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1.
BMC Endocr Disord ; 20(1): 31, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131811

RESUMO

BACKGROUND: Growing evidence suggests that leptin is critical for glycemic control. Impaired leptin signaling may also contribute to low adiponectin expression in obese individuals. We assessed the association of leptin and adiponectin with incident type 2 diabetes (T2D), their interactions with sex and obesity status, and mediation by insulin resistance. METHODS: We included study participants from the Jackson Heart Study, a prospective cohort of adult African Americans in Jackson, Mississippi, that were free of T2D at the baseline Exam 1. Incident T2D was defined as new cases at Exam 2 or Exam 3. We created separate Cox regression models (hazard ratios per log-transformed ng/mL of leptin and adiponectin) with and without insulin resistance, HOMA-IR. Mediation by insulin resistance was analyzed. Several interactions were assessed, including by sex, HbA1c, and obesity. RESULTS: Among our 3363 participants (mean age 53 years, 63% women), 584 developed incident T2D. Leptin was directly associated with incident T2D when modeled without HOMA-IR (HR = 1.29, 95% CI = 1.05-1.58). This direct association between leptin and T2D was significant among men (HR = 1.33, 95% CI = 1.05-1.69), but nonsignificant among women (HR = 1.24, 95% CI = 0.94-1.64); statistical interaction with sex was nonsignificant (p = 0.65). The associations in all participants and in men were nullified by HOMA-IR (HR = 0.99, 95% CI = 0.80-1.22; HR = 1.00, 95% CI = 0.78-1.28, respectively), indicating mediation through insulin resistance (proportion mediated: 1.04), and were not observed in abdominally obese participants. Adiponectin was inversely associated with T2D even after adjustment for HOMA-IR in women (HR = 0.68, 95% CI = 0.55-0.84), but not in men (HR = 0.80, 95% CI = 0.62-1.04). The inverse association was present only among abdominally obese participants, and persisted after adjustment for HOMA-IR. CONCLUSIONS: Among African Americans in the Jackson Heart Study the association of leptin with incident type 2 diabetes was mediated by insulin resistance. This association was present only among abdominally non-obese participants. Differences by sex appeared: men showed a significant association mediated by insulin resistance. Among abdominally obese participants, adiponectin was inversely associated with incident T2D even after adjustment for HOMA-IR. Our results should inform future clinical trials that aim to reduce the burden of type 2 diabetes through the modification of serum levels of leptin and adiponectin.

2.
J Nutr Biochem ; 79: 108330, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-32179408

RESUMO

Adjusting ω-3/ω-6 polyunsaturated fatty acids (PUFAs) ratio in high-fat diet is one potential mean to improve metabolic syndrome; however, underlying mechanisms remain unclear. Four groups of mice were fed 60% kcal diets with saturated fatty acids, three different ω-3/ω-6 PUFAs ratios (low, middle and high) for 12 weeks, respectively. Body weight, atherosclerosis marker, insulin signal index and level of lipid accumulation in liver were significantly lowered in High group compared with saturated fatty acids group and Low group at week 12. Expressions of p-mTOR and raptor were inhibited by high ω-3 PUFAs. Importantly, ω-3 PUFAs intake up-regulated mitochondrial electron transport chain and tricarboxylic acid cycle pathway through metabolomics analysis in liver. Mitochondrial complexes activities were raised, fumaric acid was reduced and oxidative stress was alleviated in High group. We conclude that consuming long-term high-fat diet with same calories but high ω-3/ω-6 PUFAs ratio relieves metabolic syndrome by regulating mTORC1 pathway to enhance mitochondrial function.

