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Esculetin, a coumarin derivative from various natural plants, has an anti-inflammatory property. In the present study, we examined if esculetin has any salutary effects against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Acute lung injury (ALI) was induced via the intratracheal administration of LPS, and esculetin (20 and 40 mg/kg) was given intraperitoneally 30 min before LPS challenge. After 6 h of LPS administration, lung tissues were collected for analysis. Pretreatment with esculetin significantly attenuated histopathological changes, inflammatory cell infiltration, and production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, in the lung tissue. Furthermore, esculetin inhibited the protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B (NF-κB) pathways and downregulated the expression of RORγt and IL-17 in LPS-induced ALI. Our results indicated that esculetin possesses anti-inflammatory and protective effects against LPS-induced ALI via inhibition of the AKT/ERK/NF-κB and RORγt/IL-17 pathways.

Acetaminophen (APAP) overdose is the major cause of drug-induced liver injury and acute liver failure. Approximately 10% of APAP is metabolized by cytochrome P450 (CYP2E1) into toxic N-acetyl-p-benzoquinone imine (NAPQI). CYP2E1 also contributes to ethanol metabolism, especially during conditions of high blood ethanol concentration. Acute and chronic ethanol consumption appears to have opposite effects on APAP-induced liver injury. We determined the effects of different doses, pre- and post-treatment, and various schedules of ethanol exposure in APAP-induced liver injury. Treatment with ethanol (0.5 g/kg) after 1 h of APAP (300 mg/kg) administration decreased serum ALT levels, histopathological features, and inflammatory cell infiltration. Moreover, ethanol treatment 1 h after APAP treatment reduced APAP-induced liver injury compared with later administration. Interestingly, ethanol pretreatment did not provide any protective effect. Furthermore, ethanol treatment was associated with a significant decrease in ERK and AKT phosphorylation during the acute injury phase. Ethanol exposure also increased CYP2E1 expression and decreased PCNA expression during the liver regeneration phase.

Purpose Dexmedetomidine [DEX; (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole] is a selective α2-adrenergic receptor (α2-AR) agonist that attenuates the liver damage associated with local or systemic inflammation. However, it remains unclear whether DEX has protective effects against acetaminophen (Paracetamol, PARA)-induced liver toxicity (PILT). Methods PILT mice were established by intraperitoneal administration of a hepatotoxic dose of acetaminophen (300 mg/kg). Thirty minutes later, the mice were treated with DEX at a concentration of 0, 5, 25, or 50 μg/kg. Blood and liver samples were obtained for further analysis. Results DEX treatment significantly attenuated PILT in mice, with the strongest beneficial effects at a dose of 25 μg/kg. The levels of hepatic cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), in addition to myeloperoxidase (MPO) activity, were significantly decreased following DEX treatment. Moreover, DEX treatment reduced macrophage recruitment around the area of hepatotoxicity and the expression levels of hepatic phosphorylated mitogen-activated protein kinase kinase 4 (MAP2K4), c-jun N-terminal kinase (JNK), and c-Jun expression induced by acetaminophen overdose. Conclusion The data suggest that DEX likely downregulates the JNK signaling pathway and its downstream effectors to promote its hepatoprotective effect, providing a clinical application of DEX for the attenuation of PILT.

Background: Dexmedetomidine [DEX; (S) 4 [1 (2,3 dimethylphenyl)ethyl] 3H imidazole] is a selective α2 adrenergic receptor (α2 AR) agonist that attenuates the liver damage associated with local or systemic inflammation. However, it remains unclear whether DEX has hepatoprotective effects against acetaminophen (APAP)-induced liver injury. Methods: APAP-induced hepatotoxic mice were established by intraperitoneal administration of a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes later, the mice were treated with DEX at a concentration of 0, 5, 25, or 50 μg/kg. Blood and liver samples were obtained for further analysis. Findings: DEX treatment significantly attenuated APAP-induced liver injury in mice, with the strongest beneficial effects at a dose of 25 μg/kg. The levels of hepatic cytokines (TNF-α and IL-6), in addition to myeloperoxidase (MPO) activity, were significantly decreased following DEX treatment. Moreover, DEX treatment reduced macrophage recruitment around the area of hepatotoxicity and the expression levels of hepatic phosphorylated mitogen-activated protein kinase 4 (MAP2K4), c-jun N-terminal kinase (JNK), and c-Jun expression induced by APAP overdose. Interpretation: The data suggests that DEX likely downregulates the JNK signaling pathway and its downstream effectors to promote its hepatoprotective effect, providing a clinical application of DEX for the attenuation of APAP-induced hepatotoxicity. Funding: The present study was supported by a grant from the Chang Gung Medical Research Project (BMRPC19, CMRPG3D1471, CMRPG3D1472, CMRPG3D1473), Chang Gung Memorial Hospital, Linkou, Taiwan, and the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-182A- 061- MY2). Declaration of Interest: The authors have declared that no conflict of interest exists. Ethical Approval: All animal study protocols were reviewed and approved by the Institutional Animal Care and Use Committee of Chang Gung University. All experiments were performed according to the guidelines of the Animal Welfare Act and the Guide for Care and Use of Laboratory Animals from the National Institutes of Health.

