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1.
J Cell Mol Med ; 25(20): 9851-9862, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34523794

RESUMO

Adiponectin is an adipocyte-derived hormone, which is closely associated with the development of Alzheimer's disease (AD) and has potential preventive and therapeutic significance. In the present study, we explored the relationship between adiponectin and circadian rhythm disorder in AD, the effect of adiponectin on the abnormal expression of Bmal1 mRNA/protein induced by amyloid-ß protein 31-35 (Aß31-35), and the underlying mechanism of action. We found that adiponectin-knockout mice exhibited amyloid-ß deposition, circadian rhythm disorders and abnormal expression of Bmal1. Adiponectin ameliorated the abnormal expression of the Bmal1 mRNA/protein caused by Aß31-35 by inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß). These results suggest that adiponectin deficiency could induce circadian rhythm disorders and abnormal expression of the Bmal1 mRNA/protein, whilst exogenous administration of adiponectin may improve Aß31-35-induced abnormal expression of Bmal1 by inhibiting the activity of GSK3ß, thus providing a novel idea for the treatment of AD.

2.
J Cell Mol Med ; 25(17): 8464-8478, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34322993

RESUMO

Cardiomyocytes autophagy is essential for maintaining cardiac function. Our previous studies have found that ß1 -adrenergic receptor autoantibody (ß1 -AA) induced the decreased myocardial autophagic flux, which resulted in cardiomyocyte death and cardiac dysfunction. And other studies demonstrated that ß1 -AA induced the decrease of AMPK phosphorylation, the key hub of autophagy pathway, while adiponectin up-regulated autophagic flux mediated by AMPK. However, it is not clear whether adiponectin improves the inhibition of myocardial autophagic flux induced by ß1 -AA by up-regulating the level of AMPK phosphorylation. In this study, it has been confirmed that ß1 -AA induced the decrease of AMPK phosphorylation level in both vivo and vitro. Moreover, pretreatment of cardiomyocytes with AMPK inhibitor Compound C could further reduce the autophagic flux induced by ß1 -AA. Adiponectin deficiency could aggravate the decrease of myocardial AMPK phosphorylation level, autophagic flux and cardiac function induced by ß1 -AA. Further, exogenous adiponectin could reverse the decline of AMPK phosphorylation level and autophagic flux induced by ß1 -AA and even reduce cardiomyocyte death. While pretreated with the Compound C, the adiponectin treatment did not improve the decreased autophagosome formation, but still improved the decreased autophagosome clearance induced by ß1 -AA in cardiomyocytes. This study is the first time to confirm that ß1 -AA could inhibit myocardial autophagic flux by down-regulating AMPK phosphorylation level. Adiponectin could improve the inhibition of myocardial autophagic flux induced by ß1 -AA partly dependent on AMPK, so as to provide an experimental basis for the treatment of patients with ß1 -AA-positive cardiac dysfunction.

3.
Am J Transl Res ; 12(7): 3476-3488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774713

RESUMO

Osteosarcoma (OS) is the most leading primary malignant tumor of the bone in adolescents and young adults worldwide. Increasing data have suggested that long non-coding RNA (lncRNA) small nucleolar RNA host gene 8 (SNHG8) plays a key role in the progression of various types of human malignancy. However, the roles and potential mechanisms of SNHG8 in OS remain unclear. In this study, we found that SNHG8 levels were obviously upregulated in OS tissues and cell lines. High expression of SNHG8 was significantly correlated with increased tumor size and advanced Enneking stage, and predicted a poor prognosis of OS patients. Functional assays revealed that SNHG8 knockdown inhibited OS cell growth and migration in vitro, and restrained tumor growth of OS in nude mice in vivo. Mechanistically, SNHG8 functioned as a competing endogenous RNA (ceRNA) of miR-876-5p in OS cells. Notably, knockdown of miR-876-5p reversed the inhibitory effects of SNHG8 inhibition on OS cell proliferation and migration. In conclusion, our study suggested that SNHG8 stimulates cell growth and migration of OS cells by functioning as a ceRNA of miR-876-5p, indicating SNHG8 may be served as a novel prognostic biomarker and therapeutic target for the treatment of OS.

4.
Int J Mol Med ; 46(2): 751-761, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468037

RESUMO

Simvastatin is effective in the treatment of osteoporosis, partly through the inhibition of the adipogenesis of bone­marrow derived mesenchymal stem cells (BMSCs). The present study focused on the mechanisms responsible for the inhibitory effects of simvastatin on adipogenesis and examined the effects of simvastatin on the expression of peroxisome proliferator­activated receptor γ (PPARγ), chemerin, chemokine­like receptor 1 (CMKLR1), G protein­coupled receptor 1 (GPR1) and the adipocyte marker gene, adiponectin. BMSCs were isolated from 4­week­old female Sprague­Dawley (SD) rats, and adipogenesis was measured by the absorbance values at 490 nm of Oil Red O dye. The expression of each gene was evaluated by western blot analysis or reverse transcription­quantitative PCR (RT­qPCR). The expression of chemerin increased during adipogenesis, while CMKLR1 exhibited a trend towards a decreased expression. On days 7 and 14, the simvastatin­treated cells exhibited a downregulated expression of chemerin, whereas the upregulated expression of its receptor, CMKLR1 was observed. The results also revealed that CMKLR1 is required for adipogenesis and the simvastatin­mediated inhibitory effect on adipogenesis. Simvastatin regulated adipogenesis by negatively modulating chemerin­CMKLR1 signaling. Importantly, simvastatin stimulation inhibited the upregulation of PPARγ and PPARγ­mediated chemerin expression to prevent adipogenesis. Treatment with the PPARγ agonist, rosiglitazone, partially reversed the negative regulatory effects of simvastatin. On the whole, the findings of the present study demonstrate that simvastatin inhibits the adipogenesis of BMSCs through the downregulation of PPARγ and subsequently prevents the PPARγ­mediated induction of chemerin/CMKLR1 signaling.


