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1.
Int J Biol Sci ; 18(4): 1651-1662, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35280686

RESUMO

Myocardial ischemia/reperfusion (I/R) injury is recognized as the leading cause of death worldwide. However, the molecular mechanisms involved in this process are still not fully understood. We previously reported that the combined action of Notch1 and Keap1-NRF2 signaling pathway can significantly increase the activity of cardiomyocytes, inhibit the apoptosis of cardiomyocytes, reduce the formation of reactive oxygen species, and improve the antioxidant activity in neonate rat myocardial cells. However, the regulatory mechanism of Notch1 signaling pathway on the NRF2 signaling pathway and its actual role on I/R injury are still unclear. Herein, we found that Keap-NRF2 signaling is activated by Notch1 in RBP-Jκ dependent manner, thus protects the heart against I/R injury via inhibiting the mitochondrial ROS generation and improves the mitochondrial bioenergetics in vitro and in vivo. These results suggest that Keap-NRF2 signaling might become a promising therapeutic strategy for treating myocardial I/R injury.


Assuntos
Traumatismo por Reperfusão Miocárdica , Traumatismo por Reperfusão , Animais , Apoptose/genética , Metabolismo Energético , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
2.
Front Cardiovasc Med ; 8: 757022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778409

RESUMO

Aortic dissection (AD) is a catastrophic cardiovascular emergency with a poor prognosis, and little preceding symptoms. Abnormal lipid metabolism is closely related to the pathogenesis of AD. However, comprehensive lipid alterations related to AD pathogenesis remain unclear. Moreover, there is an urgent need for new or better biomarkers for improved risk assessment and surveillance of AD. Therefore, an untargeted lipidomic approach based on ultra-high-performance liquid chromatograph-mass spectrometry was employed to unveil plasma lipidomic alterations and potential biomarkers for AD patients in this study. We found that 278 of 439 identified lipid species were significantly altered in AD patients (n = 35) compared to normal controls (n = 32). Notably, most lipid species, including fatty acids, acylcarnitines, cholesteryl ester, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylcholines, phosphatidylinositols, diacylglycerols, and triacylglycerols with total acyl chain carbon number ≥54 and/or total double bond number ≥4 were decreased, whereas phosphatidylethanolamines and triacylglycerols with total double bond number <4 accumulated in AD patients. Besides, the length and unsaturation of acyl chains in triacylglycerols and unsaturation of 1-acyl chain in phosphatidylethanolamines were decreased in AD patients. Moreover, lysophosphatidylcholines were the lipids with the largest alterations, at the center of correlation networks of lipid alterations, and had excellent performances in identifying AD patients. The area under the curve of 1.0 and accuracy rate of 100% could be easily obtained by lysophosphatidylcholine (20:0/0:0) or its combination with lysophosphatidylcholine (17:0/0:0) or lysophosphatidylcholine (20:1/0:0). This study provides novel and comprehensive plasma lipidomic signatures of AD patients, identifies lysophosphatidylcholines as excellent potential biomarkers, and would be beneficial to the pathogenetic study, risk assessment and timely diagnosis and treatment of AD.

3.
Surg Endosc ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845555

RESUMO

AIM: To evaluate the efficacy and safety of brachytherapy with double-strand 125I seeds and biliary drainage for malignant obstructive jaundice. METHODS AND MATERIALS: 42 patients with obstructive jaundice because of extrahepatic cholangiocarcinoma were enrolled. 22 patients (group A) received a biliary stent with common drainage tube implantation, and 20 patients (group B) received a biliary stent with double-strand 125I seeds radiotherapy drainage tube placement. The length, location and pathological stage of biliary stricture were recorded in the two groups. Total bilirubin (TBIL), direct bilirubin (DBIL), IgA, IgG, IgM, alanine aminotransferase and white blood cell (WBC) count were measured before and after percutaneous transhepatic cholangial drainage (PTCD). Tumor diameter was measured before and three months after PTCD, and the difference were calculated. Stent patency time, survival time, and complications were recorded. RESULTS: There was no significant difference in the length, location and pathological stage of biliary stenosis between the two groups. There was no significant difference in TBIL, DBIL, IgA, IgG, IgM, alanine aminotransferase and WBC count between the two groups before or after PTCD (P > 0.05). Three months after PTCD, tumors growth in group A and tumors shrinkage in group B. The difference in tumor size between the two groups before and after PTCD was statistically significant (P < 0.05). The average stent patency times in groups A and B were 3.55 ± 0.76 months and 8.76 ± 1.85 months, respectively (P < 0.05). The average survival times in groups A and B were 133.5 ± 27.8 days and 252.5 ± 114.5 days, respectively (P < 0.05). There was no statistically significant difference in the incidence of complications between the two groups (P > 0.05). CONCLUSION: Double-strand 125I seeds radiotherapy biliary drainage tubes can safely and effectively control tumors, prolong the patency of biliary stents, and prolong patient survival.

