Objective Regenerating genes express mainly in gastrointestinal tissues and the injured regenerating pancreatic tissues,which can promote the regeneration of pancreatic β cells and other tissue cells.In recent years,researches on Reg family mainly involved the gene structure of various subtypes of Reg,and its role in diabetes,gastrointestinal cancer,inflammation,anti-microbial and the related mechanisms.Among the various subtypes of Reg,regenerating geneⅢ(Reg3) plays a particularly crucial role in these diseases.Therefore,Reg3 is a promising target for the treatment of these diseases.Based on the relationships of Reg3 with a variety of diseases,our group devote to the role of Reg3 [human REG3A,and mouse Reg3γ(Reg3g)] in type 1 diabetes,inflammation-linked pancreatic carcinogenesis,and the immunological changes participated in these processes.Hence,this review will summarize serial studies on Reg3 and the feasibility of it as drug targets.

ObjectiveTo observe the effect of community-based rehabilitation (CBR) on older stroke patients in ability of activities of daily living (ADL).Methods50 older stroke patients were randomly divided into the rehabilitation group and control group. The rehabilitation group was treated with motor function exercise and ADL training, while the control group only took medicine. Two groups were evaluated with Barthel index before and after treatment. ResultsScores of Barthel index on the rehabilitation group were higher than that on the control group after treatment, and there was a significantly difference between two groups (P<0.01). Conclusions CBR has the significant effect on improving ADL in older stroke patients.

Objective To investigate the effect of recipient's pre-transplant triglyceride (TG) abnormalities on early graft function (EGF) after kidney transplantation.Methods According to the inclusion and exclusion criteria,154 identified living-kidney transplant recipients in the 309 Hospital of Chinese PLA from Jan.2011 to Dec.2014 were enrolled in present study,including 124 males and 30 females,and aged of 31.9 ± 8.4 years.The cohort was divided into two groups:TG normal group (0.40＜TG≤1.70mmol/L,n=107) and TG abnormalities group (TG＞l.70mmol/L or require lipid lowering therapy,n=47).The incidences of poor early graft renal function (PEGF),slow graft function (SGF) and delayed graft function (DGF) were compared between the two groups,and then the serum creatinine (Scr) levels were compared among the patients showing immediate graft function (IGF) at 3rd,7th and 30th day after transplantation.The ROC curve was drawn up taking TG as diagnosis index to explore the optimal cut-offvalue for predicting PEGF,SGF and DGF after transplantation.Results Compared with the TG normal group,the TG abnormalities group showed significantly higher incidence of PEGF and DGF (P＜0.05).Among the IGF patients,the TG abnormalities group showed higher Scr level at the 7th and 30th day after transplantation (P＜0.05).The area under ROC curve (AUC) reflected TG levels for PEGF,SGF and DGF were 0.774,0.704 and 0.818,respectively (P＜0.05).The optimal cut-offvalues were all 1.37mmol/L.Conclusions Recipients with abnormal pre-transplant TG level may have worse EGF after renal transplantation.The risk of developing PEGF,S GF and D GF tends to emerge when pre-transplant TG level is higher than 1.37mmol/L.

The GFP(green fluorescence protein)-streptavidin(SA) bi-functional fusion protein was generated and characterized in order to demonstrate novel platform for efficiently and durably modifying the cell surface with SA-tagged bi-functional proteins.The GFP-SA/pET24d construct was generated and expressed in BL21(DE3) host bacteria at the high level.The recombinant protein GFP-SA was purified through the Ni-NTA affinity chromatography,and then refolded.After biotinylation B16 tumor cells were modified with GFP-SA bi-functional fusion protein and then subjected to fluorescent microscopy and FACS analysis.The effect of surface modification on the viability and growth of B16.F10 tumor cells was evaluated by MTT staining.The GFP-SA recombinant fusion protein was expressed in BL21(DE3) at about 20 % of total bacterial proteins.The GFP-SA bi-functional fusion protein exhibited the bi-functionality,i.e.,SA-mediated high-affinity binding to biotinylated cell surfaces and GFP-emitted green fluorescence.The cell surface modification with GFP-SA bi-functional fusion protein did not affect the viability and growth of the modified B16.F10 tumor cells significantly.The GFP-SA bi-functional fusion protein was obtained and could be displayed efficiently on the surface of the biotinylated B16.F10 tumor cells through the specific and tight interaction between streptavidin and biotin,thus can be used as good trace protein and experimental control in the development of surface-modified tumor vaccine.

