RESUMO
Muscle atrophy occurs in many conditions, including use of glucocorticoids. N-3 (omega-3) is widely consumed due its healthy properties; however, concomitant use with glucocorticoids can increase its side effects. We evaluated the influences of N-3 on glucocorticoid atrophy considering IGF-1, Myostatin, MEK/ERK, AMPK pathways besides the ubiquitin-proteasome system (UPS) and autophagic/lysosomal systems. Sixty animals constituted six groups: CT, N-3 (EPA 100 mg/kg/day for 40 days), DEXA 1.25 (DEXA 1.25 mg/kg/day for 10 days), DEXA 1.25 + N3 (EPA for 40 days + DEXA 1.25 mg/kg/day for the last 10 days), DEXA 2.5 (DEXA 2.5 mg/kg/day for 10 days), and DEXA 2.5 + N3 (EPA for 40 days + DEXA 2.5 mg/kg/day for 10 days). Results: N-3 associated with DEXA increases atrophy (fibers 1 and 2A), FOXO3a, P-SMAD2/3, Atrogin-1/MAFbx (mRNA) expression, and autophagic protein markers (LC3II, LC3II/LC3I, LAMP-1 and acid phosphatase). Additionally, N-3 supplementation alone decreased P-FOXO3a, PGC1-alpha, and type 1 muscle fiber area. Conclusion: N-3 supplementation increases muscle atrophy caused by DEXA in an autophagic, AMPK and UPS process.
Assuntos
Autofagia , Dexametasona/efeitos adversos , Ácidos Graxos Ômega-3/efeitos adversos , Glucocorticoides/efeitos adversos , Atrofia Muscular/etiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitinas/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Ácidos Graxos Ômega-3/farmacologia , Proteína Forkhead Box O3/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Quinases/metabolismo , Ratos , Ratos Wistar , Proteínas Smad/metabolismoRESUMO
Polydatin (PD), a monocrystalline polyphenolic drug mainly found in the roots of Polygonum cuspidatum, has various pharmacological activities. Long non-coding RNAs (lncRNA) DiGeorge syndrome critical region gene 5 (DGCR5) was found to participate in the suppression of multiple cancers. Here, we proposed to study the effect of PD on myocardial infarction (MI) by inducing DGCR5. CCK-8 assay was performed to detect the viability of H9c2 cells. Flow cytometry was utilized to test apoptosis of H9c2 cells. These results determined the optimal concentration and effect time of hypoxia as well as PD. Si-DGCR5 was transfected into cells and the expression level was determined by qRT-PCR. Western blot was utilized to evaluate the expression of apoptosis-related proteins, Bcl-2, Bax, and cleaved-caspase-3, as well as autophagy-associated proteins including Beclin-1, p62, and LC3-II/LC3-I. As a result, PD efficiently attenuated hypoxia-induced apoptosis and autophagy in H9c2 cells. The expression of DGCR5 was down-regulated by hypoxia and up-regulated by PD. Besides, knocking-down the expression of DGCR5 inhibited the protection of PD in H9c2 cells. In addition, PD up-regulated the accumulation of DGCR5, DGCR5 decreased the expression of Bcl-2 and p62, raised the expression of Bax and cleaved-caspase-3, and the proportion of LC3-II/LC3-I. PD stimulated the PI3K/AKT/mTOR and MEK/ERK signaling pathways via up-regulating the expression of DGCR5. Our data demonstrated that PD reduced cell apoptosis and autophagy induced by hypoxia in cardiomyocytes. Moreover, PD activated PI3K/AKT/mTOR and MEK/ERK signaling pathways by up-regulating the expression of DGCR5.
Assuntos
Animais , Ratos , Estilbenos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , RNA Longo não Codificante/efeitos dos fármacos , Glucosídeos/farmacologia , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos , Linhagem Celular , Citoproteção , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologiaRESUMO
The RAS/RAF/MEK/ERK pathway regulates certain cellular functions, including cell proliferation, differentiation, survival, and apoptosis. Dysregulation of this pathway leads to the occurrence and progression of cancers mainly by somatic mutations. This study aimed to assess if polymorphisms of the RAS/RAF/MEK/ERK pathway are associated with gastric cancer. A case-control study of 242 gastric cancer patients and 242 controls was performed to assess the association of 27 single nucleotide polymorphisms (SNPs) in the RAS/RAF/MEK/ERK pathway genes with gastric cancer. Analyses performed under the additive model (allele) showed four significantly associated SNPs: RAF1 rs3729931 (Odds ratio (OR) = 1.54, 95%, confidence interval (CI): 1.20â»1.98, p-value = 7.95 × 10-4), HRAS rs45604736 (OR = 1.60, 95% CI: 1.16â»2.22, p-value = 4.68 × 10-3), MAPK1 rs2283792 (OR = 1.45, 95% CI: 1.12â»1.87, p-value = 4.91 × 10-3), and MAPK1 rs9610417 (OR = 0.60, 95% CI: 0.42â»0.87, p-value = 6.64 × 10-3). Functional annotation suggested that those variants or their proxy variants may have a functional effect. In conclusion, this study suggests that RAF1 rs3729931, HRAS rs45604736, MAPK1 rs2283792, and MAPK1 rs9610417 are associated with gastric cancer.