Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.
Dipeptidyl-Peptidase IV Inhibitors ; chemical synthesis ; chemistry ; Drug Design ; Drug Discovery ; methods ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; Linagliptin ; chemical synthesis ; chemistry ; Molecular Structure ; Piperidines ; chemical synthesis ; chemistry ; Structure-Activity Relationship ; Uracil ; analogs & derivatives ; chemical synthesis ; chemistry

Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes, public health decision making, and primary prevention synthesis. Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies. Biomarkers are generally classified into three groups: biomarkers of exposure, effect, and susceptibility.The main body compartments that store lead are the blood, soft tissues, and bone; the half-life of lead in these tissues is measured in weeks for blood, months for soft tissues, and years for bone. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer's disease, Parkinsons disease, and schizophrenia. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults.
Alzheimer Disease ; chemically induced ; metabolism ; pathology ; physiopathology ; psychology ; Animals ; Behavior ; drug effects ; Biomarkers ; metabolism ; Brain ; metabolism ; pathology ; physiopathology ; Brain Diseases ; chemically induced ; pathology ; physiopathology ; Environmental Exposure ; adverse effects ; Humans ; Lead ; pharmacokinetics ; toxicity ; Lead Poisoning ; etiology ; metabolism ; pathology ; physiopathology ; psychology ; Neurotoxicity Syndromes ; etiology ; metabolism ; pathology ; physiopathology ; psychology ; Parkinson Disease, Secondary ; chemically induced ; metabolism ; pathology ; physiopathology ; psychology ; Schizophrenia ; chemically induced ; metabolism ; pathology ; physiopathology

Objective To study the effect of antiapoptosis factors PED/PEA-15 and XIAP on prostate cancer cells(PC-3)apoptosis.Methods The expressions of XIAP and PED/PEA-15 in prostate cancer cells(PC-3)were respectively assayed using the RT-PCR technique.XIAP and PED/ PEA-15 specific siRNA vectors were designed and constructed and then were transiently cotransfected into PC-3 cells under induction of liposome.The effects of siRNA vectors on PED/PEA-15 and XIAP transcription were assayed by RT-PCR technique,and the effect of XIAP and PED/PEA-15 on cancer cell apoptosis were determined by flow cytometry and microscope observation.Results PED/PEA- 15 and XIAP were both highly expressed in PC-3 cells.Enzyme digestion analysis and DNA sequencing confirmed that the PED/PEA-15 and XIAP-specific siRNA expression vectors were constructed successfully.The designed siRNA sequences of PED/PEA-15 and XIAP could specifically inhibit their transcription.The PC-3 cells which were cotransfected with PED/PEA-15 and XIAP- specific siRNA vectors were more sensitive to doxorubicin.The apoptosis rate of cotransfected cells was significantly increased.Conclusions PED/PEA-15 and XIAP might be involved in the development of prostate cancer.

Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes, public health decision making, and primary prevention synthesis. Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies. Biomarkers are generally classified into three groups:biomarkers of exposure, effect, and susceptibility.The main body compartments that store lead are the blood, soft tissues, and bone;the half-life of lead in these tissues is measured in weeks for blood, months for soft tissues, and years for bone. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer’s disease, Parkinson’s disease, and schizophrenia. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults.

A quantitative analytical method of ultra-high performance liquid chromatography (UPLC) was developed for simultaneously determining twelve components in Tibetan medicine Zuozhu Daxi. SIMPCA 12.0 software was used a principal component analysis PCA) and partial small squares analysis (PLSD-DA) on the twelve components in 10 batches from four pharmaceutical factories. Acquity UPLC BEH C15 column (2.1 mm x 100 mm, 1.7 µm) was adopted at the column temperature of 35 °C and eluted with acetonitrile (A) -0.05% phosphate acid solution (B) as the mobile phase with a flow rate of 0. 3 mL · min(-1). The injection volume was 1 µL. The detection wavelengths were set at 210 nm for alantolactone, isoalantolactone and oleanolic; 260 nm for trychnine and brucine; 288 nm for protopine; 306 nm for protopine, resveratrol and piperine; 370 nm for quercetin and isorhamnetin. The results showed a good separation among index components, with a good linearity relationship (R2 = 0.999 6) within the selected concentration range. The average sample recovery rates ranged between 99.44%-101.8%, with RSD between 0.37%-1.7%, indicating the method is rapid and accurate with a good repeatability and stability. The PCA and PLSD-DA analysis on the sample determination results revealed a great difference among samples from different pharmaceutical factories. The twelve components included in this study contributed significantly to the quantitative determination of intrinsic quality of Zuozhu Daxi. The UPLC established for to the quantitative determination of the twelve components can provide scientific basis for the comprehensive quality evaluation of Zuozhu Daxi.
Chromatography, High Pressure Liquid ; methods ; Drugs, Chinese Herbal ; chemistry ; isolation & purification ; Plants, Medicinal ; chemistry ; Quality Control ; Tibet

OBJECTIVETo investigate if the interaction between TGF-beta1/Smad pathway and ERK pathway in vascular smooth muscle cells exists.

