Naringin against doxorubicin-induced hepatotoxicity in mice through reducing oxidative stress, inflammation, and apoptosis via the up-regulation of SIRT1.

Clinical application of doxorubicin is limited because of its potential side effects. The present study examined whether naringin had protective actions on doxorubicin-induced liver injury. Male BALB/c mice and alpha mouse liver 12 (AML-12) cells were used in this paper. The results showed that AML-12 cells treated with naringin significantly reduced cell injury, reactive oxygen species release and apoptosis level; Moreover, naringin notably alleviated liver injury by decreasing aspartate transaminase, alanine transaminase and malondialdehyde, and increasing superoxide dismutase, glutathione and catalase levels. Mechanism researches indicated that naringin increased the expression levels of sirtuin 1 (SIRT1), and inhibited the downstream inflammatory, apoptotic and oxidative stress signaling pathways. Further validation was obtained by knocking down SIRT1 in vitro, which proved the effects of naringin on doxorubicin-induced liver injury. Therefore, naringin is a valuable lead compound for preventing doxorubicin-induced liver damage by reducing oxidative stress, inflammation, and apoptosis via up-regulation of SIRT1.

[Preventive and therapeutic effect of bioactive component of licorice on antidepressant-induced liver injury].

Since exploding rates of modern mental diseases, application of antidepressants has increased. Worryingly, the antidepressant-induced liver injury has gradually become a serious health burden. Furthermore, since most of the knowledge about antidepressant hepatotoxicity are from pharmacovigilance and clinical case reports and lack of observational studies, the underlying mechanisms are poorly understood and there is a lack of efficient treatment strategies. In this study, antidepressant paroxetine directly triggered inflammasome activation evidenced by caspase-1 activation and downstream effector cytokines interleukin(IL)-1ß secretion. The pretreatment of echinatin, a bioactive component of licorice, completely blocked the activation. This study also found that echinatin effectively inhibited the production of inflammasome-independent tumor necrosis factor α(TNF)-α induced by paroxetine. Mechanistically, the accumulation of mitochondrial reactive oxygen species(mtROS) was a key upstream event of paroxetine-induced inflammasome activation, which was dramatically inhibited by echinatin. In the lipopolysaccharide(LPS)-mediated idiosyncratic drug-induced liver injury(IDILI) model, the combination of LPS and paroxetine triggered aberrant activation of the inflammasome to induce idiosyncratic hepatotoxicity, which was reversed by echinatin pretreatment. Notably, this study also found that various bioactive components of licorice had an inhibitory effect on paroxetine-triggered inflammasome activation. Meanwhile, multiple antidepressant-induced aberrant activation of the inflammasome could be completely blocked by echinatin pretreatment. In conclusion, this study provides a novel insight for mechanism of antidepressant-induced liver injury and a new strategy for the treatment of antidepressant-induced hepatotoxicity.

Sirtuin 6 ameliorates alcohol-induced liver injury by reducing endoplasmic reticulum stress in mice.

Alcoholic liver disease (ALD) occurs as a result of chronic and excessive alcohol consumption. It encompasses a wide spectrum of chronic liver abnormalities that range from steatosis to alcoholic hepatitis, progressive fibrosis and cirrhosis. Endoplasmic reticulum (ER) stress induced by ethanol metabolism in hepatocytes has been established as an important contributor to the pathogenesis of ALD. However, whether SIRT6 exerts regulatory effects on ethanol-induced ER stress and contributes to the pathogenesis of ALD is unclear. In this study, we developed and characterized Sirt6 hepatocyte-specific knockout and transgenic mouse models that were treated with chronic-plus-binge ethanol feeding. We observed that hepatic Sirt6 deficiency led to exacerbated ethanol-induced liver injury and aggravated hepatic ER stress. Tauroursodeoxycholic acid (TUDCA) treatment remarkably attenuated ethanol-induced ER stress and ameliorated ALD pathologies caused by Sirt6 ablation. Reciprocally, SIRT6 hepatocyte-specific transgenic mice exhibited reduced ER stress and ameliorated liver injury caused by ethanol exposure. Consistently, knockdown of Sirt6 elevated the expression of ER stress related genes in primary hepatocytes treated with ethanol, whereas overexpression of SIRT6 reduced their expression, indicating SIRT6 regulates ethanol-induced hepatic ER stress in a cell autonomous manner. Collectively, our results suggest that SIRT6 is a positive regulator of ethanol-induced ER stress in the liver and protects against ALD by relieving ER stress.

