Roles of reactive oxygen species and MAP kinases in the primary rat hepatocytes death induced by toosendanin

Tseng

Evidence-Based Complementary and Alternative Medicine

et al. 2010

The Chinese herb modified Yi Guan Jian (mYGJ) is an effective regimen that is usually used in outpatients with chronic liver diseases such as fibrosis and cirrhosis. However, the mechanism for the action of mYGJ on liver fibrosis is not yet clear. In this study, we found that mYGJ induced hepatic stellate cells (HSCs) apoptosis concomitant with the downregulation of Bcl-2 expression and slight elevation of Bax level. Moreover, the reactive oxygen species (ROS) were generated in the early stages of mYGJ-induced HSCs apoptosis to facilitate calcium and cytochrome c release from the mitochondria to cytosol. Subsequently, caspase 9 and caspase 3 were activated. Furthermore, the activation of ER stress-associated caspase 12 in HSCs was also evaluated. Together, we report the first evidence-based study to demonstrate that mYGJ decoction induces HSCs apoptosis through ROS accumulation and the intrinsic apoptosis pathway. These findings provide rationale for further clinical investigation of traditional Chinese medicine recipes against liver fibrosis.

Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

A Chinese Herbal Decoction, Modified Yi Guan Jian, Induces Apoptosis in Hepatic Stellate Cells through an ROS‐Mediated Mitochondrial/Caspase Pathway

Tseng

Evidence-Based Complementary and Alternative Medicine

et al. 2010

Antimicrob Agents Chemother

“…The assay was repeated three times, and a representative result is shown. (36,47). In our study, the selectivity index of TSN against HCV was sufficient to ascertain that the antiviral effects are not simply due to the cytotoxicity of TSN.…”

Section: Discussionmentioning

confidence: 81%

Inhibitory Effect of a Triterpenoid Compound, with or without Alpha Interferon, on Hepatitis C Virus Infection

Watanabe

Sakamoto

Nakagawa

et al. 2011

A lack of patient response to alpha interferon (␣-IFN) plus ribavirin (RBV) treatment is a major problem in eliminating hepatitis C virus (HCV). We screened chemical libraries for compounds that enhanced cellular responses to ␣-IFN and identified a triterpenoid, toosendanin (TSN).Hepatitis C virus (HCV) is one of the most important pathogens causing acute and chronic hepatitis, liver cirrhosis, and hepatocellular malignancies (29). Alpha interferon (␣-IFN) combined with ribavirin (RBV) is the standard treatment for HCV infection (6, 10). However, virus elimination rates are about 50% among treated patients, and therapy is often accompanied by substantial side effects (6, 44). It was recently reported that genetic polymorphisms of the IL28B gene, which codes for lambda IFN, are critical for predicting responses to ␣-IFN plus RBV therapy (8,35,38). Patients with minor variants of IL28B, who comprise ϳ50% of Caucasian, 25% of Asian, and ϳ70% of African populations, showed poor responses to ␣-IFN treatment. Although new specific anti-HCV drugs are under development, many of them require combined use with ␣- IFN and RBV (26). Taken together, current difficulties in eliminating HCV are mostly attributable to the limited treatment options and to the limited activity of ␣-IFN against the virus. For this reason, the development of safe and effective agents that enhance antiviral actions against HCV has been a strong motivation in academia and industry.To search for a new agent which enhances the effect of ␣-IFN, we used interferon-stimulated response element (ISRE) reporter screening. We screened a chemical library (60,500 compounds) for compounds that enhance ISRE activity when they are used in combination with ␣-IFN, using ISRE reporter screening, and identified several compounds that increased the ISRE reporter activities when they are used in combination with ␣-IFN and that did not show cytotoxicity. Among the hit compounds, toosendanin (TSN; C 30 H 38 O 11 ; molecular weight ϭ 574) (Fig. 1), which is a triterpenoid derivative extracted from the bark of Melia toosendan Sieb et Zucc, was the strongest in enhancing ␣-IFN-induced ISRE reporter activation and the expression of interferon-stimulated genes (ISGs). TSN has been used as an anthelmintic vermifuge against ascaris (31). Although TSN has some other biological effects against toxin-producing anaerobic bacteria and against carcinoma cells (32,45), antiviral activity has not been reported.In this study, we showed, using an HCV replicon system, that TSN, with or without ␣-IFN, inhibits HCV replication in a cultured human hepatoma Huh7 cell line and that the combination of TSN and ␣-IFN shows synergistic effects on viral replication. We have investigated the mechanisms of action of

“…Inhibition of ERK1/2 activation sensitizes hepatocytes for death and increases the activity of caspase-9 and -3 in response to toosendanin. In contrast, inhibition of JNK attenuates toosendanininduced cell death (960). Acetaminophen-induced liver injury involves JNK activation, due to increased ROS generated by GSH-depleted mitochondria, and translocation of activated JNK to mitochondria where JNK induces mitochondrial permeability transition (MPT) and inhibits mitochondria bioenergetics (270).…”

Section: Leukocyte Transendothelial Migration and Parenchymal Cellmentioning

confidence: 99%

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

Vollmar

Menger²

2009

Physiological Reviews

425

368

The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.