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1.
Med Hypotheses ; 146: 110370, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33308934

RESUMO

Chronic infection is considered a risk factor for atherosclerosis. The link between infectious agents and atherosclerosis is manifested by the presence of infection-induced pyroptotic cells in atherosclerotic lesions. Pyroptosis is an inflammatory form of programmed cell death that occurs most frequently upon infection. However, inflammation is not the only cause by which pyroptosis involved in atherosclerosis. During pyroptosis, a large amount of microparticles are released from pyroptotic cells, which not only transfer inflammatory mediators to arterial vessel, but also mediate the interaction between a variety of cells, leading to endothelial injury, macrophage infiltration, vascular smooth muscle cell migration and proliferation, thereby accelerating atherosclerosis. Thus, we proposed hypothesis that pyroptotic cell-derived microparticle is an atherogenic factor in infectious diseases.

2.
Nutrition ; 83: 111058, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33360033

RESUMO

Substance abuse is a chronic relapsing disorder that results in serious health and socioeconomic issues worldwide. Addictive drugs induce long-lasting morphologic and functional changes in brain circuits and account for the formation of compulsive drug-seeking and drug-taking behaviors. Yet, there remains a lack of reliable therapy. In recent years, accumulating evidence indicated that neuroinflammation was implicated in the development of drug addiction. Findings from both our and other laboratories suggest that ω-3 polyunsaturated fatty acids (PUFAs) are effective in treating neuroinflammation-related mental diseases, and indicate that they could exert positive effects in treating drug addiction. Thus, in the present review, we summarized and evaluated recently published articles reporting the neuroinflammation mechanism in drug addiction and the immune regulatory ability of ω-3 PUFAs. We also sought to identify some of the challenges ahead in the translation of ω-3 PUFAs into addiction treatment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33314677

RESUMO

During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

4.
Pharmacology ; : 1-8, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694250

RESUMO

INTRODUCTION: Homeostasis of cholesterol is crucial for cellular function, and dysregulated cholesterol biosynthesis is a metabolic event that can lead to hepatic and cardiovascular abnormalities. OBJECTIVE: The aim of this study was to investigate the effects and mechanisms of domain-associated protein (Daxx) and androgen receptor (AR) on intracellular cholesterol synthesis. METHODS: HepG2 cells were transfected with pCDNA3.1(+)/Daxx plasmid or treated with testosterone propionate to observe the effects of Daxx and AR on intracellular cholesterol levels. Co-immunoprecipitation experiments were performed to identify the interaction between Daxx and AR and to explore the regulatory effects of this interaction on cholesterol synthesis. RESULTS: Our experiments showed that AR promoted cholesterol synthesis and accumulation by activating sterol-regulatory element-binding protein isoform 2. AR-induced cholesterol synthesis was inhibited by Daxx; however, the expression of AR was not affected. Further studies demonstrated the existence of direct binding between Daxx and AR and this interaction was required to suppress AR activity. CONCLUSIONS: The Daxx-mediated antagonism of AR depicts a more complete picture as to how Daxx regulates intracellular cholesterol level and provides a new target for treatment of atherosclerosis.

5.
J Membr Biol ; 253(2): 101-108, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32140737

RESUMO

As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.

6.
Medicine (Baltimore) ; 99(2): e18467, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914018

RESUMO

BACKGROUND: Curcumin, a controversial "panacea," has been broadly studied. Its bioactivities including antioxidant, anti-inflammatory, and especially antineoplastic activities have been documented. However, due to its extensive bioactivities, some scientists hold a skeptical point of view toward curcumin and described curcumin as a "deceiver" to chemists. The objective of this study was to explore curcumin's another possibility as a potential supplementary leading compound to cancer treatments. METHODS: Literature searches were conducted using electronic databases. Search terms such as "curcumin," "curcumin analogues," and so on were used. The literatures were collected and summarized. In this article, reported targets of curcumin are reviewed. The limitations of a curcumin as a therapeutic anticancer product including low bioavailability and poor targeting are mentioned. Furthermore, modified curcumin analogues and antitumor mechanisms are listed and discussed in the aspects of cell death and tumor microenvironment including angiogenesis, tissue hypoxia status, and energy metabolism. RESULTS: Several possible modification strategies were presented by analyzing the relationships between the antitumor activity of curcumin analogues and their structural characteristics, including the introduction of hydrophilic group, shortening of redundant hydrocarbon chain, the introduction of extra chemical group, and so on. CONCLUSIONS: From our perspective, after structural modification curcumin could be more effective complementary product for cancer therapies by the enhancement of targeting abilities and the improvement of bioavailability.