3.
Eur J Heart Fail ; 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32212368

RESUMO

AIMS: Chronic hyperglycaemia, assessed by elevated glycated haemoglobin (A1C), is a known risk factor for heart failure (HF) and cardiovascular (CV) death among subjects with diabetes. Whether this risk varies with left ventricular ejection fraction (LVEF) is unknown. This study evaluated whether A1C influences a composite outcome of either HF hospitalization or CV death differently along the spectrum of LVEF. METHODS AND RESULTS: We assessed the relationships of baseline A1C and LVEF with a composite outcome of either CV death or HF hospitalization in the 4091 patients with type 2 diabetes and a recent acute coronary syndrome enrolled in the ELIXA trial who had available LVEF. We assessed for interaction between A1C and LVEF as continuous variables with respect to this outcome. During a median follow-up of 25.7 months, 343 patients (8.4%) had HF hospitalization or died of CV causes. In a multivariable model, A1C and LVEF were each associated with an increased risk of HF hospitalization or CV death [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.21 per 1% higher A1C, and adjusted HR 1.39, 95% CI 1.27-1.51 per 10% lower in LVEF]. Both A1C and LVEF were independently and incrementally associated with risk without evidence of interaction (P for interaction = 0.31). Patients with A1C ≥ 8% and LVEF <40% were at threefold higher risk than those with A1C < 7% and LVEF ≥50% (adjusted HR 3.18, 95% CI 2.03-4.98, P < 0.001). CONCLUSION: In a contemporary cohort of patients with type 2 diabetes and acute coronary syndrome, baseline chronic hyperglycaemia was associated with an increased risk of HF hospitalization or CV death independently of LVEF.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32050773

RESUMO

Significance: Epidemiological studies indicate that metabolic disorders are associated with an increased risk for Alzheimer's disease (AD). Metabolic remodeling occurs in the central nervous system (CNS) and periphery, even in the early stages of AD. Mitochondrial dysfunction has been widely accepted as a molecular mechanism underlying metabolic disorders. Therefore, focusing on early metabolic changes, especially from the perspective of mitochondria, could be of interest for early AD diagnosis and intervention. Recent Advances: We and others have identified that the levels of several metabolites are fluctuated in the periphery before their accumulation in the CNS, which plays an important role in the pathogenesis of AD. Mitochondrial remodeling is likely one of the earliest signs of AD, linking nutritional imbalance to cognitive deficits. Notably, by improving mitochondrial function, mitochondrial nutrients efficiently rescue cellular metabolic dysfunction in the CNS and periphery in individuals with AD. Critical Issues: Peripheral metabolic disorders should be intensively explored and evaluated for the early diagnosis of AD. The circulating metabolites derived from mitochondrial remodeling represent novel potential diagnostic biomarkers for AD that are more readily detected than CNS-oriented biomarkers. Moreover, mitochondrial nutrients provide a promising approach to preventing and delaying AD progression. Future Directions: Abnormal mitochondrial metabolism in the CNS and periphery is involved in AD pathogenesis. More clinical studies provide evidence for the suitability and reliability of circulating metabolites and cytokines for the early diagnosis of AD. Targeting mitochondria to rewire cellular metabolism is a promising approach to preventing AD and ameliorating AD-related metabolic disorders.

5.
Nutrients ; 12(1)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936037

RESUMO

Hyperlipidemia is associated with metabolic disorders, but the detailed mechanisms and related interventions remain largely unclear. As a functional food in Asian diets, Herba houttuyniae has been reported to have beneficial effects on health. The present research was to investigate the protective effects of Herba houttuyniae aqueous extract (HAE) on hyperlipidemia-induced liver and heart impairments and its potential mechanisms. Male C57BL/6J mice were administered with 200 or 400 mg/kg/day HAE for 9 days, followed by intraperitoneal injection with 0.5 g/kg poloxamer 407 to induce acute hyperlipidemia. HAE treatment significantly attenuated excessive serum lipids and tissue damage markers, prevented hepatic lipid deposition, improved cardiac remodeling, and ameliorated hepatic and cardiac oxidative stress induced by hyperlipidemia. More importantly, NF-E2 related factor (Nrf2)-mediated antioxidant and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathways as well as mitochondrial complex activities were downregulated in the hyperlipidemic mouse livers and hearts, which may be attributable to the loss of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity: all of these changes were reversed by HAE supplementation. Our findings link the AMPK/PGC-1α/Nrf2 cascade to hyperlipidemia-induced liver and heart impairments and demonstrate the protective effect of HAE as an AMPK activator in the prevention of hyperlipidemia-related diseases.

