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This paper studies delay-dependent asymptotical stability problems for the neural system with time-varying delay. By dividing the whole interval into multiple segments such that each segment has a different Lyapunov matrix, some improved delay-dependent stability conditions are derived by employing an integral equality technique. A numerical example is given to demonstrate the effectiveness and less conservativeness of the proposed methods. [ABSTRACT FROM AUTHOR]

Abstract Background Glucose regulated protein 78 (Grp78) is involved in the invasion and metastasis in many human cancers including gastric cancer, breast cancer, prostate cancer. But the role of Grp78 in the invasion of human hepatocellular carcinoma has not been reported. In this article, we examined if Grp78 was associated with the invasion of hepatocellular carcinoma and explored the possible underlying mechanism. Methods The Grp78 and FAK expression levels in 44 patients with hepatocellular carcinoma were examined using immunohistochemistry. Grp78 overexpressing SMMC7721 cells were established by pcDNA3.1 (+)-Grp78 transfection and screened by G418. Grp78 and FAK levels in Grp78 overexpressing cells were down-regulated by siRNA transfection. The invasion status of tumor cells was evaluated by transwell assay in vitro, and chick embryo metastasis model in vivo. Cell spreading was determined by cell spreading assay, and quantitatively measured by Orisis software HUG. Grp78, pY397 FAK, pY576/577 FAK and FAK levels were detected by western blot. RhoA activity was detected by GST pulldown assay. The distribution of actin cytoskeleton was observed by fluorescent staining. Results Grp78 expression levels in 44 patients with hepatocellular carcinoma were negatively correlated with tumor grading, and positively correlated with portal invasion and intra-hepatic invasion. Overexpression of Grp78 in SMMC7721 cells promoted the invasion of cancer cells in vitro and in vivo, and this increase in tumor cell invasion was blocked by Grp78 siRNA knockdown. Our results also revealed that overexpression of Grp78 in SMMC7721 cells accelerated the process of cell spreading and promoted lamellipodia formation. Further analysis showed that overexpression of Grp78 in SMMC7721 cells increased pY397 and pY576/577 levels of FAK. Grp78 siRNA knockdown decreased FAK activation and activity. Our results also revealed that Grp78 overexpression in SMMC7721 cells decreased RhoA-GTP level, and Grp78 siRNA knockdown rescued RhoA-GTP level in Grp78 overexpressing cells, indicating Grp78 inhibited RhoA activity in hepatocellular carcinoma cells. Furthermore, overexpression of Grp78 in SMMC7721 cells increased phospho-p190RhoGAP level. FAK siRNA knockdown in Grp78 overexpressing cells reversed phospho-p190RhoGAP level. These data suggested that Grp78 inhibited RhoA activity by up-regulated phospho-p190RhoGAP level and Grp78 mediated p190RhoGAP phosphorylation is FAK dependent. Conclusion Grp78 promoted the invasion of hepatocellular carcinoma both in vitro and in vivo. Overexpression of Grp78 in hepatocellular carcinoma cells enhanced the activation and activity of FAK which negatively regulated Rock kinase activity by promoting the phosphorylation of p190RhoGAP.

Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the arterial intima. The activated macrophages secreted more pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, which promote the development of the disease. Apolipoprotein A-I (apoA-I), the major component of high density lipoprotein, is involved in reverse cholesterol transport of lipid metabolism. Recently, it has been found that apoA-I suppresses inflammation via repression of inflammatory cytokine expression; the mechanisms of the apoA-I-suppressive action, however, are not yet well characterized. In this study, we have for the first time found that apoA-I suppresses the expression of some inflammatory cytokines induced by lipopolysaccharide via a specific post-transcriptional regulation process, namely mRNA destabilization, in macrophages. Our further studies have also shown that AU-rich elements in the 3′-untranslated region of TNF-α mRNA are responsive to the apoA-I-mediated mRNA destabilization. The apoA-I-induced inflammatory cytokine mRNA destabilization was associated with increased expression of mRNA-destabiizing protein tristetraprolin through aJAK2/STAT3 signaling pathway-dependent manner. When blocking interaction of apoA -I with ATP-binding membrane cassette transporter Al (ABCA1), a major receptor for apoA -I in macrophages, it would almost totally abolish the effect of apoA-I on tristetraprolin expression. These results present not only a novel mechanism for the apoA-I-mediated inflammation suppression in macrophages but also provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis. [ABSTRACT FROM AUTHOR]

