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In the process of internal thread cold extrusion, the extrusion tap is an indispensable tool. Therefore, it is important to improve the service life of the extrusion tap and reduce the tool wear. In this paper, using Central Composite Design response surface test, the influence of the parameters (including the guide cone angle, backhoe capacity, guide cone length and working cone length) of the extrusion tap on the forming quality of internal cold extrusion are investigated, so as to obtain the minimum extrusion torque and the minimum extrusion temperature. A polynomial regression response model of the minimum extrusion torque and minimum extrusion temperature is obtained. Using the regression model, the objective function is optimized, and a group of optimal parameters is obtained (guide cone angle: 10°, backhoe capacity: 0.32, guide cone length: 4 mm, and working cone length: 13 mm). Numerical simulation of the optimal parameters is also carried out. The results show that the measured extrusion torque and extrusion temperature are close to the predicted values with errors of 2 and 2.55%, respectively, which are well fitted by the model. [ABSTRACT FROM AUTHOR]

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase ubiquitously expressed mainly in the cytoplasm of several tissues. SHP2 modulates diverse cell signaling events that control metabolism, cell growth, differentiation, cell migration, transcription and oncogenic transformation. It interacts with diverse molecules in the cell, and regulates key signaling events including RAS/ERK, PI3K/AKT, JAK/STAT and PD-1 pathways downstream of several receptor tyrosine kinases (RTKs) upon stimulation by growth factors and cytokines. SHP2 acts as both a phosphatase and a scaffold, and plays prominently oncogenic functions but can be tumor suppressor in a context-dependent manner. It typically acts as a positive regulator of RTKs signaling with some inhibitory functions reported as well. SHP2 expression and activity is regulated by such factors as allosteric autoinhibition, microRNAs, ubiquitination and SUMOylation. Dysregulation of SHP2 expression or activity causes many developmental diseases, and hematological and solid tumors. Moreover, upregulated SHP2 expression or activity also decreases sensitivity of cancer cells to anticancer drugs. SHP2 is now considered as a compelling anticancer drug target and several classes of SHP2 inhibitors with different mode of action are developed with some already in clinical trial phases. Moreover, novel SHP2 substrates and functions are rapidly growing both in cell and cancer. In view of this, we comprehensively and thoroughly reviewed literatures about SHP2 regulatory mechanisms, substrates and binding partners, biological functions, roles in human cancers, and different classes of small molecule inhibitors target this oncoprotein in cancer. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a life-threatening condition among patients with cardiovascular diseases. MI increases the risk of stroke and heart failure and is a leading cause of morbidity and mortality worldwide. Several genetic and epigenetic factors contribute to the development of MI, suggesting that further understanding of the pathomechanism of MI might help in the early management and treatment of this disease. Toll-like receptors (TLRs) are well-known members of the pattern recognition receptor (PRR) family and contribute to both adaptive and innate immunity. Collectively, studies suggest that TLRs have a cardioprotective effect. However, prolonged TLR activation in the response to signals generated by damage-associated molecular patterns (DAMPs) results in the release of inflammatory cytokines and contributes to the development and exacerbation of myocardial inflammation, MI, ischemia–reperfusion injury, myocarditis, and heart failure. The objective of this review is to discuss and summarize the association of TLRs with MI, highlighting their therapeutic potential for the development of advanced TLR-targeted therapies for MI. [ABSTRACT FROM AUTHOR]

Background: Abnormal ion channel currents caused by myocardial electrical remodeling is one of the main causes of malignant arrhythmias. Glycogen synthase kinase 3β (GSK-3β) is the main therapeutic target following ischemia as it regulates nerve cell channels. However, few studies have investigated its role in myocardial electrical remodeling. The present study aimed to investigate the role of GSK-3β in a rat myocardial infarction (MI)–induced electrical remodeling and potential effects on cardiac ionic channels including KCNJ2/Kir2.1/IK1. Methods: Ligation of the left anterior descending artery in rats was performed to establish a MI model. The rats were randomly divided into three groups, the sham, MI, and MI + SB group. The animals in the latter group were administered SB216763 (GSK-3β inhibitor) at a dose of 0.6 mg·kg−1·day−1. The ventricular function was assessed by echocardiography, electrocardiography, and histological analysis 7 days post-surgery. Serum was collected to measure lactate dehydrogenase and cardiac troponin I levels, and the mRNA and protein levels of the KCNJ2/Kir2.1/IK1 channel in the heart tissues were assessed. H9c2 cells were cultured to examine the effects of SB216763 on the protein expression of Kir2.1 channel under hypoxic conditions. Results: The results revealed that SB216763 ameliorated acute cardiac injury and improved myocardial dysfunction. Moreover, SB216763 increased the mRNA and protein expression of Kir2.1 during MI. Furthermore, SB216763 treatment abrogated the decreased expression of Kir2.1 in H9c2 cells under hypoxic conditions. Conclusions: GSK-3β inhibition upregulates Kir2.1 expression in a rat model of MI. [ABSTRACT FROM AUTHOR]