6.
Free Radic Biol Med ; 148: 42-51, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31899342

RESUMO

DNA 5-hydroxymethylcytosine (5hmC), converted from 5-methylcytosine (5mC), is highly enriched in the central nervous system and is dynamically regulated during neural development and metabolic disorders. However, whether and how neural 5hmC is involved in metabolic disorders shows little evidence. In this study, significant downregulation of the DNA 5hmC were observed in the cerebral cortex of HFD-induced diabetic mice, while phosphated AMP-activated protein kinase (p-AMPK) and ten-eleven translocation 2 (TET2) reduced, and mitochondrial dysfunction. We futher demonstrated that dysregulation of 5hmC preceded mitochondrial dysfunction in palmitic acid-treated HT22 cells and decreased level of 5hmC led to mitochondrial respiratory activity and apoptosis in HT22 cells. Taken together, our results reveal that neural 5hmC undergoes remodeling during HFD-induced metabolic disorder, and 5hmC downregulation significantly impacts on mitochondrial respiration and cell apoptosis. This study suggests a novel link between metabolic disorder and neural impairment through neural DNA 5hmC remodeling and resultant mitochondrial dysfunction.

7.
Adv Exp Med Biol ; 1217: 123-146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31898226

RESUMO

SKP1-cullin-1-F-box-protein (SCF) E3 ubiquitin ligase complex is responsible for the degradation of proteins in a strictly regulated manner, through which it exerts pivotal roles in regulating various key cellular processes including cell cycle and division, apoptosis, and differentiation. The substrate specificity of the SCF complex largely depends on the distinct F-box proteins, which function in either tumor promotion or suppression or in a context-dependent manner. Among the 69 F-box proteins identified in human genome, FBW7, SKP2, and ß-TRCP have been extensively investigated among various types of cancer in respective of their roles in cancer development, progression, and metastasis. Moreover, several specific inhibitors have been developed to target those E3 ligases, and their efficiency in tumors has been determined. In this review, we provide a summary of the roles of SCF E3 ligases in cancer development, as well as the potential application of miRNA or specific inhibitors for cancer therapy.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteínas F-Box/metabolismo , Humanos , Neoplasias/patologia
8.
Antioxid Redox Signal ; 32(3): 193-212, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31680537

RESUMO

Aims: To study the expression and regulatory role of SOD3 in adipocytes and adipose tissue. Results: SOD3 expression was determined in various tissues of adult C57BL/6J mice, human adipose tissue and epididymal adipose tissue, subcutaneous adipose tissue and brown adipose tissue of high-fat diet (HFD)-induced obese mice. SOD3 expression and release were evaluated in adipocytes differentiated from primary human preadipocytes and murine bone marrow-derived mesenchymal stem cells (BM-MSCs). The regulatory role for SOD3 was determined by SOD3 lentivirus knockdown in human adipocytes and global sod3 knockout (KO) mice. SOD3 was expressed at high levels in white adipose tissue, and adipocytes were the main cells expressing SOD3 in adipose tissue. SOD3 expression was significantly elevated in adipose tissue of HFD-fed mice. Moreover, SOD3 expression and release were markedly increased in differentiated human adipocytes and adipocytes differentiated from mouse BM-MSCs compared with undifferentiated cells. In addition, SOD3 silencing in human adipocytes increased expression of genes involved in lipid metabolic pathways such as PPARγ and SREBP1c and promoted the accumulation of triglycerides. Finally, global sod3 KO mice were more obese and insulin resistant with enlarged adipose tissue and increased triglyceride accumulation. Innovation: Our data showed that SOD3 is secreted from adipocytes and regulates lipid metabolism in adipose tissue. This important discovery may open up new avenues of research for the cytoprotective role of SOD3 in obesity and its associated metabolic disorders. Conclusion: SOD3 is a protective factor secreted by adipocytes in response to HFD-induced obesity and regulates adipose tissue lipid metabolism.

