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1.
Cancer Sci ; 112(4): 1624-1632, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33540491

RESUMO

Lysophosphatidic acid receptor 5 (LPAR5) is involved in mediating thyroid cancer progression, but the underlying mechanism needs to be further revealed. In this study, we confirmed that LPAR5 is upregulated in papillary thyroid carcinoma (PTC), especially in BRAF-like PTC, by analyzing The Cancer Genome Atlas (TCGA) database and performing immunohistochemistry assay in human thyroid cancer tissues. LPAR5-specific antagonist TC LPA5 4 treatment inhibited CGTH-W3, TPC-1, B-CPAP, and BHT-101 cell proliferation, CGTH-W3 and TPC-1 cell migration significantly. In vivo, TC LPA5 4 treatment could delay CGTH-W3 xenograft growth in nude mice. We also found that LPAR5-specific antagonist TC LPA5 4, PI3K inhibitor wortmannin, or mTOR inhibitor rapamycin pretreatment abrogated phosphorylation of Akt and p70S6K1 stimulated by LPA in CGTH-W3 and TPC-1 cells. Stimulating CGTH-W3 cells transfected with pEGFPC1-Grp1-PH fusion protein with LPA resulted in the generation of phosphatidylinositol (3,4,5)-triphosphate, which indicates that PI3K was activated by LPA directly. The p110ß-siRNA instead of p110α-siRNA transfection abrogated the increase of levels of phosphorylated Akt and S6K1 stimulated by LPA. Furthermore, immunoprecipitation assay confirmed an interaction between LPAR5 and p110ß. Overall, we provide new insights that the downregulation of LPAR5 decreased the proliferation and migration phenotype via the PI3K/Akt pathway. Inhibition of LPAR5 or the PI3K/Akt signal may be a novel therapeutic strategy for treating thyroid cancer.


Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Animais , Domínio Catalítico/fisiologia , Linhagem Celular Tumoral , Regulação para Baixo/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/fisiologia , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia
2.
Toxicol Lett ; 342: 73-84, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33609687

RESUMO

Trovafloxacin (TVX) is associated with idiosyncratic drug-induced liver injury (iDILI) and inflammation-mediated hepatotoxicity. However, the inflammatory stress-regulated mechanisms in iDILI remain unclear. Herein, we elucidated the novel role of tumor-necrosis factor alpha (TNFα), an inflammatory stress factor, in TVX-induced in vitro hepatotoxicity and synergistic toxicity. TVX specifically induced synergistic toxicity in HepG2 cells with TNFα, which inhibits autophagy. TVX-treated HepG2 cells induced protective autophagy by inhibiting the expression of mTOR signaling proteins, while ATG5 knockdown in HepG2 cells, responsible for the impairment of autophagy, enhanced TVX-induced toxicity due to the increase in cytochrome C release and JNK pathway activation. Interestingly, the expression of mTOR signal proteins, which were suppressed by TVX, disrupted the negative feedback of the PI3K/AKT pathway and TNFα rebounded p70S6K phosphorylation. Co-treatment with TVX and TNFα inhibited protective autophagy by maintaining p70S6K activity, which enhanced TVX-induced cytotoxicity. Phosphorylation of p70S6K was inhibited by siRNA knockdown and rapamycin to restore TNFα-inhibited autophagy, which prevented the synergistic effect on TVX-induced cytotoxicity. These results indicate that TVX activates protective autophagy in HepG2 cells exposed to toxicity and an imbalance in negative feedback regulation of autophagy by TNFα synergistically enhanced the toxicity. The finding from this study may contribute to a better understanding of the mechanisms underlying iDILI associated with inflammatory stress.


Assuntos
Autofagia/efeitos dos fármacos , Fluoroquinolonas/toxicidade , Hepatócitos/efeitos dos fármacos , Naftiridinas/toxicidade , Fator de Necrose Tumoral alfa/farmacologia , Antimaláricos/toxicidade , Sobrevivência Celular , Cloroquina/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Levofloxacino/farmacologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Piperazinas/toxicidade , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/toxicidade , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Triazóis/toxicidade
3.
Metabolism ; 114: 154419, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161019

