Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2018
Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways.
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Arab Hany H, Salama Samir A, Maghrabi Ibrahim A
Аннотация
BACKGROUND/AIMS: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats.
METHODS: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting.
RESULTS: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use.
CONCLUSION: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.
METHODS: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting.
RESULTS: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use.
CONCLUSION: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.
Предметные рубрики MeSH
AnimalsAntioxidantsApoptosisBlood Urea NitrogenCamelusCell Line, TumorCreatinineCytokinesDown-RegulationFluorouracilHCT116 CellsHeme Oxygenase-1Hep G2 CellsHumansKidneyLipocalin-2MCF-7 CellsMatrix Metalloproteinase 2Matrix Metalloproteinase 9MilkMitogen-Activated Protein KinasesNADPH Oxidase 1NF-E2-Related Factor 2NF-kappa BNitric Oxide Synthase Type IIIOxidative StressPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-bcl-2RatsRats, WistarSignal TransductionTumor Suppressor Protein p53bcl-2-Associated X Protein