Green Tea Polyphenols Protect against Acetaminophen-Induced Liver Injury by Regulating the Drug Metabolizing Enzymes and Transporters.

Green tea polyphenols (GTPs) have been shown to exhibit diverse beneficial effects against a variety of diseases. Acetaminophen (APAP) overdose is one of the most frequent causes of drug-induced liver injury. In the current study, we aimed to investigate the protective effect of GTP on APAP-induced liver injury in mice and the underlying mechanisms involved. Male C57BL/6J mice were treated orally with different doses of GTP (37.5, 75, or 150 mg/kg) 4 h after APAP overdose (400 mg/kg) and continuously given every 8 h until sacrificed at 4, 12, 20, and 48 h after the first treatment of GTP. Survival rate and histological and biochemical assessments were performed to evaluate the APAP-induced liver injury. Protein expression of multiple drug metabolizing enzymes and transporters was measured to demonstrate the possible mechanisms involved. Our results revealed that administration of different doses of GTP significantly alleviated APAP-induced liver injury by improving the survival rate, hepatocellular necrosis, and ALT/AST/GSH levels after APAP overdose (400 mg/kg). The protein expression of APAP-induced drug transporters and metabolizing enzymes was mostly induced by GTP treatment, which was followed by reduction in drug transporters at the later time points. The current study collectively demonstrated that GTP protects against APAP-induced liver injury, possibly through regulating drug metabolizing enzymes and transporters after APAP overdose.

Protective Effects of Total Alkaloids from Menispermum dauricum against Airway Inflammation in Asthmatic Mice.

Menispermum dauricum is widely used to treat respiratory inflammation, including laryngopharyngitis, tonsillitis, tracheitis, and bronchitis. Total alkaloids isolated from M. dauricum have shown a variety of beneficial bioactivities. However, available data on the effects of M. dauricum total alkaloids against allergic asthma has not been reported. In present study, the protective effect of M. dauricum total alkaloids was evaluated by using an ovalbumin-induced in vivo model of asthma. The asthma model was prepared by sensitizing and challenging mice with ovalbumin, and M. dauricum total alkaloids (100, 200, and 400 mg/kg) were administrated to asthmatic mice by gavage. Histopathological analysis of pulmonary changes was detected by hematoxylin and eosin, and periodic acid-schiff staining. Inflammatory cell counts were determined in bronchoalveolar lavage fluid. Total immunoglobulin E and ovalbumin-specific immunoglobulin E levels in serum, and T-helper 2 cytokines and chemokine levels in bronchoalveolar lavage fluid were detected by an ELISA. Histological results demonstrated that M. dauricum total alkaloids significantly attenuated pulmonary inflammation in asthmatic mice. M. dauricum total alkaloid treatment exhibited marked effects on asthmatic mice in reducing inflammatory cell counts, decreasing interleukin-4, interleukin-5, and interleukin-13 concentrations, and downregulating TNF-α and eotaxin levels in bronchoalveolar lavage fluid. In addition, M. dauricum total alkaloids could also inhibit the elevated serum levels of total immunoglobulin E and ovalbumin-specific immunoglobulin E. These findings confirmed that M. dauricum total alkaloids could suppress airway inflammation in ovalbumin-induced asthma through regulating the T-helper 2 response and chemokine level. M. dauricum total alkaloids may be a potential ethnopharmacological agent for asthmatic patients.

Reversing effects of ginsenosides on LPS-induced hepatic CYP3A11/3A4 dysfunction through the pregnane X receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (Panax ginseng C. A. Meyer), a traditional Chinese medicine, is widely used in the adjunctive therapy of the liver diseases. AIM OF THE STUDY: Ginsenosides are one kind of the main active ingredients in ginseng. Although hepatoprotective mechanisms of ginsenosides, such as anti-oxidation, anti-inflammation and anti-apoptosis, have been well studies, little is known about the effect of ginsenosides on drug metabolism in liver. Since CYP3A11/3A4 is a major enzyme catalyzing the drug metabolism in liver, an investigation of the enzyme's expression during the progression of a liver disease will gain valuable information about the hepatic drug metabolism. The purpose of this study was to determine the effect of ginsenosides on the expression of hepatic CYP3A11/3A4 in the lipopolysaccharides (LPS) injured human HepG2 cells and mice. We hypothesize that ginsenosides are important to stabilize CYP3A11/3A4 expression in an injured liver. MATERIALS AND METHODS: In this study, LPS was intraperitoneally intermittently injected to induce the liver injury in mice. Ginsenosides were intragastrically administered to mice for 7 days to treat the liver injury. Serum biochemical analysis and histopathological study were taken to evaluate the hepatoprotective effect of ginsenosides. The effect of ginsenosides was also evaluated in human HepG2 cells in the presence and absence of LPS. Real-time PCR and western blotting method were used to detect the mRNA and protein levels of CYP3A11/3A4 in mouse liver tissue and human HepG2 cells. The reporter gene-transfected cells were used to identify upstream targets in HepG2 cells. RESULTS: LPS injection in mice resulted in the up-regulation of pro-inflammatory cytokines such as IL-1ß, IL-6 and TNF-α in liver, up-regulation of hepatic enzymes such as Tbil, ALT, AST and ALP in serum, and down-regulation of CYP3A11/3A4 expression in liver. Ginsenosides treatment reversed the up-regulation of pro-inflammatory cytokines and serum hepatic enzymes elicited by LPS. Pathological results suggest that ginsenosides reduced liver damage. Moreover, ginsenosides reversed the decrease of CYP3A11/3A4 expression in the liver of LPS-injured mouse and in LPS-treated HepG2 cells. To further investigate the regulatory mechanisms, we found that ginsenosides enhanced the rifampicin-induced pregnane X receptor (PXR) transactivation of the CYP3A4 promoter. Treatment of hPXR-over-expressed cells with ginsenosides increased the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. CONCLUSION: Ginsenosides reverse the effects of LPS-induced hepatic CYP3A11/3A4 dysfunction, suggesting that the stabilization of the CYP3A11/3A4 expression in an injured liver appears a novel hepatoprotective mechanism of ginsenosides.

