Exploring the hepatoprotective and cytotoxic activities of Thalictrum foliolosum and Cordia dichotoma for targeting acute liver injury

Acute liver injury (ALI) is a life-threatening clinical syndrome. Long-lasting liver injury can lead to chronic hepatic inflammation and fibrogenic responses. Zerumbone (ZER), the main constituent of rhizomes of Zingiber zerumbet Smith, has a variety of functions including anticancer activity. We investigated the role of ZER on the progression of hepatotoxin-induced liver injury. Single or repeated injection of CCl4 was used to induce acute or chronic liver injury, respectively. Mice were orally administered with ZER (10, 50mg/kg) during the experimental period. Histopathologic analysis and serum biochemical levels revealed that ZER had hepatoprotective activities against ALI. Similar effects of ZER on injured livers were confirmed by analyses of inflammation and apoptosis-related genes. Western blot analysis showed that protein levels of apoptotic molecules were decreased, whereas antiapoptotic protein levels were conversely increased in injured livers treated with ZER. Furthermore, chronic liver injury and its associated fibrogenesis in mice were reduced by ZER treatment. These findings from our in vivo experiments further indicate that ZER could alleviate hepatocellular toxicity and inhibit activation of primary hepatic stellate cells. Our results suggest that ZER might have potential as a safe and prophylactic alternative to prevent acute and chronic liver injury.

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BackgroundNitric oxide may have a protective effect on the liver during endotoxemia and chronic inflammation. There is evidence that it maintains liver and intestinal tissue integrity during inflammatory processes. We evaluated the impact of altering nitric oxide release on acute liver injury, the associated gut injury and bacterial translocation, at different time intervals.MethodsAn acute rat liver injury model induced by D-galactosamine was used. Sprague Dawley rats were divided into four main groups: normal control, acute liver injury control, acute liver injury + N-nitro-L-arginine methyl ester (L-NAME), acute liver injury + L-NAME + L-arginine. Each group was divided into three subgroups according to the different time intervals (6, 12, 24 hours) after the induction of the liver injury. Liver enzymes and bilirubin were evaluated, as well as bacterial translocation, cecal and colonic microflora, and histological study of liver, ileum and cecum.ResultsLiver enzymes increased significantly at all time intervals in acute liver injury + L-NAME compared to liver injury control groups. Bacterial translocation increased significantly in liver injury + L-NAME groups; at 6 hours to the liver, at 12 hours to the liver and mesenteric lymph nodes (MLNs), and at 24 hours to arterial and portal blood, liver and MLNS. Inhibition of nitric oxide increased significantly the Enterobacteriaceae count in cecum compared to normal and liver injury control groups. The G-negative anaerobes increased significantly in the colon compared to the liver injury control group.ConclusionInhibition of nitric oxide in an acute liver injury model potentiates the liver injury as evidenced by increased appearance of hepatocellular necrosis and elevated liver enzymes and bilirubin. It increases the Enterobacteriaceae in both cecum and colon and Gnegative anaerobes in the colon. It also increases bacterial translocation to extra-intestinal sites. The increased bacterial translocation could be one of the mechanisms potentiating liver injury and nitric oxide may be pathophysiologically involved. Further studies are required to confirm this hypothesis.