Heterosexuals have become the most prevalent group of HIV-1 in Kunming, Yunnan Province. Utilizing the principle of genetic similarity between their gene sequences, we built a molecular transmission network by gathering data from earlier molecular epidemiological studies. This allowed us to analyze the epidemiological features of this group and offer fresh concepts and approaches for the prevention and management of HIV-1 epidemics. Cytoscope was used to visualize and characterize the network following the processing of the sample gene sequences by BioEdit and HyPhy. The number of possible links and the size of the clusters were investigated as influencing factors using a zero-inflated Poisson model and a logistic regression model, respectively. A scikit-learn-based prediction model was developed to account for the dynamic changes in the HIV-1 molecular network. Six noteworthy modular clusters with network scores ranging from 4 to 9 were found from 150 clusters using Molecular Complex Detection analysis at a standard genetic distance threshold of 0.01. The size of the number of possible links and the network's clustering rate were significantly impacted by sampling time, marital status, and CD4 + T lymphocytes (all p < 0.05). The gradient boosting machine (GBM) model had the highest area under the curve value, 0.884 ± 0.051, according to scikit-learn. Though not all cluster subtypes grew equally, the network clusters were relatively specific and aggregated. The largest local transmission-risk group for HIV-1CRF08&#95;BC is now the heterosexual transmission population. The most suitable model for constructing the HIV-1 molecular network dynamics prediction model was found to be the GBM model.

The evidence from clinical studies suggests that lung carcinoma (LC) patients exhibit dysregulation in lipid metabolism. However, the causal relationship between plasma lipidome and LC, and whether inflammatory proteins mediate, remains to be determined. Genetic data for 179 plasma lipids and 91 inflammatory proteins were obtained from the latest published genome-wide association studies. Genetic data on LC and subtypes were from the largest available meta-analysis. The causal relationship between plasma lipidome and LC was determined by the two-sample Mendelian randomization (MR) method. Mediation MR analysis was employed to ascertain whether inflammatory proteins mediate the impact of plasma lipidome on LC. We identified 39 causal relationships between genetically predicted plasma lipidome and LC and subtypes. These relationships involve the influence of phosphatidylcholines, phosphatidylethanolamines, diacylglycerols, triacylglycerols, sphingomyelins, and Sterol esters. Additionally, the mediating role of 5 inflammatory proteins in the causal relationship between plasma lipidome and LC and subtypes was determined. Our results highlight the complex network of plasma lipidome and inflammatory proteins regulating LC. Integrating plasma lipidome and inflammatory proteins into clinical practice may open new avenues for the prevention and treatment of LC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The study explored the effect of salidroside(SAL) on high fat-induced apoptosis in H9 c2 cardiomyocytes based on AMPK/mTOR/p70 S6 K pathway.H9 c2 cardiomyocytes were cultured in vitro and the lipotoxicity model of H9 c2 cardiomyocytes was constructed by 0.2 mmol·L~(-1) palmitic acid(PA) treatment for 24 hours.The cells were divided into control group, PA group, and SAL group(20 μmol·L~(-1)).Cell proliferation was detected with cell proliferation kit I(MTT) assay after SAL and PA treatment.Dihydroethidium(DHE) probe, Annexin V-FITC/PI kit, and JC-1 probe were used to estimate reactive oxygen species(ROS) level, cell apoptosis, and mitochondrial membrane potential(MMP) change, respectively.The expression levels of p-AMPK/AMPK, p-mTOR/mTOR, p-p70 S6 K/p70 S6 K and apoptosis-related proteins Bax, Bcl-2, and cleaved caspase-3 were investigated with Western blot.The mRNA levels of AMPK, mTOR and p70 S6 K were determined by quantitative reverse transcription-polymerase chain reaction(qRT-PCR).RESULTS:: showed that compared with control group, PA group had decreased cell proliferation ability, MMP, Bcl-2 protein expression and AMPK protein and mRNA expression, while increased ROS level, Bax and cleaved caspase-3 protein expression, and mTOR and p70 S6 K mRNA and protein expression, and the difference was statistically significant(P&lt;0.05, P&lt;0.01).Compared with PA group, SAL improved cell proliferation ability, MMP level, Bcl-2 protein expression, and AMPK mRNA and protein expression, while down-regulated ROS level, cell apoptosis, Bax and cleaved caspase-3 protein expression, and mTOR and p70 S6 K mRNA and protein expression, and the difference was statistically significant(P&lt;0.05, P&lt;0.01).In conclusion, SAL exerted protective effects on high fat-induced lipotoxicity of H9 c2 cardiomyocytes, alleviated the oxidative stress injury and reduced cell apoptosis via regulating AMPK/mTOR/p70 S6 K signaling pathway.

