Diallyl sulfide alleviates cisplatin‐induced nephrotoxicity in rats via suppressing NF‐κB downstream inflammatory proteins and p53/Puma signalling pathway

Abstract

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo-sulfide, present in garlic, in cisplatin-induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno-protective effect of DAS in cisplatin-induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100 mg/kg, orally for 4 consecutive days, starting 1 hour after administration of single dose of cisplatin (3.5 mg/kg, intraperitoneally [i.p.]). The Cis-induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co-treated with DAS. In addition, DAS significantly restored Cis-depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis-elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis-increased renal expression of nuclear factor kappa B (NF-κB) and subsequent pro-inflammatory mediators; tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co-treatment with DAS significantly inhibited Cis-increased caspase-8 and -9 levels. Additionally, DAS significantly mitigated Cis-induced protein expression of p53, Puma, and Bax while, it significantly restored Cis-reduced protein expression of Bcl-xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin-induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.

Diallyl trisulfide, a H2S donor, inhibits cell growth of human papillary thyroid carcinoma KTC‐1 cells through a positive feedback loop between H2S and cystathionine‐gamma‐lyase

“…It has been reported that H 2 S could modify protein function through sulfhydration, activate transient receptor potential channels and ion channels, and affect some transcription factors such as Nrf‐2, HIF‐1, and NF‐κΒ (Li, Rose, & Moore, ). Of note, NF‐κΒ was previously reported to be downregulated by diallyl sulfide (DAS), an analog of DATS (Elkhoely & Kamel, ). Therefore, the effects of DATS on NF‐κΒ signaling pathway transduction were further investigated.…”

The Role of Gasotransmitter-Dependent Signaling Mechanisms in Apoptotic Cell Death in Cardiovascular, Rheumatic, Kidney, and Neurodegenerative Diseases and Mental Disorders

“…Hydrogen sulphide also has a nephroprotective effect when using nephrotoxic drugs such as cisplatin, paracetamol, gentamicin, etc. [ 174 , 175 , 176 ]. The main defense mechanisms are the suppression of inflammation, apoptosis, and oxidative stress.…”

Consumption of oil macerated with garlic produces renovascular protective effects in adult apolipoprotein E-deficient mice

“…47 In relation to renal apoptosis, our results are also in accordance with other studies which demonstrated that garlic extract was able to attenuate renal apoptosis in rats. [48][49][50] However, these authors attributed the antiapoptotic effects of garlic and its components to signaling pathways such as Nrf2/ARE and p53/Puma, instead of that of WT-1. However, Lovell et al informed that a lowered WT-1 expression may cause antiapoptotic effects p53 independent.…”