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1.
Neurosci Lett ; 792: 136942, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36328292

RESUMO

Neuregulin-1 (NRG1)/erythroblastic leukaemia viral oncogene homologues 2 (ErbB2) pathway had been implicated in promoting differentiation and suppressing apoptosis of neuronal stem cells (NSCs) isolated from cochlear nucleus. In the current study, we aimed at determining the effects of NRG1/ErbB2 on mitochondrial (mt) function of NSCs. As expected, NRG1 increased the expression of mitofusin (Mfn) 1 and Mfn2 and decreased the expression of mitochondrial fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1). However, after ErbB2 knockout, Mfn1 and Mfn2 expression decreased while Fis1 and Drp1 increased. Moreover, the increased mtDNA copy number and intracellular ATP level, elevated ATPase activities as well as decreased lactate production induced by NRG1 were partially reversed by ErbB2 knockout. Additionally, NRG1 treatment increased the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and upregulated the protein expression of catalase, manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and transcription factor A, mitochondrial (TFAM), which were also reversed by ErbB2 knockout. Furthermore, PGC-1α overexpression partially reversed the above effects of ErbB2 knockout. In conclusion, these findings suggest that the promotion of mitochondrial function of NRG1/ErbB2 axis is at least in part mediated by PGC-1α in NSCs from cochlear nucleus.


Assuntos
Núcleo Coclear , Células-Tronco Neurais , Antioxidantes/farmacologia , Catalase/metabolismo , Neuregulina-1/metabolismo , Núcleo Coclear/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Mitocôndrias/metabolismo , Células-Tronco Neurais/metabolismo
2.
Gene ; 851: 147039, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36368573

RESUMO

The prevalence of non-alcoholic fatty liver diseases (NAFLD) has reached epidemic levels during recent years and a major driver of NAFLD are diets high in fat and fructose. A common practice in the treatment of NAFLD are life-style interventions including for example increased physical activity. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) has been shown to be central in mediating the beneficial effects of exercise training by regulating the expression of key metabolic genes. However, the significance of hepatic PGC-1α for high fat high fructose (HFFD) induced changes in gene expression and metabolites associated with NAFLD has not been elucidated. Therefore the aim of the present study was to investigate the effect of hepatic PGC-1α on HFFD and exercise-induced changes in the hepatic transcriptome and metabolome in mice. Using gene-arrays and 1H NMR spectroscopy, the liver transcriptome and metabolome of liver-specific PGC-1α knock-out mice receiving either standard chow, HFFD or HFFD + exercise (HFFD + Ex) were determined. In total 122 genes were identified as differently expressed in mice receiving HFFD for 13 weeks compared to chow, while the loss of hepatic PGC-1α only had very minor effects on the transcriptome. The same was observed for the liver metabolome. The effect of 4 weeks exercise training in combination with 13 weeks of HFFD, had small effects on the transcriptome and metabolome compared to HFFD alone. Together our results highlight a minor regulatory effect of hepatic PGC-1α on the liver transcriptome during high fat high fructose diet and exercise training.


Assuntos
Frutose , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Frutose/metabolismo , Frutose/farmacologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transcriptoma , Fígado/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Camundongos Knockout , Metaboloma
3.
Nat Commun ; 13(1): 6661, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333379

RESUMO

Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis with cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA content and mitochondrial function are increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated NAD(P)H quinone dehydrogenase 1 (Nqo1). Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mitochondrial DNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.


Assuntos
Mitofagia , Biogênese de Organelas , Camundongos , Humanos , Animais , Mitofagia/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Adipócitos Brancos/metabolismo , Adiposidade , Ubiquitina-Proteína Ligases/metabolismo , Obesidade/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo
4.
Eur J Pharmacol ; 936: 175342, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36341883