RESUMO

BACKGROUND: Glycolysis controls mTORC1 signaling and protein synthesis. In skeletal muscle, glucose metabolism increases with both exercise/contraction intensity and volume, and therefore, high-intensity muscle contraction (HiMC) such as resistance exercise facilitates glycolysis including glucose uptake and glycogen breakdown. However, it is unknown whether glycolysis regulates HiMC-induced mTORC1 activation and increase in protein synthesis. METHODS: To determine whether glycolysis regulates basal and HiMC-induced mTORC1 signaling and protein synthesis, we employed 2-deoxyglucose (2-DG) to inhibit glycolysis and isometrically contracted the gastrocnemius muscle of Sprague Dawley rats using percutaneous electrical stimulation. RESULTS: Inhibition of glycolysis by 2-DG inhibited basal phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTORC1) and protein synthesis (all P < 0.05) independent of AMPK phosphorylation. AMPK phosphorylation was comparably increased after HiMC at 0 h post HiMC and returned to basal levels 6 h post HiMC in both vehicle- and 2-DG-treated groups. Glycolysis inhibition attenuated muscle contraction-induced phosphorylation of 4E-BP1 at 6 h post HiMC (P < 0.05) but not p70S6K phosphorylation and protein synthesis. CONCLUSION: Although glycolysis is involved in basal but not HiMC-induced muscle protein synthesis, it regulates both basal and HiMC-induced mTORC1 signaling, and may play key roles in skeletal muscle adaptation to HiMC.


Assuntos
Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Adenilato Quinase/metabolismo , Animais , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Contração Muscular/fisiologia , Músculo Esquelético/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
4.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339133

RESUMO

Natural killer (NK) cells are suitable targets for cancer immunotherapy owing to their potent cytotoxic activity. To maximize the therapeutic efficacy of cancer immunotherapy, adjuvants need to be identified. Resveratrol is a well-studied polyphenol with various potential health benefits, including antitumor effects. We previously found that resveratrol is an NK cell booster, suggesting that it can serve as an adjuvant for cancer immunotherapy. However, the molecular mechanism underlying the activation of NK cells by resveratrol remains unclear. The present study aimed to determine this mechanism. To this end, we investigated relevant pathways in NK cells using Western blot, real-time polymerase chain reaction, pathway inhibitor, protein/DNA array, and cytotoxicity analyses. We confirmed the synergistic effects of resveratrol and interleukin (IL)-2 on enhancing the cytolytic activity of NK cells. Resveratrol activated Akt by regulating Mammalian Target of Rapamycin (mTOR) Complex 2 (mTORC2) via phosphatase and tensin homolog (PTEN) and ribosomal protein S6 kinase beta-1 (S6K1). Moreover, resveratrol-mediated NK cell activation was more dependent on the mTOR pathway than the Akt pathway. Importantly, resveratrol increased the expression of c-Myb, a downstream transcription factor of Akt and mTORC2. Moreover, c-Myb was essential for resveratrol-induced NK cell activation in combination with IL-2. Our results demonstrate that resveratrol activates NK cells through Akt- and mTORC2-mediated c-Myb upregulation.


Assuntos
Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária , Proteínas Proto-Oncogênicas c-myb/metabolismo , Resveratrol/farmacologia , Linhagem Celular , Humanos , Células Matadoras Naturais/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Regulação para Cima
5.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321903

RESUMO

The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inibidores da Angiogênese/administração & dosagem , Animais , Antineoplásicos Imunológicos/administração & dosagem , Apoptose , Bevacizumab/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos SCID , Metástase Neoplásica , Compostos de Fenilureia/administração & dosagem , Pirimidinas/administração & dosagem , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Survivina/genética , Survivina/metabolismo , Hipóxia Tumoral , Fosfatases cdc25/genética , Fosfatases cdc25/metabolismo
6.
Life Sci ; 259: 118391, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32891610

