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1.
Eur Heart J ; 43(43): 4579-4595, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-35929617

RESUMO

AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.


Assuntos
Vesículas Extracelulares , Sirtuínas , Humanos , Camundongos , Animais , Idoso , Pré-Escolar , Fibronectinas/metabolismo , Fatores de Transcrição/metabolismo , Camundongos Knockout , Envelhecimento , Angiotensina II/farmacologia , Inflamação/metabolismo , Músculo Esquelético/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 44(6): 1107-1111, 2022 Dec.
Artigo em Zh | MEDLINE | ID: mdl-36373636

RESUMO

Sorting nexin 16(SNX16),a member of the SNX family,contains a phoxhomology domain that is prone to bind with phosphatidylinositol-3-phosphate domain and a C-terminal coiled-coil domain. SNX16 participates in diverse cellular processes such as endocytosis,protein sorting,and signal transduction. The dysfunctions of SNX16 are demonstrated to be involved in the occurrence of several diseases.Here,we review the structural characteristics and biological functions of SNX16 and discuss the regulatory role of SNX16 in diseases,surveying how SNX16 can be applied to the prevention and treatment of related disorders.


Assuntos
Endossomos , Nexinas de Classificação , Nexinas de Classificação/química , Nexinas de Classificação/metabolismo , Endossomos/metabolismo , Transporte Proteico , Transdução de Sinais
3.
Clin Exp Pharmacol Physiol ; 48(2): 238-249, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33051888

RESUMO

Glucose homeostasis is tightly controlled by balance between glucose production and uptake in liver tissue upon energy shortage condition. Altered glucose homeostasis contributes to the pathophysiology of metabolic disorders including diabetes and obesity. Here, we aimed to analyse the change of proteomic profile upon prolonged fasting in mice with isobaric tag for relative and absolute quantification (iTRAQ) labelling followed by liquid chromatography-mass spectrometry (LC/MS) technology. Adult male mice were fed or fasted for 16 hours and liver tissues were collected for iTRAQ labelling followed by LC/MS analysis. A total of 322 differentially expressed proteins were identified, including 189 upregulated and 133 downregulated proteins. Bioinformatics analyses, including Gene Ontology analysis (GO), Kyoto encyclopaedia of genes and genomes analysis (KEGG) and protein-protein interaction analysis (PPI) were conducted to understand biological process, cell component, and molecular function of the 322 differentially expressed proteins. Among 322 hepatic proteins differentially expressed between fasting and fed mice, we validated three upregulated proteins (Pqlc2, Ehhadh and Apoa4) and two downregulated proteins (Uba52 and Rpl37) by western-blotting analysis. In cultured HepG2 hepatocellular cells, we found that depletion of Pqlc2 by siRNA-mediated knockdown impaired the insulin-induced glucose uptake, inhibited GLUT2 mRNA level and suppressed the insulin-induced Akt phosphorylation. By contrast, knockdown of Pqlc2 did not affect the cAMP/dexamethasone-induced gluconeogenesis. In conclusion, our study provides important information on protein profile change during prolonged fasting with iTRAQ- and LC-MS/MS-based quantitative proteomics, and identifies Pqlc2 as a potential regulator of hepatic glucose metabolism and insulin signalling pathway in this process.


Assuntos
Proteômica , Animais , Glucose , Masculino , Camundongos , Transdução de Sinais
4.
J Pineal Res ; 67(4): e12611, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541591

RESUMO

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.


Assuntos
MAP Quinase Quinase Quinase 5/metabolismo , Melatonina/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Ubiquitinação/efeitos dos fármacos , beta-Arrestina 1/metabolismo , Animais , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Estabilidade Enzimática/efeitos dos fármacos , Estabilidade Enzimática/genética , MAP Quinase Quinase Quinase 5/genética , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Ubiquitinação/genética , beta-Arrestina 1/genética
5.
World J Gastrointest Surg ; 16(8): 2494-2502, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39220067