RESUMO

OBJECTIVES: Cardiac protection of resveratrol is related to the improvement of mitochondrial function through sirtuin1 (SIRT1) activation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation. Asymmetric dimethylarginine (ADMA) as an endogenous inhibitor of nitric oxide synthases is associated with diabetic cardiovascular complications and has a cross-talk with lysine acetylation. This study was to determine whether resveratrol reverses ADMA's pathogenic role in diabetic cardiomyopathy and elucidate the underlying mechanisms in type 2 diabetic (T2DM) rats and cardiomyocytes. METHODS: T2DM Rats were induced by high-fat diet plus small-dose streptozotocin injection (35 mg/kg). Resveratrol was given by gavage (50 mg/kg/d) to some rats for 16w. Cardiac function was measured by echocardiography, and PGC-1α acetylation was detected by immunoprecipitation. Mitochondrial DNA and ATP contents were analyzed to evaluate mitochondrial biogenesis and function. RESULTS: Endogenous ADMA accumulation and its signal disorders were associated with cardiac and mitochondrial dysfunctions in accompany with increased PGC-1α acetylation and decreased PGC-1α expression in the myocardium of T2DM rats compared with control rats. Resveratrol treatment attenuated ADMA accumulation, cardiac and mitochondrial dysfunctions in parallel with reversing altered PGC-1α expression and acetylation in the myocardium of T2DM rats. Exogenous ADMA not only reproduced mitochondrial dysfunction and cardiac hypertrophy but also reduced PGC-1α expression and enhanced PGC-1α acetylation in accompany of down-regulating SIRT1 and up-regulating acetyltransferase expression, all of which could be prevented by resveratrol pretreatment in cardiomyocytes. CONCLUSIONS: These results indicate that ADMA promotes PGC-1α acetylation as a potential therapeutic target for resveratrol of management diabetic cardiomyopathy in T2DM rats.


Assuntos
Diabetes Mellitus Tipo 2 , Cardiomiopatias Diabéticas , Animais , Ratos , Acetilação , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Miócitos Cardíacos , PPAR gama , Resveratrol/farmacologia , Sirtuína 1 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
5.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430183

RESUMO

Myostatin (Mstn) is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes. The deletion of the Mstn gene in mice leads to reduced mitochondrial functions. However, the underlying regulatory mechanisms remain unclear. In this study, we used CRISPR/Cas9 to generate myostatin-knockout (Mstn-KO) mice via pronuclear microinjection. Mstn-KO mice exhibited significantly larger skeletal muscles. Meanwhile, Mstn knockout regulated the organ weights of mice. Moreover, we found that Mstn knockout reduced the basal metabolic rate, muscle adenosine triphosphate (ATP) synthesis, activities of mitochondrial respiration chain complexes, tricarboxylic acid cycle (TCA) cycle, and thermogenesis. Mechanistically, expressions of silent information regulator 1 (SIRT1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) were down-regulated, while peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) acetylation modification increased in the Mstn-KO mice. Skeletal muscle cells from Mstn-KO and WT were treated with AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR), and the AMPK inhibitor Compound C, respectively. Compared with the wild-type (WT) group, Compound C treatment further down-regulated the expression or activity of pAMPK, SIRT1, citrate synthase (CS), isocitrate dehydrogenase (ICDHm), and α-ketoglutarate acid dehydrogenase (α-KGDH) in Mstn-KO mice, while Mstn knockout inhibited the AICAR activation effect. Therefore, Mstn knockout affects mitochondrial function by inhibiting the AMPK/SIRT1/PGC1α signaling pathway. The present study reveals a new mechanism for Mstn knockout in regulating energy homeostasis.


Assuntos
Proteínas Quinases Ativadas por AMP , Miostatina , Camundongos , Animais , Miostatina/genética , Miostatina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Camundongos Knockout , Músculo Esquelético/metabolismo , Aminoimidazol Carboxamida/farmacologia , Mitocôndrias/genética , Mitocôndrias/metabolismo
6.
Molecules ; 27(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36431802

RESUMO

Hypertension is a chronic disease related to age, which affects tens of millions of people around the world. It is an important risk factor that causes myocardial infarction, heart failure, stroke, and kidney damage. Bioactive peptide VHVV (VH-4) from soybean has shown several biological activities. Physical exercise is a cornerstone of non-pharmacologic treatment for hypertension and has established itself as an effective and complementary strategy for managing hypertension. The present study evaluates the efficacy of VH-4 supplement and swimming exercise training in preventing hypertension in spontaneously hypertensive rats (SHR). SHR animals were treated with VH-4 (25 mg/kg by intraperitoneal administration) and swimming exercise (1 h daily) for eight weeks, and the hemodynamic parameters, histology, and cell survival pathway protein expression were examined. In SHR rats, increased heart weight, blood pressure, and histological aberrations were observed. Cell survival protein p-PI3K and p-AKT and antiapoptosis proteins Bcl2 and Bcl-XL expression decreased in SHR animals. SIRT1 and FOXO3 were decreased in hypertensive rats. Both bioactive peptide VH-4 treatment and swimming exercise training in hypertensive rats increased the cell survival proteins p-PI3K and p-AKT and AMPKα1, Sirt1, PGC1α, and FoX3α proteins. Soy peptide VH-4, along with exercise, acts synergistically and prevents hypertension by activating cell survival and AMPKα1, Sirt1, PGC1α, and FoX3α proteins.


