Platelet-activating factor (PAF), an endogenous bioactive lipid generated by phospholipase A2 and other pathways, displays a variety of biological activities in the nervous system. It has been suggested that PAF plays important roles in neuronal physiological functions including acting as a retrograde messenger to enhance synapse plasticity and memory formation, via activation of its specific membrane receptors.Therefore,the drugs that mimic the action of PAF or modulate the production and inactivation of PAF maybe promising in memory-enhancing. However, under certain pathological conditions, such as Alzheimer's disease, HIV-associated dementia or post-ischemic neuronal death, acting as a potent inflammatory mediator and neurotoxin, PAF has been implicated in the pathophysiology of brain injury. So, modulating the metabolism and effects of PAF (e.g., blocking the PAF receptor) may become important strategies of intervention of Alzheimer's disease, HIV-associated dementia or post-ischemic neuronal death.

In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treatment relapsed, whereas 7 relapsed in 37 cases in mono-treatment. This is the best clinical effect achieved in treating adult acute leukemia to this day, possibly making APL the first adult curable leukemia. Based on the great success of the pathogenetic gene target therapy in APL, this strategy may extend to other leukemias. Combination of Gleevec and arsenic agents in treating chronic myeloid leukemia has already make a figure both in clinical and laboratory research, aiming at counteracting the abnormal tyrosine kinase activity of ABL and the degradating BCR-ABL fusion protein. In acute myeloid leukemia M(2b), using new target therapy degradating AML1-ETO fusion protein and reducing the abnormal tyrosine kinase activity of c-kit will also lead to new therapeutic management in acute leukemias.
Antineoplastic Agents ; therapeutic use ; Benzamides ; Fusion Proteins, bcr-abl ; genetics ; metabolism ; Humans ; Imatinib Mesylate ; Leukemia, Promyelocytic, Acute ; drug therapy ; genetics ; metabolism ; Oncogene Proteins, Fusion ; genetics ; metabolism ; Piperazines ; therapeutic use ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; metabolism ; Pyrimidines ; therapeutic use ; Receptors, Retinoic Acid ; genetics ; metabolism ; Tretinoin ; therapeutic use

Adult ; Aged ; Cone-Beam Computed Tomography ; Dental Implantation, Endosseous ; methods ; Female ; Humans ; Hydrostatic Pressure ; Male ; Maxillary Sinus ; diagnostic imaging ; surgery ; Middle Aged ; Piezosurgery ; methods ; Sinus Floor Augmentation ; methods ; Tooth Loss ; surgery

Objective To investigate the protective role of senegenin(SEN)in the mouse ischemia-reperfusion injury and its mechanism.Methods Mice were divided at random into control group(the ligature was placed but not ligated for 225 min),is-chemia-reperfusion model group(the anterior descending coronary artery remained ligated for 45 min and then reperfused for 180 min)and SEN treatment group(30 mg/kg SEN was used 10 min before reperfusion).The myocardial infarct size was meas-ured by using Evans blue-TTC staining.Fluorescence assay was employed to detect the activity of Caspase-1 2 and Caspase-3 to assess the myocardial apoptosis.Western blot was used to detect the expression of two endoplasmic reticulum stress (ERS) markers,GRP78 and CHOP,in infarcted myocardia.Results Compared with the control group,the myocardial infarct size was significantly increased,the activities of Caspase-12 and Caspase-3 were increased by 4.71 fold and 3.37 fold,respectively,and the expression levels of ERS markers GRP78 and CHOP were conspicuously elevated in the ischemia-reperfusion model group.Pretreatment with SEN(30 mg/kg)could significantly reduce the myocardial infarct size,the activities of Caspase-12 and Caspase-3 and the expression levels of GRP78 and CHOP when compared with those in the ischemia-reperfusion model group and there was significant difference between the two groups(P<0.05 or P<0.01).Conclusion SEN can protect against the myocardial ischemia-reperfusion inj ury by ameliorating ERS-mediated myocardial apoptosis in mice.

