Effect of silibinin and vitamin E on the ASK1-p38 MAPK pathway in D-galactosamine/lipopolysaccharide induced hepatotoxicity

Abstract

Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensor mitogen-activated protein kinase kinase kinase (MAPKKK) that activates p38 MAPK pathways in oxidative stress-induced hepatotoxicity in D-galactosamine/lipopolysaccharide (D-GalN/LPS) model, is a key central pathway in which specific targeting of ASK1 deactivation is of a great therapeutic potential. We tested the effect of silibinin and vitamin E in curative and prophylactic manner of treatment on the negative modulators of ASK1, thioredoxin1 (Trx1), thioredoxin reductase1 (TrxR1), and the protein phosphatase (PP5), whereas they have previously proven to have hepatoprotective effect. Either curative or prophylactic silibinin and vitamin E groups significantly decreased ASK1 and p38 MAPK levels through increasing the gene expression of Trx1, TrxR1, and PP5 to reduce the oxidative stress as demonstrated by decreasing the levels of NADPH oxidase 4 (NOX4), TBARS and conjugated diene with a concomitant increase in the levels of GSH, CAT, and SOD. These results were confirmed by histopathology examination which illustrated progressive degenerative changes of hepatocytes such as hydropic degeneration, vacuolation, pyknosis, karyolysis, and loss of architecture of some cells in D-GalN/LPS treatment, and these features were alleviated with silibinin and vitamin E administration. In conclusion, silibinin and vitamin E decreased ASK1-p38 MAPK pathway through deactivating the upstream signalling ASK1 molecule via increasing the levels of Trx1 and TrxR1 as well as the PP5 to alleviate in D-GalN/LPS induced hepatotoxicity.

Selenoprotein T protects against cisplatin‐induced acute kidney injury through suppression of oxidative stress and apoptosis

“…Numerous studies have shown that Trx1 plays an important role in ROS scavenging in various diseases through its protection against redox stress. [34][35][36][37][38] Moreover, the expression of Trx1 has been correlated with the activity of various Nox components, including Nox4, Nox2, p22 phox , and Rac. 39,40 Therefore, we presume that SelT may be a novel essential effector of the intracellular antioxidant system, which functions as Trx1, thus regulating Nox activity and ROS production.…”

“…Recently, it was reported that SelT is a thioredoxin‐like enzyme, which has an active site (Cys‐Gly‐Pro‐Cys) similar to thioredoxin 1 (Trx1). Numerous studies have shown that Trx1 plays an important role in ROS scavenging in various diseases through its protection against redox stress 34‐38 . Moreover, the expression of Trx1 has been correlated with the activity of various Nox components, including Nox4, Nox2, p22 phox , and Rac 39,40 .…”

Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure

“…More intriguingly, apart from inflammatory responses, the excessive accumulation of reactive oxygen species (ROS) is recognized to a possible mechanism of d -GalN/LPS-induced FHF ( 9 ). ROS overproduction not only directly triggers oxidative damage but also activates the MAPK and NF-κB signaling pathways, resulting in inflammatory responses that further stimulate inflammatory injury ( 10 , 11 ). Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2), which is a key transcription factor that is required to ameliorate various oxidative stress- and inflammation-associated diseases, regulates the expression of various antioxidant genes, including heme oxygenase-1 (HO-1), NAD (P) H: quinoneoxidoreductase 1 (NQO1), and the glutamate-cysteine ligase modifier (GCLM) and glutamate-cysteine ligase catalytic (GCLC) subunit ( 12 , 13 ).…”

Nephroprotective Effects of N‐Acetylcysteine Amide against Contrast‐Induced Nephropathy through Upregulating Thioredoxin‐1, Inhibiting ASK1/p38MAPK Pathway, and Suppressing Oxidative Stress and Apoptosis in Rats

“…Reduced Trx1 could be a direct inhibitor or negative regulator of ASK1, while ROS stimulation could dissociate Trx1 from Trx1/ASK1 complex and lead to ASK1 activation and in turn result in the phosphorylation of its downstream substrate p38 MAPK [22, 26]. As mentioned above, we previously reported that contrast media exposure directly increased cellular oxidation and induced p38 AMPK/iNOS pathway mediated apoptosis in renal tubular cells in vitro and vivo [6, 7].…”