RESUMO

AIMS: Dyslipidemia-associated diabetic retinopathy is featured by macular edema and retinal angiogenesis. This study investigated the in vitro lipotoxicity of free fatty acids and their modulatory roles in regulation of autophagy and angiogenic factor production in cultured human retinal pigment epithelium (RPE) ARPE-19 cells. MAIN METHODS: ARPE-19 cells were exposed to monounsaturated oleic acid (OA), saturated palmitic acid (PA), or both. Cell viability, cell cycle distribution, migration, and autophagy of the treated cells were monitored. Angiogenic factor production was determined by RT-qPCR and ELISA. KEY FINDINGS: OA, but not PA, at doses higher than 500 µM significantly induced cytostasis and lipotoxicity in ARPE-19 cells. OA exposure not only markedly enhanced autophagy flux, but also enhanced cell migration, while PA suppressed motility of RPE cells. Meanwhile, OA stimulated de novo synthesis of angiogenic factors including VEGF and bFGF in ARPE-19 cells. Mechanistically, OA treatment stimulated not only AMPK/mTOR/p70S6K signaling, but also induced hyperphosphorylation of MAPK pathway mediators, including ERK, JNK and p38 MAPK, as well as NF-κB activation. Kinase inhibition assays showed that blockade of PI3K/Akt, MAPK and NF-κB pathways prevented the OA-upregulated VEGF transcription and its peptide release. Comparatively, only NF-κB inhibition significantly suppressed bFGF peptide release from ARPE-19 cells. SIGNIFICANCE: Out findings support the OA-exhibited cytostasis, autophagy modulation and angiogenic factor production in RPE cells. This study sheds light on the interrelationship between metabolic disorder and retinopathy and provides molecular strategies for preventing and treating choroidal neovascularization in diabetic retinopathy.


Assuntos
Indutores da Angiogênese/metabolismo , Autofagia , Ácido Oleico/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Western Blotting , Movimento Celular , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Sistema de Sinalização das MAP Quinases , Ácido Palmítico/metabolismo , Epitélio Pigmentado da Retina/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
7.
Life Sci ; 259: 118284, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798557

RESUMO

AIMS: To study how to effectively prevent or reduce renal injury caused by contrast agents in diabetic patients. MAIN METHODS: Sprague Dawley (SD) rats were bred with a high-fat diet for eight weeks, then intraperitoneally injected with Streptozotocin (STZ) to prepare the diabetes model. Rats were treated with Iodixanol to prepare a contrast-induced acute kidney injury (CIAKI) model. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, was administrated to diabetic rats with or without Rapamycin treatment. Serum creatinine (SCr) and blood urea nitrogen (BUN) were examined using Biochemical detector. Kidney injury molecule-1 (KIM-1), N-acetyl-ß-D-amino glycosidase (NAG) in urine, inflammatory and oxidative stress factors in serum were determined by ELISA. The expression level of ROS was quantified by immunofluorescence (IF). The protein expressions of Bax, BCl-2, LC3, Beclin1, mTOR and p70S6K in renal tissue were detected by Western blot. KEY FINDINGS: Rapamycin was demonstrated to improve renal injury induced by Iodixanol diabetic rats, decrease the levels of SCr, BUN, KIM-1, NAG, improve renal functions, reduce inflammatory response and oxidative stress injury, down-regulate Bax, while up-regulate BCl-2 and inhibit apoptosis. Moreover, Rapamycin could inhibit the phosphorylation of mTOR/p70S6K pathway-associated proteins, activate autophagy and increase the levels of LC3 and Beclin1. After treatment with 3MA, an inhibitor of mTOR/p70S6K signaling pathway, the protective effects of Rapamycin on CIAKI were weakened. SIGNIFICANCE: Rapamycin can alleviate renal injury induced by Iodixanol diabetic rats, and its regulatory mechanisms may be related to the regulation of mTOR/p70S6K signaling pathway and the activating autophagy.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Sirolimo/metabolismo , Sirolimo/farmacologia , Lesão Renal Aguda/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Rim/metabolismo , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Ácidos Tri-Iodobenzoicos/farmacologia
8.
Gene ; 760: 145018, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758580

RESUMO

Protein turnover is a process that is regulated by several factors and can lead to muscle hypertrophy or atrophy. The purpose of the present study was to determine the effects of ß-hydroxy-ß-methylbutyrate free acid (HMB-FA) and eccentric resistance exercise on variables related to protein turnover in rats. Thirty-two male rats were randomly assigned into four groups of eight, including control, control-HMB, exercise, and exercise-HMB. Animals in HMB groups received 340 mg/kg/day for two weeks. Animals in the exercise groups performed one session of eccentric resistance exercise consisting of eight repetitions descending from a ladder with a slope of 80 degree, with an extra load of two times body weight (100% 1RM). Twenty-four hours after the exercise session, triceps brachii muscle and serum were collected for further analysis. Exercise and HMB-FA induced lower muscle myostatin and higher muscle Fibronectin type III domain containing 5 (FNDC5), P70-S6 kinase 1 gene expression, as well as higher serum irisin and IGF-1 concentrations. Exercise alone induced higher caspase-3 and caspase-8 gene expression while HMB-FA alone induced lower caspase 3 gene expression. HMB-FA supplement increased the effect of exercise on muscle FNDC5, myostatin, and P70-S6 kinase 1 gene expression. The interaction of exercise and HMBFA resulted in an additive effect, increasing serum irisin and IGF-1 concentrations. In conclusion, a 2-week HMB-FA supplementation paired with acute eccentric resistance exercise can positively affect some genes related to muscle protein turnover.