Background and Objective: Rapamycin and its semi-synthetic analogues (rapalogues) are frequently used in combination with other prescribed medications in clinical settings. Although the inhibitory effects of rapalogues on cytochrome P450 enzymes (CYPs) have been well examined, the inhibition potentials of rapalogues on human esterases have not been investigated. Herein, the inhibition potentials and inhibitory mechanisms of six marketed rapalogues on human esterases are investigated. Methods: The inhibitory effects of six marketed rapalogues (rapamycin, zotarolimus, temsirolimus, everolimus, pimecrolimus and tacrolimus) on three major esterases, including human carboxylesterases 1 (hCES1A), human carboxylesterases 2 (hCES2A) and butyrylcholinesterase (BuChE), were assayed using isozyme-specific substrates. Inhibition kinetic analyses and docking simulations were performed to investigate the inhibitory mechanisms of the rapalogues with strong hCES2A inhibition potency. Results: Zotarolimus and pimecrolimus displayed strong inhibition of human hCES2A but these agents did not inhibit hCES1A or BuChE. Further investigation demonstrated that zotarolimus could strongly inhibit intracellular hCES2A in living HepG2 cells, with an estimated IC50 value of 4.09 µM. Inhibition kinetic analyses revealed that zotarolimus inhibited hCES2A-catalyzed fluorescein diacetate hydrolysis in a mixed manner, with the Ki value of 1.61 µM. Docking simulations showed that zotarolimus could tightly bind on hCES2A at two district ligand-binding sites, consistent with its mixed inhibition mode. Conclusion: Our findings demonstrate that several marketed rapalogues are potent and specific hCES2A inhibitors, and these agents can serve as leading compounds for the development of more efficacious hCES2A inhibitors to modulate the pharmacokinetic profiles and toxicity of hCES2A-substrate drugs (such as the anticancer agent irinotecan). [ABSTRACT FROM AUTHOR]

Vein traits influence photosynthesis and drought resistance and are sensitive to climate change. It is unclear whether vein traits, similar to other leaf traits, have obvious regional characteristics and covariance with other leaf traits, especially in Tibetan Plateau grasslands. We collected 66 species from 37 sites in late July of 2012 and early August of 2013 to investigate leaf vein traits and their relationships with other leaf traits in comparison with the available global database data and to elucidate vein investment of plants with different vein types. The average vein length per area (VLA) of plants in the Tibetan Plateau was within the range of the global dataset, and the relationships among vein traits and other leaf traits of alpine plants were consistent with the global models. The VLAs of parallel-veined grasses and pinnate-veined forbs were significantly lower and higher than the global mean value, respectively. The leaf mass per area and total nitrogen content of parallel-veined grasses were significantly lower and higher, respectively, than the global mean values; the opposite was observed in pinnate-veined forbs. The parallel-veined grasses exhibited almost a four-fold higher vein biomass investment (i.e., vein mass per leaf mass) than pinnate-veined forbs in the same region. The average VLA and its relationships with other leaf traits of the alpine grassland plants on the Tibetan Plateau had no regional characteristics, suggesting a convergence in plant leaf functioning. Plants with different leaf types differ in their adaptation strategies to plateau environments, and this may relate to biomass investment into leaf veins. Our study fills the gap with regard to vein density in alpine grassland species and provides a new perspective for understanding plant physiology and ecology by calculating and comparing the proportion of vein investment among different vein types. [ABSTRACT FROM AUTHOR]

