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1.
J Med Virol ; 96(7): e29777, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38949212

RESUMO

Hepatitis E virus (HEV) is a prevalent pathogen responsible for acute viral hepatitis, HEV genotypes 3 and 4 infections causing zoonotic infections. Currently, the nucleotide similarity analysis between humans and pigs for HEV genotype 4 is limited. In this study, stool samples from an HEV-infected patient who is a pig farmer and from pigs were collected to obtain the near full-length genome of HEV, phylogenetic trees were constructed for genotyping, and similarity of HEV sequences was analyzed. The results showed that HEV-RNA was detected in the stool samples from the patient and six pigs (6/30, 20.0%). Both HEV subtype in the patient and pigs was 4b. Additionally, similarity analysis showed that the range was 99.875%-99.944% between the patient and pigs at the nucleotide level. Four isolates of amino acid sequences (ORFs 1-3) from pigs were 100% identical to the patient. Phylogenetic tree and similarity analysis of an additional nine HEV sequences isolated from other patients in this region showed that the HEV sequence from the pig farmer had the closest relationship with the pigs from his farm rather than other sources of infection in this region. This study provides indirect evidences for HEV subtype 4b can be transmitted from pigs to humans at the nucleotide level. Further research is needed to explore the characteristics of different HEV subtypes.


Assuntos
Fezes , Genoma Viral , Genótipo , Vírus da Hepatite E , Hepatite E , Filogenia , RNA Viral , Doenças dos Suínos , Animais , Vírus da Hepatite E/genética , Vírus da Hepatite E/classificação , Vírus da Hepatite E/isolamento & purificação , Suínos , Hepatite E/virologia , Hepatite E/veterinária , Hepatite E/epidemiologia , China/epidemiologia , Humanos , Fezes/virologia , Doenças dos Suínos/virologia , RNA Viral/genética , Masculino , Análise de Sequência de DNA
2.
FASEB J ; 37(12): e23294, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37966425

RESUMO

Despite promising results in myocardial infarction (MI), mesenchymal stem cell (MSC)-based therapy is limited by cell senescence. N6-methyladenosine (m6A) messenger RNA methylation has been reported to be closely associated with cell senescence. Nonetheless, its role in the regulation of MSC senescence remains unclear. We examined the role of ALKB homolog 5 (ALKBH5) in regulating MSC senescence and determined whether ALKBH5 downregulation could rejuvenate aged MSCs (AMSCs) to improve their therapeutic efficacy for MI. RNA methylation was determined by m6A dot blotting assay. MSC senescence was evaluated by senescence-associated ß-galactosidase (SA-ß-gal) staining. A mouse model of acute MI was established by ligation of the left anterior decedent coronary artery (LAD). Compared with young MSCs (YMSCs), m6A level was significantly reduced but ALKBH5 was greatly increased in AMSCs. Overexpression of ALKBH5 reduced m6A modification and accelerated YMSC senescence. Conversely, ALKBH5 knockdown increased m6A modifications and alleviated AMSC senescence. Mechanistically, ALKBH5 regulated the m6A modification and stability of CDKN1C mRNA, which further upregulated CDKN1C expression, leading to MSC senescence. CDKN1C overexpression ameliorated the inhibition of cellular senescence of ALKBH5 siRNA-treated AMSCs. More importantly, compared with AMSCs, shALKBH5-AMSCs transplantation provided a superior cardioprotective effect against MI in mice by improving MSC survival and angiogenesis. We determined that ALKBH5 accelerated MSC senescence through m6A modification-dependent stabilization of the CDKN1C transcript, providing a potential target for MSC rejuvenation. ALKBH5 knockdown rejuvenated AMSCs and enhanced cardiac function when transplanted into the mouse heart following infarction.


Assuntos
Células-Tronco Mesenquimais , Infarto do Miocárdio , Humanos , Animais , Camundongos , Idoso , Regulação para Baixo , Infarto do Miocárdio/genética , Infarto do Miocárdio/terapia , Adenosina , Senescência Celular , Fatores Imunológicos , RNA Mensageiro , Homólogo AlkB 5 da RNA Desmetilase/genética
3.
J Nanobiotechnology ; 22(1): 385, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951822

RESUMO

BACKGROUND: Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear. RESULTS: Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs. CONCLUSIONS: These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.