Assuntos
Corantes/metabolismo , Corantes/farmacologia , Curcumina/metabolismo , Curcumina/farmacologia , Antineoplásicos , Disponibilidade Biológica , Morte Celular/efeitos dos fármacos , Terapias Complementares , Curcumina/química , Humanos , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos
7.
Clin Chim Acta ; 500: 81-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31770510

RESUMO

The SREBP2/LDLR pathway is sensitive to cholesterol content in the endoplasmic reticulum (ER), while membrane low-density lipoprotein receptor (LDLR) is influenced by sterol response element binding protein 2 (SREBP2), pro-protein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL). LDL-C, one of the risk factors in cardiovascular disease, is cleared through endocytosis recycling of LDLR. Therefore, we propose that a balance between LDLR endocytosis recycling and PCSK9-mediated and IDOL-mediated lysosomal LDLR degradation is responsible for cholesterol homeostasis in the ER. For statins that decrease serum LDL-C levels via cholesterol synthesis inhibition, the mechanism by which the statins increase the membrane LDLR may be regulated by cholesterol homeostasis in the ER.


Assuntos
Colesterol/metabolismo , Receptores de LDL/metabolismo , Animais , Endocitose , Humanos , Receptores de LDL/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Transcrição Genética
8.
Pharmacol Res ; 136: 172-180, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30196102

RESUMO

Artemisinin (Qinghaosu) and its semi-synthetic derivatives have been demonstrated to alleviate neuroinflammatory response in the central nerve system (CNS). In this review, we summarized that artemisinins are capable to treat neuroinflammtion-related CNS diseases in both direct (via regulating inflammatory process in the CNS, exerting anti-oxidative stress and neuroprotective effect, and preventing Aß accumulation) and indirect (via maintaining BBB integrity, suppressing systemic inflammation and alleviating intestinal inflammtion) manner. However, the precise mechanism of their anti-neuroinflammatory effects and potential neurotoxicity, which hindered further progress in these aspects, remains unclear. We suggest that further understanding of the PK/PD properties and structure-action relationship of atemisinin and its derivatives will facilitate the development of new therapeutics with better curative effects and safety.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Artemisininas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Intestinos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
9.
Acta Pharmacol Sin ; 38(10): 1329-1339, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28504250

RESUMO

A variety of cardiovascular diseases is accompanied by the loss of vascular contractility. This study sought to investigate the effects of curcumin, a natural polyphenolic compound present in turmeric, on mouse vascular contractility and the underlying mechanisms. After mice were administered curcumin (100 mg·kg-1·d-1, ig) for 6 weeks, the contractile responses of the thoracic aorta to KCl and phenylephrine were significantly enhanced compared with the control group. Furthermore, the contractility of vascular smooth muscle (SM) was significantly enhanced after incubation in curcumin (25 µmol/L) for 4 days, which was accompanied by upregulated expression of SM marker contractile proteins SM22α and SM α-actin. In cultured vascular smooth muscle cells (VSMCs), curcumin (10, 25, 50 µmol/L) significantly increased the expression of myocardin, a "master regulator" of SM gene expression. Curcumin treatment also significantly increased the levels of caveolin-1 in VSMCs. We found that as a result of the upregulation of caveolin-1, curcumin blocked the activation of notch1 and thereby abolished Notch1-inhibited myocardin expression. Knockdown of caveolin-1 or activation of Notch1 signaling with Jagged1 (2 µg/mL) diminished these effects of curcumin in VSMCs. These findings suggest that curcumin induces the expression of myocardin in mouse smooth muscle cells via a variety of mechanisms, including caveolin-1-mediated inhibition of notch1 activation and Notch1-mediated repression of myocardin expression. This may represent a novel pathway, through which curcumin protects blood vessels via the beneficial regulation of SM contractility.