Elevated serum low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease (CHD). Many guidelines recommend LDL-C as a primary treatment target, and statins represent the cornerstone of treatment for lipid management. Recently revised guidelines recommend even more intense management of LDL-C, especially in patients at moderate and high risk. However, LDL-C levels in the Chinese population differ from those in Western populations, and the benefits and safety of the maximum allowable dose of statins have yet to be determined. Furthermore, in practice, many patients do not achieve the increasingly stringent LDL-C goals. Consequently, alternative approaches to lipid management are required. Combination therapy with ezetimibe and a statin, which have complementary mechanisms of action, is more effective than statin monotherapies, even at high doses. Several clinical studies have consistently shown that combination therapy with ezetimibe and simvastatin lowers LDL-C more potently than statin monotherapies. Moreover, the safety and tolerability profile of the combination therapy appears to be similar to that of low-dose statin monotherapies. This review discusses the role of simvastatin in combination with ezetimibe in controlling dyslipidemia in Chinese patients, particularly the efficacy and safety of combination therapy in light of recently published clinical data. [ABSTRACT FROM AUTHOR]

Purpose: Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals. Methods: Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211G˃A) and UGT1A1*28 (TA6˃TA7) polymorphisms. Results: UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 ( P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40-60 %. Conclusions: Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity. [ABSTRACT FROM AUTHOR]

Background and Objective: The polymorphic enzyme P450 oxidoreductase (POR) transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to cytochrome P450 (CYP) 3A enzyme s, which metabolize atorvastatin. This suggests that variations in the CYP3A5 and POR genes may influence the response to statins. We aimed to investigate the association and interactions between CYP3A5*3 and POR*28 polymorphisms and the lipid-lowering effects of atorvastatin in a Chinese population. Methods: Genotypes were determined by polymerase chain reaction (PCR) with restriction fragment length polymorphism analysis and by PCR with direct sequencing analysis for 179 hyperlipidaemic patients treated with atorvastatin 20 mg once daily for 4 weeks. Serum levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined before and after treatment. Results: For the 179 patients (including 100 males), the variant allele frequencies of CYP3A5*3 and POR*28 were 73.75 and 41.62 %, respectively. Among all patients, no significant association was found between CYP3A5*3 polymorphisms and TG, TC, LDL-C and HDL-C levels before and after treatment with 20 mg of atorvastatin daily for 4 weeks. Homozygotes for the POR*28 T allele showed a significantly lower mean concentration of LDL-C than homozygotes for the POR*28 C allele ( POR*28 TT vs POR*28 CC: 2.46 ± 0.37 vs 2.69 ± 0.49 mmol/L, P = 0.019) after treatment with atorvastatin 20 mg daily for 4 weeks. After adjustment for age, sex and body mass index, CYP3A5 non-expressors who were POR*28 wild-type homozygotes showed significantly higher mean TC and LDL-C levels than those who were POR*28 variant homozygotes, both at baseline (*3/CC vs *3/TT; TC: 7.30 ± 0.73 vs 6.94 ± 0.36 mmol/L, P = 0.026; LDL-C: 3.88 ± 0.70 vs 3.47 ± 0.46 mmol/L, P = 0.009) and after atorvastatin treatment (*3/CC vs *3/TT; TC: 6.03 ± 0.64 vs 5.69 ± 0.34 mmol/L, P = 0.017; LDL-C: 2.80 ± 0.62 vs 2.43 ± 0.40 mmol/L, P = 0.008). CYP3A5 non-expressors who were POR*28 wild-type homozygotes showed significantly higher TC and LDL-C levels at baseline (*3/CC vs *1/CC; TC: 7.30 ± 0.73 vs 6.95 ± 0.41 mmol/L, P = 0.010; LDL-C: 3.88 ± 0.70 vs 3.55 ± 0.39 mmol/L, P = 0.010) and showed higher TC levels after atorvastatin treatment (*3/CC vs *1/CC; 6.03 ± 0.64 vs 5.73 ± 0.27 mmol/L, P = 0.012), in comparison with patients expressing CYP3A5 who were POR*28 wild-type homozygotes. CYP3A5 non-expressors who were POR*28 heterozygotes showed significantly lower percentage changes in TC from baseline than those expressing CYP3A5 who were POR*28 heterozygotes (*3/CT vs *1/CT; 16.77 ± 3.13 vs 18.40 ± 4.16 mmol/L, P = 0.031). Conclusion: POR*28 is associated with a poorer response to atorvastatin, but there is no association of the latter with CYP3A5*3. POR*28 single nucleotide polymorphisms are associated with greater increases in the effect on plasma lipids in non-expressors of CYP3A5. Besides CYP3A5*3 genetic polymorphism, POR*28 genetic polymorphism might also be responsible for the marked interindividual variability in the lipid-lowering response to atorvastatin. [ABSTRACT FROM AUTHOR]

