotes the brown adipocyte phenotype by suppressing mitophagy, which is regulated by PKA-p38MAPK-CREB signalling in C3H10T1/2 MSCs. Thus, we propose that MF may be a good browning inducer that can ameliorate obesity.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Mitofagia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Xantonas/farmacologia , Adipócitos Marrons/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C3H , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Proteínas Quinases/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Termogênese/genética , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos
10.
Am J Physiol Renal Physiol ; 318(5): F1271-F1283, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32281418

RESUMO

PEGylated carboxyhemoglobin (PEGHbCO), which has carbon monoxide-releasing properties and plasma expansion and oxygen-carrying properties, may improve both skeletal microcirculatory flow and renal cortical microcirculatory Po2 (CµPo2) and, subsequently, limit endotoxemia-induced acute kidney injury. Anesthetized, ventilated Wistar albino rats (n = 44) underwent endotoxemic shock. CµPo2 was measured in exposed kidneys using a phosphorescence-quenching method. Rats were randomly assigned to the following five groups: 1) unresuscitated lipopolysaccharide (LPS), 2) LPS + Ringer's acetate (RA), 3) LPS + RA + 0.5 µg·kg·-1min-1 norepinephrine (NE), 4) LPS + RA + 320 mg/kg PEGHbCO, and 5) LPS + RA + PEGHbCO + NE. The total volume was 30 mL/kg in each group. A time control animal group was used. Skeletal muscle microcirculation was assessed by handheld intravital microscopy. Kidney immunohistochemistry and myeloperoxidase-stained leukocytes in glomerular and peritubular areas were analyzed. Endotoxemia-induced histological damage was assessed. Plasma levels of IL-6, heme oxygenase-1, malondialdehyde, and syndecan-1 were assessed by ELISA. CµPo2 was higher in the LPS + RA + PEGHbCO-resuscitated group, at 35 ± 6mmHg compared with 21 ± 12 mmHg for the LPS+RA group [mean difference: -13.53, 95% confidence interval: (-26.35; -0.7156), P = 0.035]. The number of nonflowing, intermittent, or sluggish capillaries was smaller in groups infused with PEGHbCO compared with RA alone (P < 0.05), while the number of normally perfused vessels was greater (P < 0.05). The addition of NE did not further improve CµPo2 or microcirculatory parameters. Endotoxemia-induced kidney immunohistochemistry and histological alterations were not mitigated by PEGHbCO 1 h after resuscitation. Renal leukocyte infiltration and plasma levels of biomarkers were similar across groups. PEGHbCO enhanced CµPo2 while restoring skeletal muscle microcirculatory flow in previously nonflowing capillaries. PEGHbCO should be further evaluated as a resuscitation fluid in mid- to long-term models of sepsis-induced acute kidney injury.


Assuntos
Lesão Renal Aguda/prevenção & controle , Substitutos Sanguíneos/administração & dosagem , Carboxihemoglobina/administração & dosagem , Endotoxemia/terapia , Hidratação , Córtex Renal/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Músculo Esquelético/irrigação sanguínea , Consumo de Oxigênio/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Circulação Renal/efeitos dos fármacos , Ressuscitação , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Endotoxemia/fisiopatologia , Córtex Renal/metabolismo , Lipopolissacarídeos , Masculino , Ratos Wistar , Fatores de Tempo
11.
J Pharmacol Sci ; 143(2): 122-126, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199747

RESUMO

Tumor blood vessels have leaky and low blood flow properties, which lead to hypoxia and low nutrient levels in the tumor tissue area known as the tumor microenvironment (TME). We reported that the prolyl-hydroxylase (PHD) inhibitor Roxadustat normalized tumor blood vessels, improved tumor tissue perfusion, and re-oxygenated the tumor tissue. Recently, several PHD inhibitors including Roxadustat, Daprodustat, Molidustat, and Vadadustat, were evaluated in clinical trials and approved for treating renal anemia. In this study, we showed that PHD inhibitors reconstituted tumor blood vessels and improved the TME, and some agents exhibited differential effects on tumors in a mouse model.