9.
Neurol Res ; 42(1): 22-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31679470

RESUMO

Objective: The protective effects of 2%-4% hydrogen gas in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) have been previously reported. This study aimed to assess the neuroprotective effects of high concentration hydrogen (HCH) on DEACMP.Methods: A total of 36 male Sprague-Dawley rats were divided into 3 groups. In the DEACMP group, rats were exposed to CO to induce CO poisoning; in the HCH group, the animals were exposed to 67% H2 and 33% O2 at 3,000 mL/min for 90 min immediately after CO poisoning. Neurological function was evaluated at 1 and 9 days after poisoning. Then, the contents of malondialdehyde, 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine, as well as superoxide dismutase activity in the serum, cortex and hippocampus were detected by ELISA. Additionally, the mRNA and protein expression levels of Nrf2 and downstream genes were detected by RT-PCR and Western blotting, respectively.Results: Our results showed that CO poisoning significantly impaired neurological function which was improved over time, and HCH markedly attenuated neurological impairment following CO poisoning. In addition, CO poisoning resulted in increased levels of malondialdehyde, 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine and markedly reduced superoxide dismutase activity at 1 and 9 days, which were significantly inhibited by HCH at 9 days. Finally, CO poisoning increased the mRNA and protein levels of Nrf2 and downstream genes, and HCH further induced the anti-oxidative capability.Conclusion: These findings indicate the neuroprotective effects of HCH on DEACMP, which are related to the activation of Nrf2 signaling pathway.

10.
Free Radic Biol Med ; 148: 52-59, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31887452

RESUMO

Oxidative stress-induced degeneration of retinal pigment epithelial (RPE) cells is known to be a key contributor to the development of age-related macular degeneration (AMD). Activation of the nuclear factor-(erythroid-derived 2)-related factor-2 (Nrf2)-mediated cellular defense system is believed to be a valid therapeutic approach. In the present study, we designed and synthesized a novel chalcone analogue, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), as a Nrf2 activator. The potency of Tak was measured in RPE cells by the induction of the Nrf2-dependent antioxidant genes HO-1, NQO-1, GCLc, and GCLm, which were regulated through the Erk pathway. We also showed that Tak could protect RPE cells against oxidative stress-induced cell death and mitochondrial dysfunction. Furthermore, by modifying the α, ß unsaturated carbonyl entity in Tak, we showed that the induction of antioxidant genes was abolished, indicating that this unique feature in Tak was responsible for the Nrf2 activation. These results suggest that Tak is a potential candidate for clinical application against AMD.

11.
Front Oncol ; 9: 1201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803610

RESUMO

Tumor cells, including cancer stem cells (CSCs) resistant to radio- and chemotherapy, must enhance metabolism to meet the extra energy demands to repair and survive such genotoxic conditions. However, such stress-induced adaptive metabolic alterations, especially in cancer cells that survive radiotherapy, remain unresolved. In this study, we found that CPT1 (Carnitine palmitoyl transferase I) and CPT2 (Carnitine palmitoyl transferase II), a pair of rate-limiting enzymes for mitochondrial fatty acid transportation, play a critical role in increasing fatty acid oxidation (FAO) required for the cellular fuel demands in radioresistant breast cancer cells (RBCs) and radiation-derived breast cancer stem cells (RD-BCSCs). Enhanced CPT1A/CPT2 expression was detected in the recurrent human breast cancers and associated with a worse prognosis in breast cancer patients. Blocking FAO via a FAO inhibitor or by CRISPR-mediated CPT1A/CPT2 gene deficiency inhibited radiation-induced ERK activation and aggressive growth and radioresistance of RBCs and RD-BCSCs. These results revealed that switching to FAO contributes to radiation-induced mitochondrial energy metabolism, and CPT1A/CPT2 is a potential metabolic target in cancer radiotherapy.

12.
Nutrients ; 11(12)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847305

RESUMO

Obesity and metabolic syndrome (MS) associated with excess calorie intake has become a great public health concern worldwide. L-arabinose, a naturally occurring plant pentose, has a promising future as a novel food ingredient with benefits in MS; yet the mechanisms remain to be further elucidated. Gut microbiota is recently recognized to play key roles in MS. Molecular hydrogen, an emerging medical gas with reported benefits in MS, can be produced and utilized by gut microbes. Here we show oral L-arabinose elicited immediate and robust release of hydrogen in mice in a dose-and-time-dependent manner while alleviating high-fat-diet (HFD) induced MS including increased body weight especially fat weight, impaired insulin sensitivity, liver steatosis, dyslipidemia and elevated inflammatory cytokines. Moreover, L-arabinose modulated gene-expressions involved in lipid metabolism and mitochondrial function in key metabolic tissues. Antibiotics treatment abolished L-arabinose-elicited hydrogen production independent of diet type, confirming gut microbes as the source of hydrogen. q-PCR of fecal 16S rDNA revealed modulation of relative abundances of hydrogen-producing and hydrogen-consuming gut microbes as well as probiotics by HFD and L-arabinose. Our data uncovered modulating gut microbiota and hydrogen yield, expression of genes governing lipid metabolism and mitochondrial function in metabolic tissues is underlying L-arabinose's benefits in MS.

