P-glycoprotein mediated efflux limits the transport of the novel anti-Parkinson's disease candidate drug FLZ across the physiological and PD pathological in vitro BBB models.

FLZ, a novel anti-Parkinson's disease (PD) candidate drug, has shown poor blood-brain barrier (BBB) penetration based on the pharmacokinetic study using rat brain. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two important transporters obstructing substrates entry into the CNS as well as in relation to PD neuropathology. However, it is unclear whether P-gp and BCRP are involved in low BBB permeability of FLZ and what the differences of FLZ brain penetration are between normal and Parkinson's conditions.

Neuroprotective effects of compound FLZ in an ischemic model mediated by improving cerebral blood flow and enhancing Hsp27 expression.

Compound FLZ is a synthetic novel derivate of natural squamosamide, which has potent neuroprotective effects based on our previous study. We are now aiming to investigate the effects of FLZ on cerebral blood flow (CBF), infarct volume, neurological function, heat shock protein 70 (Hsp70), and Hsp27 expression in transient focal ischemia. For this goal, an animal model of middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion was used, and animals received low or high doses of FLZ (150 or 300mg/kg), orally 10min after MCAO onset.

Sedative and hypnotic activity of N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2), an adenosine analog.

N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is an N(6)-substitued adenosine analog. Previous studies have shown that B2 binds to the adenosine A1 and A2A receptors with moderate affinity and produces protective effects on serum deprivation-induced cell damage. However, central nervous system effects of B2 have not been studied.

Anticonvulsant activity of B2, an adenosine analog, on chemical convulsant-induced seizures.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed.

NHBA isolated from Gastrodia elata exerts sedative and hypnotic effects in sodium pentobarbital-treated mice.

The rhizomes of Gastrodia elata have been used for the treatment of insomnia in oriental countries. N⁶-(4-hydroxybenzyl) adenine riboside (NHBA) was originally isolated from G. elata.

Partial synthesis and biological evaluation of bisbenzylisoquinoline alkaloids derivatives: potential modulators of multidrug resistance in cancer.

A series of new bisbenzylisoquinoline alkaloids was partially synthesized from tetrandrine and fangchinoline and evaluated for their ability to reverse P-glycoprotein-mediated multidrug resistance (MDR) in cancer cells. All the test compounds increased the intracellular accumulation rate of rhodamine 123 in MDR cells (Bel7402 and HCT8), and most exhibited more potent MDR-reversing activity relative to the reference compound verapamil. Compounds 8, 10, 13, and 14 enhanced intracellular accumulation of doxorubicin in Bel7402 and HCT8 cells.

Induction of cell cycle arrest by GL331 via triggering an ATM-dependent DNA damage response in HepG2 cells.

GL331, a topoisomerase II inhibitor, has been found to trigger DNA damage response (DDR) to induce cell cycle arrest. However, the underlying mechanism has not yet been fully understood. This study investigated the molecular mechanism involved in the GL331-induced cell cycle arrest via DDR in human hepatocellular carcinoma HepG2 cells.

A novel antihepatitis drug, bicyclol, prevents liver carcinogenesis in diethylnitrosamine-initiated and phenobarbital-promoted mice tumor model.

Bicyclol, an antihepatitis drug developed by Chinese scientists, has been shown to prevent the malignant transformation induced by 3-methylcholanthrene and 12-O-tetradecanoylphorbol-13-acetate in WB-F344 rat liver epithelial cells. This study provides further evidence on its role as a chemopreventive agent in experimental mice with diethylnitrosamine- (DEN-) initiated and phenobarbital- (PB-) promoted liver carcinoma. Liver tissue and serum were collected.

FLZ, synthetic squamosamide cyclic derivative, attenuates memory deficit and pathological changes in mice with experimentally induced aging.

The aim of this study was to investigate the protective effects of N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide (FLZ), a synthetic squamosamide cyclic derivative, on senescent mice induced by D: -galactose/NaNO(2) (120/90 mg/kg, i.p.) once daily for 60 days.

[Advances in the study of p53 in response to DNA damage].

p53 (encoded by TP53) is undoubtedly one of the most extensively studied genes and proteins. It is a highly potent transcription factor which, under normal circumstances, is maintained at low level. Both genotoxic and non-genotoxic stresses can induce p53 stabilized leading to changes in the expression of p53-responsive genes.

H1, a derivative of Tetrandrine, exerts anti-MDR activity by initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2.

Currently, multi-drug resistance (MDR) to anticancer drugs is a major obstacle to successful treatment of cancer. Looking for novel compounds with anti-MDR activity is an effectively way to overcome cancer drug resistance. Here, we found that H1, a novel derivate of Tetrandrine, displayed anti-MDR activity in vitro and in vivo.

[Neurodegenerative conformational disease and heat shock proteins].

Many major neurodegenerative diseases are associated with proteins misfolding and aggregation, which are also called "neurodegenerative conformational disease". The interaction of gene mutation and environmental factors are probably primary events resulting in oligomer and aggregate formations of proteins. Moreover, the dysfunctions of protein control systems, i.

FLZ, a novel HSP27 and HSP70 inducer, protects SH-SY5Y cells from apoptosis caused by MPP(+).

Heat shock proteins (HSPs) play an essential role in various neurodegenerative diseases. Manipulation of upregulation of HSPs in cells has been demonstrated to provide a therapeutic strategy to counteract the misfolding and aggregation of proteins that resulted in neurodegenerative disease. Our previous studies have shown that FLZ, a synthetic novel derivative of squamosamide from a Chinese herb, had potent neuroprotective effect against several experimental Parkinson's disease (PD) models.