RESUMO

BACKGROUND: Perianal fistulas pose dual challenges to Crohn's disease (CD) patients. Low patient compliance due to the complexity of existing examination methods plagues the treatment and follow-up management of perianal CD. AIM: To determine the accuracy of endoanal ultrasound (EUS) and shear wave elastography (SWE) for evaluating perianal fistulizing CD (PFCD) activity. METHODS: This was a retrospective cohort study. A total of 67 patients from August 2022 to December 2023 diagnosed with CD were divided into three groups: Non-anal fistula group (n = 23), low-activity perianal fistulas [n = 19, perianal disease activity index (PDAI) ≤ 4], high-activity perianal fistulas (n = 25, PDAI > 4) based on the PDAI. All patients underwent assessments including EUS + SWE, pelvic magnetic resonance [pelvic magnetic resonance imaging (MRI)], C-reactive protein, fecal calprotectin, CD activity index, PDAI. RESULTS: The percentage of fistulas indicated by pelvic MRI and EUS was consistent at 82%, and there was good consistency in the classification of perianal fistulas (Kappa = 0.752, P < 0.001). Significant differences were observed in the blood flow Limberg score (χ 2 = 8.903, P < 0.05) and shear wave velocity (t = 2.467, P < 0.05) between group 2 and 3. Shear wave velocity showed a strong negative correlation with magnetic resonance novel index for fistula imaging in CD (Magnifi-CD) score (r = -0.676, P < 0.001), a weak negative correlation with the PDAI score (r = -0.386, P < 0.05), and a weak correlation between the Limberg score and the PDAI score (r = 0.368, P < 0.05). CONCLUSION: EUS combined with SWE offers a superior method for detecting and quantitating the activity of perianal fistulas in CD patients. It may be the ideal tool to assess PFCD activity objectively for management strategies.

6.
Cell Death Differ ; 30(2): 457-474, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36477078

RESUMO

Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bisN4-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.


Assuntos
Desdiferenciação Celular , Miócitos de Músculo Liso , Camundongos , Animais , Células Cultivadas , Homeostase , Miócitos de Músculo Liso/metabolismo , Músculo Liso , Proliferação de Células
7.
Br J Pharmacol ; 178(10): 2111-2130, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32037512

RESUMO

BACKGROUND AND PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is a worldwide public health problem with no established pharmacological therapy. Here, we explored the potential benefit of P7C3-A20, a novel aminopropyl carbazole compound with neuroprotective activity, in a NAFLD model, induced in mice by a high-fat diet (HFD). EXPERIMENTAL APPROACH: C57BL/6J mice were given a HFD (42% fat content) for 16 weeks to induce NAFLD. P7C3-A20 (20 mg·kg-1 ·day-1 ) was given by gavage for 2 weeks. Indirect calorimetry, histological analysis, immunoblotting, immunohistochemistry, and biomedical examinations were performed. Gut microbiota were determined using a 16S ribosomal RNA sequencing analysis. KEY RESULTS: P7C3-A20 treatment reduced body weight gain/adiposity, improved insulin resistance, promoted energy expenditure (O2 consumption/CO2 production), inhibited lipid oxidation, suppressed hepatic inflammation (Kupffer cell number and pro-inflammatory factors), decreased necroptosis/apoptosis (receptor-interacting protein kinase 3, cleaved caspase-3, and TUNEL), and alleviated liver fibrosis and injury. Mechanistically, P7C3-A20 stimulated FGF21 and FGF1 via activating liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), which further resulted in a reduced nuclear translocation of CREB-regulated transcription coactivator 2 (CRTC2). In AMPKα2 knockout mice, the protection of P7C3-A20 against HFD-induced metabolism abnormalities and fat accumulation, as well as the elevation of blood FGF21 and FGF1, was abolished. P7C3-A20 increased the gut microbiota species richness. Moreover, it enhanced the proportions of Akkermansia, Lactobacillus, and Prevotellaceae, while reducing the proportions of Enterobacteriaceae, Escherichia, and Parasutterella. CONCLUSIONS AND IMPLICATIONS: P7C3-A20 increased levels of NAD+ and alleviated NAFLD through stimulating FGF21 and FGF1 in an LKB1/AMPK/CRTC2-dependent manner and shaping gut microbiota. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.


