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1.
J Cell Mol Med ; 24(19): 11084-11099, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32910538

RESUMO

Skeletal muscle atrophy is a common and serious complication of chronic kidney disease (CKD). Oxidative stress and autophagy are the primary molecular mechanisms involved in muscle atrophy. Calycosin, a major component of Radix astragali, exerts anti-inflammatory, anti-oxidative stress and anti-autophagy effects. We investigated the effects and mechanisms of calycosin on skeletal muscle atrophy in vivo and in vitro. 5/6 nephrectomy (5/6 Nx) rats were used as a model of CKD. We evaluated bodyweight and levels of serum creatinine (SCr), blood urea nitrogen (BUN) and serum albumin (Alb). H&E staining, cell apoptosis, oxidative stress biomarkers, autophagosome and LC3A/B levels were performed and evaluated in skeletal muscle of CKD rat. Calycosin treatment improved bodyweight and renal function, alleviated muscle atrophy (decreased the levels of MuRF1 and MAFbx), increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity and reduced malondialdehyde (MDA) levels in skeletal muscle of CKD rats. Importantly, calycosin reduced autophagosome formation, down-regulated the expression of LC3A/B and ATG7 through inhibition of AMPK and FOXO3a, and increased SKP2, which resulted in decreased expression of CARM1, H3R17me2a. Similar results were observed in C2C12 cells treated with TNF-α and calycosin. Our findings showed that calycosin inhibited oxidative stress and autophagy in CKD induced skeletal muscle atrophy and in TNF-α-induced C2C12 myotube atrophy, partially by regulating the AMPK/SKP2/CARM1 signalling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Isoflavonas/farmacologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/metabolismo , Insuficiência Renal Crônica/patologia , Animais , Apoptose/efeitos dos fármacos , Arginina/metabolismo , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Fibrose , Histonas/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Masculino , Metilação , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Nefrectomia , Ratos Sprague-Dawley , Insuficiência Renal Crônica/fisiopatologia , Proteínas Quinases Associadas a Fase S/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa
2.
Cancer Cell Int ; 18: 183, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459531

RESUMO

BACKGROUND: Cervical cancer (CC) is one of the most common cancers among females worldwide. Spindle and kinetochore-associated complex subunit 3 (SKA3), located on chromosome 13q, was identified as a novel gene involved in promoting malignant transformation in cancers. However, the function and underlying mechanisms of SKA3 in CC remain unknown. Using the Oncomine database, we found that expression of SKA3 mRNA is higher in CC tissues than in normal tissues and is linked with poor prognosis. METHODS: In our study, immunohistochemistry showed increased expression of SKA3 in CC tissues. The effect of SKA3 on cell proliferation and migration was evaluated by CCK8, clone formation, Transwell and wound-healing assays in HeLa and SiHa cells with stable SKA3 overexpression and knockdown. In addition, we established a xenograft tumor model in vivo. RESULTS: SKA3 overexpression promoted cell proliferation and migration and accelerated tumor growth. We further identified that SKA3 is involved in regulating cell cycle progression and the PI3K/Akt signaling pathway via RNA-sequencing (RNA-Seq) and gene set enrichment analyses. Western blotting results revealed that SKA3 overexpression increased levels of p-Akt, cyclin E2, CDK2, cyclin D1, CDK4, E2F1 and p-Rb in HeLa cells. Additionally, the use of an Akt inhibitor (GSK690693) significantly reversed the cell proliferation capacity induced by SKA3 overexpression in HeLa cells. CONCLUSIONS: We suggest that SKA3 overexpression contributes to CC cell growth and migration by promoting cell cycle progression and activating the PI3K-Akt signaling pathway, which may provide potential novel therapeutic targets for CC treatment.