Assuntos
Curcumina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Proteínas Nucleares/genética , Transativadores/genética , Actinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Células Cultivadas , Curcumina/administração & dosagem , Relação Dose-Resposta a Droga , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
10.
J Cell Mol Med ; 21(9): 1967-1978, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28266128

RESUMO

Accumulating evidence demonstrates that hypoxia-inducible factor (HIF-α) hydroxylase system has a critical role in vascular remodelling. Using an endothelial-specific prolyl hydroxylase domain protein-2 (PHD2) knockout (PHD2EC KO) mouse model, this study investigates the regulatory role of endothelial HIF-α hydroxylase system in the development of renal fibrosis. Knockout of PHD2 in EC up-regulated the expression of HIF-1α and HIF-2α, resulting in a significant decline of renal function as evidenced by elevated levels of serum creatinine. Deletion of PHD2 increased the expression of Notch3 and transforming growth factor (TGF-ß1) in EC, thus further causing glomerular arteriolar remodelling with an increased pericyte and pericyte coverage. This was accompanied by a significant elevation of renal resistive index (RI). Moreover, knockout of PHD2 in EC up-regulated the expression of fibroblast-specific protein-1 (FSP-1) and increased interstitial fibrosis in the kidney. These alterations were strongly associated with up-regulation of Notch3 and TGF-ß1. We concluded that the expression of PHD2 in endothelial cells plays a critical role in renal fibrosis and vascular remodelling in adult mice. Furthermore, these changes were strongly associated with up-regulation of Notch3/TGF-ß1 signalling and excessive pericyte coverage.


Assuntos
Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Rim/irrigação sanguínea , Rim/patologia , Deleção de Sequência , Remodelação Vascular , Animais , Artérias/patologia , Arteríolas/patologia , Pressão Sanguínea , Fibrose , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Camundongos Knockout , Pericitos/metabolismo , Pericitos/patologia , Fenótipo
11.
Sci Rep ; 6: 20931, 2016 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26868537

RESUMO

Recent studies reveal a crucial role of pericyte loss in sepsis-associated microvascular dysfunction. Sirtuin 3 (SIRT3) mediates histone protein post-translational modification related to aging and ischemic disease. This study investigated the involvement of SIRT3 in LPS-induced pericyte loss and microvascular dysfunction. Mice were exposed to LPS, expression of Sirt3, HIF-2α, Notch3 and angiopoietins/Tie-2, pericyte/endothelial (EC) coverage and vascular permeability were assessed. Mice treated with LPS significantly reduced the expression of SIRT3, HIF-2α and Notch3 in the lung. Furthermore, exposure to LPS increased Ang-2 while inhibited Ang-1/Tie-2 expression with a reduced pericyte/EC coverage. Intriguingly, knockout of Sirt3 upregulated Ang-2, but downregulated Tie-2 and HIF-2α/Notch3 expression which resulted in a dramatic reduction of pericyte/EC coverage and exacerbation of LPS-induced vascular leakage. Conversely, overexpression of Sirt3 reduced Ang-2 expression and increased Ang-1/Tie-2 and HIF-2α/Notch3 expression in the LPS treated mice. Overexpression of Sirt3 further prevented LPS-induced pericyte loss and vascular leakage. This was accompanied by a significant reduction of the mortality rate. Specific knockout of prolyl hydroxylase-2 (PHD2) increased HIF-2α/Notch3 expression, improved pericyte/EC coverage and reduced the mortality rate in the LPS-treated mice. Our study demonstrates the importance of SIRT3 in preserving vascular integrity by targeting pericytes in the setting of LPS-induced sepsis.


Assuntos
Angiopoietinas/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Lipopolissacarídeos/farmacologia , Microvasos/fisiopatologia , Pericitos/patologia , Receptor Notch3/metabolismo , Receptor TIE-2/metabolismo , Sirtuína 3/metabolismo , Animais , Células Endoteliais , Coração/fisiopatologia , Inflamação/patologia , Pulmão , Camundongos Knockout , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Modelos Biológicos , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Med Hypotheses ; 86: 138-42, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26601593

RESUMO

Low-density lipoprotein cholesterol (LDL-C) is the hall marker for the atherosclerotic cardiovascular disease (ASCVD). It has been shown that over 70% of circulating LDL-C is metabolized through binding and activation of hepatic LDL receptor (LDLR). Genetic LDLR mutations cause hypercholesterolemia in the patients. Therefore, elevation of LDLR levels is beneficial for the treatment of dyslipidemia. LDLR expression is regulated by the SREBP2/PCSK9 pathways. Targeting SREBP2/PCSK9 pathways by statins and human monoclonal PCSK9 antibody has been shown to reduce the progression of ASVCD. Recent studies identified that inducible degrader of LDLR (IDOL) is a novel regulator of LDLR. IDOL is an E3-ubiquitin ligase regulated via liver X receptors (LXRs) binding to the upstream of translation start site of IDOL. IDOL modulates LDLR distribution through ubiquitination and degradation of LDLR in lysosomes. Genome-wide association studies (GWAS) have revealed that the nonsynonymous substitution rs9370867 of IDOL probably contributes to the variability of circulating LDL levels. Recently studies also demonstrated that IDOL influences PCSK9 expression in a LDLR/SREBP2-dependent manner. Based upon these novel findings, we hypothesize that IDOL and PCSK9 would have a synergistic effect on LDLR distribution. Specifically, loss of IDOL increases LDLR distribution in the hepatic cell, and subsequently reduces serum LDL-C levels in dyslipidemic patients. IDOL might be a potential therapeutic target for the treatment of ASCVD.


