TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity

Abstract

Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-α) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H2S. Taken together, the present study suggested that exogenously applied H2S rather than the endogenously generated H2S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK/NF-κB pathways.

Dose-Dependent Effect of Hydrogen Sulfide in Cyclophosphamide-Induced Hepatotoxicity in Rats

“…In a previous study, NaHS was also shown to cause a reduction in TRL2/4, NF-kB, and TNF-α levels. 37 In another study, CP led to a significant elevation in the levels of proinflammatory cytokines including TNF-α and IL-6 which are involved in the mechanism of tissue damage. 44 In the study, NaHS was also able to reduce IL-6 levels which were elevated by CP administration.…”

“…This was explained by the inhibition of transduction via NF-kB. 35 In addition, H 2 S can regulate angiogenesis through selective potentiation of other molecules such as NO and CO. 36 Recently, Raina et al 37 investigated the effects of endogeneous and exogeneous H 2 S on toll-like receptors (TLRs) – mediated inflammatory response and apoptosis in the CP-induced hepatotoxicity model. In this study, NaHS, an H 2 S donor agent, at a dose of 100 µmol/kg, and dl-propargylglycine (PAG), an H 2 S blocker, at a dose of 30 mg/kg were administered to rats.…”

“…Increased NO levels were proposed to be associated with increased oxidative stress caused by CP treatment. 37 …”

Polygonatum sibiricum Saponin Prevents Immune Dysfunction and Strengthens Intestinal Mucosal Barrier Function in Cyclophosphamide-Induced Immunosuppressed BALB/c Mice

“…Cy is inactive in vitro and functions in vivo primarily through the hydrolysis by hepatic P450 enzymes into aldehyde phosphamide [ 2 ], which interferes with DNA and RNA function. Cy could affect the cell cycle, thereby inhibiting the proliferation of T and B lymphocytes [ 3 ], resulting in immune suppression [ 4 , 5 ]. At present, many natural bioactive substances are currently explored to treat immune function decline [ 6 , 7 , 8 ].…”