METHODSThe rat arota was removed. The primary VSMC were isolated and cultured in vitro, then the VSMC were divided into four groups: (1) control group, (2) (TGF-beta1 group, (3) ERK blocking agent group, (4) TGF-beta1 + ERK blocking agent group. The expression of Smad2/3, ERK1/2 proteins, the content of phosphorylated ERK1/2 and Smad2/3 proteins were detected by Western blot, and the expression of Smad2/3 mRNA was detected by reverse transcription-polymerase chain reaction(RT-PCR) .

RESULTS(1) In contrast to control group, the content of phosphorylated Smad2/3 and phosphorylated ERK1/2 proteins in TGF-beta1 group was increased (P < 0.05), that in ERK blocking agent group was decreased (P < 0.05). There was no difference between control group and TGF-beta1 + ERK blocking agent group. Compared with TGF-beta1 group, the contents of phosphorylated Smad2/3 and phosphorylated ERK1/2 proteins in TGF-beta1 + ERK blocking agent group was decreased (P < 0.05). There was no difference in the expression of Smad2/3 and ERK1/2 proteins among different groups. (2) There were no differences in expression of Smad2 and Smad3 mRNA among different groups.

CONCLUSION(1) TGF-beta1 can induce Smad2/3 proteins to be phosphorylated dependent on the activated ERK pathway. (2) ERK pathway does not effect the expression of Smad2/3 at the level of protein and mRNA.

Animals ; Aorta ; cytology ; Cells, Cultured ; Female ; MAP Kinase Signaling System ; physiology ; Male ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Muscle, Smooth, Vascular ; cytology ; physiology ; Myocytes, Smooth Muscle ; physiology ; Phosphorylation ; Rats ; Rats, Wistar ; Signal Transduction ; Smad Proteins ; metabolism ; physiology ; Transforming Growth Factor beta1 ; physiology

OBJECTIVETo define cut-off values of plasma amino-terminal pro-B-type natriuretic peptide (NT-ProBNP) for the diagnosis of congenital heart failure (CHF) and evaluate the importance of plasma NT-ProBNP measurement in the assessment of cardiac function prior to heart surgery in infants with congenital heart disease (CHD).

METHODSPlasma levels of NT-proBNP were measured in 120 infants with CHD before heart surgery and in 100 age-matched healthy infants between June 2010 and June 2013. The data were stratified based on the presence or absence of CHF in the whole group of CHD infants and on age (i.e., <1 year and ≥1 year) and time (i.e., before surgery) within the subgroup of CHF infants.

RESULTSOf the 120 infants with CHD, 41 met the criteria for CHF defined in the Ross Classification for Heart Failure in Infants.The cut-off values of plasma NT-ProBNP were ≥498 ng/L for infants of all ages, 557 ng/L for <1 year age group and 452 ng/L for ≥1 year age group, respectively, in the 41 CHF patients. In CHF infants, plasma NT-proBNP was significantly decreased after protecting of cardiac function (P<0.001).

CONCLUSIONSThe cut-off values of plasma NT-ProBNP for CHF differ between infants <1 year and infants ≥1 year. Moreover, plasma NT-ProBNP can be used as an additional parameter in the preoperative assessment of cardiac function in CHD infants.

Child ; Child, Preschool ; Female ; Heart Defects, Congenital ; blood ; Heart Failure ; blood ; Humans ; Infant ; Male ; Natriuretic Peptide, Brain ; blood ; Peptide Fragments ; blood

OBJECTIVETo explore the correlation between hOCT1 polymorphism and imatinib mesylate (IM) effectiveness in chronic myelogenous leukemia(CML) patients, and to provide for the clinical individual personalized therapy.

METHODSFifty-three CML and 23 non-CML patients were enrolled in this study. Blood or bone marrow samples were collected. Amplification refractory mutation system (ARMS)-polymerase chain reaction was used to amplify the polymorphisms gene segment of hOCT1-P283L, R287G and M408V and their frequencies were statistically analysed. With clinical outcomes, the correlation between hOCT1 polymorphism and IM effectiveness in CML was analyzed.

