PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 µM) significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3ß/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

In vivo hepatoprotective activity and the underlying mechanism of chebulinic acid from Terminalia chebula fruit.

BACKGROUND: The fruit of Terminalia chebula Retz. is one of the most widely used herbal drug in Traditional medicine prescriptions including those for liver diseases. In the screening of bioactive constituents that have potential hepatoprotective activity, chebulinic acid (CA) which is a major chemical constituent of T. chebula fruit showed potent activity. PURPOSE: This work was conducted to investigate the hepatoprotective activity and mechanisms of CA. METHODS: The hepatoprotective effect of CA was examined on hepatotoxic models of cells, zebrafish larvae and mice caused by tert-butyl hydrogen peroxide (t-BHP), acetaminophen (APAP) and CCl4, respectively. RESULTS: Pretreatment with CA could prevent t-BHP-induced damage in L-02 hepatocytes by blocking the production of ROS, reducing LDH levels and enhancing HO-1 and NQO1 expression via MAPK/Nrf2 signaling pathway. In animal experiments, CA significantly protected mice from CCl4-induced liver injury, as demonstrated by reduced ALT, AST and MDA levels, enhanced SOD activity, improved liver histopathological changes, and the activation of the Nrf2/HO-1 signaling pathway. CA metabolized to chebulic acid isomers with DPPH radical scavenging activity. In a transgenic zebrafish line with liver specific expression of DsRed RFP, CA diminished the hepatotoxicity induced by 10 mM APAP. CONCLUSION: Experiments in cell and two animal models demonstrated consistent results and comprehensively expounded the hepatoprotective effects of CA.

Structures and In Vitro Antihepatic Fibrosis Activities of Prenylated Dihydrostilbenes and Flavonoids from Glycyrrhiza uralensis Leaves.

Glycyrrhiza uralensis is the major plant source of licorice. This study was to identify bioactive compounds from the plant's leaves in order to make better use of its aerial part. An ethanol extract of the leaves was subjected to repeated chromatography to yield 15 compounds. The structures were determined to be three novel dihydrostilbenes, based on their various spectroscopic data-glycypytilbene A (1), glycydipytilbene (2), and glycypytilbene B (3)-and 12 known compounds, α,α'-dihydro-3,5,4'-trihydroxy-4,3'-diisopentenylstilbene (4), α,α'-dihydro-3,5,3',4'-tetrahydroxy-2,5'-diisopentenylstilbene (5), 6-prenyleriodictyol (6), 5'-prenyleriodictyol (7), 6-prenylquercetin-3-Me ether (8), 5'-prenylquercetin (9), 6-prenylquercetin (10), 6-prenylnaringenin (11), 3'-prenylnaringenin (12), sigmoidin C (13), 8-[(E)-3-hydroxymethyl-2- butenyl]-eriodictyol (14), and quercetin-3-Me ether (15). Most of these chemical constituents inhibited α-glucosidase activity, with the two prenylated quercetin derivatives (9 to 10) being the greatest active (IC50 < 4.0 µg/mL). Compounds 1, 3 to 4, 6 to 7, 9 to 12 impeded the growth of human hepatic stellate cells, with the prenylated flavonoids (6 to 7, 9 to 12) being more robust than their unprenylated counterparts. PRACTICAL APPLICATIONS: This study found that Glycyrrhiza uralensis leaves contain prenylated dihydrostilbenes and flavonoids with inhibiting effects on α-glucosidase and on the proliferation of human hepatic stellate cells, which should prompt the development of G. uralensis leaves for healthy products with anti-diabetic or liver fibrosis-preventing effects.

Therapeutic effects of dl-3-n-butylphthalide in a transgenic mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Transgenic mice over-expressing a mutant form of the human SOD1 gene develop an ALS-like phenotype. Currently, there is no effective treatment or drug for the fatal disease. Previous studies reported potent efficacy of dl-3-n-butylphthalide (DL-NBP) for several neurodegenerative disorders and cerebral ischemia. SOD1-G93A mice are a mouse model of ALS. In this study, we investigated the efficacy of DL-NBP on this ALS mouse model. METHODS: Sixty SOD1-G93A female mice were divided into four groups. The vehicle control group received 0 mg×kg(-1)×d(-1) DL-NBP. The experimental groups received DL-NBP with doses of 30, 60 or 120 mg×kg(-1)×d(-1), respectively. For measurement of motor activity, the hanging wire test and rotarod test were performed. Survival statistics were analyzed by Kaplan-Meier survival curves. The body weight of each mouse was recorded twice per week. The statistical motor unit number estimation (MUNE) technique was used to estimate the number of functioning motor units in gastrocnemius muscle. Muscle morphology was evaluated by hematoxylin and eosin staining. Motor neuron quantitation was performed by Nissl staining and microglia activation was observed by immunohistochemistry. RESULTS: Oral administration of 60 mg×kg(-1)×d(-1)1 DL-NBP significantly prolonged survival ((164.78 ± 16.67) days) of SOD1-G93A mice compared with vehicle control ((140.00 ± 16.89) days). Treating mice with DL-NBP (60 mg×kg(-1)×d(-1)) significantly decreased the progression rate of motor deficits and suppressed body weight reduction. Furthermore, we found that treating SOD1-G93A mice with DL-NBP (60 mg×kg(-1)×d(-1)) slowed the rate of MUNE reduction (P < 0.01). Motor neurons were remarkably preserved in the anterior horns in mice treated with DL-NBP (60 mg×kg(-1)×d(-1)) at the stage of 19 weeks (P < 0.01). Treating mice with DL-NBP (60 mg×kg(-1)×d(-1)) significantly reduced CD11b immunoreactivity compared with vehicle control mice (P < 0.05). No significant effect was observed in mice treated with DL-NBP of 30 or 120 mg×kg(-1)×d(-1). CONCLUSIONS: The post-disease-onset administration of DL-NBP significantly prolonged survival and improved motor performance in SOD1-G93A mice. DL-NBP may be a potential therapeutic agent for ALS.