Objective To screen the variation in NeuroD1 gene and to study its function in vitro and its clinical phenotypes and genetic characteristics in Chinese early-onset type 2 diabetic probands. Methods PCR-direct sequencing of NeuroD1 gene was performed in 85 early-onset type 2 diabetic probands, 95 late-onset type 2 diabetics with strong diabetic history and 87 non-diabetic control subjects. Distributions of the identified variation were calculated and compared among the three groups. Expression vectors with mouse NeuroD1 (mND1)cDNA wild type or mutant type and reporter vectors with human insulin promotor-linked luciferase were constructed. Then the above vectors were co-transfected into rat INS-1 cells. Relative luciferase activities were measured to compare transcriptional activities of insulin gene between WT and MT. Results S159P (T→C), a new mutation was identified in a proband, which was co-segregated with diabetes in 4 carriers from the paternal side. The functional study showed that the S159P mutant exhibited a 25% reduction in transcriptional activity of insulin gene as compared with the wild type. A45T (G→A), a common variation was identified. The AA + GA genotypic frequencies were markedly increased in early-onset type 2 diabetic probands as compared with late-onset type 2 diabetic probands and non-diabetic control subjects (P=0.006 and P=0.014, respectively). Conclusion The novel S159P mutation in the NeuroDl gene seems to contribute to the development of diabetes in the Chinese early-onset type 2 diabetic family. The A45T variation may increase susceptibility to or be in disequilibrium with early-onset type 2 diabetes mellitus in Chinese population. In addition, the A45T variation may affect the onset pattern of type 2 diabetes mellitns, such as early-onset but not late-onset type 2 diabetes mellitus.

Objective To investigate the expression and significance of calcyclin binding protein (CacyBP)in the brain of rat model of traumatic brain injury(TBI).Methods Sixty 60 male SD rats were divided randomly into normal control group (n=10) and TBI group (n=50).The TBI model was created by using lateral head rotation device and subdivided into 6 h,24 h,72 h,7 d and 14 d group (10 rats per group).The expression and distribution of CacyBP in the rat brain was investigated immunohistochemically.The presence of the brown stained particles was considered aspositiveand lack of the stained particles agnegative. Results CacyBP was mainly distributed in the hippocampus,dentate gyrus and cortical neuron cytoplasm.Compared with the high level expression of CacyBP in the normal control group,the expression of CacyBP was decreased to the lowest in the rat brain at 6 h post TBI (P<0.01),became stronger gradually at 24 hours and recovered to normal at day 14,with no statistical difference compared with normal control group (P>0.05). Conclusion The lowest level expression of CacyBP after TBI indicates that CacyBP may play an important role in development of brain injury under effect of difierent mechanisms.

Poly(ADP-ribose) polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. It can polymerize ADP-ribose units on its substrate proteins which are involved in the regulation of DNA repair. In this work, a novel series of para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones was designed and synthesized, and the inhibitory activities against PARP-1 of compounds 7a-7e, 8a-8f, 9a-9c and 10a-10c were evaluated. Of all the tested compounds, nine compounds displayed inhibitory activities with IC50 values ranging from 4.6 to 39.2 micromol x L(-1). In order to predict the binding modes of the potent molecules, molecular docking was performed using CDOCKER algorithm, and that will facilitate to further develop more potent PARP-1 inhibitors with a quinazolinedione scaffold.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Drug Design ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Molecular Docking Simulation ; Molecular Structure ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Quinazolinones ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship

OBJECTIVE To investigate enhanced immune function of methionine encephalin (MENK) and its anti-tumor mechanism in CT26 colon cancer mouse model. METHODS 3×106 CT26 cells were implanted subcutaneously in BALB/c mice. Four days after, MENK was peritoneally administrated at the concentration of 20 mg·kg-1 for 14 d. The percentage of MDSCs in bone marrow, spleen, blood, tumor and liver were detected by flow cytometry. Non- esterified fatty acid (NEFA), triglycerides (TG) and total cholesterol (T-CHO) in liver homogenate were tested by a NEFA test kit, a TG test kit and a T- CHO test kit respectively. qRT- PCR and Western blot were used to measure mRNA and protein levels of inflammation-, glycometabolsim- and lipometabolsim-associated indexes in liver. RESULTS MENK decreased percentages of MDSCs in bone marrow, spleen, blood and tumor in colon cancer mice. MENK-treated mice displayed elevated ratio of CD4+T and CD8+T cells in spleen as well as increased T and B lymphocytes proliferation. Meanwhile, MENK also ameliorated liver damage reflected by lower levels of GPT and GOT in serum and reduced risks of cancer- associated index including inflammation, high lipid and high glucose. Furthermore, MENK lowered down the levels of NEFA, TG and T- CHO in liver homogenate. MENK treatment decreased expression of p- STAT3, increased expression of p-AKT, IRS1 and Glut4 at protein level as well as reduced lipogenesis-associated genes and elevated glycolysis-associated genes in liver of tumor bearing mice. Also, abated expression of genes associated with MDSCs generation (M-CSF, GM-CSF, IL-6, IL-1β) and migration (S100A9, KC) was observed within shrunken subcutaneous tumor by MENK intervention. CONCLUSION MENK has the ability to strength immune function against colon cancer by reducing MDSCs and improving liver metabolism.

