Objective To explore the effect of Mcl-1 small interference RNA ( siRNA) on tumor necrosis factor-re-lated apoptosis-inducing ligand ( TRAIL)-induced apoptosis in gastric cancer HGC-27 cells. Methods The apop-totic rates of cells treated with TRAIL and pan-caspase inhibitor ( z-VAD-fmk) alone or combination were measured by propidium iodide (PI) method using flow cytometry. The activation of caspase-3, cleavage of PARP-1, as well as the protein level of anti-apoptotic Bcl-2 proteins Bcl-2, Bcl-XL and Mcl-1 before and after TRAIL treatment were monitored by Western blot analysis. Transfection of Mcl-1 siRNA was performed using Lipofectamine 2000 reagent. The efficiency of gene silencing was quantified by Western blot and the effect of Mcl-1 siRNA on TRAIL-induced apoptosis was measured using PI method. Results HGC-27 cells were resistant to TRAIL-induced apoptosis, and z-VAD-fmk pretreatment could block apoptosis nearly completely. Activation of caspase-3 and cleavage of PARP-1 occurred in the late stage of apoptosis. The expression levels of Bcl-2, Bcl-XL and Mcl-1 were not altered after exposure to TRAIL. Transfection with Mcl-1 siRNA could obviously downregulate the expression evel of Mcl-1 in HGC-27 cells and enhanced the sensitivity of cells to TRAIL-induced apoptosis. Conclusion Overexpression of Mcl-1 may account for the resistance of HGC-27 cells to TRAIL.ownregulationof Mcl-1 by siRNA can effectively enhance the sensitivity of HGC-27 cells to TRAIL-induced apoptosis.

Proteolysis-targeting chimera (PROTAC), as an emerging treatment method, has become one of the hottest technologies in the field of new drug research with a near-20-year development. PROTAC utilizes the natural ubiquitin-protease system in cells to induce targeted protein degradation, especially for protein of interest that are difficult to target by traditional small molecules. Moreover, PROTAC is expected to solve the problem of drug resistance that often occurs with small molecule drugs. However, the excessive relative molecular weight, poor solubility and membrane permeability, and low oral absorption of PROTAC make it challenging to druggability study. Currently, take pharmacokinetic characteristics as the entry point to continuously optimize and improve, so as to accelerate the transformation of PROTAC from laboratory to clinical application. Based on the basic structure and mechanism of PROTACs, this review introduces its pharmacokinetic properties, analyzes how to design efficient and stable PROTAC molecules, summarizes its current research progress in various diseases treatments, evaluates the development prospects and limitations of PROTAC, in order to provide more references for further research and application of PROTAC.

Abstract: A new selaginellin derivative named as selaginellin S (1) was isolated from the whole plants of Selaginella pulvinata (Hook. et Grev.) Maxim. (Selaginellaceae), together with a known one (selaginellin M, 2). Compounds 1 and 2 were separated and purified by silica gel and Sephadex LH-20 column chromatography. Their structures were determined on the basis of extensive spectroscopic analysis including IR, MS, 1D and 2D NMR experiments, as well as ECD calculations. Compound 1 is a key intermidiant in the biosynthesis pathway of selaginellins. Compound 2 is first reported in this plant.
Biphenyl Compounds ; chemistry ; isolation & purification ; Cyclohexanones ; chemistry ; isolation & purification ; Molecular Structure ; Selaginellaceae ; chemistry

Objective To investigate the correlation between microalbuminuria (MAU) and obesity and its indexes, including BMI, waist circumference(WC), and waist-to-hip ratio(WHR) , among partial community population in Beijing. Methods A total of 2080 subjects who took physical examination in Beijing, including 810 men and 1270 women with a mean age of(50. 9 ± 13. 1 )years, were enrolled. The informed consent has been achieved from each patients. BMI and WHR were calculated based on collected data of height, weight, WC, and hipline. Urine albumin-creatinine ratio(ACR) within the range of 30-300mg/g was classified as MAU. The subjects were divided into normal albuminuria ( NAU ) group and MAU group. The correlations between MAU and different obesity indexes including BMI, WC and WHR, were analyzed. Results Among the 2080 subjects, there was a positive correlation between BMI (r = 0. 1276,P＜0.01) and ACR, and WC (r = 0.0840, P ＜0.01) and ACR. WHR and ACR was irrelevant ( P ＞ 0. 05 ). In univariate analysis, there was significant difference in BMI ≥ 28 kg/m2 ( OR = 2. 02 ) and WC ≥85 cm (male) or≥80 cm (female) (OR = 1.69 ) between NAU group and MAU group (P ＜ 0. 05 ).There was no significant difference in BMI 24-＜ 28 kg/m2, and WHR ≥0. 90 (male) or ≥0. 85 (female)between NAU group and MAU group( P≥0. 05 ). Multivariate logistic regression analysis revealed that BMI ( OR = 1.06) was an isolated independent risk factor of MAU from age ( OR = 1.01 ), female ( OR = 1.42),systolic blood pressure (OR=1.01), TC (OR=1.93) and HDL-C (OR=0.54). Conclusions Obesity is an independent risk factor of MAU among partial community population in Beijing. The correlation between different obesity indexes and MAU also differs.