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Objective To investigate the effect of flurbiprofen axetil(FA)on the acute lung injury(ALI)induced by LPS in rats.Methods Forty male SD rats weighing 190-220 g were nmdomly divided into 3 groups:group Ⅰ control(C,n=8);groupⅡ LPS(n=16)and group Ⅲ FA+LPS(n=16).In group Ⅱ and Ⅲ LPS 5 mg/kg in 1 ml of normal saline(NS)w88 given iv.In group Ⅲ FA 6 mg/kg in NS 1 ml was given Ⅳ 0.5 hbefore LPS administration.In group Ⅱ and Ⅲ 8 animals were killed at 2 h(T1)and 4 h(T2)after LPS administration respectively.Blood samples were obtained at T1 and T2 for blood gas analysis and determination of serum TXB2,6-keto PGF1α(by radio-immuno assay),TNF-α,IL-1β,IL-6 and IL-10 concentrations(by ELISA).Lungs were removed for determination of W/D lung weight ratio,lung water content(LC)and microscopic examination.ResultsCompared with group C,LPS signitlcanfly decreased PaO2,PaO2/FiO2 and increased PaCO2,W/D lung weight ratio,LC,serum TXB2,6-keto-PGF1α concentrations,TXB2/6-keto-PGF1α ratio and serum IL-1β,TNF-α,and IL-6 concentrations in LPS group.Pulmonary edema and hemorrhage were observed in LPS group.FA pretreatment significantly attenuated LPS-induced blood gas,bio-chemical and pulmonary histological changes in group Ⅲ.Conclusion Flurbiprofen axetil pretreatment can protect the lungs against LPS-induced acute injury by down-regulating TXB2/6-keto-PGF1α ratio and inhibiting inflammatory response.

Animals ; Brain Ischemia ; complications ; physiopathology ; Excitatory Amino Acid Antagonists ; pharmacology ; Humans ; Infant, Newborn ; Leukomalacia, Periventricular ; etiology ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; physiology ; Signal Transduction ; physiology

Stroke is one of the major diseases that threaten human health, early diagnosis and treatment are very important for stroke. Carotid intima-media thickness (CIMT) is measured noninvasively to diagnosis stroke, and it is a independent predictor for stroke because its thickening can timely predict the incidence and development of stroke. As an important predictor of cardiovascular disease, more and more attention is played on CIMT. In this review, we will make a summary on the important role of CIMT in stroke and the mechanisms of carotid intima-media thickening in stroke as well as the potential use of traditional Chinese medicine in treating carotid intima-media thickening.
Animals ; Carotid Arteries ; drug effects ; physiopathology ; Carotid Intima-Media Thickness ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Stroke ; diagnosis ; drug therapy ; physiopathology

AIM: To know the psychological conditions of various cataract patients in pre- and post-operative periods.METHODS: From June 2008 to June 2009, 278 cataract patients had been asked to complete a questionnaire anonymously of their self-evaluation of symptoms scale (SCL) before and after operation. In their pre-operative and post-operative surveys, the results were compared with the norms respectively. Patients were divided into two groups. Group A were age-related cataract patients; while Group B were cataract patients with glaucoma, trauma or metabolic disease.RESULTS: When cataract patients' masculine scores of somatization, depression, anxiety and fear factors before and after the operation rank higher than the norms, the differences had statistical significance(P＜0.05), especially the somatization factor(P＜0.01).While cataract patients with diseases such as glaucoma, trauma or diabetes got higher marks than age-related cataract patients in the aspects of anxiety, somatization, depression (P<0.05), and fear factors, the differences were of statistical significance(P<0.01).CONCLUSION: Cataract patients both in pre- and post- and operative periods have somatization behaviors and emotions of depression, anxiety and fear. Cataract patients with glaucoma, trauma or diabetes especially anxiety have more obvious symptoms than age-related cataract patients.

In order to determine whether the variations in the calpain-10 gene constitutes risk of type 2 diabetes (T2DM) in Chinese, the frequency of UCSNP-43, 44 in 268 adults newly diagnosed with T2DM (according to the 1999 ADA criteria) and 153 non-diabetic control subjects was investigated. For all subjects, the height, weight, waist-to-hip ratio (W/H) and blood pressure, as well as following parameters were measured: (1) 75-g oral glucose tolerance test with insulin, C-peptide, HbA1c and blood lipid profiles; (2) Genomic DNA extracted from peripheral blood lymphocytes was genotyped for UCSNP-43 (calpain-10-g. 4852 G/A) and UCSNP-44 (calpain-10-g. 4841 T/C) by sequencing a polymerase chain reaction (PCR)-amplified fragment. PCR product was selected by single strand conformation polymorphism (SSCP) and then sequenced. The results showed that there was significant difference between T2DM group and normal control group in allele frequencies, haplotype frequencies, or haplotype combinations of UCSNP-43 and -44 either. But in newly diagnosed T2DM group, it was found that the individuals with the genotype UCSNP-44 T/C + C/C had significantly increased fasting and post-challenge insulin levels (Fins and P2hIns), consistent with reduced insulin sensitivity. In the BMI> 25 subgroup, the differences were even more significant. It was demonstrated that the Calpain-10 gene polymorphism UCSNP-44 was associated with insulin sensitivity and Fins and P2hIns in newly diagnosed T2DM, although Calpain-10 doesn't appear as a major diabetes susceptible gene in this population.
Asian Continental Ancestry Group ; Calpain/*genetics ; Diabetes Mellitus, Type 2/*genetics ; Gene Frequency ; Genetic Predisposition to Disease/genetics ; Insulin Resistance/*genetics ; Phenotype ; Point Mutation ; Polymorphism, Genetic/*genetics