RESUMO
PURPOSE: Inflammatory responses play an important role in the tissue injury during liver ischemia/reperfusion (I/R). We previously reported that resolvin D1 (RvD1) administrated prior to hepatic I/R attenuates liver injury through inhibition of inflammatory response. In this study, we investigated the effects of the aspirin-triggered resolvin D1 (AT-RvD1) on hepatic I/R and the role of miR-146b in this process. METHODS: Partial warm ischemia was performed in the left and middle hepatic lobes of Sprague-Dawley rats for 1h, followed by 6h of reperfusion. Rats received either AT-RvD1 (5µg/kg), vehicle, or AT-RvD1+miR-146b antagomir by intravenous injection 30min before ischemia. Blood and tissue samples of the rats were collected after 6-h reperfusion. RESULTS: Pretreatment with AT-RvD1 significantly diminished I/R-induced elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and significantly blunted the histological injury of the liver. Moreover, AT-RvD1 significantly inhibited inflammatory response, as indicated by attenuations of TNF-α and myeloperoxidase levels. Reduced apoptosis, and increased survival rate were observed in the AT-RvD1 group compared with the control I/R group. AT-RvD1 pretreatment increased miR-146b expression in the liver of the rats with hepatic I/R. Administration of miR-146b antagomir impaired the effects of AT-RvD1 on hepatic I/R injury in rats. Downregulation of miR-146b inhibited TRAF6 and NF-κB expression in liver. CONCLUSIONS: Pre-administration of AT-RvD1 attenuates hepatic I/R injury partly through modulation of miR-146b.
Assuntos
Anti-Inflamatórios/uso terapêutico , Aspirina/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Fígado/patologia , MicroRNAs/genética , Traumatismo por Reperfusão/tratamento farmacológico , Alanina Transaminase/sangue , Animais , Apoptose , Aspartato Aminotransferases/sangue , Fígado/efeitos dos fármacos , Masculino , Camundongos , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) play pivotal roles in the modulation of Ca(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes. Increasing evidence has implicated the dysregulation of STIM-ORAI and IP3Rs in tumorigenesis and tumor progression. By controlling the activities, structure, and/or expression levels of these Ca(2+)-transporting proteins, malignant cancer cells can hijack them to drive essential biological functions for tumor development. However, the molecular mechanisms underlying the participation of STIM-ORAI and IP3Rs in the biological behavior of cancer remain elusive. In this review, we summarize recent advances regarding STIM-ORAI and IP3Rs and discuss how they promote cell proliferation, apoptosis evasion, and cell migration through temporal and spatial rearrangements in certain types of malignant cells. An understanding of the essential roles of STIM-ORAI and IP3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.
Assuntos
Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Multidrug resistance (MDR) remains a formidable challenge in the use of chemotherapy and represents a powerful obstacle to the treatment of leukemia. ATP-binding cassette subfamily B member 1 (ABCB1) is a recognized factor which causes MDR and is closely related to poor outcome and relapse in leukemia. Ongoing research concerning the strategy for inhibiting the abnormally high activity of the ABCB1 transporter is critically needed. In the present study, we sought to elucidate the interaction between ABCB1 transporter and butorphanol. Our results showed that butorphanol significantly antagonized ABCB1-mediated drug efflux and increased the intracellular drug concentration by inhibiting the transport activity of ABCB1 in leukemia cells. Mechanistic investigations demonstrated that butorphanol did not alter the protein expression or localization of ABCB1 in HL60/VCR and K562/ADR cells. Furthermore, homology modeling indicated that butorphanol could fit into the large drug-binding cavity of ABCB1 and form a binding conformation. In conclusion, butorphanol reversed the ABCB1-mediated MDR in leukemia cells by directly suppressing the efflux activity of ABCB1.