4.
Biomed Res Int ; 2021: 5669412, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722766

RESUMO

Idiopathic pulmonary arterial hypertension (IPAH) is a rare vascular disease with a poor prognosis, and the mechanism of its development remains unclear. Further molecular pathology studies may contribute to a comprehensive understanding of IPAH and provide new insights into diagnostic markers and potential therapeutic targets. Iron deficiency has been reported in 43-63% of patients with IPAH and is associated with reduced exercise capacity and higher mortality, suggesting that dysregulated iron metabolism may play an unrecognized role in influencing the development of IPAH. In this study, we explored the regulatory mechanisms of iron metabolism in IPAH by bioinformatic analysis. The molecular function of iron metabolism-related genes (IMRGs) is mainly enriched in active transmembrane transporter activity, and they mainly affect the biological process of response to oxidative stress. Ferroptosis and fluid shear stress and atherosclerosis pathways may be the critical pathways regulating iron metabolism in IPAH. We further identified 7 key genes (BCL2, GCLM, MSMO1, SLC7A11, SRXN1, TSPAN5, and TXNRD1) and 5 of the key genes (BCL2, MSMO1, SLC7A11, TSPAN5, and TXNRD1) as target genes may be regulated by 6 dysregulated miRNAs (miR-483-5p, miR-27a-3p, miR-27b-3p, miR-26b-5p, miR-199a-5p, and miR-23b-3p) in IPAH. In addition, we predicted potential IPAH drugs-celastrol and cinnamaldehyde-that target iron metabolism based on our results. These results provide insights for further definition of the role of dysregulated iron metabolism in IPAH and contribute to a deeper understanding of the molecular mechanisms and potential therapeutic targets of IPAH.


Assuntos
Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/metabolismo , Ferro/metabolismo , China , Biologia Computacional/métodos , Bases de Dados Genéticas , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Ferroptose/fisiologia , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , MicroRNAs/genética , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Artéria Pulmonar/fisiopatologia , Transcriptoma/genética
5.
Bioengineered ; 12(2): 9976-9990, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34652258

RESUMO

Stanford type A aortic dissection (TAAD) is one of the most dangerous vascular diseases worldwide, and the mechanisms of its development remain unclear. Further molecular pathology studies may contribute to a comprehensive understanding of TAAD and provide new insights into diagnostic markers and potential therapeutic targets. Recent studies have identified that ferroptosis, a form of cell death, may play a previously unrecognized role in influencing the development of TAAD. In this study, we explored the pathological role of ferroptosis in TAAD by performing bioinformatics analyses. Gene set enrichment analysis (GSEA) showed that the ferroptosis-related gene (FRG) set was significantly different between normal and TAAD aortic samples at an overall level (p < 0.001). Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses explored the potential functions and pathways of FRG in TAAD. We further identified six key genes (CA9, HMOX1, IL6, CDKN1A, HIF1A, MYC) from differentially expressed FRGs in TAAD by constructing a protein-protein interaction (PPI) network, all key genes were upregulated in TAAD. Four of the key genes (CA9, IL6, CDKN1A, and HIF1A) were demonstrated to be correlated with cigarette smoke extract-induced ferroptosis in aortic vascular smooth muscle cells. These results suggest that ferroptosis is one of the essential pathological processes in the development of TAAD, and some FRGs affect TAAD development by mediating cellular ferroptosis, which provides deepening insights into the molecular mechanisms and potential therapeutic targets of TAAD.


