Combination of schisandrin and nootkatone exerts neuroprotective effect in Alzheimer's disease mice model.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases which seriously affect the quality of life of the elderly. Schisandrin (SCH) and nootkatone (NKT) are the two marked active components in ASHP. In this study, the effects of Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) as well as its bioactive components on cognitive deficiency and dementia were revealed via Aß1-42-induced AD in mouse. Morris water maze test showed that acute administration of ASHP and SCH + NKT treatments had higher discrimination index in the object recognition task, more quadrant dwell time and shorter escape latency compared with those in the Morris water maze. The levels of TNF-α, IL-1ß and IL-6 were decreased after ASHP and SCH + NKT treatment. The inflammatory response was attenuated by inhibiting TLR4/ NF-κB/ NLRP3 pathway. In addition, ASHP and SCH + NKT treatments significantly restored the activities of superoxide dismutase (SOD), glutathione S-transferase (GST), cyclooxygenase-2 (COX-2), total antioxidant capacity (T-AOC) and inducible nitric oxide syntheses (iNOS), and the levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO). The histopathological changes of hippocampus were noticeably improved after ASHP and SCH + NKT treatments. These findings demonstrate that ASHP as well as its bioactive components exerted a protective effects on cognitive disorder, inflammatory reaction and oxidative stress.

Intracerebroventricular injection of resveratrol ameliorated Aß-induced learning and cognitive decline in mice.

Resveratrol (RSV) is a natural plant polyphenol compound which consists in red grape skins and wine in general. Plenty of previous studies have shown that resveratrol has neuroprotective effects. The primary object of this research was to study the effects of RSV on improving the cognitive function and neurodegeneration in the mouse model of Alzheimer's disease induced by Aß1-42, and the possible mechanism about targeting on Sirt1, which results in attenuating inflammatory response and mitochondrial dysfunction. We established the AD model of intracerebroventricular (i.c.v.) injection of Aß1-42 and it was observed that the significant decrease in alternately of Y Maze and the quadrant dwell time percentage of Morris water maze test. Furthermore, there were significant upregulations of AMPK/ PGC-1α and downregulations of NF-κB/ IL-1ß/ NLRP3 signaling pathways in the hippocampus and prefrontal cortex in AD mice. The treatments with RSV and Donepezil could significantly ameliorate all the behavioral and biochemical changes induced by Aß1-42. It also noticeably improved the histopathological changes in the hippocampus and cortex. The results suggested that RSV might protect against cognitive deficits and neurodegeneration induced by Aß1-42, and serve as a potential agent in treatment of AD.

TOPP4 Regulates the Stability of PHYTOCHROME INTERACTING FACTOR5 during Photomorphogenesis in Arabidopsis.

In plants, photoreceptors transfer light signals to phytochrome-interacting factors (PIFs), inducing the rapid phosphorylation and degradation of PIFs to promote photomorphogenesis. However, the phosphatase responsible for PIF dephosphorylation remains unknown. In this study, we identified a type 1 protein phosphatase, TOPP4, that is essential for PIF5 protein stability in Arabidopsis (Arabidopsis thaliana). Compared with the wild type, the dominant-negative mutant, topp4-1, displayed reduced hypocotyl length and larger apical hook and cotyledon opening angle under red light. Overexpression of topp4-1 in the wild type led to defects that were similar to those in the topp4-1 mutant. Red light induced phytochrome B (phyB)-dependent TOPP4 expression in hypocotyls. The topp4-1 mutation weakened the closed cotyledon angle of phyB-9 and phyA-211 phyB-9, while overexpression of TOPP4 significantly repressed the short hypocotyls of phyB-green fluorescent protein seedlings, indicating that TOPP4 and phyB function in an antagonistic way during photomorphogenesis. Protein interaction assays and phosphorylation studies demonstrate that TOPP4 interacts directly with PIF5 and dephosphorylates it. Furthermore, TOPP4 inhibits the red light-induced ubiquitination and degradation of PIF5. These findings demonstrate that dephosphorylation of PIF5 by TOPP4 inhibits its ubiquitin-mediated degradation during photomorphogenesis. These data outline a novel phytochrome signaling mechanism by which TOPP4-mediated dephosphorylation of PIF5 attenuates phytochrome-dependent light responses.