RESULTS(1) For 74 Han Chinese, the allele frequencies of hOCT1-P283L, R287G and M408V were 39.86%, 29.05% and 45.27%, respectively. (2) The genotypes of hOCT1-P283L, R287G and M408V in 2 Tibetan Chinese were CC, CC, AG and CC, CG, AG, respectively. (3) In the CML patients with IM optimal response, the frequencies of 283T and 287G allele were predominant (P<0.05). No significant difference was found in the frequency distribution of hOCT1-M408V genotype and allele among the 3 different response groups (P>0.05).

CONCLUSION(1) Three single nucleotide polymorphisms (cSNP) P283L, R287G and M408V were found in the hOCT1 gene from 76 Chinese. (2) hOCT1 gene polymorphism is associated with the long-term molecular response of CML patients received IM therapy, indicating that the polymorphisms of hOCT1-283T, 287G may be good predictors for IM response. (3) There is no correlation between the polymorphisms of hOCT1-P283L, R287G, M408V and secondary IM resistance in CML patients.

Benzamides ; Female ; Gene Frequency ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; Male ; Organic Cation Transporter 1 ; genetics ; Piperazines ; therapeutic use ; Polymorphism, Genetic ; Pyrimidines ; therapeutic use ; Treatment Outcome

Objective To investigate effects of angelica polysaccharide on learning and memory abilities, Ach, ChAT, AChE, SOD, MDA in serum, APP and Aβ1-42 in hippocampus in model rats with Alzheimer disease (AD); To explore the mechanism of angelica polysaccharide for the treatment of AD. Methods Seventy SPF Wistar rats were selected for learning and memory ability by water maze. 10 rats were randomly selected (half female and half male) as sham-operation group, and the others were injected with Aβ25-35 by stereotatic techniques, copying AD model rats. 50 rats for learning and memory ability by water maze were successfully divided into model group, positive group, angelica polysaccharide low-, medium-, and high-dose groups, with 10 rats in each group. Rats in model group and sham-operation group were given normal saline for gavage, while rats in medication groups were given relevant medicine for gavage, 2 mL/(100 g?d), for 28 d. The learning and memory ability of rats in each group was tested by Morris water maze during 25-28 days, and the contents of Ach, ChAT, AChE, SOD, MDA in serum and APP and Aβ1-42 in hippocampus were determined. Results Compared with the sham-operation group, the escape latent period of model group was significantly prolonged in place navigation experiment; the target quadrant time was shortened; the latent time for the first time to reach the original escape platform was longer in spatial probe test; the residence time of crossing the original platform position and the target quadrant was shorter; the levels of Ach, the activity of ChAT and SOD in serum decreased; the levels of MDA, the activity of AChE in serum increased; the levels of APP and Aβ1-42 in hippocampus increased, with statistical significance (P<0.05, P<0.01). Compared with model group, the escape latent period of each medication group was shortened in different degrees after the intervention treatment; the residence time of target quadrant was prolonged; the latent time for the first time to reach the original escape platform was shortened; the number of cross platform increased; the levels of Ach, the activity of ChAT and SOD in serum increased; the levels of MDA and the activity of AChE in serum decreased; the levels of APP and Aβ1-42 in hippocampus significantly decreased, with statistical significance (P<0.05, P<0.01). Conclusion Angelica polysaccharide may effectively improve the learning and memory of ability of AD model rats to improve anti-free radical oxidation and promote Aβ metabolism and promote learning and memory ability of AD model rats, which have some preventive and therapeutic effects on AD.

Line scanning quantitative analysis method on silicate with small laser beam ( < 15 μm) was developed using laser ablation sector field inductively coupled plasma mass spectrometry (LA-SF-ICP-MS). Differences on signal intensity and elemental fractionation induced by different laser sampling patterns were compared. While spot ablation with small laser beam, the elemental signal intensity decreased with time significantly, and the elemental fractionation was obvious. In contrast, the elemental signal intensity by line scanning was higher and more stable and line scanning was free of elemental fractionation. Therefore, identical ablation pattern and condition should be used for the standard and the unknown sample in LA-ICP-MS quantitative analysis. A single pulse experiment was carried out to investigate the washout time when coupled to two-volume ablation cell. The result indicated that the elemental intensity decayed to the background value needed 2-3 s. The optimal parameters on SF-ICP-MS were set to reduce the effect of signal overlapping. Homogeneous sample KL2-G and titanite grains with composition zoning were analyzed by this method. Accurate element contents and element ratios indicated that fast washout time and optimal instrument parameters made it feasible to perform line scanning quantitative analysis accurately. Comparing to traditional microanalysis, line scanning quantitative analysis could reduce the laser beam size (<15 μm) and improve the spatial resolution efficiently. The potential of the technique to unveil compositional complexities in greater detail would help to improve our understanding of geochemical processes in mineral scale.