Assuntos
Aneurisma Dissecante/genética , Biologia Computacional , Ferroptose/genética , Algoritmos , Aneurisma Dissecante/imunologia , Animais , Linhagem Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Mapas de Interação de Proteínas/genética , Ratos , Reprodutibilidade dos Testes
6.
Aging (Albany NY) ; 13(5): 7538-7548, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33658391

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal disease whose molecular mechanism is unknown. The trimethylation of lysine 36 on histone 3 (H3K36me3) catalyzed by SETD2 and the modification of N6-methyladenine (m6A) mRNA mediated by METTL14 play important roles in a variety of normal and pathological biological processes. However, the role of these epigenetic controls in the pathogenesis of PAH remains unclear. In this study, the expression of SETD2 and METTL14 was elevated in pulmonary artery smooth muscle cells (PASMCs) of hypoxia-induced PAH mice. We further constructed a mouse model with SETD2 specific knockout in smooth muscle cells (SETD2SM22α Cre). Our results suggest that the lack of SETD2 in SMCs protected mice from hypoxia-induced PAH and significantly reduced right ventricular systolic pressure (RVSP), right ventricular/left ventricular plus septum [RV/(LV+S)] weight ratio, and pulmonary median width. In addition, the absence of SETD2 in SMCs alleviates the level of METTL14 expression and the m6A RNA methylation level in PAH SMCs. These results obtained from mice suggest that strategies that target the inhibition of SETD2/METTL14 activity may be a viable treatment for PAH in a clinical setting.


Assuntos
Metiltransferases/metabolismo , Hipertensão Arterial Pulmonar/etiologia , Animais , Metilação de DNA , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipóxia/complicações , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/metabolismo , Hipertensão Arterial Pulmonar/metabolismo
7.
Front Oncol ; 11: 778132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35004298

RESUMO

Despite N6-methyladenosine (m6A) is functionally important in various biological processes, its role in the underlying regulatory mechanism in TNBC are lacking. In this study, we investigate the pathological role and the underlying mechanism of the m6A methylated RNA level and its major methyltransferase METTL3 in the TNBC progression. We found that the m6A methylated RNA was dramatically decreased in TNBC tissues and cell lines. Functionally, we demonstrated that METTL3 inhibits the proliferation, migration, and invasion ability of TNBC cells. Moreover, we found METTL3 is repressed by miR-34c-3p in TNBC cells. On the mechanism, we found that circMETTL3 could act as a sponge for miR-34c-3p and inhibits cell proliferation, invasion, tumor growth and metastasis by up-regulating the expression of miR-34c-3p target gene METTL3. In conclusion, our study demonstrates the functional importance and regulatory mechanism of METTL3 in suppressing the tumor growth of TNBC.

8.
J Cell Mol Med ; 24(14): 7907-7914, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32529705

RESUMO

Increased expression and activity of cardiac and circulating cathepsin D and soluble fms-like tyrosine kinase-1 (sFlt-1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23-kD prolactin (PRL) to 16-kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY-411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt-1, reduced Hes1, phosphorylated Stat3 (p-Stat3), VEGFA and PDGFB, and promoted cleavage of 23k-D PRL to 16-kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt-1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.


Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Período Periparto/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Cardiomegalia/diagnóstico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico , Catepsina D/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ecocardiografia , Feminino , Fibrose , Proteínas de Membrana/metabolismo , Camundongos , Gravidez , Proteólise , Remodelação Ventricular
9.
Biochem Cell Biol ; 98(2): 106-111, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32069075

RESUMO

Both the Notch1 and Keap1-Nrf2 signaling pathways have cardioprotective effects, but the role of Notch1-Nrf2 crosstalk in myocardial ischemia-reperfusion injury is unclear. In this study, we established hypoxia-reoxygenation in neonate rat myocardial cells and employed γ-secretase inhibitor and curcumin to inhibit and activate the Notch1 and Keap1-Nrf2 signaling pathways, respectively. We found that the combined action of the Notch1 and Keap1-Nrf2 signaling pathways significantly increased cardiomyocyte viability, inhibited cardiomyocyte apoptosis, reduced the formation of reactive oxygen species, and increased antioxidant activities. In conclusion, these findings suggest that Notch1-Nrf2 crosstalk exerts myocardial protection by reducing the formation of reactive oxygen species.


Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor Notch1/metabolismo , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Apoptose , Hipóxia Celular , Núcleo Celular/metabolismo , Proliferação de Células , Sobrevivência Celular , Citoplasma/metabolismo , Regulação Neoplásica da Expressão Gênica , Hipóxia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais
10.
J Cell Mol Med ; 24(5): 3183-3191, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31975567

RESUMO

Mitochondrial fusion and fission dynamic are critical to the myocardial protection against ischaemia-reperfusion injury. Notch1 signalling plays an important role in heart development, maturation and repair. However, the role of Notch1 in the myocardial mitochondrial fusion and fission dynamic remains elusive. Here, we isolated myocardial cells from rats and established myocardial ischaemia-reperfusion injury (IRI) model. We modulated Notch1, MFN1 and DRP1 expression levels in myocardial cells via infection with recombinant adenoviruses. The results showed that Notch1 improves the cell viability and mitochondrial fusion in myocardiocytes exposed to IRI. These improvements were dependent on the regulation of MFN1 and DRP1. On the mechanism, we found that MNF1 is transcriptionally activated by RBP-Jk in myocardiocytes. Notch1 also improves the mitochondrial membrane potential in myocardiocytes exposed to IRI. Moreover, we further confirmed the protection of the Notch1-MFN1/Drp1 axis on the post-ischaemic recovery of myocardial performance is associated with the preservation of the mitochondrial structure. In conclusion, this study presented a detailed mechanism by which Notch1 signalling improves mitochondrial fusion during myocardial protection.


Assuntos
Dinaminas/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , Receptor Notch1/genética , Animais , Apoptose/genética , Sobrevivência Celular/genética , Regulação da Expressão Gênica/genética , Masculino , Potencial da Membrana Mitocondrial/genética , Mitocôndrias Cardíacas/genética , Dinâmica Mitocondrial/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Substâncias Protetoras/farmacologia , Ratos , Transdução de Sinais/genética
11.
Clin Sci (Lond) ; 133(9): 1085-1096, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31040165

RESUMO

Nuclear receptor binding SET domain 2 (NSD2)-mediated metabolic reprogramming has been demonstrated to regulate oncogenesis via catalyzing the methylation of histones. The present study aimed to investigate the role of NSD2-mediated metabolic abnormality in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH rat model was established and infected with adeno-associated virus carrying short hairpin RNA (shRNA) targeting NSD2. Hemodynamic parameters, ventricular function, and pathology were evaluated by microcatheter, echocardiography, and histological analysis. Metabolomics changes in lung tissue were analyzed by LC-MS. The results showed that silencing of NSD2 effectively ameliorated MCT-induced PAH and right ventricle dysfunction, and partially reversed pathological remodeling of pulmonary artery and right ventricular hypertrophy. In addition, the silencing of NSD2 markedly reduced the di-methylation level of H3K36 (H3K36me2 level) and inhibited autophagy in pulmonary artery. Non-targeted LC-MS based metabolomics analysis indicated that trehalose showed the most significant change in lung tissue. NSD2-regulated trehalose mainly affected ABC transporters, mineral absorption, protein digestion and absorption, metabolic pathways, and aminoacyl-tRNA biosynthesis. In conclusion, we reveal a new role of NSD2 in the pathogenesis of PAH related to the regulation of trehalose metabolism and autophagy via increasing the H3K36me2 level. NSD2 is a promising target for PAH therapy.


