Guizhi Fuling Wan ameliorates concanavalin A-induced autoimmune hepatitis in mice.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated hepatic disease associated with intense complications. AIH is more common in females and needs effective drugs to treat. Guizhi Fuling Wan (GZFLW) is a traditional Chinese herbal formula used to treat various gynecologic diseases. In this study, we aim to extend the new use of GZFLW for AIH. METHODS: The tandem MS-based analysis was used to identify secondary metabolites in GZFLW. Therapeutic effects of GZFLW were tested in a concanavalin A (Con A)-induced AIH model in mice. Ethnopharmacological mechanisms underlying the antiapoptotic, antioxidant, and immunomodulatory protective effects were determined. RESULTS: Oral administration of GZFLW attenuates AIH in a Con A-induced hepatotoxic model in vivo. The tandem MS-based analysis identified 15 secondary metabolites in GZFLW. The Con A-induced AIH syndromes, including hepatic apoptosis, inflammation, reactive oxygen species accumulation, function failure, and mortality, were significantly alleviated by GZFLW in mice. Mechanistically, GZFLW restrained the caspase-dependent apoptosis, restored the antioxidant system, and decreased pro-inflammatory cytokine production in the livers of Con A-treated mice. Besides, GZFLW repressed the Con A-induced hepatic infiltration of inflammatory cells, splenic T cell activation, and splenomegaly in mice. CONCLUSIONS: Our findings demonstrate the applicable potential of GZFLW in treating AIH. It prompts further investigation of GZFLW as a treatment option for AIH and possibly other hepatic diseases.

Glycyrrhetinic acid inhibits ICAM-1 expression via blocking JNK and NF-kappaB pathways in TNF-alpha-activated endothelial cells.

AIM: To investigate the effects of glycyrrhetinic acid (GA), an active component extracted from the root of Glycyrrhizae glabra, on the expression of intercellular adhesion molecule-1 (ICAM-1) in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVEC). METHODS: ICAM-1 mRNA and protein levels were detected using RT-PCR and cell enzyme-linked immunosorbent assays. The adherence of human monocytic THP-1 cells labeled with [(3)H]thymidine to HUVEC was determined by counting radioactivity with a scintillation counter. The activation of mitogen-activated protein kinases as well as the degradation of I kappaB and nuclear factor-kappaB (NF-kappaB) or phospho-c-Jun in the nucleus were detected by western blots. NF-kappaB binding activity was detected using electrophoretic mobility shift assay. RESULTS: GA (50 and 100 micromol/L) significantly inhibits TNF-alpha-induced ICAM-1 mRNA and protein expressions, as well as THP-1 cell adhesiveness in HUVEC. GA selectively inhibited TNF-alpha-activated signal pathway of c-Jun N-terminal kinase (JNK), without affecting extracellular signal-regulated kinase 1/2 and p38. Furthermore, GA apparently inhibited I kappaB/NF-kappaB signaling system by preventing I kappaB degradation, NF-kappaB translocation, and NF-kappaB/DNA binding activity. Finally, pretreatment with GA or the inhibitors of NF-kappaB, JNK, and p38 reduced the ICAM-1 protein expression induced by TNF-alpha. CONCLUSION: GA inhibits TNF-alpha-stimulated ICAM-1 expression, leading to a decrease in adherent monocytes to HUVEC. This inhibition is attributed to GA interruption of both JNK/c-Jun and I kappaB/NF-kappaB signaling pathways, which decrease activator protein-1 (AP-1) and NF-kappaB mediated ICAM-1 expressions. The results suggest that GA may provide a beneficial effect in treating vascular diseases associated with inflammation, such as atherosclerosis.

Functional Redox Proteomics Reveal That Salvia miltiorrhiza Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis.

The anticancer agent adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity, while Salvia miltiorrhiza (SM) is a Chinese herb widely used for the treatment of cardiovascular disorders and its aqueous extract (SMAE) has shown anticancer as well as antioxidant effects. In the current study, we aimed at investigating the synergistic effect and potent molecular mechanisms of SMAE with a focus on the cardioprotective benefit observed under ADR adoption. Histopathological analysis indicated that SMAE could substantially alleviate cardiomyopathy and cell apoptosis caused by ADR. Meanwhile, the two-dimensional electrophoresis (2-DE) oxyblots demonstrated that SMAE treatment could effectively reduce carbonylation of specific proteins associated with oxidative stress response and various metabolic pathways in the presence of ADR. SMAE application also showed protective efficacy against ADR-mediated H9c2 cell death in a dose-dependent manner without causing any cytotoxicity and significantly attenuated the reactive oxygen species production. Particularly, the simultaneous administration of ADR and SMAE could remarkably suppress the growth of breast cancer cells. We also noticed that there was a marked upregulation of detoxifying enzyme system in the presence of SMAE, and its exposure also contributed to an increase in Nrf2 and HO-1 content as well. SMAE also amended the ERK/p53/Bcl-xL/caspase-3 signaling pathways and the mitochondrial dysfunction, which eventually attribute to apoptotic cathepsin B/AIF cascades. Correspondingly, both the ERK1/2 inhibitor (U0126) and pan-caspase inhibitor (Z-VAD-FMK) could at least partially abolish the ADR-associated cytotoxicity in H9c2 cells. Collectively, these results support that ROS apoptosis-inducing molecule release is closely involved in ADR-induced cardiotoxicity while SMAE could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy.