Assuntos
Fabaceae , Hipertensão , Condicionamento Físico Animal , Ratos , Animais , Sirtuína 1/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Soja/metabolismo , Sobrevivência Celular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Endogâmicos SHR , Peptídeos/farmacologia , Peptídeos/metabolismo , Fabaceae/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
7.
FASEB J ; 36(12): e22628, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36322028

RESUMO

Exercise training enhances oxidative capacity whereas detraining reduces mitochondrial content in skeletal muscle. The strategy to suppress the detraining-induced reduction of mitochondrial content has not been fully elucidated. As previous studies reported that branched-chain amino acid (BCAA) ingestion increased mitochondrial content in skeletal muscle, we evaluated whether BCAA supplementation could suppress the detraining-induced reduction of mitochondrial content. Six-week-old male Institute of Cancer Research (ICR) mice were randomly divided into four groups as follows: control (Con), endurance training (Tr), detraining (DeTr), and detraining with BCAA supplementation (DeTr + BCAA). Mice in Tr, DeTr, and DeTr + BCAA performed treadmill running exercises [20-30 m/min, 60 min, 5 times/week, 4 weeks]. Then, mice in DeTr and DeTr + BCAA were administered with water or BCAA [0.6 mg/g of body weight, twice daily] for 2 weeks of detraining. In whole skeletal muscle, mitochondrial enzyme activities and protein content were decreased after 2 weeks of detraining, but the reduction was suppressed by BCAA supplementation. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein content, a master regulator of mitochondrial biogenesis, was decreased by detraining irrespective of BCAA ingestion. Regarding mitochondrial degradation, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a mitophagy-related protein, was significantly higher in the Tr group than in the DeTr + BCAA group, but not different from in the DeTr group. With respect to mitochondrial quality, BCAA ingestion did not affect oxygen consumption rate (OCR) and reactive oxygen species (ROS) production in isolated mitochondria. Our findings suggest that BCAA ingestion suppresses the detraining-induced reduction of mitochondrial content partly through inhibiting mitophagy.


Assuntos
Aminoácidos de Cadeia Ramificada , Mitocôndrias , Masculino , Camundongos , Animais , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Suplementos Nutricionais
8.
Oxid Med Cell Longev ; 2022: 1231970, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225175

RESUMO

Long-term exposure to high glucose leads to ß-cell dysfunction and death. Fibroblast growth factor 1 (FGF1) has emerged as a promising diabetes treatment, but its pharmaceutical role and mechanism against glucolipotoxicity-induced ß-cell dysfunction remain uncharacterized. Wild-type FGF1 (FGF1WT) may exhibit in vivo mitogenicity, but deletion of N-terminal residues 1-27 gives a nonmitogenic variant, ∆nFGF1, that does not promote cell proliferation and still retains the metabolic activity of FGF1WT. To investigate the roles of ∆nFGF1 on glucose regulation and potential islet ß-cell dysfunction, db/db mice were used as a model of type 2 diabetes. The results showed that insulin secretion and apoptosis of islet ß-cells were dramatically improved in ∆nFGF1-treated db/db mice. To further test the effects of ∆nFGF1 treatment, pancreatic ß-cell (MIN6) cells were exposed to a mixture of palmitic acid (PA) and high glucose (HG) to mimic glucolipotoxic conditions in vitro. Treatment with ∆nFGF1 significantly inhibited glucolipotoxicity-induced apoptosis. Mechanistically, ∆nFGF1 exerts a protective effect on ß-cells via activation of the AMPK/SIRT1/PGC-1α signaling pathway. These findings demonstrate that ∆nFGF1 protects pancreatic ß-cells against glucolipotoxicity-induced dysfunction and apoptosis.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Diabetes Mellitus Tipo 2/metabolismo , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 1 de Crescimento de Fibroblastos/farmacologia , Glucose/metabolismo , Glucose/toxicidade , Células Secretoras de Insulina/metabolismo , Camundongos , Ácido Palmítico/metabolismo , Ácido Palmítico/toxicidade , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo
9.
Cells ; 11(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36230906

