Recombinant Human HPS Protects Mice and Nonhuman Primates from Acute Liver Injury.

Acute liver injury shares a common feature of hepatocytes death, immune system disorders, and cellular stress. Hepassocin (HPS) is a hepatokine that has ability to promote hepatocytes proliferation and to protect rats from D-galactose (D-Gal)- or carbon tetrachloride (CCl4)-induced liver injury by stimulating hepatocytes proliferation and preventing the high mortality rate, hepatocyte death, and hepatic inflammation. In this paper, we generated a pharmaceutical-grade recombinant human HPS using mammalian cells expression system and evaluated the effects of HPS administration on the pathogenesis of acute liver injury in monkey and mice. In the model mice of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced liver injury, HPS treatment significantly reduced hepatocyte death and inflammation response, and consequently attenuated the development of acute liver failure. In the model monkey of D-GalN-induced liver injury, HPS administration promoted hepatocytes proliferation, prevented hepatocyte apoptosis and oxidation stress, and resulted in amelioration of liver injury. Furthermore, the primary pharmacokinetic study showed natural HPS possesses favorable pharmacokinetics; the acute toxicity study indicated no significant changes in behavioral, clinical, or histopathological parameters of HPS-treated mice, implying the clinical potential of HPS. Our results suggest that exogenous HPS has protective effects on acute liver injury in both mice and monkeys. HPS or HPS analogues and mimetics may provide novel drugs for the treatment of acute liver injury.

[Protective effect of vitamin D in mice with acute liver failure].

Objective: To explore the protective effect of vitamin D in acute liver failure through a mouse model. Methods: Acute liver failure was induced by combining D-galactosamine (D-GalN) lipopolysaccharide (LPS) to observe the effect of long-term vitamin D deficiency on liver injury and inflammatory signals in a mouse model. Acute liver failure was induced by thioacetamide (TAA) to observe the effect of vitamin D deficiency on the survival rate, and further high-dose of vitamin D supplementation protective effect was determined in a mouse model. Liver function was evaluated by measuring serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver inflammation by hematoxylin-eosin staining. The expressions of tumor necrosis factor (TNF-α), interleukin (IL) -1ß, NOD-like receptor family, pyrin domain containing 3 (NLRP-3), chemokines (CCL2, CXCL1 and CXCL2), etc. in liver tissues were detected by RT-qPCR. The quantitation of macrophages in liver tissue was detected by immunohistochemistry. The comparison between groups were performed by t-test. The survival curve was analyzed by log-rank (Mantel-Cox) test. Results: Long-term vitamin D deficiency had increased acute liver failure sensitivity in mice, which was manifested by increased blood cell extravasation, massive necrosis of parenchymal cells, up-regulation of TNF-α, IL-1ß, and NLRP-3 mRNA expression (P < 0.05), and increased macrophages quantitation (P < 0.05) in liver tissues. At the same time, vitamin D deficiency had increased the mice mortality rate because of liver injury (P < 0.01). On the contrary, pre-administration of high dose of vitamin D (100 IU/g) had significantly reduced liver injury, inhibited ALT and AST rise (P < 0.01), alleviated liver necrosis, and down-regulated the mRNA expression of inflammatory factors in liver tissues (P < 0.05). Conclusion: Mouse model shows that long-term vitamin D deficiency can aggravate drug-induced acute liver failure and reduce survival rates. Furthermore, high-dose of vitamin D has a certain hepatoprotective effect, which can significantly improve liver necrosis condition and inhibit inflammation. Therefore, adequate vitamin D can retain liver physiological balance to resist liver injury.

Niujiaodihuang Detoxify Decoction inhibits ferroptosis by enhancing glutathione synthesis in acute liver failure models.