Assuntos
Proteínas Musculares/efeitos dos fármacos , Valeratos/farmacologia , Animais , Suplementos Nutricionais , Fibronectinas/efeitos dos fármacos , Fibronectinas/metabolismo , Genes Reguladores/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miostatina/efeitos dos fármacos , Miostatina/metabolismo , Condicionamento Físico Animal/métodos , Ratos , Ratos Sprague-Dawley , Treinamento de Resistência/métodos , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
9.
Gene ; 757: 144943, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32652105

RESUMO

The growth of animal skeletal muscle is mainly determined by the synthesis processes of total proteins in skeletal muscle cells, which has a significant impact on the postnatal growth of young animals. An increasing number of studies are focusing on the functions of Tuberous sclerosis complex 2 (TSC2) during the process of cell protein synthesis and growth. However, it is still unclear the effect of whether and how TSC2 on goat myoblasts proliferation and differentiation. Here, we found that TSC2 gene has opposite expression patterns in proliferation and differentiation of myoblasts. An expression vector containing goat TSC2 cDNA sequences linked with pcDNA3.1 plasmid was constructed. Myoblasts proliferation activity was significantly inhibited and cell cycle transition slowed down after the transfection of pcDNA3.1-TSC2 plasmid into goat primary myoblasts by EdU staining, CCK-8 and flow cytometry. Mechanically, we further confirmed that the overexpression TSC2 was able to down-regulate the mRNA and protein expression of mechanistic target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 (p70S6K) and some cell cycle related genes. In addition, the expression of myogenic genes and myotube formation were attenuated. Collectively, all our results of the experiment demonstrate that TSC2 could regulate myoblasts cells proliferation and differentiation via the activation of the mTOR/p70S6K signaling pathway.


Assuntos
Diferenciação Celular , Proliferação de Células , Desenvolvimento Muscular , Mioblastos/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Cabras , Mioblastos/citologia , Mioblastos/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Regulação para Cima
10.
Life Sci ; 257: 118126, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32707053

RESUMO

AIMS: Rab31, a Rab5 subfamily member, has emerged as a modulator of membrane trafficking. Our study serves to clarify the role and mechanism of Rab31 in colorectal carcinoma (CRC) pathogenesis. MATERIALS AND METHODS: The differential expression of Rab31 was examined in paired normal and cancerous colonic tissues by quantitative PCR, western blot and immunochemistry. The prognostic significance of Rab31 was analysed by univariate and multivariate survival analyses. We also investigated the effects of Rab31 on tumour growth in vitro. KEY FINDINGS: We observed that Rab31, which is related to histological differentiation in CRC, was markedly overexpressed in CRC cells. Moreover, patients who showed higher Rab31 levels had a shortened survival period relative to those with low Rab31 levels. Rab31 knockdown significantly downregulated cyclin D1, p-mTOR, and p-p70S6K expression. Moreover, the expression of Rab31-induced p-p70S6K was almost inhibited by rapamycin, a well-established inhibitor of mTOR. Similarly, rapamycin also significantly decreased the stimulatory effect of Rab31 on the expression of cyclin D1. SIGNIFICANCE: These findings suggested that Rab31 enhanced proliferation, promoted cell cycle progression, and inhibited apoptosis of colorectal carcinoma cells through the mTOR pathway.


Assuntos
Neoplasias Colorretais/metabolismo , Ciclina D1/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Idoso , Apoptose , Western Blotting , Células CACO-2 , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Células HCT116 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida , Regulação para Cima
11.
Cardiovasc Drugs Ther ; 34(4): 463-473, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32394178