RESUMO

Transcriptional coactivator PGC-1α is a main regulator of cardiac energy metabolism. In addition to canonical PGC-1α1, other PGC-1α isoforms have been found to exert specific biological functions in a variety of tissues. We investigated the expression patterns and the biological effects of the non-canonical isoforms in the heart. We used RNA sequencing data to identify the expression patterns of PGC-1α isoforms in the heart. To evaluate the biological effects of the alternative isoform expression, we generated a transgenic mouse with cardiac-specific overexpression of PGC-1α4 and analysed the cardiac phenotype with a wide spectrum of physiological and biophysical tools. Our results show that non-canonical isoforms are expressed in the heart, and that the main variant PGC-1α4 is induced by ß-adrenergic signalling in adult cardiomyocytes. Cardiomyocyte specific PGC-1α4 overexpression in mice relieves the RE1-Silencing Transcription factor (REST)-mediated suppression of neuronal genes during foetal heart development. The resulting de-repression of REST target genes induces a cardiac phenotype with increased cellular energy consumption, resulting in postnatal dilated cardiomyopathy. These results propose a new concept for actions of the PGC-1α protein family where activation of the Pgc-1α gene, through its isoforms, induces a phenotype with concurrent supply and demand for cellular energy. These data highlight the biological roles of the different PGC-1α isoforms, which should be considered when future therapies are developed.


Assuntos
Músculo Esquelético , Miócitos Cardíacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Adrenérgicos/metabolismo , Animais , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Miócitos Cardíacos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Repressoras , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Medicina (Kaunas) ; 58(10)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36295596

RESUMO

Background and Objectives: Perilipins 1-5 (PLIN) are lipid droplet-associated proteins that participate in regulating lipid storage and metabolism, and the PLIN5 isoform is known to form a nuclear complex with peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) to regulate lipid metabolism gene expression. However, the changes in PLIN isoforms' expression in response to pregnancy-induced cardiac hypertrophy are not thoroughly studied. The aim of this study was to quantify the mRNA expression of PLIN isoforms and PGC-1α along with total triacylglycerol (TAG) and cholesterol levels during late pregnancy and the postpartum period in the rat left ventricle. Materials and Methods: Female Sprague-Dawley rats were divided into three groups: non-pregnant, late pregnancy, and postpartum. The mRNA and protein levels were evaluated using quantitative RT-PCR and Western blotting, respectively. TAG and total cholesterol content were evaluated using commercial colorimetric methods. Results: The expression of mRNAs for PLIN1, 2, and 5 increased during pregnancy and the postpartum period. PGC-1α mRNA and protein expression increased during pregnancy and the postpartum period. Moreover, TAG and total cholesterol increased during pregnancy and returned to basal levels after pregnancy. Conclusions: Our results demonstrate that pregnancy upregulates differentially the expression of PLIN isoforms along with PGC-1α, suggesting that together they might be involved in the regulation of the lipid metabolic shift induced by pregnancy.


Assuntos
Receptores Ativados por Proliferador de Peroxissomo , Fatores de Transcrição , Ratos , Feminino , Animais , Gravidez , Perilipina-1 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Cardiomegalia/genética , Cardiomegalia/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos , Colesterol
11.
Toxicol Appl Pharmacol ; 456: 116262, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36198370

RESUMO

Testicular dysgenesis syndrome in male neonates manifests as cryptorchidism and hypospadias, which can be mimicked by in utero phthalate exposure. However, the underlying phthalate mediated mechanism and therapeutic effects of taxifolin remain unclear. Di-(2-ethylhexyl) phthalate (DEHP) is the most abundantly used phthalate and can induce testicular dysgenesis syndrome in male rats. To explore the mechanism of DEHP mediated effects and develop a therapeutic drug, the natural phytomedicine taxifolin was used. Pregnant Sprague-Dawley female rats were daily gavaged with 750 mg/kg/d DEHP or 10 or 20 mg/kg/d taxifolin alone or in combination from gestational day 14 to 21, and male pup's fetal Leydig cell function, testicular MDA, and antioxidants were examined. DEHP significantly reduced serum testosterone levels of male pups, down-regulated the expression of SCARB1, CYP11A1, HSD3B1, HSD17B3, and INSL3, reduced the cell size of fetal Leydig cells, decreased the levels of antioxidant and related signals (SOD2 and CAT, SIRT1, and PGC1α), induced abnormal aggregation of fetal Leydig cells, and stimulated formation of multinucleated gonocytes and MDA levels. Taxifolin alone (10 and 20 mg/kg/d) did not affect these parameters. However, taxifolin significantly rescued DEHP-induced alterations. DEHP exposure in utero can induce testicular dysgenesis syndrome by altering the oxidative balance and SIRT1/PGC1α levels, and taxifolin is an ideal phytomedicine to prevent phthalate induced testicular dysgenesis syndrome.