Sheng-mai-san reduces adriamycin-induced cardiomyopathy in rats.

The traditional Chinese medicine prescription "sheng-mai-san (SMS)" has been used for treating patients with coronary heart disease for a long time and was found to have antioxidative effects. Here, we applied adriamycin (doxorubicin, ADR), a highly effective anticancer agent, as an inducer to establish the animal model of dose-related cardiomyopathy due to inhibition of nucleic acid as well as protein synthesis, formation of free radicals, and lipid peroxidation. The objective of this study was to investigate the protective effects of SMS on adriamycin-induced cardiomyopathy. Wistar rats were divided into four groups: CONT (control), ADR, SMS, and ADR + SMS. ADR (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks and SMS was administered via a feeding tube throughout the mouth once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5-week post-treatment period, the hearts of the rats were surgically removed for the study of synthesis rates of DNA, RNA and proteins. Besides myocardial antioxidants, lipid peroxidation and morphological ultrastructure were also evaluated. Three weeks after the treatment, cardiomyopathy and congestive heart failure were characterized according to assessment in ascites, congested liver, depressed cardiac function and myocardial cell damage. The results demonstrated that nucleic acid as well as protein synthesis was inhibited, while lipid peroxidation was increased. Myocardial glutathione peroxidase (GSHPx) activity was decreased and electron microscopic examination revealed myocardial lesion indicative of ADR-induced cardiomyopathy. In contrast, administration of SMS before and concurrent with ADR significantly attenuated the myocardial effects. It also lowered mortality as well as the amount of ascites. In addition, indexes in myocardial GSHPx, macromolecular biosynthesis and superoxide dismutase activities were increasing, with a concomitant decrease in lipid peroxidation and preserved myocardial ultrastructure. These results indicated that SMS may be partially protective against ADR-induced cardiomyopathy.

Herbal formula, Scutellariae radix and Rhei rhizoma attenuate dimethylnitrosamine-induced liver fibrosis in a rat model.

The bioactive components extracted from Scutellariae radix and Rhei rhizoma (SR) have been commonly used to treat liver diseases. The aim of this study was to verify the underlying mechanisms and antifibrotic effects of ethanol extract from the herbal combinatorial formula (SRE) in a dimethylnitrosamine (DMN)-administered rat model, with functional proteome tools. Our results indicated that the hepatic collagen content and alpha-smooth muscle actin expression were obviously alleviated by treatment with SRE. Comprehensive proteomics revealed global protein changes, and the network analysis implied that SRE application would attenuate oxidative stress and cytoskeleton dysregulation caused by DMN exposure. Next, marked downregulation of antioxidant enzymes mediated by DMN treatment was restored in the presence of SRE, while SRE treatment contributed to decreased MDA content. Moreover, protein carbonylation and DNA adduction induced by oxidative stress finally leading to liver injury were also reduced under SRE administration. These findings demonstrate that SRE could effectively prevent hepatic fibrosis mainly through regulating the redox status, and subsequently modulating the modification of intracellular molecules. Our experiments might help in developing novel therapeutic strategies against oxidation-caused liver diseases.

Antrodia cinnamomea alleviates cisplatin-induced hepatotoxicity and enhances chemo-sensitivity of line-1 lung carcinoma xenografted in BALB/cByJ mice.

Whereas cisplatin (cis-diamminedichloroplatinum II) is a first-line medicine to treat solid cancerous tumors, it often causes serious side effects. New medicines that have an equivalent or even better therapeutic effect but with free or less side effects than cisplatin are highly anticipated in cancer therapy. Recent reports revealed that Antrodia cinnamomea (AC) possesses hepatoprotective activity in addition to anticancer. In this study, we wanted to know whether AC enhances chemo-sensitivity of cisplatin and/or alleviates cisplatin-induced hepatotoxicity, as well as the underlying mechanisms thereof. Our results indicated that AC inhibited proliferation of line-1 lung carcinoma cells and rescued hepatic HepG2 cells from cisplatin-induced cell death in vitro. The fact is that AC and cisplatin synergized to constrain growth of line-1 lung carcinoma cells in BALB/cByJ mice. Quantitative real-time PCR further revealed that AC promoted expression of apoptosis-related genes, while it decreased expression of NF-κB and VEGF in tumor tissues. In liver, AC reduced cisplatin-induced liver dysfunctions, liver inflammation and hepatic apoptosis in addition to body weight restoration. In summary, AC is able to increase cisplatin efficacy by triggering expression of apoptosis-related genes in line-1 lung cancer cells as well as to protect liver from tissue damage by avoiding cisplatin-induced hepatic inflammation and cell death.

Protective effects of Danshen (Salvia miltiorrhiza) on adriamycin-induced cardiac and hepatic toxicity in rats.