Protective effect of gentiopicroside from Gentiana macrophylla Pall. in ethanol-induced gastric mucosal injury in mice.

Gentiopicroside isolated from gentiana macrophylla Pall. belongs to iridoid glycosides. This study aimed to evaluate the protective effect of gentiopicroside against ethanol-induced gastric mucosal injury in mice. Mice were proactively administrated with gentiopicroside by intragastric administration once a day for 3 consecutive days. On the 3rd day, gastric ulcer in mice was induced with 70% ethanol after the last intragastric administration. The stomach tissues were submitted for evaluation of the severity of gastric mucosal alterations. Gentiopicroside administrated orally ameliorated the severity of gastric mucosal alterations. Oral administration of gentiopicroside significantly increased heat shock protein-70 and glutathione levels and superoxide dismutase activity, normalized epidermal growth factor and vascular endothelial growth factor levels, and decreased the levels of tumour necrosis factor-α, interleukin-6 and malondialdehyde, and myeloperoxidase activity in gastric tissue. These findings demonstrated that gentiopicroside has protective effect against ethanol-induced gastric mucosal injury in mice through the improvements of antioxidative and anti-inflammatory effects, as well as up-regulation of heat shock protein-70 level and normalization of epidermal growth factor and vascular endothelial growth factor levels. The results presented in this study provide some evidence for the development of a novel antigastric ulcer agent.

Pulvis Fellis Suis extract attenuates ovalbumin-induced airway inflammation in murine model of asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulvis Fellis Suis (PFS), named with "Zhu Danfen" in China, has been extensively used for the therapy of enteritis, acute pharyngitis, whooping cough and asthma in folk medicine. Although PFS shows anti-inflammatory activities, its effect on airway inflammation in asthma has not been studied. AIM OF THE STUDY: To explore the protective effect of PFS ethanol extract against airway inflammation in asthmatic mice. MATERIALS AND METHODS: Allergic asthma in mice was sensitized and challenged by OVA. Mice were administered in oral with PFS daily at doses of 100, 200 and 400mg/kg on days 21-27. Inflammatory cell counts and classification in bronchoalveolar lavage fluid (BALF) were analyzed. Histopathological evaluation of the lung tissue was performed by hematoxylin and eosin (H&E) and periodic acid-schiff (PAS) staining. The IgE level in serum was measured by using enzyme-linked immunoassay (ELISA). ELISA was also used to detect the levels of Th1/Th2 cytokine and eotaxin in BALF. RESULTS: Histological results revealed that PFS could ameliorate OVA-induced histological changes by attenuating inflammatory cell infiltration, mucus hypersecretion and goblet cell hyperplasia in the lung. Treatment with different doses of PFS significantly decreased the elevated inflammatory cell numbers in BALF and IgE production in serum. PFS treatment reduced the production of Th2 cytokine IL-4, IL-5, IL-13, and promoted Th1 cytokine IFN-γ production in BALF. In addition, PFS also decreased the levels of eotaxin and TNF-α in BALF. CONCLUSIONS: These findings suggest that PFS has a markedly anti-inflammatory effect on OVA-induced allergic asthma in mice, and could be a promising protective agent recommended for allergic asthma patients.

Intestinal anti-inflammatory effect of the rhizome extracts of Menispermum dauricum DC. on trinitrobenzene sulfonic acid induced ulcerative colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Menispermum dauricum DC., commonly known as "Bei Dou Gen" (BDG) in China, has been used extensively in folk medicine to treat inflammatory diseases, especially intestinal inflammations such as enteritis and dysentery, and in pharyngitis, tonsillitis, rheumatism and bronchitis. Although previous studies showed that BDG has anti-inflammatory activities, its effects on ulcerative colitis (UC) have not yet been explored. AIM OF THE STUDY: To investigate the intestinal anti-inflammatory effect of the rhizome extracts of Menispermum dauricum DC. on UC model induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. MATERIALS AND METHODS: UC in mice was induced by colonic administration with TNBS. BDG (100, 200 and 400mg/kg/day) and sulfasalazine (500mg/kg/day) were administered orally for 7 consecutive days. The inflammatory degree was assessed by gross appearance, macroscopic and histological analysis, and accumulation of myeloperoxidase (MPO) activity. Pro-inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, were determined by enzyme-linked immunoassay. The expression of cyclooxygenase (COX)-2 was assessed by immunohistochemical analysis. RESULTS: Treatment with different doses of BDG significantly ameliorated macroscopic damage and histological changes, reduced the accumulation of MPO activity, depressed serum and colonic tissue levels of TNF-α, IL-1ß and IL-6 in a dose-dependent manner. In addition, administration of BDG effectively reduced COX-2 overexpression in colon. CONCLUSION: We demonstrated for the first time that BDG possessed marked intestinal anti-inflammatory effect in TNBS induced colitis in mice, which might be related to the reduction of up-regulated productions and expressions of pro-inflammatory mediators, suggesting that it may have beneficial use for the treatment of inflammatory bowel disease.