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Abnormal activation of NLRP3 inflammasome causes the progression of gout, and no small-molecule inhibitor of NLRP3 has been approved yet for clinical use. In this study we established a nigericin-induced inflammasome activation cell model for screening of a natural product library by measuring IL-1β secretion in cell supernatants. Among 432 compounds tested, we found that hypocrellin A (HA), one of the major active components of a traditional ethnic medicinal fungus Hypocrella bambuseain the Northwest Yunnan of China, exhibited the highest inhibition on IL-1β production (IC50= 0.103 μM). In PMA-primed THP-1 cells or bone marrow derived macrophages (BMDMs) treated with multiple stimuli (nigericin, ATP or MSU), HA dose-dependently suppressed the activation of NLRP3 inflammasome, reducing the subsequent release of inflammatory cytokines and LDH. Furthermore, the suppression of inflammasome activation by HA was specific to NLRP3, but not to AIM2 or NLRC4. In LPS-primed BMDMs treated with nigericin, HA inhibited ASC oligomerization and speckle formation, and blocked the NLRP3-NEK7 interaction during inflammasome assembly without influencing the priming stage. Moreover, we demonstrated that HA directly bound to the NACHT domain of NLRP3, and that Arg578 and Glu629 were the critical residues for HA binding to NLRP3. In MSU-induced peritonitis and acute gouty arthritis mouse models, administration of HA (10 mg/kg, i.p., once or twice daily) effectively suppressed the inflammatory responses mediated by NLRP3 inflammasome. We conclude that HA is a broad-spectrum and specific NLRP3 inhibitor, and a valuable lead compound to develop novel therapeutic inhibitors against NLRP3-driven diseases. This study also elucidates the anti-inflammation mechanisms and molecular targets of HA, a major active component in medicinal fungus Hypocrella bambuseathat has been long used by Chinese ethnic groups.

Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.

Oncogene HER2 is amplified in 20%–25% of human breast cancers and 6.1%–23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.

The problem of cooperative attack of multiple missiles is studied in this paper, and these missiles are supposed to suffer from external disturbances, communication delay. A kinematics model of the multi-missile under the situation of external disturbances and communication delay is firstly developed. And then based on the topology of directed graph, the problem of multi-missile convergence is transformed into the stability analysis of a closed-loop control system. A state feedback robust controller is designed by linear matrix inequality. Finally, a numerical simulation is given to demonstrate the effectiveness of the proposed control strategy.

Inhibition of glycolysis process has been an attractive approach for cancer treatment due to the evidence that tumor cells are more dependent on glycolysis rather than oxidative phosphorylation pathway. Preliminary evidence shows that inhibition of phosphoglycerate kinase 1 (PGK1) kinase activity would reverse the Warburg effect and make tumor cells lose the metabolic advantage for fueling the proliferation through restoration of the pyruvate dehydrogenase (PDH) activity and subsequently promotion of pyruvic acid to enter the Krebs cycle in glioma. However, due to the lack of small molecule inhibitors of PGK1 kinase activity to treat glioma, whether PGK1 could be a therapeutic target of glioma has not been pharmacologically verified yet. In this study we developed a high-throughput screening and discovered that NG52, previously known as a yeast cell cycle-regulating kinase inhibitor, could inhibit the kinase activity of PGK1 (the IC50= 2.5 ± 0.2 μM). We showed that NG52 dose-dependently inhibited the proliferation of glioma U87 and U251 cell lines with IC50values of 7.8 ± 1.1 and 5.2 ± 0.2 μM, respectively, meanwhile it potently inhibited the proliferation of primary glioma cells. We further revealed that NG52 (12.5–50 μM) effectively inhibited the phosphorylation of PDHK1 at Thr338 site and the phosphorylation of PDH at Ser293 site in U87 and U251 cells, resulting in more pyruvic acid entering the Krebs cycle with increased production of ATP and ROS. Therefore, NG52 could reverse the Warburg effect by inhibiting PGK1 kinase activity, and switched cellular glucose metabolism from anaerobic mode to aerobic mode. In nude mice bearing patient-derived glioma xenograft, oral administration of NG52 (50, 100, 150 mg· kg−1·d−1, for 13 days) dose-dependently suppressed the growth of glioma xenograft. Together, our results demonstrate that targeting PGK1 kinase activity might be a potential strategy for glioma treatment.

Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3?µM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC50values of 324?nM and 48.6?nM, respectively, against MNK1 and MNK2 kinases; osimertinib (0.3–3?µM) dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). In GBM patient-derived xenografts mice, oral administration of osimertinib (40?mg·?kg-1?·d-1, for 18 days) significantly suppressed the tumor growth (TGI?=?74.5%) and inhibited eIF4E phosphorylation in tumor cells. Given the fact that osimertinib could cross the blood–brain barrier and its toxicity was well tolerated in patients, our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.