3.
Eur J Pharmacol ; 867: 172797, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31747547

RESUMO

Endothelial dysfunction plays important roles in vascular dysfunction under diabetic conditions. The generation of advanced glycation end products (AGEs), which can induce inflammation and oxidative stress, is pivotal in endothelial dysfunction. Salidroside, a major active compound in Rhodiola rosea, exerts protective effects against vascular diseases. To study the effects and mechanism of salidroside in diabetes-induced vascular endothelial dysfunction, an in vitro model was established with AGEs-induced human umbilical vein endothelial cells (HUVECs). Then, cell viability, cell apoptosis, pro-inflammatory cytokines and oxidative biomarkers were tested to determine the effects of salidroside at 10, 50 and 100 µM doses on AGEs induced HUVECs. Additionally, RNA-Seq and bioinformatics analyses were used to search for the underlying mechanism of salidroside. The results showed that salidroside promoted cell viability and significantly alleviated cell apoptosis in AGEs-induced HUVECs. Furthermore, salidroside remarkably decreased the levels of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 and impeded the expression of VCAM-1 and ICAM-1 induced by AGEs. Additionally, salidroside promoted superoxide dismutase (SOD) activity and increased catalase (CAT) and glutathione peroxidase (GSH-Px) levels while inhibiting the intracellular generation of reactive oxygen species (ROS) and malondialdehyde (MDA) in AGEs-induced HUVECs. Importantly, salidroside alleviated endothelial inflammation and oxidative stress by activating AMPK phosphorylation and inhibiting NF-ĸB p65 and NLRP3 inflammasome activation. Therefore, we used compound C, an accepted AMPK inhibitor, to further demonstrate the mechanism. Interestingly, the phenomenon produced by salidroside was abolished. Our findings suggest that salidroside ameliorates AGEs-induced endothelial inflammation and oxidative stress, partially via the AMPK/NF-κB/NLRP3 signaling pathway.


Assuntos
Angiopatias Diabéticas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Glucosídeos/farmacologia , Produtos Finais de Glicação Avançada/imunologia , Inflamação/tratamento farmacológico , Fenóis/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Linhagem Celular , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Glucosídeos/uso terapêutico , Produtos Finais de Glicação Avançada/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Fenóis/uso terapêutico , RNA-Seq , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelA/metabolismo
4.
Int J Clin Exp Pathol ; 8(10): 12793-801, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26722469

RESUMO

Collagen triple helix repeats containing 1 (CTHRC1) participates in vascular remodeling, bone formation, and developmental morphogenesis. Recently, CTHRC1 has been found up-regulated in many solid tumors and contributes to tumorigenesis, but its role in the progression of human colorectal cancer (CRC), remains unclear. In this study, CTHRC1 expression in human CRC cell lines was evaluated by quantitative real-time PCR and immunoblot analyses. The role of CTHRC1 in CRC cell proliferation and extracellular matrix invasion in vitro was analyzed by gene over-expression and recombinant protein. Reporter luciferase assay was used to reveal key relevant signaling pathways involved in CRC cells. The results show that CTHRC1 is secreted both by colorectal epithelia cells and stromal fibroblasts. Recombinant CTHRC1 promotes CRC cell migration and invasion dose-dependently. CTHRC1 overexpression promotes CRC cell migration, invasion and proliferation in vitro. Wnt/PCP signaling but not Wnt/catenin signaling was activates by CTHRC1 in CRC cells. Together, CTHRC1 promotes CRC cell proliferation, migration and invasion in vitro, which is possibly mediated by activating Wnt/PCP pathway.


Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/genética , Proteínas da Matriz Extracelular/genética , Invasividade Neoplásica/genética , Transdução de Sinais/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Movimento Celular/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas da Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/patologia
5.
Mol Cell Endocrinol ; 199(1-2): 153-63, 2003 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-12581887