Assuntos
Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Hipolipemiantes/administração & dosagem , Modelos Biológicos , Receptores de LDL/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Ubiquitina-Proteína Ligases/efeitos dos fármacos
13.
Diabetes Res (Fairfax) ; 1(4): 84-91, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29167823

RESUMO

Heart failure is the leading cause of death in diabetic patients. Recently we showed that apelin gene therapy attenuates heart failure following myocardial infarction. This study further explored the potential mechanisms by which apelin may reduce cardiac injury in Postmyocardial infarction (MI)) model of diabetes. Wild type and Sirt3 knockout (Sirt3 KO) mice were induced into diabetes by intra-peritoneal (i.p.) Streptozotocin (STZ). STZ mice were then subjected to MI followed by immediate intramyocardial injection with Adenovirus-apelin (Ad-apelin). Ad-apelin treatment resulted in over expression of apelin in the ischemic hearts of STZ mice. Apelin over expression led to a significant increase in Sirt3 expression. Apelin over expression significantly reduced gp91phox expression. This was accompanied by a significant reduction of reactive oxygen species formation. Ad-apelin treatment also dramatically reduced NF-κb-p65 expression in WT-STZ mice. Over expression of apelin further enhanced autophagy markers (LC3-II and beclin-1) expression in post-MI heart. Most intriguingly, knockout of Sirt3 in STZ mice abolished these beneficial effects of apelin treatment. In vitro, knockout of Sirt3 in EPCs significantly enhanced high glucose-induced ROS formation. Conversely, treatment of Sirt3 KO-EPCs with NADPH oxidase inhibitor led to two fold increase in LC3-II levels. Our studies demonstrate that apelin increases autophagy via up regulation of Sirt3 and suppression of ROS-NF-κb pathway in diabetic heart.

14.
Pharmacology ; 94(5-6): 214-22, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25402258

RESUMO

BACKGROUND: Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efflux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions. METHODS AND RESULTS: Rat VSMCs were converted to foam cells by incubation with cholesterol:methyl-ß-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 µmol/l) or treated with 30 µmol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor α, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin-1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1. CONCLUSION: The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes.


Assuntos
Anticolesterolemiantes/farmacologia , Azetidinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Caveolina 1/genética , Colesterol/farmacologia , Ezetimiba , Metabolismo dos Lipídeos/genética , Receptores X do Fígado , Masculino , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Receptores Nucleares Órfãos/genética , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , beta-Ciclodextrinas/farmacologia
15.
Sheng Li Xue Bao ; 65(1): 89-95, 2013 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-23426519

RESUMO

Death domain-associated protein (DAXX) as a multifunctional nuclear protein widely resides in nucleolus, nucleoplasm, chromatin, promyelocytic leukaemia nuclear bodies (PML-NBs) and cytoplasm. It plays significant roles in transcriptional regulation, apoptosis, cell cycle and other biological activities. Small ubiquitin-like modifier (SUMO) is required for SUMOylation which is a highly conserved post-translational modification in a wide variety of cellular processes. Numerous studies demonstrated that SUMOylation has a great effect on the subcellular localization and functional regulation of DAXX. This review will provide a summary for SUMOylation of DAXX.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Nucleares/fisiologia , Sumoilação , Proteínas Correpressoras , Regulação da Expressão Gênica , Humanos , Chaperonas Moleculares
16.
Clin Exp Pharmacol Physiol ; 38(4): 239-46, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21291493