Assuntos
Vesículas Extracelulares , Camundongos Endogâmicos C57BL , ATPases Mitocondriais Próton-Translocadoras , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Vesículas Extracelulares/metabolismo , Ferroptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
4.
J Nanobiotechnology ; 22(1): 195, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643173

RESUMO

Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-ß-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.


Assuntos
Cardiomiopatias , Células-Tronco Pluripotentes Induzidas , MicroRNAs , Humanos , Camundongos , Animais , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Cardiomiopatias/induzido quimicamente , Transdução de Sinais , Doxorrubicina
5.
J Cell Mol Med ; 26(24): 6006-6018, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36444487

RESUMO

Extracellular vesicles (EVs) play important roles in cardiovascular diseases by delivering their RNA cargos. However, the features and possible role of the lncRNAs and mRNAs in cardiac EVs during ischemia-reperfusion (IR) remain unclear. Therefore, we performed RNA sequencing analysis to profile the features of lncRNAs and mRNAs and predicted their potential functions. Here, we demonstrated that the severity of IR injury was significantly correlated with cardiac EV production. RNA sequencing identified 73 significantly differentially expressed (DE) lncRNAs (39 upregulated and 34 downregulated) and 720 DE-mRNAs (317 upregulated and 403 downregulated). Gene Ontology (GO) and pathway analysis were performed to predict the potential functions of the DE-lncRNAs and mRNAs. The lncRNA-miRNA-mRNA ceRNA network showed the possible functions of DE-lncRNAs with DE-mRNAs which are enriched in the pathways of T cell receptor signalling pathway and cell adhesion molecules. Moreover, the expressions of ENSMUST00000146010 and ENSMUST00000180630 were negatively correlated with the severity of IR injury. A significant positive correlation was revealed between TCONS_00010866 expression and the severity of the cardiac injury. These findings revealed the lncRNA and mRNA profiles in the heart derived EVs and provided potential targets and pathways involved in cardiac IR injury.


Assuntos
Vesículas Extracelulares , MicroRNAs , RNA Longo não Codificante , Traumatismo por Reperfusão , Camundongos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Redes Reguladoras de Genes , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , MicroRNAs/genética , Traumatismo por Reperfusão/genética , Perfilação da Expressão Gênica
6.
Br J Nutr ; : 1-10, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35241186

RESUMO

Accumulating evidence suggests that supplementation of n-3 PUFA was associated with reduction in risk of major cardiovascular events. This meta-analysis was to systematically evaluate whether daily supplementation and accumulated intake of n-3 PUFA are associated with improved left ventricular (LV) remodelling in patients with chronic heart failure (CHF). Articles were obtained from Pubmed, Clinical key and Web of Science from inception to January 1 in 2021, and a total of twelve trials involving 2162 participants were eligible for inclusion. The sources of study heterogeneity were explained by I2 statistic and subgroup analysis. Compared with placebo groups, n-3 PUFA supplementation improved LV ejection fraction (LVEF) (eleven trials, 2112 participants, weighted mean difference (WMD) = 2·52, 95 % CI 1·25, 3·80, I2 = 87·8 %) and decreased LV end systolic volume (five studies, 905 participants, WMD = -3·22, 95 % CI 3·67, -2·77, I2 = 0·0 %) using the continuous variables analysis. Notably, the high accumulated n-3 PUFA dosage groups (≥ 600 g) presented a prominent improvement in LVEF, while the low and middle accumulated dosage (≤ 300 and 300-600 g) showed no effects on LVEF. In addition, n-3 PUFA supplementation decreased the levels of pro-inflammatory mediators including TNF-α, IL-6 (IL-6) and hypersensitive c-reactive protein. Therefore, the present meta-analysis demonstrated that n-3 PUFA consumption was associated with a substantial improvement of LV function and remodelling in patients subjected to CHF. The accumulated dosage of n-3 PUFA intake is vital for its cardiac protective role.