RESUMO

PURPOSE: Berberine was reported to exert beneficial effects on cardiac hypertrophy. However, its cellular and molecular mechanisms still remained unclear. METHODS: Cardiac hypertrophy was induced in male Sprague-Dawley (SD) rats by transverse aorta constriction (TAC), with or without 6-week treatment of berberine. Echocardiography was performed to evaluate cardiac function. Rats were then sacrificed for histological assay, with detection for proteins and mRNA. H9c2 cells were pretreated with berberine of different concentrations (0, 1 µM, and 10 µM), followed by treatment with 2 µM norepinephrine (NE). Cells of different groups were measured for cell surface area, with mRNA detected by qRT-PCR and proteins by western blot. RESULTS: Compared with the sham group, rats of the TAC group showed significantly increased cardiac hypertrophy and fibrosis, which could be ameliorated by treatment with berberine. Western blot showed that mammalian target of rapamycin (mTOR) signaling-related protein expressions, including phospho-mTOR, phospho-4EBP1, and phospho-p70 S6K (Thr389), but not phospho-p70 S6K (Ser371), were significantly increased in the TAC group, which were inhibited by berberine treatment. H9c2 cells were treated with NE to induce hypertrophy with increased cell surface area and mRNA expressions of anp and bnp. Berberine of 10 µM, but not 1 µM, significantly ameliorated NE-induced hypertrophy and inhibited protein expressions of mTOR signaling pathway similar to those in the rat model. CONCLUSIONS: Berberine can exert cardioprotective effects on both pressure-overloaded cardiac hypertrophy and failure in vivo and NE-induced hypertrophy in vitro. Our results suggest berberine could be a potential treatment for patients with cardiac hypertrophy and failure.


Assuntos
Berberina/farmacologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Fator Natriurético Atrial/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/metabolismo , Fosforilação , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
12.
J Virol ; 94(12)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32295907

RESUMO

Mumps virus (MuV) caused the most viral meningitis before mass immunization. Unfortunately, MuV has reemerged in the United States in the past several years. MuV is a member of the genus Rubulavirus, in the family Paramyxoviridae, and has a nonsegmented negative-strand RNA genome. The viral RNA-dependent RNA polymerase (vRdRp) of MuV consists of the large protein (L) and the phosphoprotein (P), while the nucleocapsid protein (NP) encapsulates the viral RNA genome. These proteins make up the replication and transcription machinery of MuV. The P protein is phosphorylated by host kinases, and its phosphorylation is important for its function. In this study, we performed a large-scale small interfering RNA (siRNA) screen targeting host kinases that regulated MuV replication. The human kinase ribosomal protein S6 kinase beta-1 (RPS6KB1) was shown to play a role in MuV replication and transcription. We have validated the role of RPS6KB1 in regulating MuV using siRNA knockdown, an inhibitor, and RPS6KB1 knockout cells. We found that MuV grows better in cells lacking RPS6KB1, indicating that it downregulates viral growth. Furthermore, we detected an interaction between the MuV P protein and RPS6KB1, suggesting that RPS6KB1 directly regulates MuV replication and transcription.IMPORTANCE Mumps virus is an important human pathogen. In recent years, MuV has reemerged in the United State, with outbreaks occurring in young adults who have been vaccinated. Our work provides insight into a previously unknown mumps virus-host interaction. RPS6KB1 negatively regulates MuV replication, likely through its interaction with the P protein. Understanding virus-host interactions can lead to novel antiviral drugs and enhanced vaccine production.


Assuntos
Genoma Viral , Vírus da Caxumba/genética , Proteínas do Nucleocapsídeo/genética , Fosfoproteínas/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Virais/genética , Animais , Chlorocebus aethiops , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Interações Hospedeiro-Patógeno/genética , Humanos , Vírus da Caxumba/metabolismo , Proteínas do Nucleocapsídeo/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Ligação Proteica , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Células Vero , Proteínas Virais/metabolismo , Replicação Viral
13.
Sci Rep ; 10(1): 6105, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269242

RESUMO

Myocardial remodeling represents a key factor in chronic heart failure (CHF) development, and is characterized by chronic death of cardiomyocytes. Cardiac function changes may be attributed to inflammation, apoptosis and autophagy. This study assessed the effects of Qi Dan Li Xin Pill (QD) on heart function, inflammatory factors, autophagy and apoptosis in cardiac remodeling in CHF rats upon myocardial infarction (MI) induction. Male SD rats underwent a sham procedure or left anterior descending coronary artery (LADCA) ligation, causing MI. Twenty-eight days after modeling, the animals were treated daily with QD, valsartan and saline for 4 weeks. Echocardiography after 4 weeks of drug intervention revealed substantially improved left ventricular remodeling and cardiac function following QD treatment. As demonstrated by decreased IL-1ß, IL-6 and TNF-α amounts, this treatment also inhibited the apoptotic process and protected the viability of the myocardium. These outcomes may be attributed to enhanced autophagy in cardiomyocytes, which further reduced pro-inflammatory and pro apoptotic effects. This process may be achieved by QD regulation of the mTOR/P70S6K signaling pathway, suggesting that the traditional Chinese medicine Qi Dan Li Xin pill is effective in heart protective treatment, and is worth further investigation.


