Diversity-oriented synthesis (DOS) aims to efficiently generate collections of small molecules with diverse appendages, functional groups, stereochemistry and skeletons, thus yielding diverse biological activities capable of modulating a wide variety of biological processes. In this review, we discussed the common strategies employed in DOS with specific examples from recent literature, including reagent-based approach, substrate-based approach, build-couple-pair strategy and privileged substructure-based DOS. The application of some DOS libraries in drug discovery is also presented.
Drug Design ; Drug Discovery ; Small Molecule Libraries

Objective To compare the efficiency and safety of clopidogrel of different loading-dose in acute coronary syndromes(ACS) patients with percutaneous coronary intervention(PCI) therapy, and, give an assessment of security about higher loading dose of clopidogrel. Methods 120 patients from January 2008 to January 2009 in our hospital were included.They were randomly divided into 3 groups(na=nb=nc=40)and were given 600 mg,450 mg and 300 mg clopidogrel on the 6 hour before PCI. There was no significant difference between the three groups' basic clinical information(p>0.05),such as age, sex and so on. Four points were selected to observe: the platelet aggregation induced by ADP with 5umol/L before and two hours、four hours, six hours after taking medicine; Primary endpoint events, which include shock during hospitalization, death, target revascularization, myocardial infarction, recurrent angina, stroke in 30 days,and Postoperative Bleeding events and adverse Reactions after Surgery in 30 days. Results compared to the standard dose of 300 mg clopidogrel, 600 mg doses clopidogrel can give a greater degree of inhibition on platelet activating than 450 mg doses in the pre-6 h after administration. Increase Clopidogrel loading dose can reduce the occurrence of major cardiovascular events rate. Bleeding events and the occurrence of adverse events was no significant difference among three groups. Conclusions compared to the standard dose of 300 mg clopidogrel, a higher loading dose of clopidogrel can produce much more faster, greater platelet inhibition, and similar security.

Extranodal NK/T cell lymphoma is a kind of disease that is associated with EB virus infection and characterized by progressive distruction and necrosis of the nasal cavity and midline facial tissues, with histological features of diffuse lymphomatous cells inflitrate and inflammatory cells as abackground or angiocentric and angioinvasive inflitrate.The prognosis is poor,as it is highly aggressive and it can progress rapidly.This article mainly discusses and reviews the progress in treatment methods.

This paper presented the effects of experimental hyperinsulinemia on the main apolipoproteins (At, B) and on tbe process of reverse cholesterol transport in rabbit, which consisted of 1) uptake of cholesterol from peripheral tissue by HDL; 2) cholesterol esterification and 3) cholesterol ester transfer. The results showed that insulin could significantly decrease both serum and lymph Apo A1 levels and inhibit all the three steps of reverse cholesterol transport. The larger the dose of insulin, the greater the effects. Apo B did not seem to be influenced by insulin. It was further demonstrated by a series of statistical analyses that insulin had both direct and indirect inhibitory actions, to different extent, on each of the three main steps of reverse cholesterol transport.

Objective To study changes of trigemino-cervical reflex (TCR) in patients with Kennedy's disease (KD). Methods The parameters of TCR were analyzed among patients with KD, amyotrophic lateral sclerosis and healthy controls. Results The parameters of ipsilateral P19, N31, A and contralateral P19, N31, A among patients with KD were (23.91±4.84), (35.45±4.76) ms, 1.24± 0.33 and (24.34±4.82), (36.20±4.91) ms, 1.19±0.25, respectively. Compared with the healthy controls((18.37±2.16), (28.50±1.56) ms, 1.90±0.43; (18. 72±2. 18), (29. 19±1.43) ms, 1.84 ± 0. 40), the difference in each parameter was significant (ipsilateral : t = 5.77, 8. 19, -6. 64; contralateral:5.05, 7.62, -7.77, all P<0.01). Conclusion The parameters of TCR were abnormal in KD patients, indicating that the trigeminal nerves and the bulbar may be involved in the disease.

Objective To investigate the expression of autophagy and the effect of complement C5a/C5aR pathway on autophagy induced by renal ischemia reperfusion injury (IRI).Methods MaleWT and C5aR gene knockout (BALB/C background) mice were selected.The model of renal IRI was established by occluding bilateral renal pedicles with microaneurysm clamps.Mice were divided into wild type BALB/C (WT) group and C5aR gene knock out (C5aRKO) group.The pathology of kidney was assessed by HE staining.The levels of BUN and KIM-1 were detected 24 h after reperfusion.The expression of the autophagy-associated protein (LC3 Ⅱ/LC3 Ⅰ and P62) was measured by Western blotting and immunofluorescence.In vitro,human renal tubular epithelial cells (HK2) were cultured.The expression of LC3 in HK2 cells was investigated by immunofluorescence and Western blotting after being treated with recombinant C5a or C5a combined with C5aR antagonist (C5aRA).Results As compared with WT group,the severity of kidney injury was obviously reduced in C5aRKO group (P＜0.05).After ischemia-reperfusion,the expression of autophagy-related protein LC3 gradually increased with the reperfusion time prolonged.The level of autophagy induced by ischemia-reperfusion was significantly reduced in C5aRKO group as compared with WT group (P＜0.05).In addition,the expression of autophagy-related protein LC3 Ⅱ in HK2 cells was increased with the augment of C5a stimulation concentration in vitro.Blockage of C5aR pathway by C5aRA led to a significant decrease in autophagy (P ＜ 0.05).Conclusion Complement C5a/C5aR pathway promotes renal IRI-induced autophagy.