7.
J Cell Mol Med ; 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34132029

RESUMO

Vascular smooth muscle cells (VSMCs) senescence contributes to abdominal aortic aneurysm (AAA) formation although the underlying mechanisms remain unclear. This study aimed to investigate the role of miR-199a-5p in regulating VSMC senescence in AAA. VSMC senescence was determined by a senescence-associated ß-galactosidase (SA-ß-gal) assay. RT-PCR and Western blotting were performed to measure miRNA and protein level, respectively. The generation of reactive oxygen species (ROS) was evaluated by H2DCFDA staining. Dual-luciferase reporter assay was used to validate the target gene of miR-199a-5p. VSMCs exhibited increased senescence in AAA tissue relative to healthy aortic tissue from control donors. Compared with VSMCs isolated from control donors (control-VSMCs), those derived from patients with AAA (AAA-VSMCs) exhibited increased cellular senescence and ROS production. Angiotensin II (Ang II) induced VSMC senescence by promoting ROS generation. The level of miR-199a-5p expression was upregulated in the plasma from AAA patients and Ang II-treated VSMCs. Mechanistically, Ang II treatment significantly elevated miR-199a-5p level, thereby stimulating ROS generation by repressing Sirt1 and consequent VSMC senescence. Nevertheless, Ang II-induced VSMC senescence was partially attenuated by a miR-199a-5p inhibitor or Sirt1 activator. Our study revealed that miR-199a-5p aggravates Ang II-induced VSMC senescence by targeting Sirt1 and that miR-199a-5p is a potential therapeutic target for AAA.

8.
J Nanobiotechnology ; 19(1): 332, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674708

RESUMO

BACKGROUND: Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. METHODS: MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-ß-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence RESULTS: EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. CONCLUSION: Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction.


Assuntos
Cardiotônicos , Exossomos , Hemina/farmacologia , Células-Tronco Mesenquimais/química , Infarto do Miocárdio/metabolismo , Animais , Cardiotônicos/química , Cardiotônicos/farmacologia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
9.
J Cell Mol Med ; 24(1): 431-440, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31660694

RESUMO

The cardiac protection of mesenchymal stem cell (MSC) transplantation for myocardial infarction (MI) is largely hampered by low cell survival. Haem oxygenase 1 (HO-1) plays a critical role in regulation of cell survival under many stress conditions. This study aimed to investigate whether pre-treatment with haemin, a potent HO-1 inducer, would promote the survival of MSCs under serum deprivation and hypoxia (SD/H) and enhance the cardioprotective effects of MSCs in MI. Bone marrow (BM)-MSCs were pretreated with or without haemin and then exposed to SD/H. The mitochondrial morphology of MSCs was determined by MitoTracker staining. BM-MSCs and haemin-pretreated BM-MSCs were transplanted into the peri-infarct region in MI mice. SD/H induced mitochondrial fragmentation, as shown by increased mitochondrial fission and apoptosis of BM-MSCs. Pre-treatment with haemin greatly inhibited SD/H-induced mitochondrial fragmentation and apoptosis of BM-MSCs. These effects were partially abrogated by knocking down HO-1. At 4 weeks after transplantation, compared with BM-MSCs, haemin-pretreated BM-MSCs had greatly improved the heart function of mice with MI. These cardioprotective effects were associated with increased cell survival, decreased cardiomyocytes apoptosis and enhanced angiogenesis. Collectively, our study identifies haemin as a regulator of MSC survival and suggests a novel strategy for improving MSC-based therapy for MI.


Assuntos
Cardiotônicos/farmacologia , Hemina/farmacologia , Células-Tronco Mesenquimais/citologia , Dinâmica Mitocondrial/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura Livres de Soro , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Modelos Biológicos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos
10.
J Cell Physiol ; 235(11): 8010-8022, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31960418