Assuntos
Carcinoma Pulmonar de Lewis/irrigação sanguínea , Glicina/análogos & derivados , Isoquinolinas/farmacologia , Ácidos Picolínicos/farmacologia , Inibidores de Prolil-Hidrolase/farmacologia , Animais , Carcinoma Pulmonar de Lewis/metabolismo , Glicina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Consumo de Oxigênio/efeitos dos fármacos , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos
12.
Cell Biochem Biophys ; 78(1): 111-119, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32062829

RESUMO

There are different varieties of mushrooms not yet studied spread all over the planet. The objective of this study was to evaluate biochemical properties and effects on mitochondrial respiration of eight Basidiomycete mushrooms: Flaviporus venustus EF30, Hydnopolyporus fimbriatus EF41 and EF44, Inonotus splitgerberi EF46, Oudemansiella canarii EF72, Perenniporia sp. EF79, Phellinus linteus EF81, and Pleurotus albidus EF84. Total phenols, ABTS, TEAC, FRAP, and ORAC were measured in order to determine the antioxidant capacity. Antimicrobial potential was studied by disc-diffusion and microdilution method. Cytotoxicity was determined in murine peritoneal macrophages. The bioenergetic aspects were evaluated by the uncoupling of the oxidative phosphorylation in mitochondrias. The H. fimbriatus mushroom was the one that presented the most significant results for the antioxidant assays. Three mushrooms presented antimicrobial activity, indicating a potential for formulation of drugs. The results suggest that I. spligerberi has an uncoupling activity, even at the lowest concentration tested, dissipating the mitochondrial electrochemical gradient. On the other hand, P. albidus has effect only on succinate-oxidase activity without influencing mitochondrial respiratory efficiency. Therefore, both interfere negatively in mitochondrial respiration. In relation with the cytotoxicity in peritoneal macrophages, O. canarii and F. venustus were cytotoxic in this type of cells.


Assuntos
Basidiomycota/química , Mitocôndrias/efeitos dos fármacos , Fenóis/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/metabolismo , Basidiomycota/metabolismo , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Mitocôndrias/metabolismo , Oxirredução , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fenóis/isolamento & purificação , Fenóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Ácido Succínico/química
13.
J Med Chem ; 63(5): 2511-2526, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32017849

RESUMO

Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure-activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N-H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.


Assuntos
Diaminas/uso terapêutico , Mitocôndrias Hepáticas/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirazinas/uso terapêutico , Desacopladores/uso terapêutico , Animais , Diaminas/química , Diaminas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Consumo de Oxigênio/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Desacopladores/química , Desacopladores/farmacologia
15.
Cancer Res ; 80(7): 1401-1413, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32041838

RESUMO

Pharmacologic ascorbate treatment (P-AscH-, high-dose, intravenous vitamin C) results in a transient short-term increase in the flux of hydrogen peroxide that is preferentially cytotoxic to cancer cells versus normal cells. This study examines whether an increase in hydrogen peroxide is sustained posttreatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH- was examined in tumorigenic and nontumorigenic cells. P-AscH- resulted in sustained increases in the rate of cellular oxygen consumption (OCR) and reactive oxygen species (ROS) in tumor cells, with no changes in nontumorigenic cells. Sources for this increase in ROS and OCR were DUOX 1 and 2, which are silenced in pancreatic ductal adenocarcinoma, but upregulated with P-AscH- treatment. An inducible catalase system, to test causality for the role of hydrogen peroxide, reversed the P-AscH--induced increases in DUOX, whereas DUOX inhibition partially rescued P-AscH--induced toxicity. In addition, DUOX was significantly downregulated in pancreatic cancer specimens compared with normal pancreas tissues. Together, these results suggest that P-AscH--induced toxicity may be enhanced by late metabolic shifts in tumor cells, resulting in a feed-forward mechanism for generation of hydrogen peroxide and induction of metabolic stress through enhanced DUOX expression and rate of oxygen consumption. SIGNIFICANCE: A high dose of vitamin C, in addition to delivering an acute exposure of H2O2 to tumor cells, activates DUOX in pancreatic cancer cells, which provide sustained production of H2O2.


Assuntos
Ácido Ascórbico/farmacologia , Carcinoma Ductal Pancreático/terapia , Oxidases Duais/metabolismo , Peróxido de Hidrogênio/metabolismo , Neoplasias Pancreáticas/terapia , Administração Intravenosa , Animais , Ácido Ascórbico/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Quimioterapia Adjuvante/métodos , Relação Dose-Resposta a Droga , Regulação para Baixo/genética , Oxidases Duais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Life Sci ; 245: 117307, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954746