Assuntos
Autofagia/fisiologia , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Histona-Lisina N-Metiltransferase/genética , Hipertrofia Ventricular Direita/metabolismo , Hipertensão Arterial Pulmonar/genética , Animais , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Hipertrofia Ventricular Direita/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Monocrotalina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos
12.
J Cell Physiol ; 234(6): 8834-8845, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30317638

RESUMO

PURPOSE: During myocardial infarction (MI), cardiac fibroblasts (CFs) transform into myofibroblast (CMT). This study aimed to investigate the crosstalk of Notch1 and transforming growth factor-ß1 (TGF-ß1)/Smad3 signaling in the regulation of CMT and myocardial fibrosis. METHODS: Primary CFs were isolated from young rats and treated with TGF-ß1 or adenovirus to overexpress or knockdown Notch1 intracellular domain (N1ICD) or Smad3. RESULTS: TGF-ß1 decreased the expression of fibroblast markers but increased the expression of myofibroblast markers in rat CFs. TGF-ß1 increased the proliferation, invasion, and adhesion, and the secretion of collagen I of CFs, and these effects were inhibited by N1ICD overexpression. Moreover, endogenous Smad3 phosphorylation in CFs was enhanced by N1ICD knockdown, whereas TGF-ß1 induced Smad3 phosphorylation was antagonized by the N1ICD overexpression. Conversely, endogenous N1ICD activation in CFs was antagonized by Smad3, whereas TGF-ß1 induced N1ICD inactivation was antagonized by Smad3 knockdown. Coimmunoprecipitation showed that N1ICD interacted with Smad3 and immunostaining revealed the colocalization of N1ICD and Smad3 in the nuclei of CFs. Moreover, we demonstrated the functional antagonism of N1ICD and Smad3 on the phenotypes of CFs. Finally, TGF-ß1/Smad3 signaling promoted whereas Notch signaling inhibited myocardial fibrosis in rat MI model. CONCLUSION: Notch signaling inhibits CMT by antagonizing TGF-ß1/Smad3 signaling. Notch signaling activators and TGF-ß1/Smad3 signaling inhibitors could be exploited for therapeutic intervention to inhibit myocardial fibrosis after MI.


Assuntos
Fibroblastos/metabolismo , Receptores Notch/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Adesão Celular , Diferenciação Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Masculino , Infarto do Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Notch/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/genética
13.
J Cell Physiol ; 234(7): 11835-11841, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30515819

RESUMO

Mitochondrial quality control is a new target for myocardial protection. Notch signaling plays an important role in heart development, maturation, and repair. However, the role of Notch in the myocardial mitochondrial quality control remains elusive. In this study, we isolated myocardial cells from rats and established myocardial ischemia reperfusion injury (IRI) model. We modulated Notch1 expression level in myocardial cells via infection with recombinant adenoviruses Ad-N1ICD and Ad-shN1ICD. We found that IR reduced myocardial cells viability, but Notch1 overexpression increased the viability of myocardial cells exposed to IRI. In addition, Notch1 overexpression improved ATP production, increased mitochondrial fusion and decreased mitochondrial fission, and inhibited mitophagy in myocardial cells exposed to IRI. However, N1ICD knockdown led to opposite effects. The myocardial protection role of Notch1 was related to the inhibition of Pink1 expression and Mfn2 and Parkin phosphorylation. In conclusion, Notch1 exerts myocardial protection and this is correlated with the maintenance of mitochondrial quality control and the inhibition of Pink1/Mfn2/Parkin signaling.


Assuntos
Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Receptor Notch1/metabolismo , Animais , Sobrevivência Celular , Mitocôndrias Cardíacas/ultraestrutura , Dinâmica Mitocondrial , Mitofagia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/ultraestrutura , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo
14.
J Cell Mol Med ; 23(1): 568-575, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30334333

RESUMO

Histone lysine methylation plays an important role in the regulation of ventricular remodelling. NSD2 is involved in many types of tumours through enhancing H3K36me2 expression. However, the role of NSD2 in the regulation of histone lysine methylation during ventricular remodelling remains unclear. In this study, we established cardiac hypertrophy model in C57BL/6 mice by transverse aortic constriction and found that histone lysine methylation participated in ventricular remodelling regulation via the up-regulation of H3K27me2 and H3K36me2 expression. In addition, we constructed transgenic C57BL/6 mice with conditional knockout of NSD2 (NSD2-/- ) in the myocardium. NSD2-/- C57BL/6 mice had milder ventricular remodelling and significantly improved cardiac function compared with wild-type mice, and the expression of H3K36me2 but not H3K27me2 was down-regulated. In conclusion, NSD2 promotes ventricular remodelling mediated by the regulation of H3K36me2.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Remodelação Ventricular/genética , Animais , Regulação para Baixo/genética , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/genética , Miocárdio , Regulação para Cima/genética
15.
Transl Cancer Res ; 8(6): 2470-2480, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35116999