RESUMO

Accumulating evidence has shown that mesenchymal stem cell (MSC)-derived exosomes (exo) mediate cardiac repair following myocardial infarction (MI). Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, plays a critical role in regulating cell homeostasis. This study aimed to investigate the cardioprotective effects of exo secreted from bone marrow-MSCs (BM-MSCs) overexpressing MIF in a rat model of MI. MIF plasmid was transducted in BM-MSCs. Exo were isolated from the supernatants of BM-MSCs and MIF-BM-MSCs, respectively. The morphology of mitochondria in neonatal mice cardiomyocytes (NRCMs) was determined by MitoTracker staining. The apoptosis of NRCMs was examined by deoxynucleotidyl transferase-mediated dUTP nick end-labeling. BM-MSC-exo and MIF-BM-MSC-exo were intramuscularly injected into the peri-infarct region in a rat model of MI. The heart function of rats was assessed by echocardiography. The expression of MIF was greatly enhanced in MIF-BM-MSCs compared with BM-MSCs. Both BM-MSC-exo and MIF-BM-MSC-exo expressed CD63 and CD81. NRCMs treated with MIF-BM-MSC-exo exhibited less mitochondrial fragmentation and cell apoptosis under hypoxia/serum deprivation (H/SD) challenge than those treated with BM-MSC-exo via activating adenosine 5'-monophosphate-activated protein kinase signaling. Moreover, these effects were partially abrogated by Compound C. Injection of BM-MSC-exo or MIF-BM-MSC-exo greatly restored heart function in a rat model of MI. Compared with BM-MSC-exo, injection of MIF-BM-MSC-exo was associated with enhanced heart function, reduced heart remodeling, less cardiomyocyte mitochondrial fragmentation, reactive oxygen species generation, and apoptosis. Our study reveals a new mechanism of MIF-BM-MSC-exo-based therapy for MI and provides a novel strategy for cardiovascular disease treatment.


Assuntos
Exossomos/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Infarto do Miocárdio/genética , Animais , Apoptose/genética , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Modelos Animais de Doenças , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/reabilitação , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Transdução de Sinais
11.
J Exp Zool B Mol Dev Evol ; 334(4): 235-244, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32150339

RESUMO

T-cell immunoglobulin (Ig) and mucin domain-containing 1 (Tim-1) and Tim-4 are two members of the Tim family. In mammals, Tim-1 and Tim-4 are proteins mainly expressed in immune cells and are associated with immune response. In the present study, medaka Oryzias latipes' Tim-1 (OlTim-1) and OlTim-4 were identified and characterized using bioinformatics analyses. With the use of reverse-transcription polymerase chain reaction, the expression profiles of OlTim-1 and OlTim-4 were examined in embryos and adult fish and in immune tissues following the intraperitoneal injection of stimulants. The results revealed that OlTim-1 possesses a cytoplasmic region, a transmembrane region, a mucin domain, and an Ig-like domain, while OlTim-4 is composed of two Ig-like domains and a mucin domain, but without the transmembrane region and cytoplasmic region. OlTim-1 and OlTim-4 expressions are detectable from the gastrula stage on, indicating that they are zygotic genes. Furthermore, OlTim-1 and OlTim-4 are expressed ubiquitously in the adult. Administration of immune stimulants, namely lipopolysaccharides and polyinosinic:polycytidylic acid, significantly increased the expression levels of OlTim-1 and OlTim-4 in the liver and intestine within 1 day and in the head, kidney, and spleen within 3 to 4 days postinjection. These results suggest that OlTim-1 and OlTim-4 are possibly involved in both innate and adaptive immunities.


Assuntos
Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Oryzias/metabolismo , Envelhecimento/fisiologia , Animais , Embrião não Mamífero/metabolismo , Receptor Celular 1 do Vírus da Hepatite A/genética , Modelos Moleculares , Oryzias/embriologia , Phyllachorales , Conformação Proteica
12.
FASEB J ; 33(3): 4559-4570, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30566395

RESUMO

The age-related functional exhaustion limits potential efficacy of mesenchymal stem cells (MSC) in treating cardiovascular disease. Therefore, rejuvenation of aged MSC in the elderly population is of great interest. We have previously reported that Erb-B2 receptor tyrosine kinase 4 ( ERBB4) plays a critical role in regulating MSC survival under hypoxia. The aim of this study was to investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Compared with vector aged MSC (aged-MSC), ERBB4-engineered aged MSC (ER4-aged-MSC) conferred resistance to oxidative stress-induced cell death and ameliorated the senescent phenotype in vitro. Four weeks after MI, the ER4-aged-MSC group exhibited enhanced blood vessel density, reduced cardiac remodeling and apoptosis with improved heart function compared with the aged-MSC group. Overexpression of ERBB4 caused an increase in phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT), and phosphorylated ERK expression under hypoxia. ER4-aged-MSC secreted higher levels of angiopoietin, epithelial neutrophil activating peptide 78, VEGF, and fibroblast growth factor 2, and enhanced tube formation in HUVEC. The impact of ERBB4 on protein expression, proangiogenesis, cell behavior, and cytokine secretion was abolished by inhibiting PI3K/AKT and MAPK/ERK signaling pathway.-Liang, X., Ding, Y., Lin, F., Zhang, Y., Zhou, X., Meng, Q., Lu, X., Jiang, G., Zhu, H., Chen, Y., Lian, Q., Fan, H., Liu, Z. Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways.