RESUMO

The high levels of corticosterone (CORT) that are typically achieved during stress induce apoptotic death of Leydig cells. The intracellular mechanisms by which CORT acts on Leydig cells to induce apoptosis are unknown, and the present study tested for mediation by Fas ligand (FasL), a member of the tumor necrosis factor ligand family, in association with caspase activation. In addition, another apoptotic pathway involving in the participation of mitochondria was studied by evaluation of mitochondrial membrane potential (DeltaPsi) loss and generation of reactive oxygen species (ROS), which are early apoptotic events in many cell types. Rat Leydig cells were isolated from adrenalectomized rats on day 90 postpartum at 3, 6, 12, 24 and 48 h after the start of CORT administration (at a dose of 5 mg total/100 g body weight per day intraperitoneally in two daily injections starting 3 days after surgery). Both FasL and Fas receptor protein levels, analyzed by Western blot and fluorescent immunohistochemistry, increased at 6 h after the start of CORT administration, peaking at 24 h and declining thereafter. Leydig cell caspase-3 activity was analyzed in vitro. Low molecular weight DNA fragments that are characteristic of apoptosis were evident in Leydig cells by 12 h of exposure to 100 nM CORT in vitro, and the abundance of the fragments was more pronounced at 24 h. In the presence of a specific caspase inhibitor, Ac-DEVD-CHO, Leydig cell apoptosis was suppressed, corroborating the hypothesis that caspase-3 is involved in CORT-mediated cell death. Western blotting analysis revealed that procaspase-3 was present only at low levels in untreated control Leydig cells, and increased by 6 h of CORT administration. By 12 h, however, procaspase-3 was significantly reduced, and the cleaved, active caspase-3 forms appeared and increased through 24 h. These results indicated that FasL/Fas and caspase were implicated in CORT-mediated Leydig cell apoptosis. Decreased DeltaPsi and increased ROS generation were also measurable in Leydig cells for up to 2 days following CORT administration in vitro. These data indicate that activation of the Fas system, cleavage of procaspase-3, loss of DeltaPsi and increased ROS generation are all implicated in the process of CORT-induced Leydig cell death.


Assuntos
Apoptose/efeitos dos fármacos , Corticosterona/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Animais , Caspase 3 , Caspases/metabolismo , Corticosterona/administração & dosagem , Fragmentação do DNA , Precursores Enzimáticos/metabolismo , Proteína Ligante Fas , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Células Intersticiais do Testículo/citologia , Masculino , Glicoproteínas de Membrana/análise , Potenciais da Membrana , Mitocôndrias/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
6.
Physiol Behav ; 106(4): 439-45, 2012 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-22426354

RESUMO

Ascent to high altitude is associated with decreases in cognitive function and work performance as a result of hypoxia. Some workers with special jobs typically undergo intensive mental training because they are expected to be agile, stable and error-free in their job performance. The purpose of this study was to determine the risk to cognitive function acquired from training following hypoxic exposure. The results of WHO neurobehavioral core tests battery (WHO-NCTB) and Raven's standard progressive matrices (RSPM) tests of a group of 54 highly trained military operators were compared with those of 51 non-trained ordinary people and were investigated at sea level and on the fifth day after arrival at high altitudes (3900m). Meanwhile, the plasma levels of brain-derived neurotrophic factor (BDNF), interleukin 1ß (IL-1ß) and vascular endothelial growth factor (VEGF) were examined. The result showed that at sea level, the trained group exhibited significantly better performance on neurobehavioral and RSPM tests. At high altitude, both groups had decreased accuracy in most cognitive tests and took longer to finish them. More importantly, the highly trained subjects showed more substantial declines than the non-trained subjects in visual reaction accuracy, auditory reaction speed, digit symbol scores, ability to report correct dots in a pursuit aiming test and total RSPM scores. This means that the training-dependent cognitive advantages in these areas were suppressed at high altitudes. The above phenomenon maybe associated with decreased BDNF and elevated inflammatory factor during hypoxia, and other mechanisms could not be excluded.


Assuntos
Altitude , Cognição/fisiologia , Aptidão Física/fisiologia , Aptidão Física/psicologia , Adulto , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Frequência Cardíaca/fisiologia , Humanos , Hipóxia/psicologia , Interleucina-1beta/sangue , Masculino , Militares , Testes Neuropsicológicos , Oxiemoglobinas/metabolismo , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Sono/fisiologia , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
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