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Abstract: Ethnopharmacologic relevance: The Chunggan extract (CGX) is a traditional herbal formula prescribed for patients suffering from various liver diseases, including alcoholic liver disease, in which the mechanism of CGX action remains unclear. This study aimed to investigate the anti-hepatic fibrosis effects of CGX and its underlying mechanisms in alcohol-induced rat livers. Materials and methods: To elucidate the mechanism of action of CGX, we evaluated gene expression profiles in the livers of rats treated with 30% alcohol and anti-fibrotic doses of CGX of 100 and 200mg/kg/day at 1 day, and 2 and 4 weeks using microarrays. The mRNA and protein expression levels of vascular endothelial growth factor (VEGF), one of the candidate genes selected in this study, in alcohol-induced rat livers were measured by real-time PCR and enzyme-linked immunosorbent assays, respectively. Results: We identified 4128 genes as differentially expressed by at least twofold between alcohol-only– and alcohol–CGX–fed rats at various doses and time points, compared to naïve control animals. Twenty-three of these genes were associated with liver fibrosis and oxidative stress based on the GeneCards database, resulting in p<0.05 by ANOVA between the alcohol-only and alcohol–CGX groups. Especially, Vegf was decreased in CGX 200mg/kg/day-fed rat livers at all time points evaluated, and mRNA and protein levels at the 4-week time point were validated. Conclusion: These gene expression profiles provide a better understanding of the mechanisms underlying the anti-fibrotic effects of CGX. Suppression of VEGF may play a critical role in anti-fibrotic action of CGX in alcoholic liver injury. [Copyright &y& Elsevier]

In the present study, we aimed to evaluate the hepatoprotective and antioxidant effects of Chunggan extract (CGX) in an animal model of hepatosteatosis. The C57BL/6N mice were fed either methionine- and choline-sufficient (MCS) diet (n = 10) or a methionine- and choline-deficient (MCD) diet (n = 50) for 4 weeks, and then they were treated orally with CGX (100 or 200 mg/kg), ursodeoxycholic acid (80 mg/kg, as a positive control), or distilled water (DW, MCS diet group, and MCD diet group) for the final 2 weeks (once per day). The MCD diet induced severe hepatic injury with the typical features of hepatosteatosis in both serum and hepatic tissues. CGX treatment significantly attenuated these alterations in the serum levels including triglyceride (TG), aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin. Moreover, CGX also efficiently prevented from the hepatic TG accumulation in the hepatic tissue, evidenced by histopathological findings, compared with the MCD diet. In addition, CGX treatment significantly ameliorated the excessive oxidative stress and antioxidant markers in the serum as well as the hepatic levels of reactive oxygen species, the levels of malondialdehyde, the protein carbonyl, and total antioxidant capacity, and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. In conclusion, our results indicate the experimental relevance of CGX for potential clinical application in patients with hepatosteatotic disorders and a possible mechanism related to its antioxidant properties. [ABSTRACT FROM AUTHOR]

Abstract: CGX, a traditional herbal drug, has been prescribed for patients suffering from various liver diseases, including hepatitis B, alcoholic liver disease, and fatty liver. We investigated whether CGX has hepatoprotective effects against lipopolysaccharide/d-galactosamine (LPS/d-GalN)-induced acute liver injury and its underlying mechanism(s). Mice were administered CGX orally for 7days prior to an injection of LPS (5μg/kg)/d-GalN (700mg/kg). Complete blood count, serum diagnostic markers, antioxidant activities, caspase activity, and histopathological examinations were conducted 8h after the injection. To evaluate the immunological mechanism of CGX, serum TNF-α and IL-10 were investigated 1.5h after LPS/d-GalN injection. CGX pretreatment (100, 200, and 400mg/kg) inhibited the elevation of serum AST and ALT levels as well as histopathological alterations. Moreover, CGX pretreatment inhibited activation of caspase-3/7. CGX attenuated LPS/d-GalN-induced lipid peroxidation with concomitant improvement in total antioxidant activities (superoxide dismutase, catalase, and glutathione peroxidase). CGX elevated the antioxidant capacity of the liver in both the pathological and normal conditions. Furthermore, LPS/d-GalN-induced alterations of neutrophil and lymphocyte populations were ameliorated and serum TNF-α was decreased significantly by CGX. From these data we conclude that CGX protects the liver from LPS/d-GalN-induced hepatitis through antioxidant mechanisms as well as immune modulation. [Copyright &y& Elsevier]

