Multi-target drugs attract increasing attentions for the therapy of complicated neurodegenerative diseases. In this study, a computer-assisted strategy was applied to search for multi-target compounds by the pharmacophore matching. This strategy has been successfully used to design dual-target inhibitor models against both the acetylcholinesterase (AChE) and poly (ADP-ribose) polymerase-1 (PARP-1). Based on two pharmacophore models matching and physicochemical properties filtering, one hit was identified which could inhibit AChE with IC50 value of (0.337 +/- 0.052) micromol x L(-1) and PARP-1 by 24.6% at 1 micromol x L(-1).
Acetylcholinesterase ; metabolism ; Cholinesterase Inhibitors ; pharmacology ; Computer-Aided Design ; Drug Discovery ; methods ; Poly(ADP-ribose) Polymerase Inhibitors

Dimethyl sulfide (DMS) has been historically recognized as a metabolite of the marine microorganism or a disgusting component for the smell of halitosis patients. In our recent study, DMS has been identified as a cytoprotectant that protects against oxidative-stress induced cell death and aging. We found that at near- physiological concentrations, DMS reduced reactive oxygen species (ROS) in cultured PC12 cells and alleviated oxidative stress. The radical-scavenging capacity of DMS at near-physiological concentration was equivalent to endogenous methionine(Met)-centered antioxidant defense. Methionine sulfoxidereductase A (MsrA), the key antioxidant enzyme in Met-centered defense, bound to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, Glu115, followed by the release of dimethyl sulfoxide (DMSO). MTT assay and trypan blue test indicated that supplement of DMS exhibited cytopro?tection against 6-hydroxydopamine and MPP + induced cell apoptosis. Furthermore, MsrA knockdown abolished the cytoprotective effect of DMS at near- physiological concentrations. The present study reveals new insight into the potential therapeutic value of DMS in Parkinson disease.

BACKGROUND:Anterior cruciate ligament (ACL) injury is a commonly sport-induced knee joint injury that does serious harm to the knee stability. ACL reconstruction is a commonly used treatment method, but researches on 1/2 peroneus longus tendon (PLT) graft are rarely reported. OBJECTIVE: To investigate the clinical outcomes of removing the autologous ipsilateral 1/2 PLT under arthroscopy for ACL reconstruction. METHODS:106 patients with complete ACL rupture in the Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University from December 2010 to December 2014 were enrolled, and autologous ipsilateral 1/2 PLT was removed under arthroscopy for ACL reconstruction. At baseline, 3, 6 and 12 months postoperatively, the knee stability was evaluated manually through the anterior drawer test, Lachman test, and pivot-shift test, and the knee function was evaluated by Tegner activity scale, Lysholm and International Knee Documentation Committee scores. RESULTS AND CONCLUSION: Postoperative anterior drawer test, Lachman test, and pivot-shift test tests were negative in all patients. In terms of Tegner activity scale, Lysholm and International Knee Documentation Committee scores, there were significant differences at baseline and postoperative 3 months as compared with postoperative 6 months (P < 0.05); the scores at baseline and postoperative 3 months showed significant differences compared with 12 months postoperatively (P < 0.05); the scores showed no significant difference between 6 and 12 months postoperatively (P > 0.05). These results indicate that autologous ipsilateral 1/2 PLT is a good choice for ACL reconstruction under arthroscopy, achieving rapid and satisfactory functional recovery of the knee joint, which is not only minimally invasive and easy to operate, but also exhibits good therapeutic efficacy.

BACKGROUND: Greater tuberosity of humerus, as the attachment point of rotator cuff, plays a vital role in shoulder.Neer and AO classification for proximal humeral fractures have been accepted extensively. However, the classification for single greater tuberosity fractures of the proximal humerus is little reported, and its fixation method remains controversial.OBJECTIVE: To explore the curative efficacy of the double-row suture anchors under arthroscopy for avulsion-type greater tuberosity fractures (Mutch type Ⅰ) METHODS: Clinical data of 24 patients with avulsion-type greater tuberosity fractures (Mutch type Ⅰ) undergoing double-row suture anchors under arthroscopy were analyzed retrospectively. The displacement distance of the greater tuberosity of humerus was measured on CT before and after fixation. The shoulder joint was evaluated by Constant-Murley Score and the University of California, Los Angeles score at baseline, 1, 3, 6 and 12 months postoperatively. Besides, the visual analogue scale scores were detected at baseline and 12 months postoperatively.RESULTS AND CONCLUSION: (1) Double-row suture anchors effectively improved the displacement of greater tuberosity and rotator cuff injury. (2) The patients accompanied by rotator cuff injury accounted for 79.16%. (3) The Constant-Murley Score and the University of California, Los Angeles scores were significantly improved at each time point (P < 0.05). The visual analogue scale scores after fixation were significantly superior to those before fixation (P < 0.05). (4) These results suggest that the double-row suture anchors under arthroscopy can effectively improve the displacement of greater tuberosity and alleviate the pain. Moreover, it is conductive for early recovery of the shoulder function with little trauma, so it is a good choice for avulsion-type greater tuberosity fractures (Mutch type Ⅰ).