Butyrate prevents valproate-induced liver injury: In vitro and in vivo evidence.

Sodium valproate (VPA), an antiepileptic drug, may cause dose- and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations. Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment.

Effect of carvedilol versus propranolol on acute and chronic liver toxicity in rats.

Non-selective ß-blockers have largely been used for prophylaxis of bleeding from gastroesophageal varices, but their hepatic effects and their influence on the development of varices has yet to be clarified. This study examined whether carvedilol would reduce acute and chronic liver injury in rats in comparison to propranolol. Experiment (1) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) administered daily for 7 days by gavage on paracetamol (1500 mg/kg i.p.) -induced acute liver injury in rats. Experiment (2) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) by gavage daily for 8 weeks on CCl4 -induced chronic liver injury in rats. Biochemical markers and histopathology of the livers were studied. Liver perfusion studies were carried out on CCl4 treated rats. Experiment (1) Carvedilol significantly improved the functional state of the liver in paracetamol-induced acute toxic hepatitis to a greater extent than propranolol. This was evidenced by a greater reduction in elevated serum levels of ALT and AST, hepatic MDA and TNF-α, attenuation of the paracetamol-induced decrease in GSH, together with improvement in the histological architecture of the liver. Experiment (2) Carvedilol was superior to propranolol against CCl4-induced hepatic injury and fibrogenesis. It suppressed hepatic inflammation, attenuated hepatic oxidative stress, and inhibited HSC activation. Carvedilol also decreased portal perfusion pressure. These results suggest that carvedilol might be a therapeutic anti-fibrogenic candidate against hepatic fibrosis, protecting the liver from acute and chronic toxic injury, in addition to lowering portal pressure.

Schizandrin B Mitigates Rifampicin-Induced Liver Injury by Inhibiting Endoplasmic Reticulum Stress.

Schisandra chinensis is widely used and effective in protecting liver. There are many mechanisms of drug-induced hepatocyte injury, among which endoplasmic reticulum (ER) stress-induced cell injury plays an important role. However, little is known about whether schisandra chinensis can inhibit rifampicin (RFP)-induced hepatocyte injury by affecting ER stress. In our study, firstly, L02 cells were treated with different concentrations of RFP for different time intervals, and the apoptosis, survival rate and endoplasmic reticulum stress gene and protein expressions of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), activating transcription factor (ATF)4, C/EBP-homologus protein (CHOP), ATF6, arginine-rich, mutated in early stage tumors (ARMET), p-inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP-1) were measured. We found that RFP increased apoptosis of L02 cells, decreased cell survival, and increased the gene and protein expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET, p-IRE1 and XBP-1, suggesting that RFP could induce hepatocyte injury, and the degree of injury was positively correlated with the dose and time of RFP. Next, we treated RFP-damaged hepatocytes with schizandrin B. We found that schizandrin B increased cell survival rate in dose-dependent and time-dependent manner, decreased cell apoptosis rate, and reduced protein and gene expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET and XBP-1. These results indicate that schizandrin B alleviates RFP-induced injury in L02 cells by inhibiting ER stress.

Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury.

BACKGROUND AND AIM: Impaired gut-liver axis is a potential factor contributing to alcoholic liver disease. Ethanol depletes intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is altered negatively following chronic ethanol exposure. This study aimed to determine whether prophylactic tributyrin could protect the intestinal barrier and liver in mice during combined chronic-binge ethanol exposure. METHODS: C57BL/6J mice exposed to 5% v/v ethanol-containing diet for 10 days received a single ethanol gavage (5 g/kg) 9 h before euthanasia. Control mice were isocalorically pair-fed maltose dextrin for ethanol. Diets were supplemented (5 mM) with tributyrin or glycerol. Intestine and liver disease activity was assessed histologically. Protein and mRNA expression of tight junction (TJ) proteins, toll-like receptors, and tumor necrosis factor-alpha were assessed. Caco-2 monolayers with or without ethanol exposure and/or sodium butyrate were used to test butyrate's direct effects on intestinal integrity. RESULTS: Chronic-binge ethanol feeding impaired intestinal TJ protein co-localization staining; however, tributyrin co-treatment mitigated these effects. Ethanol depleted TJ and transepithelial electrical resistance in Caco-2 monolayers, but butyrate co-treatment reduced these effects. Hepatic toll-like receptor mRNA expression and tumor necrosis factor-alpha protein expression was induced by ethanol; however, the response was significantly dampened in mice co-treated with tributyrin. Tributyrin altered localization of both neutrophils and single hepatocyte death: Leukocytes and apoptotic hepatocytes localized predominantly around the portal tract in ethanol-only treated mice, whereas localization predominated around the central vein in ethanol-tributyrin mice. CONCLUSIONS: Prophylactic tributyrin supplementation mitigated effects of combined chronic-binge ethanol exposure on disruption of intestinal TJ localization and intestinal permeability and liver injury.