Assuntos
Dietilexilftalato , Doenças Testiculares , Gravidez , Humanos , Ratos , Masculino , Feminino , Animais , Dietilexilftalato/toxicidade , Animais Recém-Nascidos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Testosterona/metabolismo , Sirtuína 1/metabolismo , Ratos Sprague-Dawley , Células Intersticiais do Testículo , Testículo , Doenças Testiculares/induzido quimicamente , Doenças Testiculares/prevenção & controle , Doenças Testiculares/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/metabolismo
12.
Food Funct ; 13(22): 11715-11732, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36279184

RESUMO

Genistein has beneficial effects on glucose metabolism and adipose tissue browning which paralleled with gut microbiota alterations. However, the causality is unclear. This study aims to evaluate whether genistein could ameliorate metabolism and activate the browning program and whether gut microbiota is indispensable for these alterations. We examined the effect of 10-week genistein gavage (30 mg kg-1 d-1) on glucose metabolism in C57BL/6J mice. Cecal contents were collected for 16s rRNA sequencing. The mRNA of browning markers was quantified in adipose tissues. Antibiotic administration was used to deplete gut microbiota. The lean mice with a normal control diet and genistein exhibited better glucose tolerance and higher expression of UCP1 and PGC1α in white fat compared with those without genistein. Markedly enriched Blautia, Ruminiclostridium_5, and Ruminiclostridium_9 in genistein-treated mice were significantly correlated with browning markers and glucose tolerance. In obese mice, genistein alleviated the detrimental effects of a high-fat diet on glucose homeostasis and increased UCP1 and PGC1α expression in brown fat. Obvious increases in Ruminiclostridium, Rikenella, and Clostridium_sensu_stricto_1 by genistein were associated with metabolic improvement. However, depleting gut microbiota abolished these benefits. Overall, our findings indicated that gut microbiota contributed to enhanced glucose metabolism and adipose tissue browning of genistein, providing a promising target for metabolic health protection.


Assuntos
Microbioma Gastrointestinal , Genisteína , Camundongos , Animais , Genisteína/farmacologia , Genisteína/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Camundongos Endogâmicos C57BL , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Marrom/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo
13.
Arch Biochem Biophys ; 730: 109419, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36183841

RESUMO

Exercise training provides several cardiovascular benefits in both physiological and pathological conditions; however, its use as a therapeutic tool for pulmonary arterial hypertension (PAH) has been poorly explored. This study aimed to extend the comprehension of the cardioprotective effects of exercise training in the set of PAH focusing on the metabolic changes promoted by exercise in the right ventricle (RV). The monocrotaline animal model of PAH was used and male Wistar rats were submitted to two weeks of treadmill exercise training (5 days/week, 60 min/day, 25 m/min) following disease establishment. Trained rats showed an improved diastolic function (lower end-diastolic pressure and tau) despite the presence of cardiac overload (increased peak systolic pressure, end-diastolic pressure and arterial elastance). This enhanced hemodynamic response was paralleled by an increased uptake of glucose to cardiomyocytes through glucose transporter type 4 (GLUT4) followed by increased lactate dehydrogenase (LDH) activity. Exercise did not reverse the decrease of fatty acid oxidation related to PAH but increased the content of the transcription factors peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Two weeks of exercise did not modulate the changes in amino acid metabolism secondary to PAH. Our work suggests that continuous aerobic exercise of moderate intensity, despite its short-term duration and application in a late stage of the disease, supports the RV response to PAH by promoting a shift in the cardiac metabolic phenotype.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Masculino , Ratos , Animais , Monocrotalina/efeitos adversos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/patologia , PPAR gama/metabolismo , Transportador de Glucose Tipo 4 , Ratos Wistar , Modelos Animais de Doenças , Glucose , Lactato Desidrogenases/metabolismo , Aminoácidos , Ácidos Graxos
14.
Acta Neurobiol Exp (Wars) ; 82(3): 373-379, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36214719

