Advances in the study of p53 in response to DNA damage / 药学学报

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. The biological outcome inducing this pathway can be either growth arrest and apoptosis or senescence to maintain the integrity of the genome or to delete the damaged cells. The biochemical activity of p53 itself and the cellular environment govern the choice between these outcomes in a cell type- and stress-specific manner. So, p53 is a pivotal tumour suppressor and a mainstay of our body's natural anticancer defence. This review could provide some useful information for further study on the mechanisms of tumorigenesis and its progression, and also could contribute to the discovery of antitumor agents.

Neurodegenerative conformational disease and heat shock proteins / 药学学报

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.e. the ubiquitin-proteasome system and autophagy-lysosomal system, also contribute to the neurodegenerative process. The present review mainly summarizes protein misfolding and aggregation in the development of neurodegenerative conformational disease and the underling mechanisms, as well as upregulation of heatshock proteins as a promising treatment method for this kind of disease.

Tumor chemosensitization strategies based on apoptosis manipulations / 中国药理学通报

MDR(multidrug-resistance)is a major obstacle in the chemotherapy of cancer.Numerous mechanisms are known to contribute to MDR,alterations at the level of apoptosis control are one of those mechanisms except overexpression of drug efflux pumps.This review focuses on the research progression of alterations at the level of apoptosis inducing MDR,and some of the strategies that have been used in an attempt to chemosensitize resistant tumors by manipulating dysregulated apoptosis pathways.

Glycogen synthase kinase-3:an emerging therapeutic target for Alzheimers disease / 中国药理学通报

Glycogen synthase kinase-3(GSK3)is a fascinating serine/threonine protein kinase which exists in cells generally.GSK3 activity is regulated by phosphorylation,protein complex formation,and its intracellular localization.GSK3 regulates many functions including cell survival and apoptosis,structure and motility,intracellular signaling pathways and so on.It is very important to keep the activity of GSK3.GSK3 has been linked to all of the primary abnomalities associated with AD.It is very important to study the inhibition of GSK3 as a therapeutic approach to treat AD.All the studies suggest that GSK3 is a promising therapeutic target for AD.

Inhibitory effect of bicyclol on iNOS expression and NF-?B activation degradation in marcrophages induced by lipopolysaccharides / 中国药理学通报

Aim Inflammation is a common characteristic of liver injury induced by hepatitis virus or other factors.The purpose of this paper was to study the modulating effect of bicyclol,a novel anti-hepatitis drug,on related inflammatory molecules.Methods Various non-cytotoxic concentrations of bicyclol were cultured with macrophage RAW264.7 line or mouse peritoneal macrophages for 1 h,and then added adequate lipopolysaccharide(LPS)to activate macrophages.NO and TNF-? levels in the supernatant of the culture medium were determined with Griess reagent and L929 cell bioassay,respectively.The iNOS expression and NF-?B activation were detected by Western blot method.Results Pretreatment of 0.1～0.5 mmol?L-1 bicyclol significantly inhibited NO release and TNF-? secretion from RAW264.7 cell line and mouse peritoneal macrophages induced by 1 mg?L-1 LPS in concentration dependent manners and 0.5 mmol?L-1 bicyclol also down-regulated LPS(1 mg?L-1)-induced iNOS expression and NF-?B activation in the cells.Conclusion Bicyclol has suppressive effect on related inflammatory molecules iNOS expression and NF-?B activation,indicating that bicyclol possesses anti-inflammatory property.

A novel therapy for PD-adenosine A_ (2A) receptor antagonist / 中国药理学通报

Adenosine A_ 2A receptors are selectively localized in basal ganglia and can affect the locomotor activity. Epidemiological and laboratory data have suggested that A_ 2A blockade may confer neuroprotection against the underlying dopaminergic neuron degeneration. A_ 2A receptor antagonist may ameliorate the symptom of Parkinsons disease (PD) and block the disease progress. Thus, the data suggested that A_ 2A receptor antagonist might be effective as a novel therapy for the management of PD.

Gap junctional intercellular communication and cancer / 中国药理学通报

Gap junctional intercellular communication (GJIC) has been specu la ted to be a necessary biological function of metazoan cells for the regulation o f growth control, differentiation and apoptosis of normal progenitor cells. Rese arches show that most transformed cells and tumor cells have reduced or abolished GJIC. The prevention of the down regulation of GJIC by the tumor promoters or the restoration of GJIC in neoplastic cells may have potential in prevention and therapy of cancer.

?-synuclein and Alzheimers disease / 中国药理学通报

syuclein is regarded as a presynaptic protein, which may play an important role in neuronal plasticity. However, abnormal accumulation of fibrillar ?-synuclein and mutation of ?-synuclein gene can affect the survival of neurons. Its aggregation and interaction with other proteins are the most critical factors. ?-synuclein is a precursor of non-amyloid component of senile plaques in Alzheimers disease. It is likely that ?-synuclein is associated with Alzheimers pathology. In this paper, we summarize the progress in the normal physical function of ?-synuclein and the mechanism in Alzheimers disease.