RESUMO

AIM: To investigate whether a chronic 5-HT reuptake inhibitor (i.e. Fluoxetine-FLX) exposure in young adult rats overfed during suckling period would modulate interscapular brown adipose tissue (iBAT) mitochondria and browning agents in white adipose tissue (WAT). METHODS: Male Wistar rats were assigned into either a normofed group (n = 9 per group) or an overfed group (n = 3 per group) induced by litter size reduction at postnatal day 3 (PND3). Pharmacological manipulation was carried out between PND39 and PND59 and groups were assigned accordingly: Normofed + vehicle solution - NaCl 0.9% (NV group), normofed + FLX solution - 10 mg/kg b.w. (NF group), overfed + vehicle (OV group) and overfed + FLX (OF group). We evaluated mitochondrial oxygen consumption and reactive species (RS) production, oxidative stress analyses (MDA concentration, carbonyl content, REDOX state [GSH/GSSG], global oxy score) in the iBAT, gene (leptin, Ucp1, Sirt1, Pgc1α and Prdm16) and protein (UCP1) expression in the iBAT and epididymal WAT (eWAT). KEY FINDINGS: OV group increased body weight gain, Lee index and oxidative stress in the iBAT. Both FLX-treated groups showed less weight gain compared to their controls. OF group showed different leptin expression in the WAT and iBAT; increased functional UCP1 content and mitochondrial activity with less oxidative stress in the iBAT and upregulation of browning genes in eWAT (Pgc1α, Prdm16 and Ucp1). CONCLUSION: Altogether our findings indicated that FLX treatment in young adult overfed animals improved the iBAT mitochondrial function, reduced oxidative stress and induced transcriptional activation of browning agents in white adipose tissue.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Fluoxetina/farmacologia , Mitocôndrias/efeitos dos fármacos , Hipernutrição/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína Desacopladora 1/metabolismo
17.
Acad Emerg Med ; 27(3): 217-227, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31894606

RESUMO

BACKGROUND: The risk of respiratory depression is increased when opioids are added to sedative agents. In our recent multicenter emergency department (ED) procedural sedation cohort, we reported a strong association between preprocedural opioids and sedation-related adverse events. We sought to examine the association between timing of opioids and the incidence of adverse sedation outcomes. METHODS: We conducted a secondary analysis of a prospective cohort of children aged 0 to 18 years who received sedation for a painful procedure in six Canadian pediatric EDs from July 2010 to February 2015. The primary risk factor was timing of opioid administration, adjusted for age, opioid type, preprocedural and sedation medications, and procedure type. Outcomes were 1) oxygen desaturation, 2) vomiting, and 3) positive pressure ventilation (PPV). RESULTS: Of the 6,295 children in the original cohort, 1,806 (29%) received a preprocedural opioid. Patients receiving preprocedural opioids had a higher incidence of oxygen desaturation (risk difference = 4.3%, 95% confidence interval [CI] = 2.9% to 5.8%), vomiting (risk difference 2.0%, 95% CI = 0.7% to 3.3%), and PPV (risk difference = 1.5%, 95% CI = 0.7% to 2.3%). Multivariable regression with timing of opioids modeled as a restricted cubic spline revealed the risk for each outcome was highest when opioids were administered in the 30 minutes prior to sedation. Timing of opioid administration was statistically significantly associated with oxygen desaturation and vomiting (p < 0.0001) but not with PPV (p = 0.113). CONCLUSIONS: Timing of opioids was significantly associated with the risk of oxygen desaturation and vomiting. Being aware of this increased risk will help clinicians prepare for sedation and the potential need for patient rescue.


Assuntos
Analgésicos Opioides/administração & dosagem , Anestesia/efeitos adversos , Hipnóticos e Sedativos/administração & dosagem , Adolescente , Analgésicos Opioides/efeitos adversos , Anestesia/métodos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Lactente , Recém-Nascido , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Vômito/etiologia
18.
FASEB J ; 34(2): 2344-2358, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908020

RESUMO

Pharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-α prolyl-4-hydroxylase domain (PHD) enzymes and HIF-α asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-α hydroxylase (broad spectrum), PHD-selective, and FIH-selective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO2 than the PHD/FIH-selective HIs. Combined knockdown of FIH and PHD-selective inhibition did not further increase pericellular pO2 . Hence, the additional increase in pericellular pO2 by pan- over PHD-selective HIs likely reflects HIF hydroxylase independent off-target effects. Overall, these analyses demonstrate that HIs can lead to oxygen redistribution within the cellular microenvironment, which should be considered as a possible contributor to HI effects in the treatment of hypoxia-associated diseases.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/metabolismo , Células HEK293 , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Domínios Proteicos
19.
Artigo em Inglês | MEDLINE | ID: mdl-31922888