BACKGROUND:Tumor stem cels are found to be involved in the recurrence, metastasis and drug resistance of the tumor.
OBJECTIVE:To explore the relationship between cel activity and multidrug resistance of CD44+CD24-/low breast cancer stem cels.
METHODS:CD44+CD24-/low breast cancer stem cels sorted from multidrug resistant breast cancer cel line MCF-7/ADR were detected as percentage using flow cytometry. P-gp fluorescence intensity of the cel membrane and MDR mRNA expression in sorted cels and MCF-7/ADR were detected using flow cytometry and RT-PCR, respectively.
RESULTS AND CONCLUSION: After sorting by flow cytometry, the proportion of CD44+CD24-/low breast cancer stem cels was more than 90%, indicating that the sorted cels could meet the needs of the subsequent experiment. CD44+CD24-/low cel subsets exhibited stronger ability to form microspheres than non- CD44+CD24-/low cel subsets. The P-gp fluorescence intensity and MDR mRNA expression of CD44+CD24-/low cels were significantly higher than those of MFC-7/ADR cel line (P < 0.05). These experimental findings suggest that CD44+CD24-/low breast cancer stem cels sorted from MCF-7/ADR cel lines have a strong ability to form cel microspheresin vitro, and significantly raise the level of P-gp protein and MDR mRNA expression, which may be one of the causes of multidrug resistance.

Objective To assess the influence of the risk factors of coronary heart disease(CHD) on the prognosis of pereutaneous coronary interventions (PCI). Methods The risk factors of CHD was retrospectively col-lected from 446 patients (mean age (SD) : 60.23(9.75) yrs,84.97% male )who were admitted to the First Affili-ated Hospital of Lanzhou University from January, 2007 to July, 2008. These patients were diagnosed as CHD and treated with PCI. Major adverse cardiac events (MACE) were followed up for 12 months after PCI,and its associatian with the risk factors of CHD was investigated. Results Among all the patients,2.24% (10/446) had family history of CHD, 20.63% (92/446) was complicated with diabetes, 52.26% (242/446) with hypertension, 42.15% (118/446) with dyslipidemia, 62.33% (278/446) of the patients was overweight, and 57.85% (258/446) was smoker. Within 12 months of follow-up, MACE incidence rate were 5.83%. Univariate analysis showed the propor-tions of female,family history of CHD, overweight, hypertension and smoker were significandy different between the patients with MACE and those without MACE (χ~2=4.133,6.848,3.997,3.939,4.120, respectively,P<0.05). Logistic regression analysis showed family history and overweight increased the risk of MACE (OR=7.383 and 10. 504,respectively,95% CI=1.639-33.246 and 1.231-59.598, P<0.05), being male protected against MACE (OR=0.058,95%CI=0.014-0.236,P<0.05). Conclusions The prognosis of patients of CHD under-went PCI was good. After PCI,the risk factors of CHD such as smoking,hypertension ,overweight,ete should be un-der control to decrease the occurrence of MACE.

Objective:To find out the existing pattern of HPV16 in tongue cancer cell and to analyze itsrole in carcinogenesis of tongue cancer. Methods :Southern blot hybridization was used to detect the HPV16sequence and its existing condition in 20 cases of fresh human tongue cancers. Results:HPV16 DNA se-quence in 5 cases of 20 tongue cancers was detected. And HPV16 DNA existed in tongue cancer cell in non-integration pattern. Conclusion:HPV16 was involved in carcinogenesis of tongue cancer through interactionof HPV gene products rather than its integration with genome of target cell.

Objective To determine the roles of MyD88 and Trif,critical adaptor proteins for TLR signaling,in production of donor-specific antibodies (DSA) and memory T cells in a presensitized mouse cardiac transplant model.Methods Skin grafts from Balb/c mice were transplanted into either wild type B6 mice or B6 Myd88 and Trif double knockout mice (Myd88/Trif DKO).The recipients were subsequently transplanted heterotopically with cardiac grafts from the same donors two weeks after skin transplantation.Plasma DSA levels and spleen phenotypical analysis were performed prior to heart transplant or at time of cardiac rejection by using flow cytometry.Results Recipients presensitized with skin grafts developed accelerated cardiac allograft rejection in the absence of Myd88 and Trif.However,plasma DSA,especially IgG2,was significantly decreased (P＜0.05) in Myd88/Trif DKO mice,compared to that in Wild Type mice at 2nd week after skin transplantation.The production of DSAs including all IgG subtypes was further reduced 3 days following heart transplantation in the Myd88/Trif DKO.In addition,MyD88/Trif DKO mice had impaired ability to generate memory T cells,as percentages of both CD44hi CD4+ and CD44hi CD8+ were significantly lower in the DKO than in Wild Type mice (P＜0.01,P＜0.05).Conclusion Simultaneous ablation of MyD88 and Trif in recipients significantly decreases the production of serum DSAs and spleen memory T cells following allogeneic skin and heart transplantation,supporting a crucial role of TLR signaling in adaptive immune responses in organ transplantation.