Organ Specific Differences in Alteration of Aquaporin Expression in Rats Treated with Sennoside A, Senna Anthraquinones and Rhubarb Anthraquinones.

Senna and rhubarb are often used as routine laxatives, but there are differences in mechanism of action and potential side effects. Here, we studied metabolites of senna anthraquinones (SAQ), rhubarb anthraquinones (RAQ) and their chemical marker, sennoside A (SA), in a rat diarrhea model. In in vitro biotransformation experiments, SAQ, RAQ and SA were incubated with rat fecal flora solution and the metabolites produced were analyzed using HPLC. In in vivo studies, the same compounds were investigated for purgation induction, with measurement of histopathology and Aqps gene expression in six organs. The results indicated that SAQ and RAQ had similar principal constituents but could be degraded into different metabolites. A similar profile of Aqps down-regulation for all compounds was seen in the colon, suggesting a similar mechanism of action for purgation. However, in the kidneys and livers of the diarrhea-rats, down-regulation of Aqps was found in the RAQ-rats whereas up-regulation of Aqps was seen in the SAQ-rats. Furthermore, the RAQ-rats showed lower Aqp2 protein expression in the kidneys, whilst the SA-rats and SAQ-rats had higher Aqp2 protein expression in the kidneys. This may have implications for side effects of SAQ or RAQ in patients with chronic kidney or liver diseases.

Identification of rhein as the metabolite responsible for toxicity of rhubarb anthraquinones.

Rhubarb is a popular food in Europe with laxative properties attributed to anthraquinones. Long term usage of rhubarb anthraquinones has been linked to colonic toxicity, including the formation of melanosis coli, which is associated with increased risk of colon cancer. The major purgative anthraquinone in rhubarb is thought to be sennoside A, which is metabolised by colonic microflora. Here, we sought to identify the toxic metabolite responsible for melanosis coli in rats dosed with rhubarb anthraquinones for up to 90 days. Three metabolites were detected in rat faeces using HPLC. Of these, rhein was identified as the metabolite that accumulated most over time. Fecal flora from treated rats were capable of greater biotransformation of sennoside A to rhein compared to that from control rats. Cell culture experiments suggested that apoptosis and autophagy induced by rhein is the likely mechanism of chronic toxicity of rhubarb anthraquinones.

Amelioration of nonalcoholic fatty liver disease by swertiamarin in fructose-fed mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Swertia bimaculata (Sieb. et Zucc.) Hook. Thoms.ex Clarke, a glabrous or procumbent perennial herb, is a traditional herb medicine. Swertiamarin, a secoiridoid glycoside, is a representative ingredient in this medical plant crude extract and shows antidiabetic and antihyperlipidaemic activities and protective effect against hepatic injury. PURPOSE: The present study aimed to determine whether swertiamarin can attenuate NAFLD in fructose-fed mice. METHODS: Healthy male mice freely drank water containing 10% fructose for 12 consecutive weeks, whereas animals in those swertiamarin tested groups received different doses of swertiamarin (25, 50 and 100 mg/kg) by intragastric administration once a day from the ninth week to the twelfth week. RESULTS: At the end of the experiment, fructose-fed mice administrated with swertiamarin showed low levels of serum glucose, triglycerides, uric acid, alanine aminotransferase and aspartate transaminase. Histological examinations suggested the alleviation of hepatic ballooning degeneration and steatosis by swertiamarin treatment. Moreover, swertiamarin administration mitigated hepatic oxidative stress along with decreases of hepatic pro-inflammation cytokines, which was associated with decrease of hepatic xanthine oxidase (XO) activity and enhancements of anti-oxidant defense system enzymes, as well as activation of nuclear factor E2-related factor 2 (Nrf2) in fructose-fed mice. In addition, swertiamarin down-regulated expression of sterol-regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1) in liver of fructose-fed mice. CONCLUSION: The present study demonstrates that swertiamarin alleviates NAFLD and metabolic alterations in fructose-fed mice.

Aquaporins Alteration Profiles Revealed Different Actions of Senna, Sennosides, and Sennoside A in Diarrhea-Rats.

Senna and its main components sennosides are well-known effective laxative drugs and are used in the treatment of intestinal constipation in the world. Their potential side effects have attracted more attention in clinics but have little scientific justification. In this study, senna extract (SE), sennosides (SS), and sennoside A (SA) were prepared and used to generate diarrhea rats. The diarrhea rats were investigated with behaviors, clinical signs, organ index, pathological examination, and gene expression on multiple aquaporins (Aqps) including Aqp1, Aqp2, Aqp3, Aqp4, Aqp5, Aqp6, Aqp7, Aqp8, Aqp9, and Aqp11. Using qRT-PCR, the Aqp expression profiles were constructed for six organs including colon, kidney, liver, spleen, lung, and stomach. The Aqp alteration profiles were characterized and was performed with Principle Component Analysis (PCA). The SE treatments on the rats resulted in a significant body weight loss (p < 0.001), significant increases (p < 0.001) on the kidney index (27.72%) and liver index (42.55%), and distinguished changes with up-regulation on Aqps expressions in the kidneys and livers. The SS treatments showed prominent laxative actions and down regulation on Aqps expression in the colons. The study results indicated that the SE had more influence/toxicity on the kidneys and livers. The SS showed more powerful actions on the colons. We suggest that the caution should be particularly exercised in the patients with kidney and liver diseases when chronic using senna-based products.

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.