The present study was carried out to investigate the protective effects of Danshen (DS, Salvia miltiorrhiza) on adriamycin (ADR)-induced cardiac and hepatic toxicity. Wistar rats were divided into six groups: control group, 10 animals received saline (i.p.); 15 animals received ADR (3 mg/kg, i.p.) three times weekly, for 2 weeks; 10 animals each received DS(1) (20 mg/kg, oral) and DS(2) (100 mg/kg, oral) for 30 days; 15 animals each received DS(1) + ADR and DS(2) + ADR. The ADR-induced cardiac and hepatic toxicity and protective action of DS were determined and quantitated with the use of hemodynamic measurements, biochemical analyses of serum, synthesis rates of DNA, RNA and protein, myocardial antioxidants, lipid peroxidation and histopathological procedure. Liver function was damaged. Nucleic acid as well as protein synthesis was inhibited, while lipid peroxidation was increased. Myocardial glutathione peroxidase (GSHPx) activity and superoxide dismutase activities (SOD) were decreased and histopathology revealed myocardial lesions indicative of ADR-induced cardiac and hepatic toxicity. In contrast, administration of DS before and concurrent with ADR significantly attenuated these effects. In conclusion, DS is potentially protective against ADR-induced cardiac and hepatic toxicity.

Schisandra chinensis protects against adriamycin-induced cardiotoxicity in rats.

BACKGROUND: Adriamycin (ADR) is an effective chemotherapeutic agent against cancers but its clinical use is limited due to its cardiotoxicity. It has been suggested that the pathogenesis involves inhibition of nucleic acid and protein synthesis, free radical formation and lipid peroxidation. Schisandra (SC) has strong antioxidant activity. We investigate the protective effects of SC on adriamycin-induced cardiotoxicity. METHODS: Wistar rats were divided into four groups: CONT (control), ADR, SC and SC + ADR. After treatment, the hearts of the rats were surgically removed and studied for synthesis rates of nucleic acid and protein, myocardial antioxidants and lipid peroxidation. RESULTS: Cardiotoxicity was characterized by ascites, congested liver and depressed cardiac function. Nucleic acid and protein synthesis were inhibited, malondialdehyde (MDA) was increased, while myocardial glutathione peroxidase (GSHPx) activity and superoxide dismutase (SOD) were decreased by ADR. In contrast, administration of SC before and concurrent with ADR significantly reduced mortality and the amount of ascites. Indexes in myocardial GSHPx, macromolecular biosynthesis and SOD activities increased with a concomitant decrease in lipid peroxidation. CONCLUSION: These results suggest that ADR cardiotoxicity is associated with antioxidant deficit and SC treatment changes the antioxidant status of the heart and improves cardiac function.

Panax ginseng reduces adriamycin-induced heart failure in rats.

The purpose of this study was to investigate the protective effects of Panax ginseng on adriamycin-induced heart failure. Wistar rats were divided into four groups: control, adriamycin, ginseng and adriamycin with ginseng. Adriamycin (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks. Ginseng was administered via an oral feeding tube once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5 week post-treatment period, the hearts of the rats were used to study the synthesis rates of DNA, RNA and protein, myocardial antioxidants and lipid peroxidation. At the end of 3 weeks treatment, heart failure was characterized by ascites, congested liver and depressed cardiac function. Nucleic acid as well as protein synthesis was inhibited, lipid peroxidation was increased and myocardial glutathione peroxidase activity was decreased indicating adriamycin-induced heart failure. In contrast, the administration of ginseng, before and concurrent with adriamycin, significantly attenuated the myocardial effects, lowered the mortality as well as the amount of ascites, increased in myocardial glutathione peroxidase, macromolecular biosynthesis and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation. These findings indicated that ginseng may be partially protective against adriamycin-induced heart failure.

Effects of Xuefu Zhuyu Tang and mitomycin C on liver tumors in mice.

BACKGROUND: Carcinogenesis, in traditional Chinese medicine, is defined as resulting from the accumulation of stagnant and toxic substances within the human body. Xuefu zhuyu tang (XZT) represents a group of herbs for 'destagnation'; and mitomycin C (MMC) is currently and widely used for cancer therapy. We investigated the combined effects of XZT and MMC on mice bearing liver tumors. METHODS: Mice bearing experimental liver tumors were divided into 4 groups, including tumor control, XZT-, MMC-, and combined-treatment groups. Several effects were observed in this study including survival rate, increase of life span, and mean survival time within 60 days after treatment. Survival rates and biosynthesis activities of tumor and liver cells were also evaluated. RESULTS: Oral administration of XZT, an intraperitoneal injection of MMC, and a combination of the two increased the mean survival time of tumor-bearing mice by 12.5, 14.1, and 17.2 days, respectively. These 3 treatments were cytotoxic to sarcoma-180-induced liver tumor cells. The synthesis rates of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein by tumor cells were all measurably inhibited by the combined treatment. CONCLUSION: XZT combined with MMC may be an effective modality in cancer therapy. The detailed mechanisms of these combinations in human liver neoplasms use to be further studied.