RESUMO

1. Adipocyte hypertrophy and hyperplasia are important processes in the development of obesity. To understand obesity and its associated diseases, it is important to elucidate the molecular mechanisms governing adipogenesis. MicroRNA-375 has been shown to inhibit differentiation of neurites, and participate in the regulation of insulin secretion and blood homeostasis. However, it is unknown whether miR-375 plays a role in adipocyte differentiation. 2. To investigate the role of miR-375 in adipocyte differentiation, we compared the miR-375 expression level between 3T3-L1 pre-adipocytes and adipocytes using miRNA microarray and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis. Furthermore, we evaluated the effects of overexpression or inhibition of miR-375 on 3T3-L1 adipocyte differentiation. 3. In the present study, we found that miR-375 expression was increased after induction of adipogenic differentiation. Overexpression of miR-375 enhanced 3T3-L1 adipocyte differentiation, as evidenced by its ability to increase mRNA levels of both CCAAT/enhancer binding protein-α (C/EBPα) and peroxisome proliferator-activated receptor-γ (PPARγ2), and induction of adipocyte fatty acid-binding protein (aP2) and triglyceride (TG) accumulation. Furthermore, we found overexpression of miR-375 suppressed phosphorylation levels of extracellular signal-regulated kinases 1/2 (ERK1/2). In contrast, anti-miR-375 increased ERK1/2 phosphorylation levels and inhibited mRNA expression of C/EBPα, PPARγ2 and aP2 in 3T3-L1 adipocyte, accompanied by decreased adipocyte differentiation. 4. Taken together, these data suggest that miR-375 promotes 3T3-L1 adipocyte differentiation, possibly through modulating the ERK-PPARγ2-aP2 pathway.


Assuntos
Adipócitos/citologia , Adipócitos/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , MicroRNAs/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/genética , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
17.
Acta Pharmacol Sin ; 32(1): 45-51, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21113176

RESUMO

AIM: To evaluate the effects of angiopoietin-1 (Ang-1) on myocardial endothelial cell function under high glucose (HG) condition. METHODS: Mouse heart myocardial endothelial cells (MHMECs) were cultured and incubated under HG (25 mmol/L) or normal glucose (NG, 5 mmol/L) conditions for 72 h. MTT was used to determine cellular viability, and TUNEL assay and caspase-3 enzyme linked immunosorbent assays were used to assay endothelial apoptosis induced by serum starvation. Immunoprecipitation and Western blot analysis were used to analyze protein phosphorylation and expression. Endothelial tube formation was used as an in vitro assay for angiogenesis. RESULTS: Exposure of MHMECs to HG resulted in dramatic decreases in phosphorylation of the Tie-2 receptor and its downstream signaling partners, Akt/eNOS, compared to that under NG conditions. Ang-1 (250 ng/mL) increased Tie-2 activation, inhibited cell apoptosis, and promoted angiogenesis. Ang-1-mediated protection of endothelial function was blunted by Ang-2 (25 ng/mL). CONCLUSION: Ang-1 activates the Tie-2 pathway and restores hyperglycemia-induced myocardial microvascular endothelial dysfunction. This suggests a protective role of Ang-1 in the ischemic myocardium, particularly in hearts affected by hyperglycemia or diabetes.


Assuntos
Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Células Endoteliais/metabolismo , Glucose/metabolismo , Miocárdio/metabolismo , Animais , Células Cultivadas , Camundongos , Miocárdio/citologia , Receptor TIE-2/metabolismo
18.
Acta Pharmacol Sin ; 31(10): 1336-42, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20835266

RESUMO

AIM: To explore the mechanisms involved in ox-LDL transcytosis across endothelial cells and the role of caveolae in this process. METHODS: An in vitro model was established to investigate the passage of oxidized low density lipoprotein (ox-LDL) through a tight monolayer of human umbilical vein endothelial cells (HUVEC) cultured on a collagen-coated filter. Passage of DiI-labeled ox-LDL through the monolayer was measured using a fluorescence spectrophotometer. The uptake and efflux of ox-LDL by HUVEC were determined using fluorescence microscopy and HPLC. RESULTS: Caveolae inhibitors - carrageenan (250 µg/mL), filipin (5 µg/mL), and nocodazole (33 µmol/L)-decreased the transport of ox-LDL across the monolayer by 48.9%, 72.4%, and 79.8% as compared to the control group. In addition, they effectively decreased ox-LDL uptake and inhibited the efflux of ox-LDL. Caveolin-1 and LOX-1 were up-regulated by ox-LDL in a time-dependent manner and decreased gradually after depletion of ox-LDL (P<0.05). After treatment HUVEC with ox-LDL and silencing caveolin-1, NF-κB translocation to the nucleus was blocked and LOX-1 expression decreased (P<0.05). CONCLUSION: Caveolae can be a carrier for ox-LDL and may be involved in the uptake and transcytosis of ox-LDL by HUVEC.