Objectives. To investigate the protective effects of tropisetron on acetaminophen- (APAP-) induced liver injury in a mice model.Methods. C57BL/6 male mice were given tropisetron (0.3 to 10 mg/kg) 30 minutes before a hepatotoxic dose of acetaminophen (300 mg/kg) intraperitoneally. Twenty hours after APAP intoxication, sera alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activities, and liver histopathological changes were examined. The MAP kinases were also detected by western blotting.Results. Our results showed that tropisetron pretreatment significantly attenuated the acute elevations of the liver enzyme ALT level, hepatic MPO activity, and hepatocytes necrosis in a dose-dependent manner (0.3–10 mg/kg) in APAP-induced hepatotoxicity mice. Tropisetron (1 and 3 mg/kg) suppressed APAP-induced hepatic lipid peroxidation expression and alleviated GSH and SOD depletion. Administration of tropisetron also attenuated the phosphorylation of c-Jun-NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) caused by APAP.Conclusion. Our data demonstrated that tropisetron’s hepatoprotective effect was in part correlated with the antioxidant, which were mediated via JNK and ERK pathways on acetaminophen-induced liver injury in mice.

Acetaminophen (APAP) overdose results in the production of reactive oxygen species (ROS), hepatocyte necrosis, and cell death, and leads to acute liver failure. Interleukin-17 (IL-17), a pro-inflammatory cytokine, plays a key role in the recruitment of neutrophils into sites of inflammation and subsequent damage after liver ischemia-reperfusion injury. In this study, we employed IL-17 knockout (KO) mice to investigate the role of IL-17 in APAP-induced hepatotoxicity. IL-17 wide type (WT) and IL-17 KO mice received an intraperitoneal injection of APAP (300 mg/kg). After 16 h of treatment, the hepatic injury, inflammatory mediators, immune cell infiltration, and western blotting were examined and analyzed. The serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity were significantly elevated 16 h after APAP treatment in the WT mice. IL-17 deficiency significantly attenuates APAP-induced liver injury, MPO activity, pro-inflammatory cytokines (tumor necrosis factor-α, IL-6 and interferon-γ) levels and inflammatory cell (neutrophils, macrophage) infiltration in the liver. Moreover, phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased at 16 h after APAP treatment in the IL-17 KO mice compared with the IL-17 WT mice. Our data suggests that IL-17 plays a pivotal role in APAP-induced hepatotoxicity through modulation of inflammatory response, and perhaps in part through the ERK signaling pathway. Blockade of IL-17 could be a potential therapeutic target for APAP-induced hepatotoxicity.

Interleukin-17 (IL-17) is involved in a wide range of inflammatory disorders and in recruitment of inflammatory cells to injury sites. A recent study of IL-17 knock-out mice revealed that IL-17 contributes to neuroinflammation and neuropathic pain after peripheral nerve injury. Surprisingly, little is known of micro-environment modulation by IL-17 in injured sites and in pathologically related neuroinflammation and chronic neuropathic pain. Therefore, we investigated nociceptive sensitization, immune cell infiltration, myeloperoxidase (MPO) activity, and expression of multiple cytokines and opioid peptides in damaged nerves of wild-type (IL-17(+/+)) and IL-17 knock-out (IL-17(-/-)) mice after partial sciatic nerve ligation. Our results demonstrated that the IL-17(-/-) mice had less behavioral hypersensitivity after partial sciatic nerve ligation, and inflammatory cell infiltration and pro-inflammatory cytokine (tumor necrosis factor-α, IL-6, and interferon-γ) levels in damaged nerves were significantly decreased, with the levels of anti-inflammatory cytokines IL-10 and IL-13, and expressions of enkephalin, β-endorphin, and dynorphin were also decreased compared to those in wild-type control mice. In conclusion, we provided evidence that IL-17 modulates the micro-environment at the level of the peripheral injured nerve site and regulates progression of behavioral hypersensitivity in a murine chronic neuropathic pain model. The attenuated behavioral hypersensitivity in IL-17(-/-) mice could be a result of decreased inflammatory cell infiltration to the injured site, resulting in modulation of the pro- and anti-inflammatory cytokine milieu within the injured nerve. Therefore, IL-17 may be a critical component for neuropathic pain pathogenesis and a novel target for therapeutic intervention for this and other chronic pain states.

Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15–60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

Background IL-17 has been shown to be involved in liver inflammatory disorders in both mice and humans. Baicalin (BA), a major compound extracted from traditional herb medicine (Scutellariae radix), has potent hepatoprotective properties. Previous study showed that BA inhibits IL-17-mediated lymphocyte adhesion and downregulates joint inflammation. The aim of this study is to investigate the role of IL-17 in the hepatoprotective effects of BA in an acetaminophen (APAP)-induced liver injury mouse model. Methods Eight weeks male C57BL/6 (B6) mice were used for this study. Mice received intraperitoneal hepatotoxic injection of APAP (300 mg/kg) and after 30 min of injection, the mice were treated with BA at a concentration of 30 mg/kg. After 16 h of treatment, mice were killed. Blood samples and liver tissues were harvested for analysis of liver injury parameters. Results APAP overdose significantly increased the serum alanine transferase (ALT) levels, hepatic activities of myeloperoxidase (MPO), expression of cytokines (TNF-α, IL-6, and IL-17), and malondialdehyde (MDA) activity when compared with the control animals. BA treatment after APAP administration significantly attenuated the elevation of these parameters in APAP-induced liver injury mice. Furthermore, BA treatment could also decrease hepatic IL-17-producing γδT cells recruitment, which was induced after APAP overdose. Conclusion Our data suggested that baicalin treatment could effectively decrease APAP-induced liver injury in part through attenuation of hepatic IL-17 expression. These results indicate that baicalin is a potential hepatoprotective agent.