We observed the effect of 2-deoxy-D-glucose (2-DG) on the brain tissue in rat cerebral ischemia-reperfusion (I/R) and explored its mechanism. After observing the effect of 2-DG on endoplasmic reticulum stress (ERS), rats were randomly divided into sham-operation group, I/R group and I/R+2-DG group (each group with 60 rats). I/R models were prepared by middle cerebral artery occlusion. In I/R+2-DG group, each rat was given intraperitoneal 2-DG of 100 mg/kg once a day for 7 days before brain ischemia. According to different time points (3h, 6h, 12h, 24h and 48h) after I/R, each group was divided into 5 subgroups (each subgroup with 12 rats). Nerve cell apoptosis, and the expressions of mRNA and protein of glucose regulated protein 78 (GRP78), cleaved-caspase-9 and cleaved-caspase-3 were determined with TUNEL, Western blotting and RT-PCR, respectively, in rat cerebral hippocampal CA1 area at each time point. TUNEL-positive cells were significantly less in I/R+2-DG group than in I/R group at each time point (all P<0.01). In I/R and I/R+2-DG groups, the expressions of mRNA and protein of GRP78 reached the maximum 12 h after I/R, and cleaved-caspase-9 and cleaved-caspase-3 reached the maximum 24 h after I/R. Compared with sham-operation group, the expressions of mRNA and protein of GRP78, cleaved-caspase-9 and cleaved-caspase-3 were all significantly increased (all P<0.01) in I/R and I/R+2-DG groups. However, the expressions of mRNA and protein of GRP78 were significantly higher in I/R+2-DG group than in I/R group (all P<0.05), but the expressions of mRNA and protein of cleaved-caspase-9 and cleaved-caspase-3 were all significantly lower in I/R+2-DG group than in I/R group (all P<0.05). We conclude that 2-DG has a neuroprotective effect on the brain tissue in rat cerebral ischemia-reperfusion models. The mechanism may be that 2-DG starts ERS followed by up-regulation of mRNA and protein of GRP78 and down-regulation of mRNA and protein of cleaved-caspase-9 and cleaved-caspase-3, which blocks the apoptotic pathway.

To investigate the effect and possible mechanism of echinacoside-containing serum on the osteogenic differentiation in rat bone marrow mesenchymal stem cells. Rat bone marrow mesenchymal stem cells were cultivated by the whole bone marrow adherence method. The 3rd generation of cells were divided into 3 groups: the blank control group, the classic osteogenic-induced group and the 10% echinacoside-containing serum group. The expression of alkaline phosphatase and osteocalcin were detected by ELISA. The ex- pression of ZHX, protein was detected by Western blot technique. RT-PCR technique was used to detect the expression of ZHX₃mRNA. According to the result, the expressions of the alkaline phosphatase and osteocalcin in the classic osteogenic-induced group and the 10% echinacoside-containing serum group were significantly higher than that of the blank control group (P <0. 01). And expressions of the alkaline phosphatase activity and osteocalcin in the 10% echinacoside-containing serum group were significantly higher than that in the classic osteogenic-induced group (P < 0.01). Meanwhile, the classic osteogenic-induced group and the 10% echinacoside-containing serum group showed obviously higher ZHX₃ protain and mRNA expression than that of the black control group, with significant differences (P < 0.01); the 10% echinacoside-containing serum group showed obviously higher ZHX₃ protain and mRNA expression than that of the classic osteogenic-induced group, with a significant difference (P < 0.01). In conclusion, 10% echinacoside-containing serum can promote the differentiation of the bone marrow mesenchymal stem cells cultured in vitro. Its mechanism may be correlated with the increase in the ZHX₃expression.