Protection of Ginkgo biloba extract (EGb761) against doxorubicin-induced cardiotoxicity without interfering with its antitumor activity / 中国药学杂志

OJECTIVE：To explore whether EGb761 could protect against doxorubicin-induced cardiotoxicity, and whether it affects on doxorubicin antitumor activity. METHOD： Doxorubicin-induced rat heart mitochondria damage in vitro and doxorubicin-induced cardiotoxicity in mice were used. The cardiotoxicity were evaluated via spectrophotography, electromicrography and other methods.RESULTS： Doxorubicin markedly induced malondialdehyde formation, adenosine 5′-triphosphatase activity loss, membrane rigidification, swelling, disintegration and lysis of rat heart mitochondria in vitro, all the above pathological and biochemical damages were reduced significantly by EGb761. Cardiotoxicity of doxorubicin in mice as measured by increases of heart Malondialdehyde level and serum creatine phosphokinase activity was significantly alleviated by EGb761. Moreover. The antitumor activity of doxorubicin, as assayed by prolonged life span of mice bearing with H22 hepatoma, was not reduced by EGb761 treatment. CONCLUSION：Ginkgo biloba extract may protect heart against doxorubicin-induced cardiotoxicity without interfering with its antitumor activity in mice.

Role of adhesion molecules in neutrophil-mediated inflammation / 中国药理学通报

Adhesion molecules are involved in neutrophil-mediated inflammation. Neutropil adhesion to endothelial cell mediated by cell adhesion molecules (CAMs) is the first and critical step during the process of inflammation. Three families of CAMs play a central role in neutrophil-endothe-lial cell interactions : the selectins, the integrins, and the immunoglobulin superfamily. These different types of CAMs interact in a programmed, sequential manner to form neutrophil-endothelial cell adhesion cascade. The initial phase of inflammation, neulrophil slowing and rolling, is mediated by selectins; subsequently, firm adhesion of neu-trophils to vessel endothelial cells occurs via binding of the activated integrins and the endothelial receptors such as intercellular adhesion molecule-1 (ICAM-1); Then, neutrophils transmigrate into the tissues, this process requires chemotactic factors, integrins and PEC AM-1. Because of the important role of CAMs in the process of inflammation. Agents may be used to block the function of CAMs as a strategy of antiinflammatory therapy.

Inflammatory cytokines and Alzheimer disease / 中国药理学通报

Inflammatory response clearly occured in pathologically vulnerable regions of the Alzheimers disease (AD) brain. Many proinflammatory mediators, such as IL-1, IL-6,TNF-? and TGF-?, were significantly up-regulated in the pathophysiological process of AD. In addition to their traditional actions as proinflammatory molecules, AD-specific interactions of the cytokines and amyloid ?(A?) may be pathophysiologically relevant, and there was a reciprocal relationship within the cytokines inducing and being induced by A?.

Parkinsons disease and oxygen free radicals / 中国药理学通报

The recent advances in research of oxygen free radicals and its relation to Parkinsons disease (PD) was reviewed. Though there is no exact knowledge of the causes of PD, the role of oxidative stress in the etiology of PD has been focused on. Investigations on patients have shown that PD is under a status of oxidative stress. The biochemical features of dopaminergic neurons in the pathologic site of PD implicate the close relation of oxygen free radicals' generation with the pathogenesis of PD. Besides the oxidative stress hypothesis, other proposed hypotheses are also direct or indirect related to oxidative stress.

The immunopathogenesis of viral hepatitis and its implications in developing new anti-hepatitis drug / 中国药理学通报

Immune mediated liver injury plays a key role in the immunopathogenesis of viral hepatitis and autoimmune hepatitis. The phathogenesis of liver injury involved various kinds of cells including lymphocytes, mononuclear macrophages (Kupffer cells), endothelial cells, stallete cells and liver parenchymal cells. Activation of lymphocytes is the initial step of liver damage, and then that the liver macrophages and NK cells. Crosstalk between these cells expands the damage of liver tissues. Cytokines produced by CD8 + cytotoxic T lymphocytes (CTLs) and CD4 + Th cells and other inflammatory cells lead to the persistent infection and liver injury of patients. To protect hepatocytes against cytopathic effect induced by invalid immune response will provide further insight into the development of new anti hepatitis drugs.

Advance in research on liver cell injury and its initiation in developing new drugs for treating liver diseases / 中国药理学通报

Liver cell death,including apoptosis and necrosis, is triggered by a number of insults. The apoptotic cascade involving the participation of proteolytic caspases is an important pathway of cell death. Mitochondria play a key role in liver cell death. TNF as an important mediator plays an crucial action in liver cell death. Reactive oxygen metabolites may act directly or through immunological mechanism as initiating factors and modulators in liver cell necrosis and apoptosis. Some intrinsic factors may act on the cascade of liver cell death. The extensive knowledge gained in recent years about the mechanisms of hepatocyte death will lead to new and exciting advances in the prevention and treatment of liver diseases.

Relation of vascular endothelial inflammatory reaction and atherosclerosis and its enlightenment for research of anti-atherosclerotic drug / 中国药理学通报

The accumulated evidence indicated atherosclerosis (AS) is associated with a chronic inflammatory reaction. Either by secretion of inflammatory mediator or by modulation of expression of adhesive molecules onvascular surface, vascular endothelial cells play a key role in initiation and amplification of inflammation in artery. The NF ?B transcription factor family is a pleiotropic regulatory of endothelial cells activation and the multiple genes relevant inflammatory cytokines are regulated by NF ?B transcriptional activation in endothelial cells. Selective protection of vascular endothelium and regulation of endothelial inflammation may be rational as the target for anti AS.