RESUMO

Nitric oxide (NO) is known to exert inhibitory control on mitochondrial respiration in the heart and brain. Evidence supports the presence of NO synthase (NOS) in the mitochondria (mtNOS) of cells; however, the functional role of mtNOS in the regulation of mitochondrial respiration is unclear. Our objective was to examine the effect of NOS inhibitors on mitochondrial respiration and protein S-nitrosylation. Freshly isolated cardiac and brain nonsynaptosomal mitochondria were incubated with selective inhibitors of neuronal (nNOS; ARL-17477, 1 µmol/L) or endothelial [eNOS; N5-(1-iminoethyl)-l-ornithine, NIO, 1 µmol/L] NOS isoforms. Mitochondrial respiratory parameters were calculated from the oxygen consumption rates measured using Agilent Seahorse XFe24 analyzer. Expression of NOS isoforms in the mitochondria was confirmed by immunoprecipitation and Western blot analysis. In addition, we determined the protein S-nitrosylation by biotin-switch method followed by immunoblotting. nNOS inhibitor decreased the state IIIu respiration in cardiac mitochondria and both state III and state IIIu respiration in brain mitochondria. In contrast, eNOS inhibitor had no effect on the respiration in the mitochondria from both heart and brain. Interestingly, NOS inhibitors reduced the levels of protein S-nitrosylation only in brain mitochondria, but nNOS and eNOS immunoreactivity was observed in the cardiac and brain mitochondrial lysates. Thus, the effects of NOS inhibitors on S-nitrosylation of mitochondrial proteins and mitochondrial respiration confirm the existence of functionally active NOS isoforms in the mitochondria. Notably, our study presents first evidence of the positive regulation of mitochondrial respiration by mitochondrial nNOS contrary to the current dogma representing the inhibitory role attributed to NOS isoforms.NEW & NOTEWORTHY Existence and the role of nitric oxide synthases in the mitochondria are controversial. We report for the first time that mitochondrial nNOS positively regulates respiration in isolated heart and brain mitochondria, thus challenging the existing dogma that NO is inhibitory to mitochondrial respiration. We have also demonstrated reduced protein S-nitrosylation by NOS inhibition in isolated mitochondria, supporting the presence of functional mitochondrial NOS.


Assuntos
Inibidores Enzimáticos/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Consumo de Oxigênio/efeitos dos fármacos , Amidinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Ornitina/análogos & derivados , Ornitina/farmacologia
20.
Acad Med ; 95(1): 145-150, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425191

RESUMO

PURPOSE: Course evaluations by students are a standard tool that U.S. universities use to monitor the quality of their product. Here, the authors examine an alternative method of monitoring instructional quality that differs from traditional approaches in that it does not rely on students' ratings. The authors sought to glean relevant diagnostic information about course effectiveness from in-class exams used to assess students' learning progress (i.e., cognitively diagnostic assessments that explicitly target instructional content). METHOD: The authors used data from an end-of-course, cumulative exam given in 2015 and in 2016 to 200 first-year medical students. They mapped the exam questions to 4 attributes and analyzed the students' overall mastery of the content tested and the percentage of students mastering each attribute. RESULTS: Analyses of the cognitively diagnostic assessment data revealed the percentage of the cohort who achieved/failed to achieve mastery of each of the attributes, discreet mastery profiles that distinguish among students with similar scores, and the percentage of the cohort within each of the 16 attribute mastery profiles. Analysis allowed the authors to evaluate how well the course content was delivered. CONCLUSIONS: Cognitively diagnostic assessments enable in-class tests to appraise which skills specified in the curriculum have/have not been mastered by the students and how many students have mastered/failed to master which particular skills. Hence, if the learning goals have been well defined at the beginning of a course, then cognitively diagnostic assessments can show to what degree the instructional objectives have actually been accomplished.


Assuntos
Educação de Graduação em Medicina/métodos , Avaliação Educacional/métodos , Testes de Estado Mental e Demência/normas , Estudantes de Medicina/estatística & dados numéricos , Logro , Adulto , Algoritmos , Competência Clínica/estatística & dados numéricos , Confusão/diagnóstico , Confusão/etiologia , Currículo/normas , Confiabilidade dos Dados , Educação de Graduação em Medicina/estatística & dados numéricos , Inibidores Enzimáticos/toxicidade , Feminino , Febre/diagnóstico , Febre/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos , Pentaclorofenol/toxicidade , Estados Unidos/epidemiologia , Universidades/normas
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