RESUMO

Postoperative cognitive dysfunction is a severe neurological complication. How to improve the cognitive impairment caused by sevoflurane, a most common inhaled anesthetic, remains a question worthy of studying. Isovitexin (IVX) is a trihydroxyl flavonoid that is a naturally bioactive ingredient found in various medicinal plants and has antioxidant, anti­inflammatory and neuroprotective properties. The role of IVX in anesthetic­induced nerve injury is rarely reported and the mechanisms are unclear. In this study, we found that IVX improved the cognitive dysfunction induced by sevoflurane in rats. It inhibited sevoflurane­induced cell apoptosis. In addition, IVX increased sevoflurane­induced autophagy in rat brain. Mechanically, IVX activated the PGC­1α/FNDC5 pathway in rat brain, and depletion of FNDC5 could inhibit the neuroprotective function of IVX. In conclusion, our results suggested that IVX restored sevoflurane­induced cognitive dysfunction by mediating autophagy through the activation of the PGC­1α/FNDC5 pathway.


Assuntos
Antioxidantes , Apigenina , Disfunção Cognitiva , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apigenina/farmacologia , Apoptose , Autofagia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Fibronectinas/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Sprague-Dawley , Sevoflurano/efeitos adversos , Transdução de Sinais
15.
Clin Nutr ESPEN ; 51: 1-6, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36184193

RESUMO

Caffeine is one of the most widely used substances as recreational drug for performance-enhancement in sport, underpinned by a strong evidence base. Although the effects of caffeine are widely investigated within the scope of performance physiology, the molecular effects of caffeine within skeletal muscle remain unclear. Evidence from in vitro and in vivo models suggest that caffeine regulates the glucose metabolism in the skeletal muscle. Moreover, caffeine seems to stimulate CaMKII, PPARδ/ß, AMPK and PGC1α, classical markers of exercise-adaptations, including mitochondrial biogenesis and mitochondrial content. This review summarizes evidence to suggest caffeine-effects within skeletal muscle fibers, focusing on the putative role of caffeine on mitochondrial biogenesis to explore whether caffeine supplementation might be a strategy to enhance mitochondrial biogenesis.


Assuntos
Drogas Ilícitas , PPAR delta , Proteínas Quinases Ativadas por AMP/metabolismo , Cafeína/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/farmacologia , Glucose/metabolismo , Humanos , Drogas Ilícitas/metabolismo , Drogas Ilícitas/farmacologia , Músculo Esquelético/metabolismo , Biogênese de Organelas , PPAR delta/metabolismo , PPAR delta/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/farmacologia
16.
Nutrients ; 14(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36235564

RESUMO

The purpose of this study was to examine whether Limonium tetragonum, cultivated in a smart-farming system with LED lamps, could increase exercise capacity in mice. C57BL/6 male mice were orally administered vehicle or Limonium tetragonum water extract (LTE), either 30 or 100 mg/kg, and were subjected to moderate intensity treadmill exercise for 4 weeks. Running distance markedly increased in the LTE group (100 mg/kg) by 80 ± 4% compared to the vehicle group, which was accompanied by a higher proportion of oxidative fibers (6 ± 6% vs. 10 ± 4%). Mitochondrial DNA content and gene expressions related to mitochondrial biogenesis were significantly increased in LTE-supplemented gastrocnemius muscles. At the molecular level, the expression of PGC-1α, a master regulator of fast-to-slow fiber-type transition, was increased downstream of the PKA/CREB signaling pathway. LTE induction of the PKA/CREB signaling pathway was also observed in C2C12 cells, which was effectively suppressed by PKA inhibitors H89 and Rp-cAMP. Altogether, these findings indicate that LTE treatment enhanced endurance exercise capacity via an improvement in mitochondrial biosynthesis and the increases in the formation of oxidative slow-twitch fibers. Future study is warranted to validate the exercise-enhancing effect of LTE in the human.