Protective effect of pravastatin on doxorubicin-induced hepatotoxicity.

OBJECTIVE: The present study was designed to investigate the possible protection of pravastatin against hepatic oxidative stress and dysfunctions induced by doxorubicin in rats. BACKGROUND: Statins have beneficial effects on oxidative stress and inflammation. METHODS: Male Sprague-Dawley rats were divided into four groups. Control group (received saline orally), Group 2 received pravastatin (20 mg/kg, i.p. for 15 days), Group 3 received single dose doxorubicin (15 mg/kg, i.p.), Group 4 was treated with pravastatin (20 mg/kg, i.p.) daily from 5 days before to 10 days after injection of doxorubicin (15 mg/kg, i.p.). Hepatic toxicity was estimated by biochemical parameters and oxidative stress and histopathological studies. RESULTS: Administration of doxorubicin indicated an increase in ALT, AST, ALP, TG, cholesterol, LDL and total bilirubin levels (p < 0.01). Doxorubicin caused a reduction in HDL and albumin levels (p < 0.01) as well as superoxide dismutase, glutathione peroxidase and catalase activities (p < 0.05) with a concomitant increase in liver malondialdehyde (p < 0.05) and liver damage (p < 0.001). Pravastatin reduced the scale liver injury (p < 0.001) and protected liver functions and other biochemical parameters (p < 0.01). Increase in malondialdehyde level associated with a reduction in antioxidant activities in the doxorubicin group was attenuated by pravastatin treatment (p < 0.05). CONCLUSION: Results indicated that pravastatin has a protective effect on the liver against doxorubicin-induced hepatotoxicity in rats (Tab. 3, Fig. 2, Ref. 34).

Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride-induced chronic injury in rats.

CONTEXT: Bovine pancreatic trypsin inhibitor (BPTI) has been reported to relieve liver ischemia-reperfusion-induced injury in rats. OBJECTIVE: This study was designed to determine whether the recombinant BPTI (rBPTI) can prevent the chronic liver injury induced by CCl4 in rats. MATERIALS AND METHODS: Fifty male Wistar rats were divided into five groups. Rats were treated with 40% CCl4 at a dose of 2 ml/kg body weight twice a week subcutaneously for 12 weeks. In the 8th week, they were administered intraperitoneally with rBPTI (80 MU/kg), BPTI (80 MU/kg) or hepatocyte growth-promoting factor (pHGF; 100 mg/kg) daily for the next 4 weeks. RESULTS: rBPTI significantly prevented the disruption of liver function of alanine aminotransferase (ALT; 172.7 ± 18.16 versus 141.2 ± 15.28, p=0.003), aspartate aminotransferase (AST; 225.10 ± 36.54 versus 170.06 ± 27.14, p=0.007) and hydroxyproline (Hyp; 1.14 ± 0.27 versus 0.62 ± 0.17, p=0.001). rBPTI significantly decreased the level of thiobarbituric acid reactive substances (TBARS; 1.15 ± 0.16 versus 0.87 ± 0.15, p=0.003) and increased the activities of superoxide dismutase (SOD; 6.07 ± 0.95 versus 7.75 ± 1.12, p=0.007). rBPTI reduced the production of cytokines of IL-1ß and TGF-ß. The hepatocyte necrosis, fibrosis, fatty degeneration and inflammatory cell infiltration were ameliorated by rBPTI administration. CONCLUSION: This study demonstrated that rBPTI exerted a hepatoprotective effect on chronic liver fibrosis induced by CCl4, which suggests that rBPTI may have the potential application for chronic liver injury induced by drugs metabolism and toxic substances.

