A new gentiopicroside derivative improves cognitive deficits of AD mice via activation of Wnt signaling pathway and regulation of gut microbiota homeostasis.

BACKGROUND: In our previous study, we found that gentiopicroside (GPS) isolated from Gentiana rigescens Franch has a significant antiaging activity via regulation of mitophagy and oxidative stress. In order to increase the anti-aging activity of GPS, several compounds based on the chemical structure of GPS were synthesized and evaluated for bioactivity with yeast replicative lifespan assay, and 2H-gentiopicroside (2H-GPS) as leading compound was selected for AD treatment. PURPOSE AND METHODS: To investigate whether 2H-GPS has anti- Alzheimer's disease effects, we used D-galactose (Dgal)-induced model mice to evaluate the effect of 2H-GPS on AD mice. Furthermore, we explored the action mechanism of this compound with RT-PCR, Western Blot, ELISA and 16S rRNA gene sequence analysis. RESULTS: Memory dysfunction and reduction in the number of neurons in the brain of mice were observed in Dgal treated group. These symptoms of AD mice were significantly relieved by administering 2H-GPS and donepezil (Done), respectively. In the Dgal only treated group, the protein levels of ß-catenin, REST and phosphorylated GSK-3ß, involved in the Wnt signaling pathway were significantly decreased, whereas the protein levels of GSK-3ß, Tau, phosphorylated Tau, P35 and PEN-2 were significantly increased. Importantly, treatment with 2H-GPS resulted in restoration of memory dysfunction and levels of these proteins. Furthermore, the composition of the gut microbiota after 2H-GPS administration was explored through 16S rRNA gene sequence analysis. Moreover, the mice, in which depleted gut microbiota with antibiotic cocktail (ABX), were used for evaluation of whether the gut microbiota is involved to the effect of 2H-GPS. Significant changes in gut microbiota composition were observed between AD and 2H-GPS-treated AD mice, and ABX partially eliminated the AD-restoring effect of 2H-GPS. CONCLUSION: 2H-GPS improves the symptoms of AD mice through combination of the regulation of Wnt signaling pathway and the microbiota-gut-brain axis, and the mechanism of action of 2H-GPS is distinct from that of Done.

Hepatoprotective effect of methanolic extract of Iris florentina L. on paracetamol-induced liver toxicity in rats.

Despite of plethora of research on hepatoprotective potential of medicinal plants, there is still need to discover potential plants with hepatoprotective activity. Iris florentina L. is a medicinal plant with traditional claims but ignored investigation regarding its hepatoprotective effects. The current study is aimed to investigate the hepatoprotective potential of I. florentina L. methanolic extract on paracetamol (PCM)-induced liver injury. The phytochemical and HPLC screening was done which showed the presence of potential constituents including flavonoids and phenols. For investigating the hepatoprotective effect of I. florentina L. methanolic extract, rats were given five different treatments for seven consecutive days. The normal control (group 1) was administered with normal saline, group 2 (Diseased) received paracetamol and group 3 (Standard) was given silymarin as reference drug. In group 4 and 5 (Treated), I. florentina L. methanolic extract (250 and 500mg/kg) were administered. Different serum biomarkers and histopathological studies were performed to assess the recovery caused by PCM in comparison to diseased group. The treatment of I. florentina methanolic extract significantly improve the serum biomarkers and restored the hepatic injury towards normal, indicating the hepatoprotective potential. Thus, we can conclude that I. florentina have significantly reversed the damage caused by paracetamol in hepatotoxic rat model due to their potential phytochemical constituents.

Evaluation of the hepatoprotective activity of hydroalcoholic extract of Alhagi camelorum against valproic acid-induced hepatotoxicity in rats.

BACKGROUND AND PURPOSE: Despite many liver disorders, clinically useful drugs are scarce. Moreover, the available therapies are facing the challenges of efficacy and safety. Alhagi camelorum has been used in folk medicine globally for millennia to treat several ailments. Alhagi camelorum (Ac) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. Our goal was to determine the hepatoprotective activity of Alhagi camelorum against valproic acid induced hepatotoxicity using an animal model. EXPERIMENTAL APPROACH: The animals were segregated in 4-groups (6 male rats each) weighing 250-290 g. Group-1 animals were treated with normal saline, Group-2 animals were treated with VPA at the dose of 500 mg/kg i.p for 14 days consecutively, while Group-3 and 4 were treated with valproic acid (VPA) at the dose of 500 mg/kg i.p for 14 days along with 400 mg/kg and 600 mg/kg of Ac hydroalcoholic extract respectively. Subsequently, blood serum samples and liver tissues were collected for biochemical and histopathological analysis. Phytochemical screening was carried out to screen for phytochemical classes and HPLC analysis was conducted to screen polyphenols. The antioxidant activity was carried by different assays such as DPPH, SOD, NO etc. KEY RESULTS: The administration of Ac showed hepatoprotection at the doses of 400 and 600 mg/kg. Ac significantly reduces the elevated serum levels of liver biomarkers compared to the valproic acid-induced hepatotoxic group. These findings were confirmed with histopathological changes where Ac was capable of reversing the toxic effects of valproic acid on liver cells CONCLUSION: It is concluded that Ac showed significant hepatoprotective effects at different doses in the animal model used in this study.

Amarogentin from Gentiana rigescens Franch Exhibits Antiaging and Neuroprotective Effects through Antioxidative Stress.

In the present study, the replicative lifespan assay of yeast was used to guide the isolation of antiaging substance from Gentiana rigescens Franch, a traditional Chinese medicine. A compound with antiaging effect was isolated, and the chemical structure of this molecule as amarogentin was identified by spectral analysis and compared with the reported data. It significantly extended the replicative lifespan of K6001 yeast at doses of 1, 3, and 10 µM. Furthermore, amarogentin improved the survival rate of yeast under oxidative stress by increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), and these enzymes' gene expression. In addition, this compound did not extend the replicative lifespan of sod1, sod2, uth1, and skn7 mutants with K6001 background. These results suggested that amarogentin exhibited antiaging effect on yeast via increase of SOD2, CAT, GPx gene expression, enzyme activity, and antioxidative stress. Moreover, we evaluated antioxidant activity of this natural products using PC12 cell system, a useful model for studying the nervous system at the cellular level. Amarogentin significantly improved the survival rate of PC12 cells under H2O2-induced oxidative stress and increased the activities of SOD and SOD2, and gene expression of SOD2, CAT, GPx, Nrf2, and Bcl-x1. Meanwhile, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) of PC12 cells were significantly reduced after treatment of the amarogentin. These results indicated that antioxidative stress play an important role for antiaging and neuroprotection of amarogentin. Interestingly, amarogentin exhibited neuritogenic activity in PC12 cells. Therefore, the natural products, amarogentin from G. rigescens with antioxidant activity could be a good candidate molecule to develop drug for treating neurodegenerative diseases.