Assuntos
Cavéolas/metabolismo , Caveolina 1/metabolismo , Endocitose , Células Endoteliais/metabolismo , Lipoproteínas LDL/metabolismo , Veias Umbilicais/metabolismo , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Humanos , Microscopia de Fluorescência , Receptores Depuradores Classe E/biossíntese , Espectrometria de Fluorescência , Transcitose
19.
Clin Exp Pharmacol Physiol ; 36(9): e32-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19473196

RESUMO

1. MicroRNAs (miRNAs) play essential roles in many biological processes. It is known that aberrant miRNA expression contributes to some pathological conditions. However, it is not known whether miRNAs play any role in the development of insulin resistance in adipocytes, a key pathophysiological link between obesity and diabetes. 2. To investigate the function of miRNAs in the development of insulin resistance, using miRNA microarray analysis we compared miRNA expression profiles between normal insulinsensitive 3T3-L1 adipocytes and 3T3-L1 adipocytes rendered insulin resistant following treatment with high glucose (25mmol/L) and high insulin (1 mol/L). Furthermore, adipocytes were transfected with specific antisense oligonucleotides against miRNA-320 (anti-miR-320 oligo) and the effects on the development of insulin resistance were evaluated. 3. We identified 50 upregulated and 29 downregulated miRNAs in insulin-resistant (IR) adipocytes, including a 50-fold increase in miRNA-320 (miR-320) expression. Using bioinformatic techniques, the p85 subunit of phosphatidylinositol 3-kinase (PI3-K) was found to be a potential target of miR-320. In experiments with anti-miR-320 oligo, insulin sensitivity was increased in IR adipocytes, as evidenced by increases in p85 expression, phosphorylation of Akt and the protein expression of the glucose transporter GLUT-4, as well as insulin-stimulated glucose uptake. These beneficial effects of anti-miR-320 oligo were observed only in IR adipocytes and not in normal adipocytes. 4. In conclusion, the miRNA profile changes in IR adipocytes compared with normal 3T3-L1 adipocytes. Anti-miR-320 oligo was found to regulate insulin resistance in adipocytes by improving insulin­PI3-K signalling pathways. The findings provide information regarding a potentially new therapeutic strategy to control insulin resistance.


Assuntos
Adipócitos/metabolismo , Perfilação da Expressão Gênica , Resistência à Insulina/genética , Insulina/metabolismo , MicroRNAs/metabolismo , Células 3T3-L1 , Adipogenia/genética , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Biologia Computacional , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Oligonucleotídeos Antissenso/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Fatores de Tempo , Transfecção
20.
Biochem Biophys Res Commun ; 379(2): 277-82, 2009 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-19101502

RESUMO

Proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of various cardiovascular diseases. Curcumin, extracted from Curcumae longae, has been shown a variety of beneficial effects on human health, including anti-atherosclerosis by mechanisms poorly understood. In the present study, we attempted to investigate whether curcumin has any effect on VSMCs proliferation and the potential mechanisms involved. Our data showed curcumin concentration-dependently abrogated the proliferation of primary rat VSMCs induced by Chol:MbetaCD. To explore the underlying cellular and molecular mechanisms, we found that curcumin was capable of restoring caveolin-1 expression which was reduced by Chol:MbetaCD treatment. Moreover, curcumin abrogated the increment of phospho-ERK1/2 and nuclear accumulation of ERK1/2 in primary rat VSMCs induced by Chol:MbetaCD, which led to a suppression of AP-1 promoter activity stimulated by Chol:MbetaCD. In addition, curcumin was able to reverse cell cycle progression induced by Chol:MbetaCD, which was further supported by its down-regulation of cyclinD1 and E2F promoter activities in the presence of Chol:MbetaCD. Taking together, our data suggest curcumin inhibits Chol:MbetaCD-induced VSMCs proliferation via restoring caveolin-1 expression that leads to the suppression of over-activated ERK signaling and causes cell cycle arrest at G1/S phase. These novel findings support the beneficial potential of curcumin in cardiovascular disease.


Assuntos
Proliferação de Células/efeitos dos fármacos , Colesterol/farmacologia , Curcumina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Animais , Caveolina 1/metabolismo , Ciclo Celular/efeitos dos fármacos , Colesterol/metabolismo , Ciclina D1/metabolismo , Regulação para Baixo , Fatores de Transcrição E2F/metabolismo , Humanos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologia , Ratos , Ratos Sprague-Dawley , beta-Ciclodextrinas/farmacologia
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