Aim:Atazanavir (ATV) is a HIV-1 protease inhibitor for the treatment of AIDS patients, which is recently reported to provoke excessive prolongation of the QT interval and torsades de pointes (TdP). In order to elucidate its arrhythmogenic mechanisms, we investigated the effects of ATV on the hERG K+ channels expressed in HEK293 cells.Methods:hERG K+ currents were detected using whole-cell patch clamp recording in HEK293 cells transfected with EGFP-hERG plasmids. The expression of hERG protein was measured with Western blotting. Two mutants (Y652A and F656C) were constructed in the S6 domain within the inner helices of hERG K+ channels that were responsible for binding of various drugs. The trafficking of hERG protein was studied with confocal microscopy.Results:Application of ATV (0.01-30 μmol/L) concentration-dependently decreased hERG K+ currents with an IC50 of 5.7±1.8 μmol/L. ATV (10 μmol/L) did not affect the activation and steady-state inactivation of hERG K+ currents. Compared with the wild type hERG K+ channels, both Y652A and F656C mutants significantly reduced the inhibition of ATV on hERG K+ currents. Overnight treatment with ATV (0.1-30 μmol/L) concentration-dependently reduced the amount of fully glycosylated 155 kDa hERG protein without significantly affecting the core-glycosylated 135 kDa hERG protein in the cells expressing the WT-hERG protein. Confocal microscopy studies confirmed that overnight treatment with ATV obstructed the trafficking of hERG protein to the cell membrane.Conclusion:ATV directly blocks hERG K+ channels via binding to the residues Y652 and F656 in the S6 domain, and indirectly obstructs the transport of the hERG protein to the cell membrane. [ABSTRACT FROM AUTHOR]

A series of pyrazolyl-acylhydrazone derivatives ( 1e- 20e) have been designed and synthesized and their biologic activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds, 12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC values of 0.57 ± 0.03 and 0.49 ± 0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC = 1.9 ± 0.43 μM). The result of flow cytometry demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Purpose: There is significant inter-individual variability in the lipid-lowering effects of atorvastatin and simvastatin. Our goal was to investigate the impact of SLCO1B1 genetic polymorphism on the lipid-lowering effects of atorvastatin and simvastatin. Methods: We recruited 363 unrelated hyperlipidemic patients with the CYP3A4* 1/* 1, CYP3A5* 1/* 1, and CYP3AP1* 1/* 1 genotypes: 189 of these were treated with atorvastatin and 174 were treated with simvastatin as a single-agent therapy (20 mg day orally) for 4 weeks. The genotyping of SLCO1B1 c.521T > C (p.V174A, OATP- C* 5) was performed with allele-specific polymerase chain reaction (AS-PCR), and PCR restriction fragment length polymorphism (RFLP) was performed to detect the carriers of SLCO1B1 c.388A > G (p.N130D, OATP-C*1b). Serum triglyceride (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were determined before and after treatment. Results: The frequencies of the SLCO1B1 521T > C and 388A > G variant alleles in Chinese hyperlipidemic patients were found to be 16.2% and 72.1% respectively. After treatment with 20 mg simvastatin or atorvastatin daily for 4 weeks, TC, TG, and LDL-C concentrations were lower than at baseline, on average, by 18.1 ± 3.7%, 25.8 ± 9.7%, 27.7 ± 5.4% in the simvastatin-treated group, and 17.5 ± 3.7%, 22.6 ± 8.6%, 27.5 ± 5.5% in the atorvastatin-treated group respectively, and the mean relative reduction in serum HDL cholesterol did not reach statistical significance (−1.0 ± 10.9%, 0.5 ± 9.3%). However, no significant differences were observed in the lipid-lowering effects of atorvastatin and simvastatin between subjects with different SLCO1B1 genotypes. Conclusion: The SLCO1B1 521T > C and 388A > G variants were found to be relatively common in Chinese patients with essential hyperlipidemia. These frequencies were found to be similar to those observed in healthy Chinese and Japanese individuals, but significantly different from Caucasians and blacks. SLCO1B1 521T > C and 388A > G polymorphisms may not be associated with the lipid-lowering effects of atorvastatin and simvastatin. [ABSTRACT FROM AUTHOR]