Abstract: Concanavalin A (Con A)-induced acute liver injury model is well established as a model of T cell-mediated liver injury, in which T cells and NKT cells exert their cytotoxicity towards liver cells. In this study, we investigated the protective effects of CGX, a traditional Korean medicine against Con A-induced liver injury and its underlying mechanisms. After pretreatment with CGX (po, 50, 100 or 200mg/kg) or distilled water once daily during 7days, Con A (15mg/kg) was injected intravenously. Thereafter serum level of AST and ALT, lipid peroxidation and cytokines in the liver tissue, and immune cell population in blood and the spleen were analyzed. CGX treatment reduced serum ALT, AST level in a dose-dependent manner. CGX treatment significantly decreased the lipid peroxidation and glutathione depletion in the liver tissue, and also lowered tissue levels of tumor necrotic factor-α and interferon-γ. CGX treatment attenuated the compositional alteration of Tc, Th, NKT, and B cells in blood as well as in the spleen. These results suggest that CGX has hepatoprotective property against Con A-induced liver injury through antioxidant action and immune regulation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance: CGX is a traditional Korean herbal medicine used to treat chronic liver diseases. Aim of study: The purpose of this study was to evaluate the pharmaceutical safety of hepatoprotective herbal medicine, CGX via systemic 6-month repeated dose toxicity study in SD rats. Materials and methods: Male and female SD rats were administered CGX for 6 months (0, 100, 200, or 400mgkg−1, respectively). The rats were visually inspected for changes in behavior, body weight, food and water consumption, and appearance during the experiment period. At the end of the experiment, urine, hematological, biochemical analysis, and histopathological examination were carried out. Results: No drug-induced abnormalities were found as clinical signs or in the histopathology, hematology, blood biochemistry, and urinalysis results for any administered doses of CGX. Conclusion: The results suggest that CGX is safe and could be considered as an effective and prospective herbal formulation in clinical applications with a wide therapeutic index. [Copyright &y& Elsevier]

Abstract: CGX is a potential hepatoprotective herbal medicine used to treat various chronic liver disorders. The purpose of the study was to evaluate the pharmaceutical safety of CGX via a systemic 13-week repeated dose toxicity test in beagle dogs. Male and female beagle dogs were divided into four groups and two animals each from the control and high-dose group (400mg/kg) were allocated into recovery groups. The dogs were administered with CGX (0, 100, 200, 400mg/kg) for 13weeks. During the experimental period, the dogs were observed for signs of gross toxicity and for behavioral changes; body weight and food consumption were measured. An ophthalmologic examination and urinalysis were performed at 0 and 13th week and blood biochemistry and hematological parameters analyses were performed at 0, 6th, and 13th week. A histopathological examination was also performed at the end of the experiment. There were no CGX-induced abnormalities in clinical signs, organ weights, food consumption, hematological, urine, and blood biochemical parameters, or histopathological findings in any of the groups during or after the 13weeks. We demonstrated the safety of CGX for 13-week repeated dose and considered that it is safe for chronic clinical use. [Copyright &y& Elsevier]

Abstract: Aim: CGX, a modified traditional Chinese herbal drug whose name means “liver cleaning,” is used to treat various liver disorders. This study investigated the protective effects of CGX and its mechanisms. Material and methods: After pretreating ICR mice twice daily with CGX (po, 50 or 100mg/kg) or distilled water for three consecutive days, acute liver injury was induced by a single injection of CCl4 (ip, 10mL/kg of 0.2% in olive oil) (n =8 per group). Results: Pretreatment with CGX significantly attenuated the elevation in biochemical parameters, such as alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) in serum, and the malondialdehyde concentrations in liver tissue. Pretreatment with CGX significantly restored the reduction of catalase activity and glutathione (GSH) content, but not superoxide dismutase (SOD) activity, and it inhibited the CCl4-induced high expression of iNOS and TNF-α in hepatic tissue. Conclusion: This study showed that CGX has hepatoprotective effects against free radical-induced acute injury via primarily antioxidative properties. [Copyright &y& Elsevier]

Abstract: The primary structure of cangitoxin (CGX), a 4958Da peptide from the sea anemone Bunodosoma cangicum, was determined: GVACRCDSDGPTVRGNSLSGTLWLTGGCPSGWHNCRGSGPFIGYCCKK. CGX contains all the 11 residues that are conserved and the 5 that are conservatively substituted within or between the type 1 and type 2 sequences of sea anemone peptides with specific action on voltage-sensitive sodium channels. Furthermore, it also has 6 identities (Asp9, Arg14, Asn16, Leu18, Trp33 and Lys48) and 1 homology (Arg36) in the 8 residues of the pharmacophore of the sea anemone ApB which are essential for interaction with mammalian sodium channels. The intrahippocampal injection of CGX induces several sequential behavioral alterations—episodes of akinesia alternating with facial automatisms and head tremor, salivation, rearing, jumping, barrel-rolling, wet dog shakes and forelimb clonic movements–and the electroencephalography analysis shows that they were followed by important seizure periods that gradually evolved to status epilepticus that lasted 8–12h, similar to that observed in the acute phase of the pilocarpine model of epilepsy. These results suggest that CGX may be an important tool to develop a new experimental model of status epilepticus which may contribute to understanding the etiology of epilepsy and to test the effects of new antiepileptic drugs. [Copyright &y& Elsevier]

After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson's trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU + cardiomyocytes. Meanwhile, CGX1321 increased Ki67 + and phosphohistone H3 (PH3 + ) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1 CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP-independent pathway., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)