Assuntos
Apoptose , Autofagia , Cardiotônicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Animais , Cardiotônicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Arch Biochem Biophys ; 685: 108352, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32240637

RESUMO

Rab1A, a member of the Ras-like protein in rat brain (Rab) family, acts as an oncogene in a variety of malignant tumors. Previous studies reported that Rab1A was highly expressed in GC tissues. However, the function and molecular mechanism of Rab1A in gastric cancer (GC) development remain far from being addressed. Rab1A mRNA and protein levels were detected by qRT-PCR and western blot, respectively. Cell proliferation was evaluated by CCK-8 and BrdU incorporation assays. Apoptosis was estimated by flow cytometry analysis and western blot analysis of B cell lymphoma 2 (Bcl-2), myeloid cell leukemia 1 (Mcl-1), Bcl-2 associated X (Bax), and Bcl-2 homologous antagonist/killer (Bak) expression. Alteration of the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling pathway was detected by western blot. We found that Rab1A expression at both mRNA and protein was upregulated in GC cells. Rab1A knockdown significantly inhibited cell proliferation and induced apoptosis in GC cells. Rab1A overexpression promoted proliferation, inhibited cisplatin-induced apoptosis, and increased xenograft growth. In addition, we found that Rab1A knockdown suppressed the mTOR/p70S6K pathway in GC cells. Moreover, activation of mTOR/p70S6K pathway by MHY1485 abolished the effects of Rab1A knockdown on cell proliferation and apoptosis. In conclusion, Rab1A knockdown repressed proliferation and promoted apoptosis in GC cells by inhibition of the mTOR/p70S6K pathway.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Transdução de Sinais/fisiologia , Neoplasias Gástricas/metabolismo , Proteínas rab1 de Ligação ao GTP/metabolismo , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Morfolinas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Triazinas/farmacologia , Regulação para Cima , Proteínas rab1 de Ligação ao GTP/genética
15.
Hum Cell ; 33(3): 768-779, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32166565

RESUMO

Non-catalytic region of tyrosine kinase adaptor protein 1 (Nck1) is crucial for the progression of cancers. However, little is known on the role of Nck1 in the progression of ovarian carcinoma (OC). Here, we show that Nck1 expression is up-regulated in 176 OC tissues, compared with non-carcinoma ovarian tissues, and the up-regulated Nck1 expression is associated with the aggressiveness of OC and shorter overall and disease-free survival in this population. Higher Nck1 expression was an independent risk factor for poor prognosis of OC. Furthermore, Nck1 silencing by short hairpin RNA (shRNA) technology significantly inhibited the proliferation, migration and invasion of OC cells in vitro and the growth and metastasis of implanted OC tumors in vivo. Human kinase phosphorylation array indicated that Nck1 silencing significantly reduced the relative levels of 11 kinase expression and phosphorylation in OC cells, particularly for decreased levels of p70S6 kinase (p70S6K) and protein kinase B (AKT) expression in SKOV3 cells. Actually, Nck1 silencing significantly decreased PI3K and AKT expression, and reduced AKT and p70S6K phosphorylation while Nck1 over-expression had opposite effects in OC cells. Therefore, our data indicate that Nck1 promotes the progression of OC by enhancing the PI3k/AKT/p70S6K signaling in OC. Our findings suggest that Nck1 expression may be valuable for evaluating the prognosis of OC and as a target for design of new therapies for OC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Carcinoma/genética , Proteínas Oncogênicas/fisiologia , Neoplasias Ovarianas/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/fisiologia , Carcinoma/terapia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Terapia de Alvo Molecular , Neoplasias Ovarianas/terapia , Prognóstico , Transdução de Sinais/genética
16.
J Athl Train ; 55(4): 336-342, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32196379