13.
FASEB J ; 33(12): 14296-14306, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31645130

RESUMO

Growing evidence has suggested that autophagy-related protein 7 (ATG7) plays an important role in insulin signaling, but the mechanism of ATG7 in hepatic insulin sensitivity is not fully understood. The purpose of the present study is to clarify the underlying molecular mechanisms of ATG7 in obesity development. Serum and liver samples from mice fed a high fat diet (HFD) were evaluated for metabolic profile data and ATG expressions during obesity development. We found that compared with other ATGs, ATG7 expression increased earlier with lower hepatic insulin sensitivity in the 4-wk HFD-fed mice. For in vitro analyses, silencing ATG7 significantly up-regulated insulin-stimulated phosphorylation of protein kinase B (Akt) and down-regulated phosphatase and tension homolog deleted on chromosome ten (PTEN) in HepG2 cells. Replenishing PTEN to ATG7-silenced hepatocytes restored the phosphorylated Akt level. Furthermore, ATG7 silencing led to higher c-JUN expression, which transcriptionally reduced PTEN expression. These results reveal a novel mechanism by which ATG7 regulates Akt phosphorylation via the c-JUN/PTEN pathway at the early stage of HFD-induced metabolic disorder.-Zhao, D., Zhang, S., Wang, X., Gao, D., Liu, J., Cao, K., Chen, L., Liu, R., Liu, J., Long, J. ATG7 regulates hepatic Akt phosphorylation through the c-JUN/PTEN pathway in high fat diet-induced metabolic disorder.

14.
Free Radic Biol Med ; 145: 103-117, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31553938

RESUMO

Mitochondrial dysfunction is associated with obesity-induced cardiac remodelling. Recent research suggests that the cristae are the true bioenergetic components of cells. Acetylcholine (ACh), the major neurotransmitter of the vagus nerve, exerts cardio-protective effects against ischaemia. This study investigated the role of cristae remodelling in palmitate (PA)-induced neonatal rat cardiomyocyte hypertrophy and explored the beneficial effects of ACh. We found loose, fragmented and even lysed cristae in PA-treated neonatal cardiomyocytes along with declines in mitochondrial network and complex expression and overproduction of mitochondrial reactive oxygen species (ROS); these changes ultimately resulted in increased myocardial size. Overexpression of mitofilin by adenoviral infection partly improved cristae shape, mitochondrial network, and ATP content and attenuated cell hypertrophy. Interestingly, siRNA-mediated AMP-activated protein kinase (AMPK) silencing increased the number of cristae with a balloon-like morphology without disturbing mitofilin expression. Furthermore, AMPK knockdown abolished the effects of mitofilin overexpression on cristae remodelling and inhibited the interaction of mitofilin with sorting and assembly machinery 50 (Sam50) and coiled-coil helix coiled-coil helix domain-containing protein 3 (CHCHD3), two core components of the mitochondrial contact site and cristae organizing system (MICOS) complex. Intriguingly, ACh upregulated mitofilin expression and AMPK phosphorylation via the muscarinic ACh receptor (MAChR). Moreover, ACh enhanced protein-protein interactions between mitofilin and other components of the MICOS complex, thereby preventing PA-induced mitochondrial dysfunction and cardiomyocyte hypertrophy; however, these effects were abolished by AMPK silencing. Taken together, our data suggest that ACh improves cristae remodelling to defend against PA-induced myocardial hypertrophy, presumably by increasing mitofilin expression and activating AMPK to form the MICOS complex through MAChR. These results suggest new and promising therapeutic approaches targeting mitochondria to prevent lipotoxic cardiomyopathy.