Assuntos
Envelhecimento/patologia , Senescência Celular/fisiologia , Células-Tronco Mesenquimais/citologia , Receptor ErbB-4/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Células Cultivadas , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Neovascularização Fisiológica , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Distribuição Aleatória , Receptor ErbB-4/genética , Proteínas Recombinantes/metabolismo , Homeostase do Telômero , Remodelação Ventricular , Adulto Jovem
13.
J Biochem Mol Toxicol ; 34(5): e22471, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32057176

RESUMO

BACKGROUND: Medulloblastoma is a common tumor originates from central nervous system in children with metastatic potential. Geniposide is the major active ingredient separated from the fruit of Gardenia jasminoides Ellis. Herein, we tested the possible anticancer activity of geniposide on human medulloblastoma cells, as well as the potential underlying molecular mechanisms. METHODS: Firstly, followed by geniposide incubation, cell viability, proliferation, apoptosis, migration, and invasion of medulloblastoma Daoy cells, along with microRNA-373 (miR-373) expression were tested, respectively. Then, the influences of miR-373 overexpression in the reduction of medulloblastoma cell proliferation, migration, and invasion and the elevation of apoptosis, triggered by geniposide treatment, were re-investigated. Finally, the Ras/Raf/MEK/ERK pathway activity was analyzed. RESULTS: Geniposide treatment inhibited medulloblastoma cell viability, proliferation, migration, and invasion, but promoted cell apoptosis. Surprisingly, miR-373 expression in medulloblastoma cells was obviously downregulated by geniposide treatment. miR-373 overexpression reversed the effects of geniposide on Daoy cells. Furthermore, geniposide hindered the Ras/Raf/MEK/ERK pathway by downregulating miR-373 expression. CONCLUSION: Geniposide exhibited anticancer activity on human medulloblastoma cells and blocked Ras/Raf/MEK/ERK pathway by downregulating miR-373 expression.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Cerebelares/metabolismo , Regulação para Baixo/efeitos dos fármacos , Frutas/química , Gardenia/química , Iridoides/farmacologia , Meduloblastoma/metabolismo , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cerebelares/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Meduloblastoma/patologia , MicroRNAs/genética , Invasividade Neoplásica/genética , Transfecção
14.
J Exp Zool B Mol Dev Evol ; 332(1-2): 17-25, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30680935

RESUMO

B-cell lymphoma-6 (Bcl6) is a transcriptional repressor that plays important roles in various physiological activities such as innate and adaptive immune response, lymphocyte differentiation, and cell cycle regulation in mammals. Two homologs of Bcl6a, namely Bcl6aa and Bcl6ab, are identified in teleost fish including medaka Oryzias latipes. The expression profiles of bcl6aa and bcl6ab in medaka were studied using reverse-transcription polymerase chain reaction and in situ hybridization. The transcripts of bcl6aa and bcl6ab were detected from very early embryos such as the four-cell stage until hatching. Bcl6aa and bcl6ab were clearly detected in the embryonic body from 5 days postfertilization onward by in situ hybridization. Bcl6aa was specifically expressed in the retina, whereas bcl6ab was expressed in entire embryonic body. The results referred to that both bcl6aa and bcl6ab originate maternally in the zygotes and may play major roles in embryogenesis of medaka. The transcripts of bcl6aa and bcl6ab were detected in all examined adult tissues, including immune organs such as the gill, spleen, kidney, liver, and intestine. The expression of bcl6aa and bcl6ab in the liver, spleen, head-kidney, and intestine could be upregulated or downregulated by lipopolysaccharide and polyriboinosinic-polyribocytidylic acid. These results indicate that both bcl6aa and bcl6ab may be involved in immune response in medaka.