RESUMO

CONTEXT: Long-term eccentric exercise is known to promote muscle growth better than concentric exercise, but its acute effect on muscle is not well understood because of misinterpreted modeling and in situ and in vitro stretch protocols. Knowing if the initial bout of eccentric exercise promotes muscle growth and limits damage is critical to understanding the effect of this mode of exercise. OBJECTIVE: To directly evaluate the immediate effects of eccentric and concentric exercises on untrained muscle when fiber strains were physiological and exercise doses were comparable. DESIGN: Controlled laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 40 skeletally mature male Long-Evans rats (age = 16 weeks, mass = 452.1 ± 35.2 g) were randomly assigned to an eccentric exercise (downhill walking, n = 16), concentric exercise (uphill walking, n = 16), or control (no exercise, n = 8) group. INTERVENTION(S): Rats were exposed to a single 15-minute bout of eccentric or concentric exercise on a motorized treadmill and then were euthanized at 6 or 24 hours postexercise. We harvested the vastus lateralis muscle bilaterally. MAIN OUTCOME MEASURE(S): The percentage increase or decrease in protein abundance in exercised animals relative to that in unexercised control animals was evaluated as elevated phosphorylated p70S6k relative to total p70S6k. Fiber damage was quantified using immunoglobulin G permeability staining. One-way analysis of variance and post hoc Tukey tests were performed. RESULTS: Rats exposed to eccentric exercise and euthanized at 24 hours had higher percentage response protein synthesis rates than rats exposed to eccentric exercise and euthanized at 6 hours (P = .02) or to concentric exercise and euthanized at 6 (P = .03) or 24 (P = .03) hours. We assessed 9446 fibers for damage and found only 1 fiber was infiltrated (in the concentric exercise group euthanized at 6 hours). Furthermore, no between-groups differences in immunoglobulin G fluorescent intensity were detected (P = .94). CONCLUSIONS: Incorporating eccentric exercise is a simple, universally available therapeutic intervention for promoting muscle recovery. A single 15-minute dose of eccentric exercise to a novice muscle can better exert an anabolic effect than a comparable dose of concentric exercise, with very limited evidence of fiber damage.


Assuntos
Contração Muscular/fisiologia , Músculo Esquelético , Condicionamento Físico Animal/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Teste de Esforço , Masculino , Metabolismo/fisiologia , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Ratos , Ratos Long-Evans , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
17.
Clin Sci (Lond) ; 134(6): 609-628, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32175563

RESUMO

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-ß (TGF-ß) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.


Assuntos
Bexaroteno/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Proteínas Serina-Treonina Quinases/metabolismo , Receptores X Retinoide/agonistas , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-Dawley , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Estreptozocina
18.
Apunts, Med. esport (Internet) ; 55(205): 21-27, ene.-mar. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-192334

RESUMO

INTRODUCTION: The present study was to determine the effect of 8-week of the concurrent exercise training on Murf-l and Atrogin-1 Gene Expression of the vastus lateralis muscle in male Wistar rats. MATERIAL AND METHODS: This study was conducted as an experimental project consisting of four groups of 35 two-month-old male Wistar rats. The animals were randomly divided in 4 groups: (1) endurance training, (2) resistance training, (3) combined training, and (4) control. The animals in the training groups took part in training programs for 8-week. 48h after the last exercise session, the Murf-1 and Atrogin-1 genes of the vastus lateralis muscle were examined through the use of qPCR method. RESULTS: The results obtained from this study revealed that after 8-week of endurance exercise, Murf-1 and Arogin-1 gene expression significantly increased compared to the control group (p = 0.04 and p = 0.043). In contrast, in the resistance training group, the gene expression of Murf-1 and Atrogin-1 decreased significantly in comparison with the control group (p = 0.02 and p = 0.04). In addition, the concurrent training group showed no difference in Murf-1 and Atrogin-1 gene expression after 8-week of exercise compared to that of the control group (p = 0.43 and p = 0.38). CONCLUSIONS: Based on the results of the present research, it can be expressed that resistance training prevents muscular atrophy by decreasing Murf-1 and Atrogin-1 gene expression. Conversely, endurance exercises cause an increase in the expression of these genes, thereby leading to atrophy in the muscles. The results also showed that concurrent exercises do not have a meaningful effect on muscular atrophy


No disponible


Assuntos
Animais , Masculino , Ratos , Expressão Gênica/fisiologia , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas Musculares/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Musculares/efeitos dos fármacos , Condicionamento Físico Animal , Ratos Wistar , Resistência Física/efeitos dos fármacos
19.
Oxid Med Cell Longev ; 2020: 5363546, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064026