15.
Ecol Evol ; 9(6): 3367-3377, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30962898

RESUMO

Grazing is one of the major anthropogenic driving factors influencing community structure and ecological function of grasslands. Fencing has been proved to be one of the main measures for rehabilitating degraded grasslands in northwestern China. However, data from combined empirical studies on the effects of different management regimes in desert grasslands are lacking. So we selected long-term fencing (fenced since 1991), mid-term fencing and seasonal fencing (fenced since 2002), and adjacent free-grazing grasslands to investigate vegetation and soil properties on southwest Mu Us desert. Our results showed that fencing increased plant cover, height, aboveground biomass (AGB) of different plant life-form groups, Shannon-Wiener diversity index, Evenness index, Simpson index, total soil nitrogen, total soil phosphorus, and soil organic matter, but decreased plant density, species richness, Richness index, soil bulk density, water content, and pH. However, 22-24 years of long-term complete fencing might cause redegradation of vegetation and soil nutrients, characterized by the reduction of some vegetation properties, biodiversity, total AGB, and some soil properties. Seasonal fencing with 11-13 year was more beneficial to vegetation restoration than that with completely fencing measures. Our study suggests that appropriate artificial disturbances, such as seasonal fencing (winter grazing and summer fencing), should be used after long-term fencing in order to maintain grassland productivity and biodiversity. These findings will help to provide theoretical support for vegetation restoration and sustainable management in grassland under grazing prohibition at Mu Us desert.

16.
Hum Genet ; 138(6): 613-624, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968252

RESUMO

Variations in mitochondrial DNA (mtDNA) have been fundamental for understanding human evolution and are causative for a plethora of inherited mitochondrial diseases, but the mutation signatures of germline mtDNA and their value in understanding mitochondrial pathogenicity remain unknown. Here, we carried out a systematic analysis of mutation patterns in germline mtDNA based on 97,566 mtDNA variants from 45,494 full-length sequences and revealed a highly non-stochastic and replication-coupled mutation signature characterized by nucleotide-specific mutation pressure (G > T>A > C) and position-specific selection pressure, suggesting the existence of an intensive mutation-selection interplay in germline mtDNA. We provide evidence that this mutation-selection interplay has strongly shaped the mtDNA sequence during evolution, which not only manifests as an oriented alteration of amino acid compositions of mitochondrial encoded proteins, but also explains the long-lasting mystery of CpG depletion in mitochondrial genome. Finally, we demonstrated that these insights may be integrated to better understand the pathogenicity of disease-implicated mitochondrial variants.


Assuntos
DNA Mitocondrial/genética , Evolução Molecular , Genoma Mitocondrial/genética , Mutação em Linhagem Germinativa , Doenças Mitocondriais/genética , Sequência de Bases , Mapeamento Cromossômico/métodos , Análise Mutacional de DNA/métodos , Humanos , Doenças Mitocondriais/diagnóstico , Proteínas Mitocondriais/genética
17.
Free Radic Biol Med ; 135: 251-260, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30878647

RESUMO

Accumulating evidence has elucidated that hyperlipidemia is closely associated with an increasing prevalence of CVDs (cardiovascular diseases) because of endothelial dysfunction. In the present study, we investigated the effect and mechanism of PU (Punicalagin), a major ellagitannin in pomegranate, on endothelial dysfunction both in vivo and in vitro. In vivo, PU significantly ameliorated hyperlipidemia-induced accumulation of serum triglyceride and cholesterol as well as endothelial and mitochondrial dysfunction of thoracic aorta. Intriguingly, the FoxO1 (forkhead box O1) pathway was activated, which may account for prevention of vascular dysfunction and mitochondrial loss via upregulating mitochondrial biogenesis. In line, through in vitro cell cultures, our study demonstrated that PU not only increased the total FoxO1 protein, but also enhanced its nuclear translocation. In addition, silencing of FoxO1 remarkably abolished the ability of PU to augment the mitochondrial biogenesis, eNOS (endothelial NO synthase) expression, and oxidative stress, implying the irreplaceable role of FoxO1 in regulating endothelial function in the presence of PU. Conversely, suppression of excessive ROS (reactive oxygen species) secured the PA (palmitate)-induced decrease of FoxO1 expression, implying that there was a cross-talk between FoxO1 pathway and ROS. Concomitantly, the inflammatory response in current study was primarily mediated via p38 MAPK/NF-κB signaling pathway besides of FoxO1 pathway. Taken together, our findings suggest that PU ameliorates endothelial dysfunction by activating FoxO1 pathway, a pivotal regulating switch of mitochondrial biogenesis.