AIM　To investigate the transdermal delivery effects of cyclosporine A solubilized in mixed micelles composed of phospholipid and different surfactants. METHODS　When applied onto the excised abdominal skin of the mice occlusively, the enhancing effects of various mixed micelles on the penetration of cyclosporin A were assessed by an in vitro permeation technique. In vivo study was carried out by topical application of sodium cholate-phospholipid mixed micelles onto the mice skin and drug blood concentration was detected. RESULTS　In vitro, mixed micelles containing different surfactants displayed distinct permeability and corresponded to the following order: sodium cholate > sodium deoxycholate > Trition X-100 > Tween-20. In vivo, peak drug concentration was detected at 5 h and after that the concentration fell down slowly. CONCLUSION　Mixed micelles were shown to be efficient carrier for the transdermal delivery of the lipophilic polypeptide when kept in solution during the application process.

Objective To observe the protection effects of sodium ?-aescinate(SA) on the nervous function in the rats with early spinal cord injury(SCI). Methods One hundred and twenty SD rats were randomly divided into four groups(n=30).Rats in the blank control group were performed laminectomy only,while those in the other three groups were injured at the level of Tl1 spinal segment by Allen's weight drop method(10 g ?10 cm) and immediately intraperitoneally given normal saline(5.0 mg/kg)(control group), SA(5.0 mg/kg)(SA group) and methylprednisolone(100 mg/kg)(MP group) once daily,respectively.After 8 h,24 h,96 h,7 d and 14 d,spinal cord function change of posterior limb were determined with Rivlin method.The rats were sacrificed and the injured segments were resected for pathological analysis. Results As time prolonged,the rehabilitation of spinal cord function with various degree could be observed in each group.Function rehabilitation was found among the rats in the control group,SA group and MP group 96 h after injury,and more rehabilitation was gained later in the latter two groups,while that was not the case in the control group.Rats in the SA and MP group gained more significant rehabilitation than those in the control group(P0.05).It was revealed by pathological analysis that no necrotic neurons was found in the blank control group,and the necrotic neurons in the SA group and MP group were significantly less than the control group at the same time points(P

AIM:To observe the expression of tumor necrosis factor-alpha ( TNF- α) and its receptor I ( P55 ) in different pterygium and discuss the role of TNF-α and receptor I (P55) in pterygium.
METHODS: Immunohistochemistical staining method ( PV) was adopted to detect the expression of TNF-α and receptor I in pterygium ( 72 eyes ) and para-pterygium conjunctival tissue ( 30 eyes ) . The relationship between the expression and clinical-pathological parameters was also analyzed.
RESULTS:The positive rates of TNF-αwere 65. 3% (47/72), 26. 7% (8/30) in pterygium and para-pterygium conjunctival tissue. The positive expression of TNF-α had statistic difference between the two groups (χ2=12. 706, P<0. 01). The positive rates of TNF-α receptor I were 56. 9% (41/72), 16. 7% (5/30) in pterygium and para-pterygium conjunctival tissue. The positive expression of P55 had statistic difference between the two groups (χ2=13. 875, P<0. 01). The positive rate of TNF-αin recurrent pterygium group was higher than primary pterygium group (χ2=6. 547, P=0. 011). There had no statistically significance of the expression intensity between the two groups (F=1. 288, P=0. 393); the positive rate in advanced pterygium group was higher than quiescent pterygium group (χ2=4. 082, P=0. 043). The expression intensity had no statistically significance between the two groups (F=0. 489, P=0. 708). The positive rate of P55 in recurrent pterygium group was higher than primary pterygium group (χ2 =9. 907, P= 0. 002). There had no statistically significance of the two group's expression intensity ( F = 1. 175, P = 0. 424 ); the positive rate in advanced pterygium group was higher than in quiescent pterygium group (χ2=11. 140, P=0. 001). The expression intensity had no statistically significance between the two groups (F=0. 665, P=0. 621).
CONCLUSION:The expression of TNF-α and P55 are changing according to the development of clinical staging and onset. The expression of TNF-α and P55 may be related to clinical classification, staging and patient's working conditions of pterygium. There has no significant difference expression intensity of TNF - α and P55 in clinical staging and onset of pterygium.

Objective To explore the role of intercellular adhesion molecule-1(ICAM-1)and lym- phocyte function-associated antigen-I(LFA-1)in the pathogenesis of Sjgren's syndrome(SS)and provide a theoretical basis for clinical therapy.Methods Immunohistochemical method was used to detect these two cellular adhesion molecules in labial salivary glands of primary Sjgren's syndrome patients and 15 healthy controls.Semiquantitative analysis was performed by image analysis software.Results①In salivary gland samples,the expression of both ICAM-1 and LFA-1 was significantly higher compared to that of controls(P

The effects of continuous subcutaneous insulin injection (CSII, n=306) and multiple subcutaneous insulin injection (MSII, n=310)on hyperglycemia in patients with diabetes mellitus were compared. The results suggest that the effect of CSII is more prompt and efficient with lower incidence of hypoglycemia as compared with MSII.

Objective To evaluate the feasibility, toxicity and clinical efficacy of simultaneous modulated accelerated radiation therapy(SMART)for nasopharyngeal carcinoma. Methods Thirty eight patients with nasopharyngeal carcinoma were treated by SMART with 2.5?Gy/fraction at gross tumor volume(GTV)to a total dose of 70?Gy and 2.0?Gy/fraction at the clinical treatment volume(CTV)to a total dose of 56?Gy in 38 days. Quantitative 99m Tc pertechnetate salivary scintigraphy was used to assess the uptake and excretion index (EI、UI) of parotid gland in order to validate the value of IMRT in parotid gland sparing. Results The mean doses delivered to the GTV and CTV were 67.2?Gy and 57.0?Gy, respectively. An average of 1% of GTV and 2% of CTV received less than 90% or 95% of the prescribed dose. The mean dose to the contralateral parotid were 23?Gy and no significant decline in EI and UI as compared with significant decline in the ipsilateral parotid by 43.6% and 26.3%(P