RESUMEN
Histone deacetylase inhibitors (HDACis) are the recommended treatment for many solid tumors; however, resistance is a major clinical obstacle for their efficacy. High levels of the transcription factor nuclear factor erythroid 2 like-2 (Nrf2) in cancer cells suggest a vital role in chemoresistance, and regulation of autophagy is one mechanism by which Nrf2 mediates chemoresistance. Although the molecular mechanisms underlying this activity are unclear, understanding them may ultimately improve therapeutic outcomes following HDACi treatment. In this study, we found that HDACi treatment increased Nrf2 mRNA and protein levels and enhanced Nrf2 transcriptional activity. Conversely, Nrf2 knockdown or inhibition blocked HDACi-induced autophagy. In addition, a microRNA (miRNA) array identified upregulation of miR-129-3p in response to Nrf2 overexpression. Chromatin immunoprecipitation assays confirmed miR-129-3p to be a direct Nrf2 target. RepTar and RNAhybrid databases indicated mammalian target of rapamycin (mTOR) as a potential miR-129-3p target, which we experimentally confirmed. Finally, Nrf2 inhibition or miR-129-3p in combination with HDACis increased cell death in vitro and in vivo. Collectively, these results demonstrated that Nrf2 regulates mTOR during HDACi-induced autophagy through miRNA-129-3p and inhibition of this pathway could enhance HDACi-mediated cell death.
Asunto(s)
MicroARNs/genética , Factor 2 Relacionado con NF-E2/genética , Neoplasias/tratamiento farmacológico , Serina-Treonina Quinasas TOR/genética , Animales , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Redes Reguladoras de Genes/genética , Xenoinjertos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ratones , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Neoplasias/genética , Neoplasias/patologíaRESUMEN
OBJECTIVE: Current research is controversial about whether metformin can improve the survival rate of patients with colon cancer. Therefore, we conducted a meta-analysis to identify the association between metformin and the survival rate of colorectal cancer (CRC) patients with type II diabetes. METHODS: We conducted a search in databases including Pubmed, EMBASE and Cochrane Library. All articles were published in the last decade, and the quality of each study was evaluated by the Newcastle-Ottawa Scale. Odds ratios (ORs) and its corresponding 95% confidence intervals (CIs) for each study were calculated and summary relative risk estimates with corresponding 95% CIs were generated using the random-effects model. Heterogeneity and publication bias were assessed. RESULTS: Ten articles were included in this meta-analysis. The included articles were all cohort studies. In a pooled analysis of all studies, metformin using was associated with increased overall survival (OS) rate (OR, 0.54; 95% CI, 0.47 to 0.63) and cancer-specific survival (CS) rate (OR 0.59; 95% CI 0.43 to 0.82) of CRC patients with diabetes. We found that the effect of metformin is associated with geographical region through subgroup meta-analysis. CONCLUSIONS: Metformin using was associated with an increased OS rate and CS rate of colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/mortalidad , Complicaciones de la Diabetes/mortalidad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Neoplasias Colorrectales/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Tasa de SupervivenciaRESUMEN
The aim of this study was to investigate the possible effect of orally administered isavuconazole, ketoconazole, or voriconazole on the pharmacokinetics of methadone in rats. Twenty Sprague-Dawley (SD) rats were divided randomly into four groups: Group A (control), group B (5 mg/kg isavuconazole), group C (5 mg/kg ketoconazole), and group D (5 mg/kg voriconazole). A single dose of methadone was administrated half an hour later. Methadone in plasma concentrations and its metabolite EDDP in microsomes were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS), and pharmacokinetic parameters were calculated by DAS version 3.0. The Cmax of methadone in groups C and D increased to 2.7-fold and 5-fold, respectively. While AUC increased in three groups and group D increased the most. Also, isavuconazole, ketoconazole, and voriconazole showed inhibitory effect on human and rat microsomes. The inhibition ratios of isavuconazole, ketoconazole, and voriconazole in rat liver microsome were 97.87%, 96.74% and 78.9%, respectively (p < 0.01), while in human liver microsome, inhibition ratios were 86.97%, 96.46%, and 53.11%, respectively. And the IC50 for inhibition activity of isavuconazole, ketoconazole, and voriconazole in rat microsomes were 7.76 µM, 8.33 µM, and 4.45 µM, respectively. Our study indicated that taking methadone combine with ketoconazole, isavuconazole, or voriconazole could reduce the metabolism rate of methadone and prolong the pharmacological effects in vivo and in vitro.
Asunto(s)
Analgésicos Opioides/farmacocinética , Antifúngicos/farmacología , Cetoconazol/farmacología , Metadona/farmacocinética , Nitrilos/farmacología , Piridinas/farmacología , Triazoles/farmacología , Voriconazol/farmacología , Analgésicos Opioides/sangre , Animales , Masculino , Metadona/sangre , Ratas Sprague-DawleyRESUMEN
Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.
Asunto(s)
Enfermedades Autoinmunes/metabolismo , Inflamación/inmunología , Células Mieloides/metabolismo , Receptor Activador Expresado en Células Mieloides 1/metabolismo , HumanosRESUMEN
PURPOSE: Gastric carcinoma is the second most frequently diagnosed cancer and leading cause of cancer death in China. As a new generation of cancer therapeutic drug, CL-6, a curcumin derivative, shows better bioavailability than curcumin, which has shown anticancer effects in gastric cancer (GC). However, whether CL-6 shows similar activities in GC has not been examined. MATERIALS AND METHODS: Cell proliferation assay, colony-forming assay, flow cytometric analysis, wound healing assay, and Transwell invasion assay were performed to examine the effects of CL-6 on proliferation, apoptosis, migration, and invasion on human AGS and MGC-803 cell lines. Western blot was used to evaluate protein levels of Bax, Bcl-2, YAP, p-YAP, and Lats, and gene expression was measured by real-time quantitative PCR (RT-qPCR). RESULTS: CL-6 dose dependently reduced proliferation, increased apoptosis, and inhibited the migration and invasion abilities of AGS and MGC-803 cells. CL-6 also increased levels of pro-apoptotic protein Bax, decreased levels of antiapoptotic protein Bcl-2, and increased the Bax/Bcl-2 ratio. CL-6 treatment also inhibited YAP and YAP protein and mRNA expression, while it induced the expression of Lats and p-YAP (Ser127). CONCLUSION: CL-6 induces apoptosis of GC cells by activating the Hippo-YAP signaling pathway. These results indicate the therapeutic potential of the novel curcumin derivative CL-6 in GC.