Aliskiren attenuates chronic carbon tetrachloride-induced liver injury in mice.

BACKGROUND: Increased angiotensin II (Ang II) plays an important role in liver inflammation and fibrogenesis. Chronic administration of aliskiren, a newly developed direct renin inhibitor, decreases Ang II in the hypertensive patients and animals. AIMS: Our study aims to evaluate the possible protective effects of chronic administration of aliskiren in a chronic liver injury model. METHODS: C57BL6 mice were injected intraperitoneally with carbon tetrachloride (CCl(4)) to induce chronic liver injury. The injured mice were randomly assigned to aliskiren-treated (25 mg/kg per day for 2 weeks, the CCl(4) + Ali group) or untreated group (the CCl(4) group). Mice without CCl(4) and aliskiren administration served as the normal control. RESULTS: In the CCl(4)-injured mice, aliskiren attenuated liver inflammation and fibrosis. The levels of hepatocyte apoptosis, lipid peroxidation production, the activation of hepatic stellate cells and Kupffer cells, hepatic expression of p47 phox, inflammatory mediators and profibrotic markers were reduced in the CCl(4) + Ali group. Furthermore, aliskiren decreased Ang II, activated the renal expression of renin, but down-regulated the hepatic expression of renin and renin receptor in the CCl(4)-injected mice. CONCLUSIONS: Aliskiren attenuates chronic liver injury in the CCl(4)-treated mice by reducing Ang II. Direct renin inhibition may serve as a potential treatment for chronic liver injury.

Ipomoea aquatica extract shows protective action against thioacetamide-induced hepatotoxicity.

In the Indian system of traditional medicine (Ayurveda) it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA)-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD) rats were orally fed with I. aquatica (250 and 500 mg/kg) for two months along with administration of TAA (i.p injection 200 mg/kg three times a week for two months). The results showed that the treatment of I. aquatica significantly lowered the TAA-induced serum levels of hepatic enzyme markers (ALP, ALT, AST, protein, albumin, bilirubin and prothrombin time). The hepatic content of activities and expressions SOD and CAT that were reduced by TAA were brought back to control levels by the plant extract supplement. Meanwhile, the rise in MDA level in the TAA receiving groups also were significantly reduced by I. aquatica treatment. Histopathology of hepatic tissues by H&E and Masson trichrome stains displayed that I. aquatica has reduced the incidence of liver lesions, including hepatic cells cloudy swelling, infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by TAA in rats. Therefore, the results of this study show that the protective effect of I. aquatica in TAA-induced liver damage might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects. Moreover, it confirms a scientific basis for the traditional use of I. aquatica for the treatment of liver disorders.

4-Phenylbutyrate protects against rifampin-induced liver injury via regulating MRP2 ubiquitination through inhibiting endoplasmic reticulum stress.

Rifampin (RFP), a first-line anti-tuberculosis drug, often induces cholestatic liver injury and hyperbilirubinemia which limits its clinical use. Multidrug resistance-associated protein 2 (MRP2) localizes to the hepatocyte apical membrane and plays a pivotal role in the biliary excretion of bilirubin glucuronides. RFP is discovered to reduce MRP2 expression in liver cells. 4-Phenylbutyrate (4-PBA), a drug used to treat ornithine transcarbamylase deficiency (DILI), is reported to alleviate RFP-induced liver cell injury. However, the underlying mechanism still remains unclear. In the current study, we discovered that RFP induced HepG2 cell viability reduction, apoptosis and MRP2 ubiquitination degradation. Administration of 4-PBA alleviated the effect of RFP on HepG2 cell viability reduction, apoptosis and MRP2 ubiquitination degradation. In mechanism, 4-PBA suppressed RPF-caused intracellular Ca2+ disorder and endoplasmic reticulum (ER) stress, as well as the increases of Clathrin and adapter protein 2 (AP2). ER stress marker protein C/EBP homologous protein took part in the modulation of AP2 and clathrin. Besides, 4-PBA reduced the serum bilirubin level in RFP-induced cholestasis mouse model, along with raised the MRP2 expression in liver tissues. These findings indicated that 4-PBA could alleviate RFP-induced cholestatic liver injury and thereby decreased serum total bilirubin concentration via inhibiting ER stress and ubiquitination degradation of MRP2, which provides new insights into the mechanism of 4-PBA in the treatment of RFP-induced cholestasis and liver damage.