Assuntos
Carbazóis/farmacologia , Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Proteínas Quinases Ativadas por AMP , Animais , Dieta Hiperlipídica , Fator 1 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico
8.
Br J Pharmacol ; 176(22): 4388-4401, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30270436

RESUMO

BACKGROUND AND PURPOSE: PDGF-BB is an angiogenic factor involved in cardiovascular diseases. Here, we investigated the possible effects of activation of the nicotinic ACh receptor α7 subtype (α7nAChR) on PDGF-BB-induced proliferation and migration in vascular smooth muscle cells (VSMCs). EXPERIMENTAL APPROACH: PNU-282987, a selective α7nAChR pharmacological agonist, was used to activate α7nAChR. The influences of α7nAChR activation on PDGF-BB-induced proliferation and migration, as well as the phosphorylation of focal adhesion kinase (FAK)/Src, a pro-migration signalling pathway, were determined in VSMCs. A variety of biochemical assays were applied to explore the underlying molecular mechanisms. KEY RESULTS: PDGF-BB induced pronounced migration and proliferation of VSMCs. Activation of α7nAChRs by PNU-282987 blocked PDGF-BB-induced migration but not proliferation in wild-type (WT) VSMCs, whereas this effect was absent in α7nAChR-knockout VSMCs. Accordingly, PNU-282987 attenuated PDGF-BB-induced phosphorylation of FAKTyr397 and SrcTyr416 in WT VSMCs. Mechanistically, PNU-282987 suppressed PDGF-BB-induced oxidative stress, as demonstrated by the alterations in ROS, H2 O2 content, superoxide anion and total antioxidant activity. A sirtuin 3 (SIRT3) inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine or shRNA-mediated SIRT3 knockdown abolished the inhibitory effect of PNU-282987. PNU-282987 did not modulate SIRT3 protein expression but enhanced mitochondrial SIRT3 deacetylase activity. In line with this action, PNU-282987 enhanced the deacetylation of mitochondrial FoxO3. Lastly, PNU-282987 corrected the PDGF-BB-induced mitochondrial dysfunction by increasing mitochondrial citrate synthase activity, ATP content and nicotinamide adenine dinucleotide pool. CONCLUSIONS: Pharmacological activation of α7nAChRs inhibits PDGF-BB-induced VSMC migration by activating the mitochondrial deacetylase SIRT3, implying an important role for α7nAChRs in mitochondria biology and PDGF-related diseases. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.


Assuntos
Becaplermina/metabolismo , Sirtuína 3/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/genética , Quinases da Família src/metabolismo
9.
Artigo em Zh | MEDLINE | ID: mdl-12567574

RESUMO

OBJECTIVE: To detect the value of qualitative and orientating diagnosis in the degeneration stage of cerebral cysticercosis with Gd-DTPA enhanced MR. METHODS: Sixty-nine cases of cerebral cysticercosis were diagnosed by enhanced MR as degeneration stage, and confirmed by immunological examination and/or by surgery. MR plain scanning was conducted for the same cases. RESULTS: The plain scanning showed single or multiple lesions with long T1 and long T2 signals, and the enhanced scanning showed nodular or annular lesions. The diameter of the lesion after enhanced scan was not more than 22 mm with an average value of 8.1 mm. Some cases showed single lesion on plain scanning but showed multiple lesions after enhanced scan. CONCLUSION: The enhanced MR shows more typical features of the degeneration stage cerebral cysticercosis. It can define the number, position and range of the lesions, and can improve the accuracy of differential diagnosis, and therefore be of importance in formulating treatment scheme and prognosis.


Assuntos
Gadolínio DTPA , Imageamento por Ressonância Magnética/métodos , Neurocisticercose/diagnóstico , Adolescente , Adulto , Idoso , Criança , Diagnóstico Diferencial , Feminino , Humanos , Aumento da Imagem , Masculino , Pessoa de Meia-Idade , Prognóstico
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