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are crucial regulators in the pathological processes and drug resistance of lung cancer. In this study, we investigated the role of miR-497-5p in modulating the function of non-small cell lung cancer (NSCLC). METHODS: MiR-497-5p expression in lung cancer tissues and cells was evaluated by qRT-PCR. Cell proliferation was evaluated by CCK-8 assay and colony-formation assay. Cell cycle and cell apoptosis were detected by flow cytometry. The effect of miR-497-5p on the expression of Yes-associated protein 1 (YAP1) and TEA domain family member 1 (TEAD1) was analyzed by qRT-PCR, Western blot and luciferase activity assay. RESULTS: The expression of miR-497-5p was significantly downregulated in lung cancer tissues and cells compared with paired normal tissues and cells. Overexpression of miR-497-5p induced growth retardation and apoptosis of A549 lung cancer cells. Mechanistically, YAP1 and TEAD1 were targeted and downregulated by miR-497-5p. Finally, we found that miR-497-5p increased cisplatin chemosensitivity in A549 cells. CONCLUSIONS: MiR-497-5p suppresses cell proliferation and resistance to cisplatin in NSCLC by downregulating the expression of YAP1 and TEAD1.

16.
J Cell Biochem ; 119(8): 7105-7112, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29737557

RESUMO

Currently, the role of Notch signaling during myocardial infarction (MI) remains controversy. In this study we used in vitro and in vivo approaches to investigate the role of Notch signaling in MI. Using cultured human umbilical vein endothelial cells exposed to hypoxia/reoxygenation (H/R), we demonstrated that H/R inhibited the proliferation, VEGF secretion, and tube formation of HUVECs, and these effects were correlated with the inhibition of Notch signaling. Furthermore, these effects were antagonized by overexpression of NICD but aggravated by knockdown of NICD. In addition, in MI model rats we found that heart dysfunction and angiogenesis in model rats was partly improved by NICD overexpression but was aggravated by knockdown of NICD. In conclusion, these data demonstrate that Notch signaling is downregulated in H/R injury in the hearts. Artificial activation of Notch signaling could promote myocardial survival and angiogenesis and improve cardiac function following H/R injury.


Assuntos
Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Neovascularização Fisiológica , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
17.
J Cell Mol Med ; 2018 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-29808534

RESUMO

Myocardial fibrosis after myocardial infarction (MI) is a leading cause of heart diseases. MI activates cardiac fibroblasts (CFs) and promotes CF to myofibroblast transformation (CMT). This study aimed to investigate the role of miR-21 in the regulation of CMT and myocardial fibrosis. Primary rat CFs were isolated from young SD rats and treated with TGF-ß1, miR-21 sponge or Jagged1 siRNA. Cell proliferation, invasion and adhesion were detected. MI model was established in male SD rats using LAD ligation method and infected with recombinant adenovirus. The heart function and morphology was evaluated by ultrasonic and histological analysis. We found that TGF-ß1 induced the up-regulation of miR-21 and down-regulation of Jagged1 in rat CFs. Luciferase assay showed that miR-21 targeted 3'-UTR of Jagged1 in rat CFs. miR-21 sponge inhibited the transformation of rat CFs into myofibroblasts, and abolished the inhibition of Jagged1 mRNA and protein expression by TGF-ß1. Furthermore, these effects of miR-21 sponge on rat CFS were reversed by siRNA mediated knockdown of Jagged1. In vivo, heart dysfunction and myocardial fibrosis in MI model rats were partly improved by miR-21 sponge but were aggravated by Jagged1 knockdown. Taken together, these results suggest that miR-21 promotes cardiac fibroblast-to-myofibroblast transformation and myocardial fibrosis by targeting Jagged1. miR-21 and Jagged1 are potential therapeutic targets for myocardial fibrosis.