ETHNOPHARMACOLOGICAL RELEVANCE: Niujiaodihuang Detoxify Decoction (NDD) is an integrated traditional Chinese medicine prescription that has been used as a therapeutic agent for the treatment of acute liver failure (ALF). However, the mechanisms underlying its action remain unclear. AIM OF THE STUDY: To determine the protective effect of NDD on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF and explore the underlying mechanisms. MATERIALS AND METHODS: We characterized the NDD fingerprint by HPLC and established D-GalN/LPS-induced ALF models in Sprague-Dawley rats and LO2 cells. Next, we measured the protective and antiferroptotic effects of NDD in vivo and in vitro. To further investigate the molecular mechanisms underlying the effects of NDD, we performed metabolomic analysis of the liver tissue using LC-MS/MS. RESULTS: Results of serum biochemical analysis, liver histopathology, and cell viability showed that NDD effectively relieved the liver injury. It reduced the accumulation of labile iron and alleviated lipid peroxidation by enhancing GPX4 activity. The mitochondrial morphology indicated that NDD exerted its hepatoprotective effect through an antiferroptotic activity. Metabolomic analysis showed that NDD treatment increased the levels of cysteine, decreased those of glutamate, and ameliorated the D-GalN/LPS-induced reduction in the levels of glutathione (GSH). The results for intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were consistent with those of metabolomic analysis. CONCLUSION: Our findings indicate that NDD exerts hepatoprotective activity by evoking the reprogramming of GSH metabolism, and thereby, inhibiting ferroptosis.

ORY supplementation mitigates acetaminophen-induced acute liver failure in male mice: role of oxidative stress and apoptotic markers.

The aim of the present study was to assess the possible protective effect of γ-oryzanol (ORY) supplementation in a model of acute liver failure (ALF) induced by acetaminophen (APAP) in mice. Male Swiss strain mice were supplemented with ORY (10 and 50 mg/kg, per oral route) daily for 7 days. One hour after the last supplementation, animals received APAP (300 mg/kg, intraperitoneal). Twenty-four hours after APAP administration, mice were euthanized, and biochemical and histopathological determinations were performed. Histopathological analysis revealed that APAP caused vascular congestion, loss of cellular structure, and cellular infiltration in hepatocytes. Moreover, it caused oxidative damage (enzymatic and non-enzymatic analysis of oxidative stress), with loss of hepatic function leading to cell apoptosis (apoptotic parameters). ORY supplementation (ORY-10 and ORY-50) protected against all changes in ALF model. Thus, the protective effect of ORY supplementation was due to modulation of antioxidant defenses avoiding the apoptotic process.

Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure.

Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.

Hepato-protective effects of Glossogyne tenuifolia in Streptozotocin-nicotinamide-induced diabetic rats on high fat diet.

BACKGROUND: Glossogyne tenuifolia (GT) is a traditional herbal tea in Penghu Island, Taiwan. Its extract is traditionally been used as an antipyretic, hepatoprotective and anti-inflammatory remedy in folk medicine among local residents. The present study investigated whether GT could improve streptozotocin-induced acute liver injury of type 2 diabetes mellitus. METHODS: Male Wistar rats aged eight weeks were induced to be hyperglycemic by the subcutaneous injection of streptozotocin-nicotinamide (STZ-NA) and a combination of a high-fat diet (HFD) (N group). The animals were given GT extracts at a low dose (50 mg/kg) (L group) or a high dose (150 mg/kg) (H group) or an anti-diabetic drug (acarbose) (P group) in drinking water for 4 weeks. RESULTS: The results revealed that STZ-NA increased hepatomegaly, hepatocyte cross-sectional area, hypertrophy-related pathways (IL6/STAT3-MEK5-ERK5, NFATc3, p38 and JNK MAPK), proapoptotic molecules (cytochrome C, cleaved caspase-3), and fibrosis-related pathways (FGF-2, pERK1/2). These pathway components were then expressed at lower levels in the L and H group when compared with the N group. The liver-protective effect of GT in STZ-NA-induced diabetic rats with hyperlipidemia was through an enhancement in the activation of the compensatory PI3K-Akt and Bcl2 survival-related pathway. CONCLUSION: The results demonstrate that the hot water extracts of GT efficiently ameliorates the STZ-NA-induced diabetes associated liver damage in rat models.

Using the 150 rule to prevent hepatotoxicity from acetaminophen.

Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure in adults and a major cause of acute liver failure in children. Prompt treatment with N-acetylcysteine can mitigate hepatotoxicity and progression to liver failure. This article describes a 16-year-old girl who ingested a large dose of extra-strength acetaminophen, and how the 150 rule was used in her management.

The underlying mechanisms of Jie-Du-Hua-Yu granule for protecting rat liver failure.

OBJECTIVES: Jie-Du-Hua-Yu (JDHY) granule is a combination of six traditional Chinese medicines with known therapeutic effect in treating acute liver failure (ALF). The aim of this study was to investigate the amelioration efficacy of JDHY in lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF in rat and explore the possible molecular mechanism underlying the therapeutic efficacy. MATERIALS AND METHODS: The efficacy of JDHY was determined by assessing hepatic pathology and function in LPS and D-GalN challenged Wistar rat. We also evaluated the effect of JDHY on LPS-induced Kupffer cells by measuring inflammatory cytokines and determining the phenotypic function. By means of bioinformatics analysis of liver tissue and validation in Kupffer cells, we identified possible pathways involved in the pharmacologic action of mechanism of JDHY. RESULTS: JDHY could attenuate LPS-induced liver injury in rat by inhibiting apoptosis and increasing hepatic activity. In vitro study showed that JDHY could decrease the production of proinflammatory cytokines (tumor necrosis factor-α, IL6, and interferon-γ), increase anti-inflammatory cytokines (IL10, IL13), and promote cell survival and proliferation, possibly due to inhibition of IκB/nuclear factor-κB (NF-κB) signaling pathway and expression of CD14 and CXCL2, which was consistent with the findings from bioinformatics analysis. CONCLUSION: Our results revealed that JDHY protected against LPS-induced liver damage both in vitro and in vivo, by inhibiting the NF-κB-mediated inflammatory pathway, indicating its potential function to treat liver diseases.

Tectorigenin protects against experimental fulminant hepatic failure by regulating the TLR4/mitogen-activated protein kinase and TLR4/nuclear factor-κB pathways and autophagy.

Tectorigenin has received attention due to its antiproliferation, anti-inflammatory, and antioxidant activities. In this study, we investigated the effects of tectorigenin on lipopolysaccharide (LPS)/D-galactosamine(D-GalN)-induced fulminant hepatic failure (FHF) in mice and LPS-stimulated macrophages (RAW 264.7 cells). Pretreatment with tectorigenin significantly reduced the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histological injury, apoptosis, and the mortality of FHF mice, by suppressing the production of inflammatory cytokines such as TNF-α and IL-6. Tectorigenin also suppressed the activation of the inflammatory response in LPS-stimulated RAW 264.7 cells. Tectorigenin-induced protection is mediated through its mitigation of TLR4 expression, inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathway activation, and promotion of autophagy in FHF mice and LPS-stimulated RAW 264.7 cells. Therefore, tectorigenin has therapeutic potential for FHF in mice via the regulation of TLR4/MAPK and TLR4/NF-κB pathways and autophagy.

Proline supplementation mitigates the early stage of liver injury in bile duct ligated rats.

Background Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis. Methods BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery). Results Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery). Conclusions The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences.

Protective effect of Coptisine from Rhizoma Coptidis on LPS/D-GalN-induced acute liver failure in mice through up-regulating expression of miR-122.