Background: Nitric oxide may have a protective effect on the liver during endotoxemia and chronic inflammation. There is evidence that it maintains liver and intestinal tissue integrity during inflammatory processes. We evaluated the impact of altering nitric oxide release on acute liver injury, the associated gut injury and bacterial translocation, at different time intervals. Methods: An acute rat liver injury model induced by D-galactosamine was used. Sprague Dawley rats were divided into four main groups: normal control, acute liver injury control, acute liver injury + N-nitro-L-arginine methyl ester (L-NAME), acute liver injury + L-NAME + L-arginine. Each group was divided into three subgroups according to the different time intervals (6, 12, 24 hours) after the induction of the liver injury. Liver enzymes and bilirubin were evaluated, as well as bacterial translocation, cecal and colonic microflora, and histological study of liver, ileum and cecum. Results:Liver enzymes increased significantly at all time intervals in acute liver injury + L-NAME compared to liver injury control groups. Bacterial translocation increased significantly in liver injury + L-NAME groups; at 6 hours to the liver, at 12 hours to the liver and mesenteric lymph nodes (MLNs), and at 24 hours to arterial and portal blood, liver and MLNS. Inhibition of nitric oxide increased significantly the Enterobacteriaceae count in cecum compared to normal and liver injury control groups. The G-negative anaerobes increased significantly in the colon compared to the liver injury control group. Conclusion: Inhibition of nitric oxide in an acute liver injury model potentiates the liver injury as evidenced by increased appearance of hepatocellular necrosis and elevated liver enzymes and bilirubin. It increases the Enterobacteriaceae in both cecum and colon and Gnegative anaerobes in the colon. It also increases bacterial translocation to extra-intestinal sites. The increased bacterial translocation could be one of the mechanisms potentiating liver injury and nitric oxide may be pathophysiologically involved. Further studies are required to confirm this hypothesis.

Purpose: To investigate the protective effects of aqueous and methanol extracts of Bidens pilosa using various in vivo and in vitro models of hepatic injury. Methods: One kilogram of the aerial parts of Bidens pilosa was used to prepare 80 % methanol and aqueous extracts of the plant (500 g for each extract). The total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity of both extracts were evaluated. The hepatoprotective activity of these extracts in carbon tetrachloride (CCl 4 , 0.1 %) and D-galactosamine (700 mg/kg)-induced liver injury, respectively, was investigated in mice. Paracetamol-induced liver injury was used as in vitro reference standard. Results: TPC and TFC of methanol extract were higher than those of the aqueous extract. The combination of methanol extract and silymarin showed the highest antioxidant activity. In vivo administration of CCl 4 and D-galactosamine significantly increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), but decreased the total protein, albumin and glutathione (GSH) contents of liver. Co-administration of the extracts (50 mg/kg) and silymarin (100 mg/kg) effectively countered the effects of CCl 4 and Dgalactosamine, while also exerting their antioxidant properties. Both methanol and aqueous extracts showed hepatoprotective activity in paracetamol-induced cytotoxicity in primary cultures of rat hepatocytes. Conclusion: Bidens pilosa possesses significant in vivo and in vitro hepatoprotective activity in mice and may be therapeutically useful as a protective agent in acute liver injury. Keywords: Bidens pilosa , D-galactosamine, Carbon tetrachloride, Paracetamol, Liver injury, Hepatoprotective, Antioxidant, Silymarin, Hepatocytes

Transforming growth factor-beta1 (TGF-β1) is a major factor in pathogenesis of chronic hepatic injury. Carbon tetrachloride (CCl4) is a liver toxicant, and CCl4-induced liver injury in mouse is a classical animal model of chemical liver injury. However, it is still unclear whether TGF-β1 is involved in the process of CCl4-induced acute chemical liver injury. The present study aimed to evaluate the role of TGF-β1 and its signaling molecule Smad3 in the acute liver injury induce by CCl4. The results showed that CCl4 induced acute liver injury in mice effectively confirmed by H&E staining of liver tissues, and levels of not only liver injury markers serum ALT and AST, but also serum TGF-β1 were elevated significantly in CCl4-treated mice, compared with the control mice treated with olive oil. Our data further revealed that TGF-β1 levels in hepatic tissue homogenate increased significantly, and type II receptor of TGF-β (TβRII) and signaling molecules Smad2, 3, mRNA expressions and Smad3 and phospho-Smad3 protein levels also increased obviously in livers of CCl4-treated mice. To clarify the effect of the elevated TGF-β1/Smad3 signaling on CCl4-induced acute liver injury, Smad3 in mouse liver was overexpressed in vivo by tail vein injection of Smad3-expressing plasmids. Upon CCl4 treatment, Smad3-overexpressing mice showed more severe liver injury identified by H&E staining of liver tissues and higher serum ALT and AST levels. Simultaneously, we found that Smad3-overexpressing mice treated with CCl4 showed more macrophages and neutrophils infiltration in liver and inflammatory cytokines IL-1β and IL-6 levels increment in serum when compared with those in control mice treated with CCl4. Moreover, the results showed that the apoptosis of hepatocytes increased significantly, and apoptosis-associated proteins Bax, cytochrome C and the cleaved caspase 3 expressions were up-regulated in CCl4-treated Smad3-overexpressing mice as well. These results suggested that TGF-β1/Smad3 signaling was activated during CCl4-induced acute liver injury in mice, and Smad3 overexpression aggravated acute liver injury by promoting inflammatory cells infiltration, inflammatory cytokines release and hepatocytes apoptosis. In conclusion, the activation of TGF-β signaling contributes to the CCl4-induced acute liver injury. Thus, TGF-β1/Smad3 may serve as a potential target for acute liver injury therapy.