18.
Oncol Lett ; 15(3): 3415-3421, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29467866

RESUMO

Lung cancer is the leading cause of cancer-associated mortality worldwide. Elucidation of the pathogenesis and biology of lung cancer is critical for the design of an effective treatment for patients. Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases. The abnormal expression of Notch signaling pathway members is a relatively frequent event in NSCLC. The Notch signaling pathway serves important roles in cell fate determination, proliferation, differentiation and apoptosis. Increasing evidence supports the association of Notch signaling dysregulation with various types of malignant tumor, including NSCLC. Several studies have demonstrated that members of the Notch signaling pathway may be potential biomarkers for predicting the progression and prognosis of patients with NSCLC. Furthermore, Notch signaling serves critical roles in the tumorigenesis and treatment resistance of NSCLC cells by promoting the proliferation or inhibiting the apoptosis of NSCLC cells. The present review provides a detailed summary of the roles of Notch signaling in NSCLC.

19.
Oncotarget ; 8(33): 55622-55631, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903449

RESUMO

OBJECTIVES: The objective of this study was to evaluate the association between metformin therapy and the incidence of gastric cancer (GC) in patients with type 2 diabetes mellitus (T2DM). METHODS: We systemically searched the following databases for studies published between the databases' dates of inception and Nov. 2016: PubMed, Embase, the Cochrane Library, the Web of Science, and the China National Knowledge Infrastructure (CNKI). Hazard ratios (HR)and corresponding 95% confidence intervals (CIs) for the association between metformin therapy and the incidence of GC in patients with T2DM were the outcome measures assessed in this study. STATA 12.0 (Stata Corporation, College Station, Texas, USA) was used to conduct the statistical analysis. RESULTS: A total of seven cohort studies including 591,077 patients met all the criteria for inclusion in the analysis. Our data showed that metformin therapy was associated with a significantly lower incidence of GC in patients with T2DM than other types of therapy (HR=0.763, 95% CI: 0.642˜0.905). Subgroup analysis showed that patients living in Taiwan benefitted more from metformin therapy than patients living in any other region, as metformin significantly decreased the risk of GC in patients living in Taiwan but did not significantly decrease the risk of GC in patients living in other regions (HR=0.514, 95% CI: 0.384-0.688). The results of the present analysis support the idea that metformin facilitates reductions in the risk of T2DM-related GC. CONCLUSIONS: The risk of GC among patients with T2DM is lower in patients receiving metformin therapy than in patients not receiving metformin therapy.

20.
Oncotarget ; 8(16): 26492-26504, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28404917

RESUMO

Cancer stem cells (CSCs) are defined as a rare subpopulation of undifferentiated cells with biological characteristics that include the capacity for self-renewal, differentiation into various lineages, and tumor initiation. To explore the mechanism of CSCs in esophageal squamous cell carcinoma (ESCC), we focused on Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), a target gene of the Wnt signaling pathway, which has been identified as a marker of intestinal stem cells and shown to be overexpressed in several human malignancies. Lgr5 expression was significantly correlated with lymph node metastasis, increased depth of invasion, increased tumor size, advanced differentiation, higher AJCC stage and poorer survival. Silencing of Lgr5 expression in the ESCC cell line KYSE450 by small interfering RNA (siRNA) strongly inhibited cell proliferation, migration and invasion ability, the expression of CSCs-related genes and Wnt/ß-catenin signaling. In addition, Lgr5 was highly expressed in ESCC spheroid body cells, which were identified by high expression of CSCs-related genes, and high tumorigenicity in vivo. Taken together, these results demonstrate that Lgr5 activation of Wnt/ß-catenin signaling is a potential mechanism to promote the progression of ESCC and ESCC stem cell renewal, and Lgr5 may be used as a molecular target for the development of treatments for ESCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , Receptores Acoplados a Proteínas G/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Inativação Gênica , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Via de Sinalização Wnt
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