Some studies have suggested that blood glucose fluctuation and C-peptide level were considered as predictive factors for carotid artery intima–media thickness (CIMT). However, the relationships of these variables are unclear. This research was aimed to identify the potential effects of blood glucose fluctuation, C-peptide level and conventional risk factors on CIMT. A total of 280 type 2 diabetes mellitus (T2DM) patients were enrolled into this study. Population characteristics were obtained through medical history and clinical parameters. The patients were divided into two groups according to the critical value of CIMT (0.9). Research data were analyzed to identify risk factors of CIMT between the two groups. The comparison results of basic information showed that differences in age and illness years between the two groups were statistically significant (p= 0.0002 and p= 0.0063). Logistic regression analysis results indicated that smoking, uric acid (UA) levels, 2 h C-peptide and standard deviation of blood glucose (SDBG) were the influence factors for CIMT thickening (p= 0.032, p= 0.047, p= 0.049 and p= 0.042, respectively). Blood glucose fluctuation could affect the risk of some complications. In largest amplitude of glycemic excursions (LAGE) > 4.4 group, the CIMT abnormal rate was 27.10%, which was significantly higher than 12.12% in the LAGE ≤ 4.4 group (p= 0.012). The CIMT abnormal rate of SDBG > 2.0 group was 27.81%, which was significantly higher than that of the SDBG ≤ 2.0 group (p= 0.018). Blood glucose fluctuation is an independent risk factor associated with CIMT in T2DM patients, in addition to conventional risk factors, such as smoking, high UA level and 2 h C-peptide. Therefore, more attention should be given to the change of CIMT and the complications.

Perovskite solar cells exhibit one of the most noticeable photovoltaic technologies; however, the buried defects under perovskite films reduce both power conversion efficiency (PCE) and long-term stability, particularly in large-area modules. Reasonable seeding layers can address the above issues to achieve stable and effective perovskite photovoltaic devices. Herein, trimethylsulfide iodine ((CH3)3SI) was utilized to passivate the buried interface and act as one-dimensional (1D) seeding mediator to regulate the air-processed perovskite growth for inverted photovoltaic module with high stability and over 20% efficiency. The strong interaction Pb-S bond is formed between (CH3)3SI and Pb2+to inhibit the production of Pb0. Importantly, the 1D (CH3)3SPbI3seeding layer can promote perovskite crystallization, improve NiOxconductivity for hole transfer, optimize energy level arrangement to reduce interfacial band offset, and improve open-circuit voltage. As a result, the PCE of inverted photovoltaic modules based on 10.0 × 10.0 cm2substrate was significantly improved from 18.47% to 20.03%. Meanwhile, the optimized device module without encapsulation maintained over 85% of the original PCE value during 1000h storing under 40-60% humidity and 30-36℃.

It is reported that glutathione S-transferase mu (GSTM1) polymorphism is associated with non-viral hepatic cirrhosis (HC). However, some studies showed different views. Therefore, in this paper, a meta-analysis was conducted to get a more comprehensive understanding of GSTM1 polymorphisms in non-viral HC susceptibility. The results showed that GSTM1 null was associated with the increased risk of non-viral HC (OR = 1.337, 95% CI 1.112–1.804, p= 0.005). Subgroup analysis of cirrhosis type revealed that GSTM1 null was a prominent risk factor for alcoholic HC (OR = 1.416, 95% CI 1.112–1.804, p= 0.005). Meanwhile, subgroup analysis of population indicated that the significant differences only existed in Asian population (OR = 1.719, 95% CI 1.212–2.438, p= 0.002). In hospital-based studies, patients with GSTM1 null were more likely in risk of HC (OR = 1.426, 95% CI 1.092–1.863, p= 0.009). Subgroup analysis using genotyping method showed a significant association between GSTM1 null genotype and HC occurrence in the studies employing the multiple PCR genotyping method (OR = 1.559, 95% CI 1.171–2.076, p= 0.002). Based on the results of this analysis, it was concluded that GSTM1 null genotype could increase the susceptibility of non-viral hepatic cirrhosis. In addition, alcohol intake, Asian ethnicity, sample source from hospital and multiple PCR genotyping method may also influence the susceptibility of hepatic cirrhosis.

To investigate the effects of low-dose ketamine combined with propofol on the antidepressant efficacy in stressed rats undergoing electroconvulsive shock (ECS) and its impact on phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit glutamate receptor 1 (GluR1) and -aminobutyric acid receptor subunit A (GABAAR).

Objective To undertake a meta-analysis to investigate if there is an association between the glutathione S-transferase mu 1 (GSTM1) gene polymorphism, coronary artery disease (CAD) susceptibility and smoking.Methods Electronic databases, including PubMed®, Web of Science and Embase®, were searched for relevant case–control studies. Data were extracted and the odds ratio (OR) was calculated and appropriate statistical methods were used for the meta-analysis.Results The analysis included eight studies with a total of 1880 cases with CAD and 1758 control subjects. The results of this meta-analysis demonstrated that there is no association between the GSTM1null and CAD (OR 1.24, 95% confidence interval [CI] 1.00, 1.55). An increased risk of CAD was observed in the smoking population with the GSTM1null genotype (OR 1.48, 95% CI 1.02, 2.15). Subgroup analyses of geographical region, genotyping method and publication language category demonstrated potential relationships among gene polymorphism, smoking and CAD.Conclusions Based on the current literature, the GSTM1null genotype was associated to CAD in the smoking population. The interaction between smoking and GSTM1polymorphism may contribute to the susceptibility of CAD.