Acute liver injury is a serious state of extensive damage of liver tissue caused by various reasons. In traditional medicine, certain medicinal plants have been used to cure and prevent some liver diseases. The objective of this study was to evaluate the hepatoprotective activity of oil extract of Nigella sativa seeds in rabbit models with induced acute liver injury. Carbon tetrachloride (CCl4) was used to induce hepatotoxicity at a dose of 1.25 ml/kg as a mixture with olive oil. N. sativa oil extract was administered at a dose of 0.2 ml/kg/day orally for 7 days. The hepatoprotective effect was assessed by liver function tests and histopathological sections of the liver. Significant reduction in the liver damage was found in animals treated with the extract, as indicated by low levels of serum enzymes, serum bilirubin and improvement of serum protein. Besides, restoration of hepatocellular architecture was evident, as indicated by the presence of normal hepatic vessels, absence of necrosis, and fatty infiltration. The oil extract of N. sativa seeds showed significant hepatoprotective activity. Key words: Black cumin, hepatocellular architecture, nigellone, thymoquinone

Intrahepatic gene silencing by RNA interference

Acute organ injuries, such as acute kidney injury (AKI) and acute liver injury (ALI), usually present high morbidity and mortality in patients. However, the current clinical treatments remain limited, especially the lack of effective drug-based treatment. Since these acute injuries are often associated with reactive oxygen species (ROS) overproduction, it is a promising strategy to develop therapeutic agents with potent ROS scavenging ability and excellent biocompatibility for efficient antioxidation therapy. Black phosphorus quantum dots (BPQDs), low-dimensional nanomaterials prepared through a straightforward one-step method and capable of complete controllable biodegradation, offer significant potential. This study comprehensively explores the extensive free-radical scavenging capabilities of BPQDs, underscoring their immense potential in treating ROS-related organ injuries. BPQDs could simultaneously achieve radical scavenging of DPPH, ABTS·, OH·, and O2 -· and exhibit excellent cytoprotective effects against ROS-mediated damage even at extremely low dosages. Besides, the ultrasmall size of BPQDs (≈3-5nm) allows them to effectively penetrate the glomerular filtration barrier (≈6nm), significantly improving the symptoms of AKI and ALI in vivo. The therapeutic efficacy and great biocompatibility of BPQDs facilitate the clinical management of ROS-related diseases, which will broaden the applications of QDs in the field of biomedicine.