Assuntos
Proteínas de Peixes/metabolismo , Lipopolissacarídeos/farmacologia , Oryzias/metabolismo , Poli I-C/farmacologia , Proteínas Repressoras/metabolismo , Animais , Proteínas de Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hibridização In Situ , Oryzias/embriologia , Oryzias/genética , Filogenia , Proteínas Repressoras/genética
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(9): 919-923, 2019 Sep.
Artigo em Zh | MEDLINE | ID: mdl-31506154

RESUMO

A girl, aged 15 months, attended the hospital due to recurrent skin erythema, blisters, and desquamation for more than 7 months. Giemsa staining and immunohistochemical staining showed mast cell infiltration and degranulation. Hematoxylin staining showed spinous layer edema and blister formation under the epidermis, with a large amount of serous fluid and a small number of inflammatory cells in the blister. Marked edema was observed in the dermis, with diffused mononuclear cell infiltration. The girl was diagnosed with mastocytosis. Mastocytosis should be considered for children with recurrent skin erythema and blisters.


Assuntos
Vesícula , Mastócitos , Feminino , Humanos , Lactente , Pele
16.
Exp Cell Res ; 356(1): 74-84, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28412246

RESUMO

Bone marrow-derived mesenchymal stem cells (BM-MSCs) contribute to myocardial repair after myocardial infarction (MI) by secreting a panel of growth factors and cytokines. This study was to investigate the potential mechanisms of the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS) in regulation of the profiles of BM-MSCs secretion and compare the therapeutic efficacy of NUCKS-/-- and wide type-BM-MSCs (WT-BM-MSCs) on MI. The secretion profiles between NUCKS-/-- and WT-BM-MSCs under hypoxia (1%O2) were analyzed. Gene function analysis showed that compared with WT-BM-MSCs-conditioned medium (CdM), some genes over-presented in NUCKS-/--BM-MSCs-CdM were closely associated with inflammatory response, regulation of cell proliferation, death, migration and secretion. Notably, VEGFa in NUCKS-/--BM-MSCs-CdM was higher than that of WT-BM-MSCs-CdM. WT-BM-MSCs and NUCKS-/--BM-MSCs were transplanted into the peri-infarct region in mice of MI. At 4 weeks after cell transplantation, NUCKS-/-- or WT-BM-MSCs group significantly improved heart function and vessels density and reduced infarction size and apoptosis of cardiomyocytes. Furthermore, NUCKS-/--BM-MSCs provided better cardioprotective effects than WT-BM-MSCs against MI. Our study demonstrates that depletion of NUCKS enhances the therapeutic efficacy of BM-MSCs for MI via regulating the secretion.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/terapia , Miócitos Cardíacos/fisiologia , Proteínas Nucleares/genética , Fosfoproteínas/genética , Regeneração/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose/genética , Cardiotônicos , Hipóxia Celular/fisiologia , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Knockout , Infarto do Miocárdio/patologia , NF-kappa B/metabolismo
17.
Exp Cell Res ; 344(1): 30-39, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27025401

RESUMO

Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.


Assuntos
Cardiotônicos/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/terapia , Comunicação Parácrina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Fibrose , Humanos , Transplante de Células-Tronco Mesenquimais , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Ratos Wistar , Cordão Umbilical/citologia
18.
Stem Cells ; 33(12): 3452-67, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26175298