Coptisine (COP), one of the main active ingredients of Rhizoma Coptidis, reportedly has anti-inflammatory, anti-colon cancer properties, but it remains elusive whether COP owns hepatoprotective activity. Mice were pretreated with COP for 7d prior to lipopolysaccharide/d-galactosamine (LPS/D-GalN) administration to detect the hepatic protective effects of COP. The mechanism was explored in using HepG2 cells with low level of miR-122 and LO2 cells with high level of miR-122, combining with miR-122 agomir transfection by means of detecting the expression of miR-122 and proteins, clinical index and apoptosis. COP ameliorated the LPS/D-GalN-induced liver failure by lowering serum levels of ALT and AST, raising hepatic GSH and SOD levels, and maintaining the morphology of hepatocytes, along with an increase in miR-122 expression in mice. The results in vitro indicated that, after miR-122 mimic administration, the alone treatment of COP and the co-treatment of COP and LPS transfection obviously promoted the apoptosis of HepG2, which was increased by 152.67% and 113.97% compared with NC (P < 0.05 vs NC). LPS significantly induced the apoptosis of L02 cells, but COP treatment attenuated that of L02 cells. Further analysis showed that COP increased the miR-122 level and the expression of Bax, cleaved-casp3 and decreased Bcl-2, Bcl-xL in LPS-treated HepG2 cells. COP increased the miR-122 level but decreased the expression of TLR4, Bcl-2, Bcl-xL in LPS-treated L02 cells. COP attenuated LPS/D-GalN-induced ALF by up-regulating the level of miR-122, synergistically promoting apoptosis, and suggesting COP which showed a potential protective effect on ALF.

Reversal of bioenergetics dysfunction by diphenyl diselenide is critical to protection against the acetaminophen-induced acute liver failure.

Physiopathological conditions such as acute liver failure (ALF) induced by acetaminophen (APAP) can often impair the mitochondrial bioenergetics. Diphenyl diselenide [(PhSe)2] has been shown protects against APAP-induced ALF. The present study aimed to clarify the signaling mechanism involved in the protection of bioenergetics dysfunction associated with ALF-induced by APAP overdose. Mice received APAP (600mg/kg) or (PhSe)2 (15.6mg/kg) alone, or APAP+(PhSe)2, all the solutions were administered by the intraperitoneal (i.p.). Samples of liver, blood and liver mitochondria were collected at 2 and 4h after APAP administration. APAP-induced ALF was able to induce ALF by means of alteration on liver injury biomarkers, increased Nitrite and Nitrate levels and the impairment of oxidative phosphorylation capacity (OXPHOS). In parallel, APAP overdose promoted activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Heat shock protein 70 (HSP70) expression. (PhSe)2 was able to abolish the APAP-induced decline of OXPHOS and changes on the Nrf2-ARE pathway. In addition, (PhSe)2 elevated the levels of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), helping to restore the levels of nuclear respiratory factor 1 (NRF1) associated with mitochondrial biogenesis. In summary, the treatment with (PhSe)2 maintained mitochondrial function, promoted genes related to mitochondrial dynamic and demonstrating to play critical role in the modulation of cellular protective responses during ALF.

Hepatoprotective activity of Lepidium sativum seeds against D-galactosamine/lipopolysaccharide induced hepatotoxicity in animal model.

BACKGROUND: Fulminant hepatic failure (FHF) is clinical syndrome with very poor prognosis and high mortality there is urgent need for the development of safe and non-toxic hepatoprotective agents for the adequate management of hepatitis. Hepatoprotective effect of the Lepidium sativum ethanolic extract (LSEE) was assessed by D-galactosamine-induced/lipopolysaccharide (400 mg/kg and 30 µg/kg) liver damage model in rats. METHODS: Hepatoprotective activity of LSEE (150 and 300 mg/kg) and silymarin on D-GalN/LPS induced FHF in rat was assessed using several liver function enzyme parameters. Antioxidant properties as antioxidant stress enzymes were assessed in hepatic Liver as well as mRNA expression of cytokines genes such as TNF-α, IL-6, and IL-10 and stress related genes iNOS and HO-1 were determined by RT-PCR. Protein expression of apoptotic genes were evaluated through western blot. MPO and NF-κB DNA-binding activity was analyzed by ELISA. The magnitude of hepatic impairment was investigated through histopathological evaluation. RESULTS: Marked amelioration of hepatic injuries by attenuation of serum and lipid peroxidation has been observed as comparable with silymarin (25 mg/kg p.o). D-GalN/LPS induced significant decrease in oxidative stress markers protein level, and albumin. LSEE significantly down-regulated the D-GalN/LPS induced pro-inflammatory cytokines TNFα and IL-6 mRNA expression in dose dependent fashion about 0.47 and 0.26 fold and up-regulates the IL-10 by 1.9 and 2.8 fold, respectively. While encourages hepatoprotective activity by down-regulating mRNA expression of iNOS and HO-1. MPO activity and NF-κB DNA-binding effect significantly increased and was mitigated by LSEE in a dose-dependent style as paralleled with silymarin. CONCLUSION: Our data suggests that pretreatment of LSEE down regulates the caspase 3 and up-regulates the BCl2 protein expression. The above findings revealed that Lepidium sativum has significant hepatoprotective activity.