Augmenter of liver regeneration (ALR) gene therapy attenuates CCl4-induced liver injury and fibrosis in rats.

Liver fibrosis represents a process of healing and scarring in response to chronic liver injury. Augmenter of liver regeneration (ALR) has been shown to protect hepatocytes from various toxins. The aim of this study was to investigate the effects of ALR gene therapy on liver injury and fibrosis induced by CCl(4) in rats and further explore the underlying mechanisms. Human ALR expression plasmid was delivered via the tail vein. ALR gene therapy might protect the liver from CCl(4)-induced injury and fibrogenesis by attenuating the mitochondrial dysfunction, suppressing oxidative stress, and inhibiting activation of HSCs. This report demonstrated that ALR gene therapy protected against the ATP loss, increased the activity of ATPase, decreased intrahepatic reactive oxygen species level, and down-regulated transforming growth factor-ß1, platelet-derived growth factor-BB, and α-smooth muscle actin expression. Following gene transfer liver function tests were significantly improved. In brief, ALR gene therapy might be an effective therapeutic reagent for liver fibrosis with potential clinical applications.

AP39 ameliorates high fat diet-induced liver injury in young rats via alleviation of oxidative stress and mitochondrial impairment.

Non-alcoholic fatty liver disease (NAFLD) is a complication of childhood obesity and an oxidative stress-related multisystem disease. A mitochondria-targeting hydrogen sulfide (H2S) donor AP39 has antioxidant property, while the mechanism underlying the function of AP39 on pediatric NAFLD remains undefined. Here, 3-week-old SD rats were received a high-fat diet (HFD) feeding and injected with AP39 (0.05 or 0.1 mg/kg/day) via the tail vein for up to 7 weeks. AP39 reduced weight gain of HFD rats and improved HFD-caused liver injury, as evidenced by reduced liver index, improved liver pathological damage, decreased NAFLD activity score, as well as low alanine transaminase (ALT) and aspartate transaminase (AST) activities. AP39 also reduced serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) concentrations but increased high-density lipoprotein-cholesterol (HDL-C). Moreover, AP39 prevented reactive oxygen species (ROS) generation, reduced MDA content and increased glutathione (GSH) level and superoxide dismutase (SOD) activity. Furthermore, AP39 increased H2S level, protected mitochondrial DNA (mtDNA), reduced mitochondrial swelling, and restored mitochondrial membrane potential (MMP) alteration. Notably, AP39 diminished HIF-1α mRNA and protein level, possibly indicating the alleviation in mitochondrial damage. In short, AP39 protects against HFD-induced liver injury in young rats probably through attenuating lipid accumulation, oxidative stress and mitochondrial dysfunction.

Protective effect of ISO-1 with inhibition of RIPK3 up-regulation and neutrophilic accumulation on acetaminophen-induced liver injury in mice.

Overdose use of acetaminophen (APAP) often occurs a severe liver injury, and its liver injury is lethal in some cases. Macrophage migration inhibitory factor (MIF) is expressed in a variety of cells and has multifunctional roles. However, the role of MIF in APAP-induced liver injury has not been fully investigated. In this study, we investigated whether treatment with (S,R)-3-(4-hydroxyphenil)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), a MIF inhibitor, protected mice from acute APAP-induced liver injury. Acute liver injury was induced by injection of APAP (300 mg/kg body weight). Mice were treated with a single injection of ISO-1(15 mg/kg body weight) 1 h (h) before APAP administration. Histological, biochemical and molecular analyses were performed in liver of mice 12 h after APAP administration. ISO-1 remarkably improved the histological findings of APAP-induced liver injury in mice. The increases in serum levels of alanine aminotransferase (ALT), and macrophage inflammatory protein-2 (MIP-2) by APAP were inhibited by ISO-1. In addition, ISO-1 reduced the increased number of the myeloperoxidase-staining cells and that of TUNEL-positive staining cells in the liver of mice with APAP-induced liver injury. Up-regulation of hepatic receptor interacting protein kinase (RIPK)3 and heat shock protein70 by APAP was suppressed in the liver of mice given ISO-1. These results provide the additional evidence that inhibition of MIF activity may be clinically effective for treatment of acute APAP-induced liver injury.

Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-ß1/Smad and PI3K/AKT Signaling Pathways.

Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-ß1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-ß1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.