RESUMO

The present study was performed to evaluate the antioxidant and intestinal protective effects of baicalin-copper on deoxynivalenol-challenged piglets. Forty weaned piglets were randomly divided into four groups and assigned to different diets: (1) basal diet (Con), (2) 4 mg/kg deoxynivalenol of basal diet (DON), (3) 5 g/kg baicalin-copper of basal diet (BCU); and (4) 4 mg/kg deoxynivalenol + 5 g/kg baicalin-copper of basal diet (DBCU). The results showed that the ADFI and ADG of piglets in the DON group were markedly lower than those in the Con group, but the ADFI and ADG of the DBCU group were not significantly different from those of the Con group. In piglets fed a DON-contaminated diet, dietary supplementation with BCU significantly decreased the mRNA levels of P70S6K, 4E-BP1, and HSP70 in the liver, the protein expression of HO-1 in the jejunum, and the expression of p-Nrf2 and p-NF-κB in the ileum but increased Mn-SOD activity in serum. Dietary supplementation with BCU increased jejunal maltase, ZIP4 and MT mRNA levels, and serum concentrations of Arg, Val, Ile, Leu, Lys, and Tyr in DON-contaminated piglets. In summary, BCU can alleviate the growth impairment induced by DON and enhance antioxidant capacity and nutrition absorption in piglets fed DON-contaminated diets.


Assuntos
Antioxidantes/metabolismo , Flavonoides/farmacologia , Íleo/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tricotecenos/toxicidade , Aminoácidos/sangue , Ração Animal , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobre/química , Dieta , Suplementos Nutricionais , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Íleo/metabolismo , Jejuno/citologia , Jejuno/enzimologia , Jejuno/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Soro/enzimologia , Soro/metabolismo , Superóxido Dismutase-1/sangue , Suínos , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
20.
Life Sci ; 247: 117425, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32057904

RESUMO

AIMS: Glioma is the most common type of malignant tumor of the nervous system, and aggressiveness and recurrence are major obstacles for treatment. This study is designed to explore the effects of amentoflavone (AF) on glioma, and to investigate the underlying mechanism of the anti-cancer activities of AF. METHODS: Cell morphology was recorded under microscopy. Cell viability and cell death ratio were determined by CCK-8 assay and lactate dehydrogenase (LDH) release assay, respectively. Cell cycle progression was assessed by flow cytometry. The levels of iron, MDA (malondialdehyde), lipid ROS, and GSH (reduced glutathione) were assessed by ELISA kit. The cycle-related proteins, ferroptosis-related protein, autophagy-related protein, and the phosphorylation of AMPK, mTOR and p70S6K were analyzed by western blotting. The autophagic flux was observed by transfecting cells with mRFP-GFP-LC3 plasmids. The xenograft murine models were established to analyze the effects of amentoflavone in vivo. The immunohistochemistry assay was performed to analyze the expression of LC3B, Beclin1, ATG5, ATG7, and ferritin heavy chain (FTH). RESULTS: Our results showed that AF treatment led to reduction in cell viability and cell death. In addition, AF was found to block cell cycle progression in a dose-dependent manner in vitro. Following treatment with AF, the intracellular levels of iron, MDA, and lipid OS were increased, and the levels of GSH and the mitochondrial membrane potential were reduced. In addition, our results showed that AF promoted the autophagic by regulating autophagy-relevant proteins. Our results also showed that the autophagy-induction by AF was associated with regulation of AMPK/mTOR signaling. Mechanistically, the inhibition effects of AF on glioma cell were reversed by DFO, ferreostatin-1 as well as upregulation of FTH. Meanwhile, the FTH levels were increased by compound C and knockdown of ATG7. Moreover, both autophagy inhibitor Baf A1 and knockdown of ATG7 were able to compromising AF-induce ferroptosis and cell death. In vivo, the tumor growth was suppressed by AF in a dose-dependent manner. The level of MDA in the tumor tissue was increased while the level of GSH in tumor tissue was decreased by AF in a dose-dependent manner. Furthermore, the expression of LC3B, Beclin1, ATG5, ATG7 were increased, and the expression of FTH were decreased by AF in a dose-dependent manner in vivo. Conclusion These results demonstrate that AF triggered ferroptosis in autophagy-dependent manner. Our results suggest that AF has the potential to be considered as a novel treatment agent in glioma.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Biflavonoides/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Ferroptose/efeitos dos fármacos , Glioma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Biflavonoides/farmacologia , Linhagem Celular Tumoral , Inibidores do Citocromo P-450 CYP3A/farmacologia , Glioma/metabolismo , Glioma/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo
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