Assuntos
Condicionamento Físico Animal , Extratos Vegetais , Plumbaginaceae , Corrida , Animais , DNA Mitocondrial/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Biogênese de Organelas , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Condicionamento Físico Animal/fisiologia , Resistência Física , Extratos Vegetais/farmacologia , Plumbaginaceae/química
17.
Biomed Res Int ; 2022: 6560693, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36277894

RESUMO

The objective of this research is to investigate the mediating impact of salvianolic acid B (SalB) on SIRT1 signaling pathway and the mechanism by which it inhibits Nod-like receptor protein 3 (NLRP3), as well as to examine how SalB affects myocardial injury brought on by tumor lesions at the junction of the tube and the stomach. Through the establishment of the integration of a stomach tube tumor lesion rats combined with the experimental rat model, this study establishes the normal group, model group, and different SalB dose groups. For each group of cells, cell activity and cell apoptosis were determined and compared using colorimetry and enzyme-linked immunosorbent method about lactate dehydrogenase (LDH). Interleukin-1 beta levels are measured. DCFH-DA fluorescent probe was applied to identify intracellular "reactive oxygen species" (ROS). "Western blot" was used to determine NLRP3, caspase-1, and apoptosis-related spotted protein (ASC) in each group of cells. And SIRT1 signaling pathway related to SIRT1, phosphorylated AMP protein-activated kinase α (P-AMPK α), AMP protein-activated kinase α (AMPKα), and "peroxisome-proliferator-activated receptor γ coactivator 1α (PGC-1α) protein expression" are used. According to the final findings, SalB mediated the SIRT1 signaling pathway and had a beneficial impact on the upregulation of SIRT1, P-AMPK/AMPK, and PGC-1 protein expressions. SalB positively affects the downregulation of NLRP3 inflammasome-related proteins. Caspase-1 and ASC protein expression suggesting that SalB may inhibit the activation of NLRP3 inflammasome induced by oxidative stress by activating SIRT1/AMPK/PGC-1α signaling pathway. This plays an antimyocardial injury effect.


Assuntos
Neoplasias , Sirtuína 1 , Ratos , Animais , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-1beta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas NLR/metabolismo , Inflamassomos/metabolismo , Corantes Fluorescentes , Imunoadsorventes , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Caspase 1/metabolismo , Oxigênio/metabolismo , Lactato Desidrogenases/metabolismo , Monofosfato de Adenosina
18.
J Virol ; 96(20): e0082822, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36197108

RESUMO

Mitochondrial fitness is governed by mitochondrial quality control pathways comprising mitochondrial dynamics and mitochondrial-selective autophagy (mitophagy). Disruption of these processes has been implicated in many human diseases, including viral infections. Here, we report a comprehensive analysis of the effect of dengue infection on host mitochondrial homeostasis and its significance in dengue disease pathogenesis. Despite severe mitochondrial stress and injury, we observed that the pathways of mitochondrial quality control and mitochondrial biogenesis are paradoxically downregulated in dengue-infected human liver cells. This leads to the disruption of mitochondrial homeostasis and the onset of cellular injury and necrotic death in the infected cells. Interestingly, dengue promotes global autophagy but selectively disrupts mitochondrial-selective autophagy (mitophagy). Dengue downregulates the expression of PINK1 and Parkin, the two major proteins involved in tagging the damaged mitochondria for elimination through mitophagy. Mitophagy flux assays also suggest that Parkin-independent pathways of mitophagy are also inactive during dengue infection. Dengue infection also disrupts mitochondrial biogenesis by downregulating the master regulators PPARγ and PGC1α. Dengue-infected cells release mitochondrial damage-associated molecular patterns (mtDAMPs) such as mitochondrial DNA into the cytosol and extracellular milieu. Furthermore, the challenge of naive immune cells with culture supernatants from dengue-infected liver cells was sufficient to trigger proinflammatory signaling. In correlation with our in vitro observations, dengue patients have high levels of cell-free mitochondrial DNA in their blood in proportion to the degree of thrombocytopenia. Overall, our study shows how defective mitochondrial homeostasis in dengue-infected liver cells can drive dengue disease pathogenesis. IMPORTANCE Many viruses target host cell mitochondria to create a microenvironment conducive to viral dissemination. Dengue virus also exploits host cell mitochondria to facilitate its viral life cycle. Dengue infection of liver cells leads to severe mitochondrial injury and inhibition of proteins that regulate mitochondrial quality control and biogenesis, thereby disrupting mitochondrial homeostasis. A defect in mitochondrial quality control leads to the accumulation of damaged mitochondria and promotes cellular injury. This leads to the release of mitochondrial damage-associated molecular patterns (mt-DAMPs) into the cell cytoplasm and extracellular milieu. These mt-DAMPs activate the naive immune cells and trigger proinflammatory signaling, leading to the release of cytokines and chemokines, which may trigger systemic inflammation and contribute to dengue disease pathogenesis. In correlation with this, we observed high levels of cell-free mitochondrial DNA in dengue patient blood. This study provides insight into how the disruption of mitochondrial quality control in dengue-infected cells can trigger inflammation and drive dengue disease pathogenesis.