Studies on hepatoprotective and antioxidant actions of Strychnos potatorum Linn. seeds on CCl 4-induced acute hepatic injury in experimental rats

Incidence of idiopathic acute liver failure and hospitalized liver injury in patients treated with troglitazone

Troglitazone, a thiazolidinedione antidiabetic agent, was withdrawn from the U.S. market in March, 2000, after 94 cases of acute liver failure (ALF) were reported with its use. Based on a literature review, the estimated background rate of hospitalization for idiopathic acute liver injury is 22 per million person-years and for idiopathic ALF, less than 1 per million person-years. This study was conducted to estimate the incidence rates of hospitalized idiopathic acute liver injury and ALF among troglitazone-treated patients. An observational retrospective inception cohort of patients treated with troglitazone was assembled using claims data from a large multistate health care organization. Patients with at least 90 days of health plan enrollment before their first troglitazone prescription between April, 1997 and December, 1998 were enrolled. Hospitalized cases of potential troglitazone-induced acute liver injury or ALF were identified from claims data based on International Classification of Diseases, 9th Revision, coding. Primary medical records were reviewed for case validation, and incidence rates of acute liver injury were calculated using person-years of troglitazone exposure as the denominator. A total of 7568 patients contributed 4020 person-years of troglitazone exposure. Of these, five were hospitalized with acute liver injury attributed to the drug and not explained by other causes. Incidence rates (95% CI) per million person-years of acute idiopathic liver injury were as follows: hospitalization (n = 5), 1244 (404, 2900); hospitalized jaundice (n = 4), 995 (271, 2546); and ALF (n = 1), 240 (6.3, 1385). Troglitazone use was associated with a marked increase in risk of hospitalized acute idiopathic liver injury and ALF.

Induction of Hepatic Tissue-Type Plasminogen Activator and Type 1 Plasminogen Activator–Inhibitor Gene Expressions and Appearance of Their Translation Products in the Bile Following Acute Liver Injury in Rats

Objectives:The present study was aimed at assessing the hepatoprotective activity of 1:1:1 petroleum ether, diethyl ether, and methanol (PDM) extract of Scoparia dulcis L. against carbon tetrachloride-induced acute liver injury in mice.Materials and Methods:The PDM extract (50, 200, and 800 mg/kg, p.o.) and standard, silymarin (100 mg/kg, p.o) were tested for their antihepatotoxic activity against CCl4-induced acute liver injury in mice. The hepatoprotective activity was evaluated by measuring aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total proteins in serum, glycogen, lipid peroxides, superoxide dismutase, and glutathione reductase levels in liver homogenate and by histopathological analysis of the liver tissue. In addition, the extract was also evaluated for its in vitro antioxidant activity using 1, 1-Diphenyl-2-picrylhydrazyl scavenging assay.Results:The extract at the dose of 800 mg/kg, p.o., significantly prevented CCl4-induced changes in the serum and liver biochemistry (P < 0.05) and changes in liver histopathology. The above results are comparable to standard, silymarin (100 mg/kg, p.o.). In the in vitro 1, 1-diphenyl-2-picrylhydrazyl scavenging assay, the extract showed good free radical scavenging potential (IC 50 38.9 ± 1.0 μg/ml).Conclusions:The results of the study indicate that the PDM extract of Scoparia dulcis L. possesses potential hepatoprotective activity, which may be attributed to its free radical scavenging potential, due to the terpenoid constituents.

The precise mechanisms leading to the coagulopathy of acute liver injury are unclear. To study this further, coagulation and immune changes have been compared in patients with acute liver injury secondary to paracetamol overdose, with chronic cirrhosis, and normal healthy controls. In acute liver injury, coagulation factors II, V, VII and X were reduced to a similar degree, and were significantly lower than factors IX and XI. In cirrhosis, by contrast, these coagulation factors were reduced to similar levels. Factor VIII increased in acute liver injury, but was normal in cirrhosis. Interleukin-6 and tumour necrosis factor-alpha levels increased in both patient groups, but were higher in paracetamol overdose. Thrombin-antithrombin and soluble tissue factor levels increased in those with acute liver injury, but were normal in patients with cirrhosis. Functional antithrombin was reduced in both acute liver injury and cirrhosis. It is hypothesized that in acute paracetamol-induced liver injury, immune activation leads to tissue factor-initiated consumption of factors II, V, VII and X, but that levels of factors IX and XI are better preserved because of inhibition of the thrombin-induced amplification phase of coagulation. These findings have implications for appropriate coagulation factor support for patients with acute liver injury.