RESUMO

Adult mesenchymal stem cells (MSCs) are immunoprivileged cells due to the low expression of major histocompatibility complex (MHC) II molecules. However, the expression of MHC molecules in human-induced pluripotent stem cells (iPSCs)-derived MSCs has not been investigated. Here, we examined the expression of human leukocyte antigen (HLA) in human MSCs derived from iPSCs, fetuses, and adult bone marrow (BM) after stimulation with interferon-γ (IFN-γ), compared their repair efficacy, cell retention, inflammation, and HLA II expression in immune humanized NOD Scid gamma (NSG) mice of hind limb ischemia. In the absence of IFN-γ stimulation, HLA-II was expressed only in BM-MSCs after 7 days. Two and seven days after stimulation, high levels of HLA-II were observed in BM-MSCs, intermediate levels were found in fetal-MSCs, and very low levels in iPSC-MSCs. The levels of p-STAT1, interferon regulatory factor 1, and class II transactivator exhibited similar phenomena. Moreover, p-STAT1 antagonist significantly reversed the high expression of HLA-II in BM-MSCs. Compared to adult BM-MSCs, transplanting iPSC-MSCs into hu-PBMNC NSG mice revealed markedly more survival iPSC-MSCs, less inflammatory cell accumulations, and better recovery of hind limb ischemia. The expression of HLA-II in MSCs in the ischemia limbs was detected in BM-MSCs group but not in iPSC-MSCs group at 7 and 21 days after transplantation. Our results demonstrate that, compared to adult MSCs, human iPSC-MSCs are insensitive to proinflammatory IFN-γ-induced HLA-II expression and iPSC-MSCs have a stronger immune privilege after transplantation. It may attribute to a better therapeutic efficacy in allogeneic transplantation.


Assuntos
Membro Posterior/irrigação sanguínea , Antígenos de Histocompatibilidade Classe II/biossíntese , Células-Tronco Pluripotentes Induzidas/metabolismo , Interferon gama/farmacologia , Isquemia/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Animais , Xenoenxertos , Humanos , Isquemia/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
19.
Am J Respir Cell Mol Biol ; 51(3): 455-65, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24738760

RESUMO

Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for 1 hour daily for 56 days. At Days 29 and, human iPSC-MSCs or adult bone marrow-derived MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (P < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (P < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than in the BM-MSC-treated group (P < 0.05). This might have contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs, with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes. Inhibition of tunneling nanotube formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Mesenquimais/citologia , Mitocôndrias/metabolismo , Mucosa Respiratória/citologia , Fumaça/efeitos adversos , Animais , Células da Medula Óssea/citologia , Linhagem Celular , Separação Celular , Técnicas de Cocultura , Células Epiteliais/citologia , Citometria de Fluxo , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Ratos , Ratos Sprague-Dawley , Mucosa Respiratória/efeitos dos fármacos , Nicotiana
20.
Free Radic Biol Med ; 223: 172-183, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39097205

RESUMO

Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and aging-related diseases, its role in the regulation of human mesenchymal stem cell (MSC) senescence has not been investigated. This study aimed to determine the role of ALDH2 in regulating MSC senescence and illustrate the potential mechanisms. MSCs were isolated from young (YMSCs) and aged donors (AMSCs). Senescence-associated ß-galactosidase (SA-ß-gal) staining and Western blotting were used to assess MSC senescence. Reactive oxygen species (ROS) generation and mitochondrial membrane potential were determined to evaluate mitochondrial function. We showed that the expression of ALDH2 increased alongside cellular senescence of MSCs. Overexpression of ALDH2 accelerated YMSC senescence whereas down-regulation alleviated premature senescent phenotypes of AMSCs. Transcriptome and biochemical analyses revealed that an elevated ROS level and mitochondrial dysfunction contributed to ALDH2 function in MSC senescence. Using molecular docking, we identified interferon regulatory factor 7 (IRF7) as the potential target of ALDH2. Mechanistically, ectopic expression of ALDH2 led to mitochondrial dysfunction and accelerated senescence of MSCs by increasing the stability of IRF7 through a direct physical interaction. These effects were partially reversed by knockdown of IRF7. These findings highlight a crucial role of ALDH2 in driving MSC senescence by regulating mitochondrial homeostasis, providing a novel potential strategy against human aging-related diseases.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Senescência Celular , Células-Tronco Mesenquimais , Mitocôndrias , Espécies Reativas de Oxigênio , Células-Tronco Mesenquimais/metabolismo , Humanos , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/genética , Espécies Reativas de Oxigênio/metabolismo , Homeostase , Potencial da Membrana Mitocondrial , Adulto , Envelhecimento/metabolismo , Envelhecimento/genética , Células Cultivadas , Simulação de Acoplamento Molecular , Idoso , Regulação da Expressão Gênica
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