Assuntos
Dengue , PPAR gama , Humanos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Mitocôndrias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , DNA Mitocondrial/metabolismo , DNA Mitocondrial/farmacologia , Proteínas Quinases/metabolismo , Citocinas/metabolismo , Inflamação/patologia , Dengue/patologia
19.
Medicina (Kaunas) ; 58(9)2022 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-36143977

RESUMO

Introduction: Despite decades of research, obesity and its related medical complications remain a major health concern globally. Therefore, novel therapeutic strategies are needed to combat obesity and its numerous debilitating complications. Resveratrol (RES) has a potential therapeutic effect in obesity and diabetes by improving oxidative metabolism and insulin signaling. Background and Objectives: The aim of this study was to investigate the effect of RES treatment on weight loss and glucose and fatty acid metabolism. Methods: Obesity was induced in 24 mice by exposure to a high-fat diet (HFD) for 8 weeks. Mice were randomly assigned to one group of either: group 1: control, non-treated low-fat diet (LFD) for 12 weeks (n = 8), group 2: non-treated high-fat diet (HFD) for 12 weeks (n = 8), group 3: RES-treated HFD (HFD + RES) (n = 8), or group 4: RES-treated and switched to LFD (HFD-LFD + RES) (n = 8). HFD + RES mice were first fed an HFD for 8 weeks followed by 4 weeks of RES. The HFD-LFD + RES group was first fed an HFD for 8 weeks and then treated with RES and switched to an LFD for 4 weeks. Results: After 12 weeks, group 2 mice had significantly higher body weights compared to group 1 (23.71 ± 1.95 vs. 47.83 ± 2.27; p < 0.05). Group 4 had a significant decrease in body weight and improvement in glucose tolerance compared to mice in group 2 (71.3 ± 1.17 vs. 46.1 ± 1.82 and 40.9 ± 1.75, respectively; p < 0.05). Skeletal muscles expression of SIRT1, SIRT3, and PGC1α were induced in group 3 and 4 mice compared to group 2 (p < 0.01), with no changes in AMP-activated protein kinase expression levels. Furthermore, combination of RES and diet ameliorated skeletal muscle intermediate lipid accumulation and significantly improved insulin sensitivity and secretion. Conclusions: The results of this study suggest a synergistic beneficial effect of LFD and RES to lower body weight and enhance glucose and fatty acid metabolism.


Assuntos
Dieta Hiperlipídica , Sirtuína 3 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Glucose , Insulina/metabolismo , Lipídeos , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Sirtuína 1/metabolismo , Sirtuína 3/metabolismo
20.
Mediators Inflamm ; 2022: 8373389, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081650

RESUMO

Diabetes is well recognized to increase the risk of heart failure, which is associated with higher mortality and morbidity. It is important for the development of novel therapeutic methods targeting heart failure in diabetic patients. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the progression of diabetes-induced heart failure (DIHF). This study was designed to investigate the contribution of Nr2f2 to the activation of ferroptosis and mitochondrial dysfunction in DIHF. We established a diabetic model by a high-fat feeding diet combined with an intraperitoneal injection of streptozotocin. After 16 weeks, Nr2f2 expression was increased in heart tissue of DIHF mice. In vivo, DIHF mice overexpressing Nr2f2 (AAV9-cTNT-Nr2f2) exhibited severe heart failure and enhanced cardiac ferroptosis compared with DIHF control mice (AAV9-cTNT-ctrl), accompanied by mitochondrial dysfunction and aggravated oxidative stress reaction. In vitro, Nr2f2 knockdown ameliorated ferroptosis and mitochondrial dysfunction by negatively regulating PGC-1α, a crucial metabolic regulator. PGC-1α knockdown counteracted the protective effect of Nr2f2 knockdown. These data suggest that Nr2f2 promotes heart failure and ferroptosis in DIHF by modulating the PGC-1α signaling. Our study provides a new idea for the treatment of diabetes-induced heart failure.


Assuntos
Fator II de Transcrição COUP , Diabetes Mellitus , Ferroptose , Insuficiência Cardíaca , Animais , Fator II de Transcrição COUP/genética , Fator II de Transcrição COUP/metabolismo , Diabetes Mellitus/metabolismo , Insuficiência Cardíaca/metabolismo , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais
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