In this work, MoS2 microsphere was synthesized by hydrothermal reaction, in which thiourea (CS(NH2)2) was used as S-source and reducing agent, ammonium heptamolybdate ((NH4)6Mo7O24.4H2O) was used as Mo-source. The influence of temperature, as well as different dispersing agents, on the reaction product’s morphology, structure and phase composition was discussed. X-ray diffraction results show that all the as-synthesized products are the hexagonal 2H-MoS2 without impurity. SEM images of the as-prepared MoS2 samples without adding any dispersing agent present spherical morphology with sheet-like structures shaped on the surface. A possible formation mechanism of the MoS2 microsphere is that of self-assembly growth process; In addition, for the samples adding surfactant CTAB, SDBS or PVP in the reactants, the MoS2 is confined to layered structure. Compared with SDBS and PVP, CTAB has the best dispersion effect which ensure the as-synthesized microsphere with about 300nm average diameter, and the influence mechanism of which can be deduced as electrostatic interaction and stereo-hindrance effect.

Design of antibacterial woven fabrics was discussed in view of visual impact and antibacterial activity. Antibacterial yarns can be obtained from blending and combining of silver-coated fibers. Analysis of manufacturing process and cost shows that core-spinning and sirofil spinning are preferable. Core-spun yarns can be used in filling if silver color is not desired. If silver color is desirable, sirofil yarns can be spaced at regular intervals in filling direction.

Metal content of metallized fiber can be determined by density testing and calculating. The weight of plated metal’s percentage of metallized fiber can be derived form measuring the weight of metallized fiber, and using the density formula and the law of conservation of mass with knowing the density of plated metal and the basic fiber. The characterization and measurement of the metal content of the metallized fiber at home and abroad is compared, the principle of the determination method by density testing is analyzed, the principle of the determination method by density testing is analyzed, and the specific operation is discussed while the silver content determination of silver-plated fiber is as an example, which provides a simple and convenient means for the determination of metal content of the metallized fiber..

This study investigated the relationship between the delta-aminolevulinate dehydratase (ALAD) isozymes and the blood lead levels of Chinese children. The purpose of this study was to determine the precise ALAD genotyping in Chinese children and identify the contribution of the ALAD genotype to the body lead burden. Blood samples were obtained from 109 boys and 120 girls. These children were 6–10 years old and from a single primary school. Both the school and their homes were within a community in which a large smelter was located. An environmental questionnaire was obtained for each subject, and blood lead levels and ALAD isozyme phenotype were analyzed in a double-blinded fashion. The blood lead levels of 229 children ranged from 4.5 to 26.4 μg/dl; the mean was 10.3 μg/dl and the standard deviation was 3.3 μg/dl. The gene distribution of the ALAD isozyme phenotypes in these environmentally exposed children was ALAD 1-1 (92%), ALAD 1-2, (8%), and ALAD 2-2 (0%). The mean blood level of the environmentally exposed children, who were homozygous for the ALAD1allele, was 9.7 μg/dl; the mean for those who were heterozygous for the ALAD2allele was 11.7 μg/dl. Using the ttest, the means of the groups were different at the level of t=2.2058, P<0.05. Step-wise regression and multiple analyses of covariance were employed to control the confounders to measuring the independent contribution of the ALAD genotype on blood lead levels. After controlling the confounders, the contribution of the ALAD genotype to the blood lead level was greater and still statistically significant (F=7.3201, P<0.01). These results indicate that individuals carrying the ALAD2 allele are more likely to have sustained increases in blood lead levels when exposed to a lead-contaminated environment.

We used a prospective study design to assess the effects of prenatal low-level lead exposure on the development of urban, inner-city children in Shanghai. Umbilical cord blood samples were consecutively collected from 605 live newborns. Two hundred and fifty-seven samples were excluded from the study due to clotting. Lead levels were determined on 348 cord blood samples. The geometric mean was 9.2 μg/dl. Based on their cord blood lead levels, infants were classified into two exposure groups: 104 in a relatively low lead group (lead levels ≤30 percentile), and 104 in a relatively high lead group (lead levels ≥70 percentile). Seventy-five subjects failed to complete the study, and 133 babies were included in the final cohort: 69 babies in the high lead group and 64 in the low lead group. At 3, 6, and 12 months, the Bayley Scales of Infant Development were administered and capillary blood lead levels were measured. Detailed information was obtained on a wide range of variables relevant to infant development. At all three ages, the Mental Development Index (MDI) scores, adjusted for confounders, were inversely related to the infants' cord blood lead levels. The difference of the mean adjusted MDI scores between low and high lead groups was 3.4 at 3 months, 6.3 at 6 months, and 5.2 at 12 months of age. These differences were statistically significant at all time points. No significant association between cord blood lead levels and the Psychomotor Development Index (PDI) scores was detected at all three visits after adjustment for confounders. Postnatal lead levels were unrelated to concurrent developmental status. We conclude that prenatal low-level lead exposure, which is relatively common in Shanghai, is associated with an adverse developmental impact on children through the first year of life.