Diallyl Trisulfide Suppresses Oxidative Stress‐Induced Activation of Hepatic Stellate Cells through Production of Hydrogen Sulfide

Abstract

Accumulating data reveal that garlic has beneficial effects against chronic liver disease. We previously reported that diallyl trisulfide (DATS), the primary organosulfur compound in garlic, reduced fibrosis and attenuated oxidative stress in rat fibrotic liver. The present study was aimed at elucidating the underlying mechanisms. The primary rat hepatic stellate cells (HSCs) were cultured and stimulated with hydrogen peroxide (H2O2) for inducing HSC activation under oxidative stress. We examined the effects of DATS on the profibrogenic properties and oxidative stress in H2O2-treated HSCs. The results showed that DATS suppressed and reduced fibrotic marker expression in HSCs. DATS arrested cell cycle at G2/M checkpoint associated with downregulating cyclin B1 and cyclin-dependent kinase 1, induced caspase-dependent apoptosis, and reduced migration in HSCs. Moreover, intracellular levels of reactive oxygen species and lipid peroxide were decreased by DATS, but intracellular levels of glutathione were increased in HSCs. Furthermore, DATS significantly elevated hydrogen sulfide (H2S) levels within HSCs, but iodoacetamide (IAM) reduced H2S levels and significantly abrogated DATS production of H2S within HSCs. IAM also abolished all the inhibitory effects of DATS on the profibrogenic properties and oxidative stress in HSCs. Altogether, we demonstrated an H2S-associated mechanism underlying DATS inhibition of profibrogenic properties and alleviation of oxidative stress in HSCs. Modulation of H2S production may represent a therapeutic remedy for liver fibrosis.

Implications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential

“…In the pathological process of hepatic fibrosis, it is well accepted that activated hepatic stellate cells (HSCs) is fundamental for the overproduction of extracellular matrix (ECM) in hepatic interstitium, thus resulting in hepatic fibrosis [82] . Current evidence suggests that inactivation of HSCs is an important mechanism for H 2 S to prevent and treat liver fibrosis [83] . However, a recent report has illustrated that the H 2 S production and CSE expression are incremented during HSC activation, and exogenous H 2 S promotes the proliferation of HSCs and evokes the fibrotic maker expressions of HSCs [84] .…”

Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur

“…Polysulfanes have also been investigated as potent H 2 S donors in the presence of thiols [ 84 , 85 ]. Preclinical studies have shown that enhancement of endogenous H 2 S has an impact on vascular reactivity.…”

Exploring the role and mechanisms of diallyl trisulfide and diallyl disulfide in chronic constriction-induced neuropathic pain in rats

“…It signifies that a decrease in the BDNF, H 2 S, and Nrf2 levels may contribute to the pathogenesis of neuropathic pain, while their restoration in the presence of diallyl sulfide and triallyl sulfide may possibly contribute in attenuating neuropathic pain. Diallyl sulfide and triallyl sulfide are reported to release H 2 S endogenously, and the usefulness of diallyl sulfide and triallyl sulfide in a number of diseases has been attributed to an increase in H 2 S levels [29,30]. Moreover, there have been studies showing that H 2 S donors may contribute in ameliorating neuropathic pain [31].…”