Comparative pharmacokinetic study of the components in Alpinia oxyphylla Miq.-Schisandra chinensis (Turcz.) Baill. herb pair and its single herb between normal and Alzheimer's disease rats by UPLC-MS/MS.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects daily life. Schisandra chinensis (Turcz.) Baill. Fructus (SCF) and Alpinia oxyphylla Miq. Fructus (AOF) have been regarded as classical herbs for dementia since ancient times. Alpinia oxyphylla Miq.-Schisandra chinensis (Turcz.) Baill. herb pair (ASHP) is the compatible form of the two herbs. Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established for the simultaneous determination of protocatechuic acid, chrysin, schisandrin, gomisin A, gomisin B, nootkatone, deoxyschizandrin, schisandrin B and schisandrin C in rat plasma. The pharmacokinetic differences of the above nine active components in normal rats and AD model rats after oral administration of SCF, AOF, and ASHP ethanol extracts were investigated. Chloramphenicol and bifendate were used as the internal standards. Extraction of plasma sample was by liquid-liquid extraction with ethyl acetate. A SBC18 column (2.1 mm × 100 mm, 1.8 µm) was used in this experiment at a flow rate of 0.3 mL/min at 30 °C with linear gradient elution using acetonitrile and water containing 0.1% formic acid. This study showed ASHP can improve the absorption of protocatechuic acid, chrysin, schisandrin, gomisin B, nootkatone, deoxyschizandrin, schisandrin B and schisandrin C in vivo and slow down part of these components' elimination. In addition, compared with normal rats, the pharmacokinetic parameters changed significantly in AD model rats' plasma after oral administration of ASHP. Hence, these may be the pharmacokinetic mechanism of ASHP, in addition to serving as a potential agent in the treatment of AD.

Alpinia oxyphylla-Schisandra chinensis Herb Pair Alleviates Amyloid-ß Induced Cognitive Deficits via PI3K/Akt/Gsk-3ß/CREB Pathway.

Alzheimer's disease (AD), one of the most common neurodegenerative diseases, threatens people's health. Based on the theory of traditional Chinese medicine (TCM) efficacy and treatment theory, we first proposed the Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) for finding a candidate of AD treatment. This study aimed at exploring the effects of ASHP on improving the cognitive function and neurodegeneration, and revealing the possible mechanism. In this study, an amyloid-ß (Aß) induced AD model was established in mice via intracerebroventricular injection. The Y-maze test and Morris water maze test were carried out to observe the behavioral change of mice, which showed that ASHP significantly ameliorated cognitive impairment. In addition, ASHP reduced amyloid-ß deposition and downregulated the hyperphosphorylation of tau via immunofluorescence assay and western blot analysis, respectively. Subsequently we focused on the PI3K/Akt pathway that is a classical pathway related to nervous system diseases. It also noticeably ASHP improved the histopathological changes in the hippocampus and cortex. Moreover, it was found that ASHP could upregulate the PI3K/Akt/Gsk-3ß/CREB signaling pathway in N2a-SwedAPP cells. Taken together, it suggests that ASHP might reverse cognitive deficits and neurodegeneration via PI3K/Akt/Gsk-3ß/CREB pathway.

Effect of Alpinia oxyphylla-Schisandra chinensis herb pair on inflammation and apoptosis in Alzheimer's disease mice model.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP), composed of Alpinia oxyphylla Miq. Fructus (Yizhi, in Chinese) and Schisandra chinensis (Turcz.) Baill Fructus (Wuweizi, in Chinese) has been used in many traditional Chinese prescriptions such as Yizhi Wuwei pill and Jiannao pill. AIMS OF THE STUDY: This study was primarily dealt with studying the effects of Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) on learning and cognitive impairment in the Aß1-42 induced mouse model. MATERIALS AND METHODS: The chemical composition quantitative analysis was by UPLC. Then the Y maze and Morris water maze test were used to determine the capability of ASHP extracts on improving memory. Histological changes and apoptotic features were detected by HE staining and TUNEL staining, respectively. qPCR was used to detect the changes in the mRNA of caspase3, caspase8 and caspase9 and western-blot was used to detect the changes in the levels of cleaved-caspase3, cleaved-caspase8 and cleaved-caspase9. The levels of some inflammatory factors such as IKK, IκB and NF-κB; anti-apoptotic factors such as bcl-2, bcl-xl, pro-apoptotic factors including bad, bax, p53 were assessed via immunohistochemistry (IHC) and western-blot. RESULTS: Administration of ASHP extracts had higher spontaneous alternation ratio in the Y maze, more quadrant dwell time and shorter escape latency compared with model group in the Morris water maze. ASHP treated groups significantly inhibited NF-κB pathway and apoptosis-related pathway in the hippocampus. CONCLUSIONS: This study demonstrated that ASHP had the ability to ameliorate abnormal changes in cognitive behavior, biochemical and histopathology induced by Aß1-42 in the mouse model. The powerful role of ASHP is to inhibit the NF-κB inflammatory signaling pathway and cut down the damage of apoptosis. This study revealed ASHP might be a potential therapy for cognitive and behavioral deficits.