Cudratricusxanthone A protect pancreatic beta cells from cytokines-mediated toxicity through the inhibition of NF-κB and STAT pathways.
Cudratricusxanthone A (CTXA) has an isoprenylated xanthone skeleton that is known to exert a variety of biological activities, including anti-inflammatory, neuroprotective, hepatoprotective, anti-proliferative, and mono-amine oxidase inhibitory effects. In this study, we investigated the effect of CTXA on IL-1β (5 ng/ml) and IFN-γ (100 U/ml)-induced β-cell damage. Pre-treatment with CTXA increased the viability and reactive oxygen species (ROS) inhibition of cytokine-treated RINm5F cells at concentrations of 1-10 μM. CTXA prevented nitric oxide (NO) production, and this effect was correlated with reduced levels of protein and mRNA expression of inducible nitric oxide synthase (iNOS). The molecular mechanism by which CTXA inhibits iNOS gene expression appeared to involve the inhibition of NF-κB activation. Moreover, pancreatic β-cells treated with cytokines upregulated the phosphorylation of STAT-1, STAT-3 and STAT-5; however, pretreatment with CTXA attenuated these effects. Additionally, in a second set of experiments in which rat islets were used, the protective effects of CTXA in rat islets were essentially the same as those observed when RINm5F cells were used. CTXA prevented cytokines-induced NO production, iNOS expression, JAK/STAT activation, and NF-κB activation and inhibition of glucose-stimulated insulin secretion (GSIS). Collectively, these results suggest that CTXA can be used for the prevention of functional β-cell damage.
Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 570-749, Republic of Korea.
Dong-Sung
DS
Lee
College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Daegu 704-701, Republic of Korea. Electronic address: gsjeong@kmu.ac.kr.
Gil-Saeng
GS
Jeong
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008297:Male; D029586:Moraceae / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology*
D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; D050791:STAT Transcription Factors; D044004:Xanthones; C533013:cudratricusxanthone A; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II
Cudratricusxanthone A; Cytokines; Cytoprotection; Glucose-stimulated insulin secretion; NF-κB; Pancreatic β-cell