Dietary iso-α-acids prevent acetaldehyde-induced liver injury through Nrf2-mediated gene expression.

Acetaldehyde is the major toxic metabolite of alcohol (ethanol) and enhances fibrosis of the liver through hepatic stellate cells. Additionally, alcohol administration causes the accumulation of reactive oxygen species (ROS), which induce hepatocyte injury-mediated lipid peroxidation. Iso-α-acids, called isohumulones, are bitter acids in beer. The purpose of this study was to investigate the protective effects of iso-α-acids against alcoholic liver injury in hepatocytes in mice. C57BL/6N mice were fed diets containing isomerized hop extract, which mainly consists of iso-α-acids. After 7 days of feeding, acetaldehyde was administered by a single intraperitoneal injection. The acetaldehyde-induced increases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were suppressed by iso-α-acids intake. Hepatic gene expression analyses showed the upregulation of detoxifying enzyme genes, glutathione-S-transferase (GST) and aldehyde dehydrogenase (ALDH). In vitro, iso-α-acids upregulated the enzymatic activities of GST and ALDH and induced the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nfe2l2; Nrf2), a master regulator of antioxidant and detoxifying systems. These results suggest that iso-α-acid intake prevents acetaldehyde-induced liver injury by reducing oxidative stress via Nrf2-mediated gene expression.

Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children's Oncology Group.

Curative therapy for childhood and adolescent cancer translates to 1 in 640 young adults being a survivor of cancer. Although acute hepato-biliary toxicity occurs commonly during pediatric cancer therapy, the impact of antineoplastic therapy on long-term liver health in childhood/adolescent cancer survivors is unknown. This article reviews the medical literature on late liver dysfunction following treatment for childhood/adolescent cancer. We also outline the Children's Oncology Group (COG) guidelines for screening and follow-up of hepato-biliary sequelae. As the population of survivors grow and age, vigilance for risks to hepatic health needs to continue based on specific exposures during curative cancer therapy.

[Severe hepatitis and subacute liver failure with "fast track" cirrhosis in an elderly lady]. / Schwere Hepatopathie und subakutes Leberversagen mit "Fast-track"-Leberzirrhose bei älterer Patientin.

We report the case of a 74-year-old lady who presented at our clinic with icterus and cholestatic hepatitis. For atrial fibrillation she had been prescribed a medication with phenprocoumone. After ruling out viral, autoimmune, and metabolic causes of hepatitis, we performed a liver biopsy which led to the diagnosis of phenprocoumone-related liver damage. The patient was discharged without phenprocoumone and completely compensated liver function. Five weeks later she returned to the hospital with encephalopathy, ascites, coagulopathy, varices, and signs of cirrhosis in abdominal ultrasound. In spite of treatment with steroids, the patient died of subacute liver failure several weeks later. This case illustrates the occasionally poor course of toxic hepatitis even after discontinuation of the responsible medication, potential treatment options are discussed.

Assessing Effects of BHV-0223 40 mg Zydis Sublingual Formulation and Riluzole 50 mg Oral Tablet on Liver Function Test Parameters Utilizing DILIsym.

For patients with amyotrophic lateral sclerosis who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3× ULN, and 2% above 5× ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of liver toxicity. DILIsym is a validated multiscale computational model that supports evaluation of liver toxicity risks. DILIsym was used to compare the hepatotoxicity potential of oral riluzole tablets (50 mg BID) versus BHV-0223 (40 mg BID) by integrating clinical data and in vitro toxicity data. In a simulated population (SimPops), ALT levels > 3× ULN were predicted in 3.9% (11/285) versus 1.4% (4/285) of individuals with oral riluzole tablets and sublingual BHV-0223, respectively. This represents a relative risk reduction of 64% associated with BHV-0223 versus conventional riluzole tablets. Mechanistic investigations revealed that oxidative stress was responsible for the predicted ALT elevations. The validity of the DILIsym representation of riluzole and assumptions is supported by its ability to predict rates of ALT elevations for riluzole oral tablets comparable with that observed in clinical data. Combining a mechanistic, quantitative representation of hepatotoxicity with interindividual variability in both susceptibility and liver exposure suggests that sublingual BHV-0223 confers diminished rates of liver toxicity compared with oral tablets of riluzole, consistent with having a lower overall dose of riluzole and bypassing first-pass liver metabolism.