Anti-Inflammatory Activities and Liver Protection of Alisol F and 25-Anhydroalisol F through the Inhibition of MAPK, STAT3, and NF-κB Activation In Vitro and In Vivo

Abstract

Alisol F and 25-anhydroalisol F isolated from Alisma orientale, were proved to exhibit anti-inflammatory potential in our previous work. In the current study, the anti-inflammatory effects and action mechanisms of alisol F and 25-anhydroalisol F were investigated in vitro. Moreover, the pharmacological effects of alisol F in lipopolysaccharide (LPS)/d-galactosamine (d-gal)-induced acute liver-injured mice were evaluated. The results demonstrated that alisol F and 25-anhydroalisol F could suppress LPS-induced production of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), as well as inhibit the mRNA and protein levels of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2). In addition, we investigated the role of alisol F and 25-anhydroalisol F in mediating mitogen-activated protein kinases (MAPKs), signal transducers, and activators of transcription 3 (STAT3) and nuclear factor κB (NF-κB) pathways involved in the inflammation process of LPS-stimulated RAW 264.7 cells. The phosphorylation of ERK, JNK, p38, and STAT3, and the NF-κB signaling pathway, were obviously suppressed in alisol F and 25-anhydroalisol F treated cells. Results obtained from in vitro experiments suggested alisol F obviously improved liver pathological injury by inhibiting the production of TNF-α, IL-1β, and IL-6, and significantly decreasing the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in LPS/d-gal-induced mice. Furthermore, the reduction of phosphorylation of ERK and JNK, as well as suppression of the NF-κB signaling pathway, were also observed in liver tissues of the alisol F-treated mice model. Alisol F and 25-anhydroalisol F may serve as potential leads for development of anti-inflammatory agents for acute liver failure treatment.

Quantitative Proteomic Analysis Reveals the Sites Related to Acetylation and Mechanism of ACY-1215 in Acute Liver Failure Mice

“…Lipopolysaccharide (LPS) and d-galactosamine (d-GalN) are commonly used as the experimental ALF animal model which can precisely reflect human liver failure (Kim and Lee, 2013). Endotoxemia and hepatic toxic substances play important roles in the occurrence and development of liver failure, and in LPS/d-GalN-induced ALF model, d-GalN plays a hepatotoxic role, whereas LPS-induced inflammatory response can also aggravate the injury of hepatocytes and further aggravate liver failure (Zong et al, 2014; Bi et al, 2017).…”

Pharmacological Activities of Alisma orientale against Nonalcoholic Fatty Liver Disease and Metabolic Syndrome: Literature Review

“…Apart from its antiviral effect, Alisol F has been mainly investigated to check its pharmacological activities against inflammation. Alisol F suppressed a variety of powerful inflammatory mediators such as iNOS, NO, COX-2, TNF- α , IL-6, and IL-1 β elevated by lipopolysaccharide (LPS) in macrophages and LPS or D- gal injection in mice [48–50]. The molecular mechanism of Alisol F against LPS-induced inflammation is reported to involve activation of NF- κ B and phosphorylation of its upstream molecules mitogen-activated protein kinase (MAPK)s (extracellular-signal-regulated kinase (ERK), p38, JNK) [48].…”

“…Alisol F suppressed a variety of powerful inflammatory mediators such as iNOS, NO, COX-2, TNF- α , IL-6, and IL-1 β elevated by lipopolysaccharide (LPS) in macrophages and LPS or D- gal injection in mice [48–50]. The molecular mechanism of Alisol F against LPS-induced inflammation is reported to involve activation of NF- κ B and phosphorylation of its upstream molecules mitogen-activated protein kinase (MAPK)s (extracellular-signal-regulated kinase (ERK), p38, JNK) [48]. Additionally, Alisol F alleviated acute hepatic failure induced by LPS and D- gal injection by lowering AST and ALT levels in mice [48].…”

“…The molecular mechanism of Alisol F against LPS-induced inflammation is reported to involve activation of NF- κ B and phosphorylation of its upstream molecules mitogen-activated protein kinase (MAPK)s (extracellular-signal-regulated kinase (ERK), p38, JNK) [48]. Additionally, Alisol F alleviated acute hepatic failure induced by LPS and D- gal injection by lowering AST and ALT levels in mice [48]. Besides, Alisol F could regulate hyperglycemia via α -glucosidase activity inhibition without adipose cell differentiation and lipogenesis unlike thiazolidinedione (TZD)s [40].…”

Integrating Network Pharmacology and RT-qPCR Analysis to Investigate the Mechanisms Underlying ZeXie Decoction-Mediated Treatment of Non-alcoholic Fatty Liver Disease

“…(Hoang et al, 2016;Liu et al, 2019). Several mechanistic studies have found that ZXD, ZX, BZ, and other active derivatives could treat NAFLD through the modulation of insulin, and PI3K/AKT/ NF-κB and PPAR pathways, thereby suppressing inflammation and lowering lipid levels in treated individuals (Dan et al, 2011;Song et al, 2014;Li et al, 2016;Bi et al, 2017;Tang et al, 2017;Wu et al, 2018). ZXD is a promising complementary therapy for the treatment of NAFLD.…”