OBJECTIVE: To compare randomized controlled trial (RCT) study and observational study systematically, and to provide reference for selecting suitable study design types for clinical researchers. METHODS: RCT study and observational study were compared in respects of study design and study report paradigm. Relevant literatures were retrieved from PubMed database and Chinese Journal Full-text Database. The differences of literature publication of RCT study and observational study were compared at home and abroad. RESULTS: There were differences in design principles, objectives, subjects, interventions and validity between RCT study and observational study. The requirements of CONSORT statemtnt and STROBE statement to the topics, abstracts, introduction, results and discussions of report paradigm of two studies were basically consistent, and main difference of them were in aspects of methods and other information. The number of literatures about RCT study and observational study had little gap at abroad, but had great gap at home, especially in cohort study with high-level evidence of evidence-based medicine. CONCLUSIONS: The observational study has developed rapidly in recent years, but RCT study is still a "gold standard" to evaluate the causal effect of clinical study. The researchers should choose the appropriate type of design according to the actual situation.

The Micro-infusion syringe pump has been widely used in infusion of various vasoactive agents. There are several modes of syringe replacement with advantages or limitations respectively. It is important to maintain the stability of hemodynamic parameters during the syringe replacement. In the times of the reformation of medical and medical insurance payment, it is worth paying attention to monitor costs of medical consumables. The large sample multicenter study is needed to reveal the relationships between the hemodynamic parameters and the sorts and volume of various vasoactive agents. It will provide the basis for the clinical choice of syringe replacement modes.

Objective:To study the feasibility of transplantation of normal rat penile corpus cavernosum and major pelvic ganglion (MPG)into the renal subserous region of a Nu /Nu mouse based on allograft technology.Methods:Penile corpus cavernosum and MPG,harvested from Sprague-Dawley (SD)rats under sterile condition,were transplanted underneath the kidney capsule of Nu /Nu mice through the mi-crosurgery instruments and surgery microscope.The histopathologic changes and cellular proliferation in the transplanted penile corpus cavernosum and MPG were then analyzed at the end of 1week and 4 weeks after transplantation.Histological staining and immunohistochemical staining were used to evaluate the main outcome measures.Results:After 1 week,the tissue morphology of the transplanted corpus caverno-sum underneath the kidney capsule of Nu /Nu mice was consistent with normal penile corpus cavernosum, and blood could be observed in the penis cavernous sinus of the graft;after 4 weeks,the mophorlogy of the tranplanted corpus cavernosum near the kidney was consistent with normal penile corpus cavernosum, while fibrosis was noteworthy in the graft away from the kidney,but blood could still be seen in the penis cavernous sinus.After 1 week,the tissue morphology of the transplanted MPG was consistent with normal MPG,multiple islet-like cell clusters could be seen in the transplanted MPG in the renal subserous re-gion,and angiogenesis could be observed near the kidney;after 4 weeks,a network of blood vessels was clearly visible away from the kidney,and islet-like cell clusters were still clearly observed in the trans-planted MPG.In addition,ki67 positive cells were observed in the transplanted penile corpus cavernosum and MPG after 4 weeks of transplantation,which indicated that there was still cell proliferation activity in the grafts.Conclusion:The transplanted corpus cavernosum and MPG underneath the kidney capsule of Nu /Nu mice could survive at least 4 weeks.Moreover,the inner structure of the transplanted corpus ca-vernosum and MPG was close to the normal tissue.The underlining mechanism may be related to the lo-cal microenvironment underneath the kidney capsule of Nu /Nu mice and the neovascularization in the transplanted grafts.