Subchronic treatment with acai frozen pulp prevents the brain oxidative damage in rats with acute liver failure.

Acai has been used by the population due to its high nutritional value and its benefits to health, such as its antioxidant properties. The aim of this study was to evaluate the protective effect of acai frozen pulp on oxidative stress parameters in cerebral cortex, hippocampus and cerebellum of Wistar rats treated with carbon tetrachloride (CCl4). Thirty male Wistar rats (90-day-old) were orally treated with water or acai frozen pulp for 14 days (7 µL/g). On the 15th day, half of the animals received treatment with mineral oil and the other half with CCl4 (3.0 mL/kg). The cerebral cortex, hippocampus and cerebellum were dissected and used for analysis of creatine kinase activity (CK), thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, and the activity of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Statistical analysis was performed by ANOVA followed by Tukey's post-test. CCl4 was able to inhibit CK activity in all tissues tested and to provoke lipid damage in cerebral cortex and cerebellum, and protein damage in the three tissues tested. CCl4 enhanced CAT activity in the cerebral cortex, and inhibited CAT activity in the hippocampus and cerebellum and reduced SOD activity in all tissues studied. Acai frozen pulp prevented the inhibition of CK, TBARS, carbonyl and CAT activity in all brain structures and only in hippocampus for SOD activity. Therefore, acai frozen pulp has antioxidant properties and maybe could be useful in the treatment of some diseases that affect the central nervous system that are associated with oxidative damage.

MicroRNA-125b-5p mimic inhibits acute liver failure.

The lack of broad-spectrum anti-acute liver failure (ALF) therapeutic agents contributes to ALF-related mortality. MicroRNAs (miRNAs) are suggested to be potent serum biomarkers for ALF, but their functional and therapeutic relevance in ALF are unclear. Here we show an unbiased approach, using two complementary miRNA screens, to identify miRNAs that can attenuate ALF. We identify miR-125b-5p as a regulator of cell death that attenuates paracetamol-induced and FAS-induced toxicity in mouse and human hepatocytes. Importantly, administration of miR-125b-5p mimic in mouse liver prevents injury and improves survival in models of ALF. Functional studies show that miR-125b-5p ameliorates ALF by directly regulating kelch-like ECH-associated protein 1, in turn elevating expression of nuclear factor-E2-related factor 2, a known regulator in ALF. Collectively, our findings establish miR-125b-5p as an important regulator of paracetamol-induced and FAS-induced cell death. Thus, miR-125b-5p mimic may serve as a broad-spectrum therapeutic attenuator of cell death during ALF.

Improved prescription of taohechengqi-tang alleviates D-galactosamine acute liver failure in rats.

