Hepatoprotective effect of allicin against acetaminophen‐induced liver injury: Role of inflammasome pathway, apoptosis, and liver regeneration

Abstract

Acetaminophen (APAP) overdose leads to liver injury. NLRP3 inflammasome is a key player in APAP-induced inflammation. Also, apoptosis and liver regeneration play an important role in liver injury. Therefore, we assessed allicin's protective effect on APAP-induced hepatotoxicity and studied its effect on NLRP3 inflammasome and apoptosis. Mice in the APAP group were injected by APAP (250 mg/kg, intraperitoneal). The allicin-treated group received allicin orally (10 mg/kg/d) during 7 days before APAP injection. Serum and hepatic tissues were separated 24 hours after APAP injection. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline phosphatase (ALP), and hepatic malondialdehyde (MDA) were assessed using the colorimetric method. Hepatic NLRP3 inflammasome, caspase-1, and interleukin-1β (IL-1β) were estimated using enzyme-linked immunosorbent assay. Hepatic Bcl-2 and Ki-67 were investigated by immunohistochemistry. APAP significantly increased AST, ALT, and ALP, whereas allicin significantly decreased their levels. Also, APAP significantly decreased albumin and allicin significantly improved it. APAP produced changes in liver morphology, including inflammation and massive coagulative necrosis. Allicin protected the liver from APAP-induced necrosis, apoptosis, and hepatocellular degeneration via increasing Bcl-2 and Ki-67 levels. APAP significantly increased the hepatic MDA, whereas allicin significantly prevented this increase. APAP markedly activated the NLRP3 inflammasome pathway and consequently increased the production of caspase-1 and IL-1β.Interestingly, we found that allicin significantly inhibited NLRP3 inflammasome activation, which resulted in decreased caspase-1 and IL-1β levels. Allicin has a hepatoprotective effect against APAP-induced liver injury via the decline of oxidative stress and inhibition of the inflammasome pathway and apoptosis. Therefore, allicin might be a novel tool to halt the progression of APAP-stimulated hepatotoxicity.

The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury

“…Although the time course of APAP-induced hepatotoxicity as well as the role of inflammasome in the process have been extensively investigated, the relationship between necroptosis and inflammasome remains largely unknown. 25,37,38 To further testify the mechanistic linkage between necroptosis and NLRP3 inflammasome in APAP liver injury, we next examined whether the necroptosis-inhibiting drug could reduce the upregulation of NLRP3 inflammasome Figure 7. Nec-1 treatment inhibited the activation of NLRP3 inflammasome signaling pathway in liver tissues of C57BL/6 mice following APAP administration.…”

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

“…However, acetaminophen overdose is the most frequent cause of acute liver failure in the United States and many European countries (Larson et al, 2005;Yano et al, 2014). Severe liver injury, along with increasing expressions of NLRP3 and IL-1β, occurred in acetaminophen-treated mice liver or liver cell lines Lv et al, 2020;Samra et al, 2020;Shi et al, 2020). Imaeda et al (2009) found that genetic deficiencies in NLRP3 inflammasome components (NLRP3, ASC, and caspase-1) provided protection from acetaminophen-induced mice death and liver injury.…”

“…Similarly. Allicin (an active sulfur species isolated from garlic) also protected the mouse liver from acetaminopheninduced necrosis, apoptosis, and hepatocellular degeneration via inhibiting the hepatic NLRP3 inflammasome activation and IL-1β secretion and increasing Ki-67 level (Samra et al, 2020).…”

Emodin Attenuates Acetaminophen-Induced Hepatotoxicity via the cGAS-STING Pathway

“…Intercellular contents released from these damaged cells, called damage-associated molecular patterns (DAMPs), which can stimulate nonparenchymal cells to produce and release in ammatory mediators and chemokines [12]. Under the action of chemokines, a variety of immune and in ammatory cells, such as monocytes and neutrophils, are recruited into the liver and promote in ammatory responses via the activation of innate immune signal transduction pathways, resulting in the necrosis and apoptosis of liver cells [13]. Importantly, blocking oxidative stress and inhibiting in ammation are important targets for protecting hepatocytes from hepatotoxicity of APAP.…”