Objective To detect 10 kinds of human milk oligosaccharides (HMOS) and compare their amounts during lactational stage.Methods Breast milk samples in different stages of lactation as colostrum (day 0-7 postpartum),transitional milk (day 8-15 postpartum),and mature milk (day 16-180 postpartum) were collected and 10 HMOS in those samples were detected and quantified by ultra high performance liquid chromatography-fluorescence detection after fluorescence labeling by using standard curves.Correlations between HMOS and lactation day were conducted by Person correlation analysis method,while the differences among three stages were calculated by ANOVA test.Results Ten HMOS were successfully separated and quantified under chosen chromatographic parameters.2'FL,3'SL,6'SL,LNT,LNnT and LNFP-I were negatively correlated and 3'FL was positively correlated with lactation days.They were different in three lactational stages (P ＜ 0.05),while P1,LNFP-V and LNnFP-V showed no correlation and difference (P ＞ 0.05).Conclusion The amount of HMOS changed during lactational stages.Seven HMOS were correlated with lactation days and different in three lactational stages (P ＜ 0.05).

OBJECTIVETo investigate the relationship between gene polymorphism of CYP2E1, CYP1A1, IL-4 and susceptibility of medicamentosa-like dermatitis induced by trichloroethylene (TCE).

METHODS35 patients with medicamentosa-like dermatitis induced by TCE were chosen as the patient group, and 35 healthy workers as control group. The real-time quantitative polymerase chain reaction (PCR) with TaqMan minor groove binding (MGB) probes was used to test single nucleotide polymorphisms (SNP) of CYP2E1, CYP1A1 and IL-4 in the patients with medicamentosa-like dermatitis as well as in the control. The genotypes and the frequency of genotype or allele were compared between the patients and control with statistical analysis.

RESULTSThe frequency of allele G within CYP1A1 gene (rs1048943) was significantly higher in TCE patients (37.1%) than that in control (P<0.05); the frequency of allele T within CYP2E1-1053 C/T was significantly higher in TCE patients (41.4%) than that in control (P<0.01); the frequency of T/T within IL-4-588 C/T (rs2243250) was significantly higher in TCE patients (75.0%) than that in control (P<0.01), and the frequency of allele T within IL-4-588 C/T (rs2243250) was also significantly higher in TCE patients (87.5%) than that in control (P<0.01).

CONCLUSIONThe gene polymorphism of CYP2E1, CYP1A1, IL-4 is probably associated with hypersensitivity for the TCE patients with medicamentosa-like dermatitis, and could be one of the genetic factors related to the individual susceptibility to TCE exposure.

Cytochrome P-450 CYP1A1 ; genetics ; Cytochrome P-450 CYP2E1 ; genetics ; Dermatitis, Occupational ; genetics ; Genetic Predisposition to Disease ; Humans ; Interleukin-4 ; genetics ; Polymorphism, Single Nucleotide ; Trichloroethylene ; adverse effects

BACKGROUNDBlocking the 4-1BB/4-1BB ligand (4-1BBL) signal may modulate the secretion of Th1/Th2 cytokines and prolong the survival of the grafts, which play a key role in organ transplantation tolerance. The aim of this study was to investigate the role of blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody (mAB) in acute rejection of rat orthotopic liver transplantation.

METHODSThe orthotopic liver transplantation model was set up, while male Lewis rats were used as liver donors and Brown-Norway rats as recipients. The recipient rats were intravenously injected with anti 4-1BBL mAB or isotype control antibody. Groups were monitored for graft survival after transplantation. Plasma chemistry, including aspartate transaminase (AST), alanine aminotransferase (ALT), and bilirubin (BIL), was assayed. The concentrations of interleukin (IL)-2, IL-10 and interferon (IFN)-gamma in plasma were also measured by enzyme-linked immunosorbent assay. Allograft histology images were collected under light microscope and electron microscope.

RESULTSIsotype antibody treated recipients exhibited elevated plasma levels of liver injury markers including AST, ALT and BIL, progressive portal and venous inflammation and cellular infiltration of the liver allografts, and a mean graft survival time (MST) of 10.9 days. Administration of anti 4-1BBL mAB resulted in a decrease in plasma levels of liver injury markers and the concentrations of IL-2, IL-10 and IFN-gamma. The histological grade of rejection on day 7 decreased and MST (17.3 days) increased substantially.

CONCLUSIONSThese results demonstrate that attenuation of acute rejection follows the blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody and strongly suggest it is a promising strategy to prevent progression of graft rejection by suppressing T cell-mediated immunity.

4-1BB Ligand ; immunology ; Alanine Transaminase ; metabolism ; Animals ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Aspartate Aminotransferases ; metabolism ; Bilirubin ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Graft Rejection ; immunology ; prevention & control ; Graft Survival ; drug effects ; Interferon-gamma ; blood ; Interleukin-10 ; blood ; Interleukin-2 ; blood ; Liver Transplantation ; adverse effects ; Male ; Rats ; Rats, Inbred Lew