AIM: To investigate the hepatoprotective effect of improved prescription of Taohechengqi-tang (IPTT) against acute liver failure (ALF) in rats. METHODS: Seventy specific pathogen free male Wistar rats were randomly divided into four groups: control group (normal rats, n = 10), ALF group (ALF model, n = 20), Stronger Neo-Minophagen C (SNMC) group (ALF model + SNMC, n = 20), and IPTT group (ALF model + IPTT, n = 20). The ALF model group was administered an intraperitoneal injection of D-galactosamine (1.4 g/kg), and the control group received normal saline intraperitoneally. The SNMC and IPTT groups were treated with SMMC (15.6 mg/kg) or IPTT (28.6 g/kg) by gavage at 24 h intervals, and the ALF and control groups were treated with normal saline. At 36 h after injection, serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, and cholinesterase and prothrombin time were determined, and liver histopathological scores were observed by microscopy after hematoxylin and eosin staining. mRNA expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-κB) and caspase-3 were analyzed via fluorescence quantitative reverse transcriptase polymerase chain reaction. Proliferating cell nuclear antigen (PCNA) immunohistochemistry in liver tissue was also performed. RESULTS: D-galactosamine notably decreased the biochemical and coagulation profiles in serum. IPTT not only improved liver function and histopathology but also normalized the gene expression levels in liver tissue. Compared with the model group, in the IPTT and SNMC groups, HMGB1 mRNA/ß-actin (0.06 ± 0.03, 0.11 ± 0.04 vs 0.25 ± 0.04, P < 0.05); TLR4 mRNA/ß-actin (0.07 ± 0.02, 0.22 ± 0.08 vs 0.41 ± 0.22, P < 0.05); NF-κB mRNA/ß-actin (0.74 ± 0.41, 1.78 ± 0.64 vs 2.68 ± 1.35, P < 0.05); and caspase-3 mRNA/ß-actin levels were all significantly reduced (1.61 ± 0.45, 2.57 ± 1.04 vs 3.41 ± 0.85, P < 0.05). The gene expression levels were significantly lower in the IPTT group than in the SNMC group (P < 0.05). Compared with the model group, the PCNA expression in liver tissue was significantly enhanced in the IPTT and SNMC groups (36.34 ± 4.91, 25.57 ± 2.94 vs 17.55 ± 2.40, P < 0.05). CONCLUSION: IPTT attenuates inflammation in ALF via inhibition of HMGB1 production, which may contribute to limited liver regeneration.

Ketone Body Therapy Protects From Lipotoxicity and Acute Liver Failure Upon Pparα Deficiency.

Acute liver failure (ALF) is a severe and rapid liver injury, often occurring without any preexisting liver disease, which may precipitate multiorgan failure and death. ALF is often associated with impaired ß-oxidation and increased oxidative stress (OS), characterized by elevated levels of hepatic reactive oxygen species (ROS) and lipid peroxidation (LPO) products. Peroxisome proliferator-activated receptor (PPAR)α has been shown to confer hepatoprotection in acute and chronic liver injury, at least in part, related to its ability to control peroxisomal and mitochondrial ß-oxidation. To study the pathophysiological role of PPARα in hepatic response to high OS, we induced a pronounced LPO by treating wild-type and Pparα-deficient mice with high doses of fish oil (FO), containing n-3 polyunsaturated fatty acids. FO feeding of Pparα-deficient mice, in contrast to control sunflower oil, surprisingly induced coma and death due to ALF as indicated by elevated serum alanine aminotransferase, aspartate aminotransferase, ammonia, and a liver-specific increase of ROS and LPO-derived malondialdehyde. Reconstitution of PPARα specifically in the liver using adeno-associated serotype 8 virus-PPARα in Pparα-deficient mice restored ß-oxidation and ketogenesis and protected mice from FO-induced lipotoxicity and death. Interestingly, administration of the ketone body ß-hydroxybutyrate prevented FO-induced ALF in Pparα-deficient mice, and normalized liver ROS and malondialdehyde levels. Therefore, PPARα protects the liver from FO-induced OS through its regulatory actions on ketone body levels. ß-Hydroxybutyrate treatment could thus be an option to prevent LPO-induced liver damage.

Antagonistic interaction between cordyceps sinensis and exercise on protection in fulminant hepatic failure.