H1, a novel derivative of tetrandrine reverse P-glycoprotein-mediated multidrug resistance by inhibiting transport function and expression of P-glycoprotein.

Purpose: H1 is a novel derivative of tetrandrine (Tet). Here we investigate the ability of H1 to reverse P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) and its mechanisms.

Methods: KBv200, MCF-7/adr and their parental sensitive cell lines KB, MCF-7 were used for reversal study.

Synthesis and MDR inhibitory activity evaluation of derivatives of schizandrin A.

Eighteen schizandrin A derivatives, possessing an acyl group at 7-OH and/or halogen(s) at C-4 and C-11, were designed and synthesized for evaluation of their in vitro ability to inhibit multidrug resistance (MDR). They exhibit weak ability to restore the intracellular Rhodamine 123 in human hepatocarcinoma MDR cell lines Bel7402 and HCT8 relative to the reference drug verapamil.

Long-term deprivation of gonadal hormone accelerates brain aging in mice.

Objective: The purpose of this study was to assess the effect of long-term deprivation of gonadal hormone on brain aging in mice to develop a model of gonadectomy-accelerated brain aging.

Methods: Male and female mice at 2 months old were orchiectomized (ORX) or ovarectomized (OVX) bilaterally or sham operated, and then they were fed for 10 months. The spatial learning and memory ability was tested using Morris Water Maze.

Involvement of HSP70 in the protection of bicyclol on apoptosis of HepG2 cells intoxicated by d-galactosamine.

Heat shock proteins (HSPs), the best known endogenous factors, play important roles in the cytoprotection and repair of cells and tissues against the harmful effects of stress and insults. In this study, RNAi technology was used to identify whether HSP70 was involved in the protection of bicyclol against d-galactosamine (d-GaIN)-induced apoptosis in HepG2 cells. As a result, bicyclol induced HSP70 in a time- and dose-dependent manner in HepG2 cells.

Scutellarin protects against lipopolysaccharide-induced acute lung injury via inhibition of NF-kappaB activation in mice.

This paper investigates the effect of natural scutellarin on acute lung injury (ALI) induced by Escherichia coli endotoxin lipopolysaccharide (LPS) in mice and its mechanism of action. Mouse ALI was induced by the injection of LPS (15 mg/kg) via the tail vein, and mice were intraperitoneally injected with 50 and 25 mg/kg of scutellarin before the LPS injection. The lung index, serum NO2(-)/NO3(-), and tumor necrosis factor-alpha (TNF-alpha) levels were determined using kits.

Inhibitory effect of anti-hepatitis drug bicyclol on invasion of human hepatocellular carcinoma MHCC97-H cells with high metastasis potential and its relative mechanisms.

To assess the anti-invasion effect of bicyclol (1) and its mechanism in human hepatocellular carcinoma (HCC) MHCC97-H cells with high metastatic potential. MTT assay was performed to evaluate the cytotoxicity of 1 to MHCC97-H cells and its inhibitory effect on the adhesion of these cells to laminin (LN) and fibronectin (FN). The anti-invasion effect of 1 was detected in an experiment using a transwell chamber.

The novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice.

Aim: The aim of this study was to study the effects of compound FLZ, a novel cyclic derivative of squamosamide from Annona glabra, on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis in the hippocampus of the amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice.

Methods: APP/PS1 mice at the age of 5 months and age-matched wild-type mice (WT) were intragastrically administered FLZ (150 mg/kg) or vehicle [0.05% carboxymethyl cellulose sodium (CMC-Na)] daily for 20 weeks.

Bicyclol protects HepG2 cells against D-galactosamine-induced apoptosis through inducing heat shock protein 27 and mitochondria associated pathway.

Aim: To study the inducing effect of bicyclol on heat shock protein 27 (HSP27) and its role on anti-apoptosis in HepG2 cells intoxicated with D-galactosamine (D-GaIN).

Methods: HepG2 cells were treated with various concentrations of bicyclol and then subjected to D-GaIN intoxication. Apoptosis was assayed by hoechst 33258 staining and flow cytometry analysis.

[The role of vitagene in aging and Alzheimer's disease and relevant advances of pharmacological study].

Free radical hypothesis of aging emphasized that the age-related accumulation of free radicals results in cell injury. Alzheimer's disease (AD) is the most common form of neurodegenerative disease characterized by impaired cognition and memory of the elderly. Aging is a key risk factor in AD.

Modulating expression of brain heat shock proteins by estrogen in ovariectomized mice model of aging.

Heat shock proteins (HSPs) serve as molecular chaperones and endogenous cytoprotective factors. Two of the well-studied HSPs, HSP70, and HSP27 can be significantly induced in many areas of brain by a variety of stressors. A decrease in expression of brain HSPs has been documented in aged brain.

A natural squamosamide derivative FLZ reduces amyloid-beta production by increasing non-amyloidogenic AbetaPP processing.

Substantial evidence supports a central role of Abeta in the pathogenesis of Alzheimer's disease (AD). We have demonstrated that FLZ, a synthetic cyclic analogue of natural squamosamide, exhibits neuroprotective actions in cells and mouse models, suggesting future investigation of FLZ as a candidate compound for the treatment of AD. In this study, we found that the production of amyloid-beta (Abeta) was reduced by FLZ in Abeta-expressing neuroblastoma cells, and correlated with an increase in the soluble alpha-secretase derived fragment of the amyloid-beta protein precursor (sAbetaPPalpha) in the medium.