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.

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.

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.

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 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.

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.

We developed a three-dimensional finite element model of the shoulder glenohumeral joint after shoulder arthroplasty including humerus shaft, scapular, scapular cartilage and eight muscles, while each of the muscles was simulated with 50 spring elements. To reduce the element number and improve the analytical precision, we used mixed tetrahedral and hexahedral elements in the model. We then used the model to calculate the biomechanics of the shoulder glenohumeral joint after hemiarthroplasty during humeral external rotation. Results showed that the maximum joint reaction force was 374.72 N and the maximum contact stress was 6. 573 MPa together with the contact areas at 40 degrees external rotation. These might be one of the reasons for prosthetic disarticulation, and would provide theoretical bases to prosthetic design.
Biomechanical Phenomena ; Finite Element Analysis ; Humans ; Humeral Head ; anatomy & histology ; Models, Anatomic ; Prosthesis Design ; Range of Motion, Articular ; Rotation ; Shoulder Joint ; anatomy & histology

BACKGROUND:Tantalum rod implant technology is a new method of early osteonecrosis treatment. Current research on stress distribution before and after tantalum rod implant in different sizes of femoral head necrosis area is few. OBJECTIVE:To analyze the stress distribution before and after tantalum rod implantation in different sizes of necrotic femoral head area using three-dimensional finite element method. METHODS:Three-dimensional finite element models of normal femoral head and necrotic femoral head of 15, 20 and 30 mm diameterwere constructed. Eight measuring points were chosen on two tiers of each necrotic model to detect the stress distribution and its alteration before and after tantalum rod implantation. RESULTS AND CONCLUSION:(1) Stress concentration werefound on every necrotic femoral head, most pronounced on the one with 30 mm lesion. (2) Tantalum implant appeared to reduce the stress concentration generaly. Comparison of the peak points of these models indicated most significant benefit in 15 mm lesion, next in 30 mm lesion, last in 20 mm lesion. (3) Results indicate that larger lesion entails more concentrated stress distribution and more likely to colapse. Tantalum rod implantation can delay the development of necrosis of the femoral head, andismost effective in smal lesion.

OBJECTIVE:To establish the quality standard for Compound huaihua granules.METHODS:Sophora japonica,salvia miltiorrhiza,and Lonicera joponica in the formulation were identified qualitatively by TLC,and the content of rutin in Sophora japonica was determined by UV spectrophotometry.RESULTS: The TLC spots were clear and well-separated.The linear range of rutin was 2.904～14.52 ?g?mL-1(r=0.997 7) and its average recovery was 98.43%(RSD=0.55%,n=6).CONCLUSION: The established standard is suitable for the quality control of Compound huaihua granules.