Herb supplements are widely used by Asian athletes; however, there are no studies evaluated the co-effects of exercise and herb supplements on hepatic failure. In this study, D-GalN/LPS-induced fulminant hepatic failure was used to examine whether there are synergistic or antagonistic effects of exercise and Cordyceps sinensis (CS). Mice were randomly divided into eight groups: control, swimming exercise for four weeks, D-GalN/LPS challenge, swimming exercise plus D-GalN/LPS, 20 mg/kg or 40 mg/kg CS pretreated for four weeks plus D-GalN/LPS, and swimming exercise combined with 20 mg/kg or 40 mg/kg CS pretreatment plus D-GalN/LPS. Either exercise or 40 mg/kg CS pretreatment alone significantly decreased D-GalN/LPS-induced TNF-α, AST, NO, apoptotic-related proteins, and hepatocyte apoptosis. Exercise or 40 mg/kg CS alone increased the IL-10 and D-GalN/LPS-suppressed Superoxide Dismutase (SOD) level. However, no protective or worse effect was observed in the mice treated with exercise preconditioning combined 40 mg/kg CS compared to those receive exercise alone or CS alone. TNF-α, AST, NO level, caspase-3 activity, and hepatocytes apoptosis were not significantly different in the exercise combined with 40 mg/kg CS compared to mice challenged with D-GalN/LPS. The IL-10 level was significantly decreased after D-GalN/LPS stimulation in the mice received exercise combined with 40 mg/kg CS, indicating the combination strongly reduced the anti-inflammatory effect. In summary, preconditioning exercise or CS pretreatment alone can protect mice from septic liver damage, but in contrast, the combination of exercise and CS does not produce any benefit. The antagonistic interactions between exercise and CS imply taking CS is not recommended for people who undertake regular exercise.

[Sanhuangyinchi decoction pretreatment ameliorates acute hepatic failure in rats by suppressing antioxidant stress and caspase-3 expression].

OBJECTIVE: To observe the effects of Sanhuangyinchi decoction (SHYCD) pretreatment on acute hepatic failure (AHF) induced by D-galactosamine and lipopolysaccharide (LPS) in rats and explore the possible mechanisms involving antioxidant stress and cell apoptosis-related protein expression. METHODS: Forty-eight SD rats were randomized equally into control group, AHF model group, high-, medium- and low-dose SHYCD groups, and Bicyclol group. Five days after administration of the corresponding drugs, the rats were challenged with peritoneal D-galactosamine (700 mg/kg) plus LPS (10 ug/kg) injections to induce AHF acute hepatic failure except for those in the control group. At 48 h after the injections, blood samples were collected from the rats to detect the levels of ALT, AST, TBIL, PT, INR and FIB, and pathological changes and superoxide dismutase (SOD) and malondialdehyde (MDA) contents in the liver were examined; immunohistochemistry and western blotting were used to detect caspase-3 protein expression in the liver. RESULTS: The levels of ALT, AST, TBIL, TP and INR in the 3 SHYCD groups and Bicyclol group significantly decreased (P<0.05) while FIB significantly increased in comparison with those in the model group. SHYCD obviously ameliorated the pathological changes, enhanced SOD activity (P<0.05), and decreased MDA levels (P<0.05) and caspase-3 expression (P<0.05) in the liver tissue. SHYCD at the medium dose produced similar effects to Bicyclol (P>0.05) and showed better effects at the high dose than Bicyclol (P<0.05). CONCLUSION: SHYCD pretreatment can dose-dependently ameliorate AHF in rats possibly by suppressing antioxidant stress and caspase-3 expression to decrease hepatic cell apoptosis.

Cordyceps sinensis prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

Cordyceps sinensis (C. sinensis) has long been considered to be an herbal medicine and has been used in the treatment of various inflammatory diseases. The present study examined the cytoprotective properties of C. sinensis on D(+)-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were randomly assigned into control, GalN/LPS, CS 20 mg and CS 40 mg groups (C. sinensis, oral gavage, five days/week, four weeks). After receiving saline or C. sinensis, mice were intraperitoneally given GalN (800 mg/kg)/LPS (10 µg/kg). The effects of C. sinensis on TNF-α, IL-10, AST, NO, SOD, and apoptoticrelated proteins after the onset of endotoxin intoxication were determined. Data demonstrated that GalN/LPS increased hepatocyte degeneration, circulating AST, TNF-α, IL-10, and hepatic apoptosis and caspase activity. C. sinensis pre-treatment reduced AST, TNF-α, and NO and increased IL-10 and SOD in GalN/LPS induced fulminant hepatic failure. C. sinensis attenuated the apoptosis of hepatocytes, as evidenced by the TUNEL and capase-3, 6 activity analyses. In summary, C. sinensis alleviates GalN/LPS-induced liver injury by modulating the cytokine response and inhibiting apoptosis.