18.
Diabetes Res Clin Pract ; 150: 1-7, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30794834

RESUMO

INTRODUCTION: Accurate dosing of medications for glycemic control is a challenge for clinicians in diabetic patients with kidney disease. Diminishing glomerular filtration rates are associated with decreased renal clearance of insulin and increased prevalence of hypoglycemic episodes. Measurement of glucose/C peptide ratios may be useful to guide dosing in those patients who receive powerful insulin secretogogues as glomerular function decreases with age and disease. METHODS: In order to determine the relationship between glucose, C-peptide and renal function, we reviewed the records of patients with type 2 diabetes followed in our kidney hypertension clinic who met the following criteria: age 35-90 years, requirement of medications to control glycemia, at least 4 simultaneous measurements of C peptide, HbA1c, creatinine and blood glucose. RESULTS: 87 patients (67 males, 20 females), ages 67.1 ±â€¯10.6 years, BMI 32.5 ±â€¯5.2, A1c 8.2 ±â€¯1.2%, eGFR 73 ±â€¯27.2 ml/min, had glucose/C-peptide ratios 60.7 ±â€¯46.4. 59% of the total group were taking insulin secretogogues. Patients were divided into groups based upon mean eGFR and use or absence of insulin secretogogues. Glucose C-peptide ratios were lowest in the quartile of patients with the lowest eGFR (<50 ml/min). CONCLUSION: Diminished renal function and advanced age are associated with the lowest glucose/C-peptide ratios, independent of achieved glycemic control. With similar use of secretogogues, glucose/C-peptide ratio were lower when eGFR was ≤49 ml/min compared to >50-80 ml/min. Use of secretogogues was associated with decreased glucose/C-peptide levels. In patients with reduced renal function (eGFR < 50 ml/min), use of insulin secretogogues may be associated with lower glucose/C-peptide ratios associated with higher risks for hypoglycemic reactions.


Assuntos
Biomarcadores/sangue , Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/diagnóstico , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico
19.
J Mol Cell Cardiol ; 128: 26-37, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660679

RESUMO

DNA methylation is a well-defined epigenetic modification that regulates gene transcription. However, the role of DNA methylation in the cardiac hypertrophy seen in hypertension is unclear. This study was performed to investigate genome-wide DNA methylation profiles in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKY), and the cardioprotective effect of choline. Eight-week-old male SHRs received intraperitoneal injections of choline (8 mg/kg/day) for 8 weeks. SHRs showed aberrant methylation distribution on chromosomes and genome regions, with decreased methylation levels at CHG and CHH sites. A total of 91,559 differentially methylated regions (DMRs) were detected between SHRs and WKY rats, of which 28,197 were demethylated and 63,362 were methylated. Choline treatment partly restored the DMRs in SHRs, which were related to 131 genes. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis of DMRs suggested that choline partly reversed the dysfunctions of biological processes, cellular components and molecular functions in SHRs. Moreover, the inhibition of 2-oxoglutarate accumulation by choline, thereby inhibiting excessive activation of ten-eleven translocation methylcytosine dioxygenase enzymes, may correlate with the beneficial effects of choline on methylation levels, cardiac hypertrophy and cardiac function of SHRs, as indicated by decreased heart rate and blood pressure, and increased ejection fraction and fractional shortening. This study provides the first genome-wide DNA methylation profile of the hypertrophic myocardium of SHRs and suggests a novel role for this epigenetic modification in hypertension. Choline treatment may represent a promising approach for modification of DNA methylation and optimization of the epigenetic profile for antihypertensive therapy.

20.
Diabetes Obes Metab ; 21(5): 1199-1208, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30672083

RESUMO

AIMS: Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) because of a concern that it may increase the risk of lactic acidosis. MATERIALS AND METHODS: All-cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non-users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT) (NCT00093015). Outcomes were compared after propensity matching of users and non-users and in multivariable proportional hazards models. RESULTS: There were 591 individuals who used metformin at baseline and 3447 non-users. Among propensity-matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than in non-users, but ESRD was marginally higher (4.0% vs 3.6%). Metformin use was independently associated with a reduced risk of all-cause mortality (HR, 0.49; 95% CI, 0.36-0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32-0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51-0.88) and the kidney disease composite (HR, 0.77; 95% CI, 0.61-0.98). Associations with ESRD (HR, 1.01; 95% CI, 0.65-1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed. CONCLUSIONS: Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.

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