To comparatively study the biodegradation of phthalic acid esters (PAEs) in sewage sludge by composting with pig manure or with rice straw, four composting modes were designed: Mode 1 (sewage sludge + pig manure + intermittent aeration), Mode 2 (sewage sludge + pig manure + continuous aeration), Mode 3 (sewage sludge + rice straw + intermittent aeration) and Mode 4 (sewage sludge + rice straw + continuous aeration). Physicochemical parameters of composts were measured according to standard methods and PAEs were analyzed by gas chromatography coupled with mass spectrometry (GC/MS). The biodegradation of each PAE was also discussed. The results showed that Mode 1 was the best mode to biodegrade PAEs, which might be related to the wide class of indigenous microbial communities in pig manure and high efficiency of intermittent ventilation for providing oxygen. During the biodegradation process, di(2-ethylhexyl) phthalate was the most abundant and decisive for the removal of total PAEs. It showed a first-order kinetic degradation model. In conclusion, composting with pig manure could be suggested as an effective detoxification process for the removal of PAEs from sewage sludge, providing a safe end product. [ABSTRACT FROM AUTHOR]

Inflammation is a key component of Alzheimer's disease (AD), and we have examined the effect of two polymorphisms (-174G/C and -572C/G) in the promoter of the inflammatory cytokine interleukin-6 (IL-6) gene on risk of AD in 318 AD patients. Significant differences in genotype and allele frequencies of -572C/G IL-6 promoter polymorphism were observed between AD patients and controls. The GG genotype was associated with a decreased risk of developing AD (OR 0.423, 95% CI 0.200-0.894). Similarly, logistic regression analysis revealed that G allele was a protective factor for AD (OR 0.732, 95% CI 0.567-0.945). For -174G/C variability, no C variability was found in all the subjects. The frequency of the IL-6 -174G/C promoter polymorphism is very low or no variability in Henan Han population. The -572C/G polymorphism of IL-6 gene promoter region is associated with AD, and G allele is an independent protective factor for AD. [ABSTRACT FROM AUTHOR]

To investigate whether the CYP3A4*1G genetic polymorphism contributes to the variability in CYP3A activity and response to fentanyl. One hundred and forty-three gynecologic patients who were scheduled to undergo abdominal total hysterectomy or myomectomy with general anesthesia were enrolled in this study. Intravenous fentanyl patient-controlled analgesia was provided postoperatively for satisfactory analgesia. The degrees of pain at rest during PCA treatment were assessed with visual analog scale. The fentanyl consumption and occurrence of any adverse effects were recorded in the first 24 h postoperatively. CYP3A activity was measured by plasma 1′-hydroxymidazolam-to-midazolam ratio 1 h after intravenous administration of 0.1 mg/kg midazolam. CYP3A4*1G variant allele was genotyped using the polymerase chain reaction–restriction fragment length polymorphism method. The frequency of the CYP3A4*1G variant allele was 0.269 in 143 Chinese gynecologic patients. The activity of CYP3A4 in patients homozygous for the * 1G/*1G variant (0.34 ± 0.15) was significantly lower than that in patients bearing the wild-type allele (* 1/* 1) (0.46 ± 0.14) or in patients heterozygous for the * 1/* 1G variant (0.46 ± 0.12) ( P < 0.05). The patients with the CYP3A4* 1G/* 1G genotype needed less fentanyl (227.8 ± 55.2 μg) to achieve pain control than patients carrying the CYP3A4* 1/* 1 (381.6 ± 163.6 μg) and CYP3A4* 1/* 1G (371.9 ± 180.1 μg) genotypes ( P < 0.05) during the first 24 h postoperatively. There was no significant difference in incidence of adverse events among the different genotype groups ( P > 0.05). CYP3A4* 1G genetic polymorphism decreases CYP3A activity and fentanyl consumption for postoperative pain control. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/srep42192 [ABSTRACT FROM AUTHOR]

Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the 'derivation cohort' to develop dose-prediction algorithm, while the remaining 20% constituted the 'validation cohort' to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future. [ABSTRACT FROM AUTHOR]