OBJECTIVE To map a comprehensive metabolic pathway of herbacetin in rats, specifically, to elucidate the biotransformation of herbacetin in vivo and to simultaneously monitor the pharmacokinetic process of both parent drug and its major metabolites. METHODS liquid chromatography/ion trap mass spectrometry (LC/MSn) and ultra-liquid chromatography coupled with mass spectrometry (UPLC/MS) were combined in the current study for qualitative and quantitative determinations of herbacetin and its metabolites in bile, urine and feces after both oral and intravenous administration of herbacetin to rats. Enzyme kinetic studies on the intestinal and hepatic metabolism of herbacetin were further conducted to elucidate metabolic profiles of herbacetin in rat tissues and organs. Additionally, plasma concentration profiles of herbacetin and its metabolites in rats were obtained to characterize the overall pharmacokinetic behavior of herbacetin. RESULTS It was found that herbacetin was excreted primarily from rat urine in the form of glucuronide-conjugations. Subsequent in vitro enzyme kinetic studies and in vivo pharmacokinetic investigations suggested an extensive hepatic metabolism of herbacetin and the high exposure of herbacetin- glucuronides in systemic circulation. The clearance, half- life and bioavailability of herbacetin in rats were determined as (16.4±1.92)mL·kg-1·min-1, (11.9±2.7)min, and 1.32%, respectively. On basis of these findings, a comprehensive metabolic pathway of herbacetin in rats was composed. In addition, a physiology based pharmacokinetic (PBPK) model was successfully developed with the aid of the GastroPlus to simulate the pharmacokinetic process of herbacetin in rats. Application of the PBPK modeling can provide a useful starting point to understand and extrapolate pharmacokinetic parameters among different species, populations, and disease states. CONCLUSION After oral administration, herbacetin was subjected to colonic degradation and extensive first pass metabolism, with glucuronidation as its dominating in vivo metabolic pathway.

OBJECTIVE To investigate the effect of hypoxia on the pharmacokinetic process of salidrosidein rats and to explore its underlying mechanisms. METHODS The Caco-2 cell monolayerwas exposed to 1% oxygen (O2) concentration for 24 h to build the hypoxiccell model. The transportation mode of salidroside was investigated with the aid of this hypoxia model by detecting the apparent permeability coefficient(Papp). Healthy Sprague Dawley (SD) rats were exposed to 9% O2 for 72 h for the construction of hypoxic rat model. Liver sample was subsequently collected from the hypoxic rats with an aim to identify enzymes responsible for salidroside metabolism. The expression levels of sali?droside-transporting and salidroside-metabolizing enzymes, including Sodium-dependent glucose cotrans?porters (SGLT1), β-glucosidase (GBA3)and sulfotransferase (SULT2A1), were thereafter detected by RT-PCR and Western blot. The metabolic activity of GBA3 and SULT2A1 was monitored by rat liver microsome incubation.In addition, the renal function of rats under hypoxia was assessed by detecting concentrations of blood urea nitrogen and creatinine. RESULTS The AUC and t1/2 values of salidroside in hypoxic rats were more than doubled, while the in vivo clearance was significantly reduced. Mechanistic study demonstrated that the PappA- B/PappB- A eualsto 10.3, indicating the potential active transport of salidrosile. The expression of SGLT1 and GBA3 was significantly decreased, which indicated a reduced metabolism of salidroside under hypoxia. Moreover, rat under hypoxia was found to suffer from renal dysfunction, with an abnormal value of blood urea nitrogen. CONCLUSION Due to the reduced metabolism and the abnormal renal function under hypoxia, the systemic exposure of salidroside in rats was signifi?cantly enhanced.