Assuntos
Adipogenia/efeitos dos fármacos , Quimiocinas/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Receptores de Quimiocinas/metabolismo , Sinvastatina/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Quimiocinas/genética , Feminino , Células-Tronco Mesenquimais/citologia , PPAR gama/agonistas , Ratos , Ratos Sprague-Dawley , Receptores de Quimiocinas/genética , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos
5.
Neurosci Lett ; 573: 46-51, 2014 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-24837681

RESUMO

Spinal cord injury (SCI) is one of the most disabling diseases. Cell-based gene therapy is becoming a major focus for the treatment of SCI. Bone marrow-derived mesenchymal stem cells (BMSCs) are a promising stem cell type useful for repairing SCI. However, the effects of BMSCs transplants are likely limited because of low transplant survival after SCI. Sonic hedgehog (Shh) is a multifunctional growth factor which can facilitate neuronal and BMSCs survival, promote axonal growth, prevent activation of the astrocyte lineage, and enhance the delivery of neurotrophic factors in BMSCs. However, treatment of SCI with Shh alone also has limited effects on recovery, because the protein is cleared quickly. In this study, we investigated the use of BMSCs overexpressing the Shh transgene (Shh-BMSCs) in the treatment of rats with SCI, which could stably secrete Shh and thereby enhance the effects of BMSCs, in an attempt to combine the advantages of Shh and BMSCs and so to promote functional recovery. After Shh-BMSCs treatment of SCI via the subarachnoid, we detected significantly greater damage recovery compared with that seen in rats treated with phosphate-buffered saline (PBS) and BMSCs. Use of Shh-BMSCs increased the expression and secretion of Shh, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), improved the behavioral function, enhanced the BMSCs survival, promoted the expression level of neurofilament 200 (NF200), and reduced the expression of glial fibrillary acidic protein (GFAP). Thus, our results indicated that Shh-BMSCs enhanced recovery of neurological function after SCI in rats and could be a potential valuable therapeutic intervention for SCI in humans.


Assuntos
Proteínas Hedgehog/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Traumatismos da Medula Espinal/terapia , Animais , Sobrevivência Celular , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas Hedgehog/genética , Células-Tronco Mesenquimais/patologia , Atividade Motora , Proteínas de Neurofilamentos/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Transgenes , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
PLoS One ; 8(11): e81296, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24278413

RESUMO

It has been recognized that changes in mitochondrial structure plays a key role in development of cardiac dysfunction, and autophagy has been shown to exert maintenance of mitochondrial homeostasis effects. Our previous study found that anti-ß1-adrenergic receptor autoantibodies (ß1-AABs) could lead to cardiac dysfunction along with abnormalities in mitochondrial structure. The present study tested the hypothesis that ß1-AABs may induce the decline in mitochondrial membrane potential (ΔΨm) by suppression of cardiac autophagy, which contributed to cardiac dysfunction. Male adult rats were randomized to receive a vehicle or peptide corresponding to the second extracellular loop of the ß1 adrenergic receptor (ß1-AAB group, 0.4 µg/g every two weeks for 12 weeks) and treated with rapamycin (RAPA, an autophagy agonist) at 5 mg/kg/day for two days before detection. At the 4th week, 8th week and 12th week of active immunization, the rats were sacrificed and cardiac function and the levels of cardiac LC3 and Beclin-1 were detected. ΔΨm in cardiac myocytes was determined by myocardial radionuclide imaging technology and JC-1 staining. In the present study, ß1-AABs caused cardiac dysfunction, reduced ΔΨm and decreased cardiac autophagy. Treatment with RAPA markedly attenuated ß1-AABs-induced cardiac injury evidenced by recovered ΔΨm. Taken together, these results suggested that ß1-AABs exerted significant decreased ΔΨm, which may contribute to cardiac dysfunction, most likely by decreasing cardiac autophagy in vivo. Moreover, myocardial radionuclide imaging technology may be needed to assess the risk in developing cardiac dysfunction for the people who have ß1-AABs in their blood.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Autoanticorpos/farmacologia , Autofagia/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miocárdio/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Animais , Linhagem Celular , Imunoglobulina G , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos
7.
Neurosci Bull ; 29(4): 484-92, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23852559

RESUMO

Secondary damage is a critical determinant of the functional outcome in patients with spinal cord injury (SCI), and involves multiple mechanisms of which the most important is the loss of nerve cells mediated by multiple factors. Autophagy can result in cell death, and plays a key role in the development of SCI. It has been recognized that valproic acid (VPA) is neuroprotective in certain experimental animal models, however, the levels of autophagic changes in the process of neuroprotection by VPA treatment following SCI are still unknown. In the present study, we determined the extent of autophagy after VPA treatment in a rat model of SCI. We found that both the mRNA and protein levels of Beclin-1 and LC3 were significantly increased at 1, 2, and 6 h after SCI and peaked at 2 h; however, Western blot showed that autophagy was markedly decreased by VPA treatment at 2 h post-injury. Besides, post-SCI treatment with VPA improved the Basso-Beattie-Bresnahan scale, increased the number of ventral horn motoneurons, and reduced myelin sheath damage compared with vehicle-treated animals at 42 days after SCI. Together, our results demonstrated the characteristics of autophagy expression following SCI, and found that VPA reduced autophagy and enhanced motor function.


Assuntos
Autofagia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Ácido Valproico/farmacologia , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Proteína Beclina-1 , Western Blotting , Modelos Animais de Doenças , Feminino , Imunofluorescência , Proteínas Associadas aos Microtúbulos/biossíntese , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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