Objective: To identify potential mutations of ED1 gene in six pedigrees with hypohidrotic ectodermal dysplasia (HED), and to provide genetic counseling and prenatal diagnosis., Methods: Eight coding exons of ED1 gene of patients with clinically diagnosed HED and their relatives were amplified by polymerase chain reaction (PCR). The products were further analyzed by direct sequencing., Results: Various mutations of ED1 gene were detected, which included R153C, A349T, G299S, A349T and X392Q. Heterozygous double peaks at the same position were found in female carriers. Deletion of exon 9 was detected in one pedigree. R153C, X392Q and deletion of exon 9 were first identified in ethnic Han Chinese., Conclusion: The identified mutations of ED1 gene may be responsible for the disease. Genetic counseling, prenatal diagnosis and carrier screening are now available for these families.

Osteosarcoma is the most common primary bone malignancy in children and adolescents, and its clinical outcome is poor. We evaluated the influence of GSTP1, ERCC1 and ERCC2 polymorphisms on response to chemotherapy among osteosarcoma patients, and the significnace of these genes for prognosis. A total of 187 patients with osteosarcoma were administered methotrexate, cisplatin/adriamycin, actinomycin D, cyclophosphamide, or vincristine. GSTP1, ERCC1 and ERCC2 polymorphisms were genotyped by PCR-RFLP assay. The results showed the average survival time of 187 patients were 38.4 months. Some 97 patients showed response to neoadjuvant chemotherapy. The GSTP1 Val and ERCC2 A/A genotypes had significantly higher rates of response to chemotherapy, with adjusted OR (95% CI) of 2.19 (1.15-6.21) and 2.88 (1.14-13.3). Individuals with the ERCC2 A/A genotype were likely to have a lower risk of death from oseosarcoma, and the adjusted HR was 0.32 (0.13-0.95). Our study indicated that GSTP1 and ERCC2 Lys751Gln polymorphisms might be candidate pharmacogenomic factors to be explored in the future to identify osteosarcoma patients who might benefit from chemotherapy.

Objective: To establish a mice model of cisplatin-induced ototoxicity, and to investigate the effect of cisplatin on apoptosis of spiral ganglion cell and expression of caspase-3 in mouse cochlea., Methods: Terminal deoxynucleotidyl transferase-mediated nick end labeling method (TUNEL) was used to monitor the apoptosis of spiral ganglion cell. Envision method of immunohistochemistry was applied to detect the expression of caspase-3 in cochlea. Auditory brainstem response (ABR) was measured to observe the change of hearing., Results: The weight and hearing of mice in different dose of cisplatin groups were declined significantly as compared with those of control group (P < 0.05, P < 0.01), and the TUNEL positive cell number and expression of caspase-3 were greater remarkably with the more cisplatin injected., Conclusion: A mouse model of cisplatin-induced ototoxicity can be established. Cisplatin can lead to the apoptosis of spiral ganglion cells, and caspase-3 has participated in this apoptosis process, which approves further that apoptosis might be one of the mechanisms of cisplatin ototoxicity.

The study on biological effects of SDF-1/CXCR4 axis composed of stromal cell derived factor-1 (SDF-1) and its receptor CXCR4 is progressing rapidly in the recent years. The SDF-1/CXCR4 axis plays an important role in occurrence and development of tumors and closely correlate with angiogenesis of tumors. This review focuses the progress of study on SDF-1/CXCR4 axis and angiogenesis in leukemia including SDF-1/ and its receptor CXCR4, the expression of SDF-1/CXCR4 axis in leukemic cells, the mechanism of relation between SDF-1/CXCR4 axis and angiogenesis in leukemia, the application of inhibitors against SDF-1/CXCR4 in treatment of angiogenesis and so on.

In order to investigate the effect of autologous and allogeneic anti-CD3 McAb activated killer cells (CD3AK) on normal hematopoietic cells, the immobilized anti-CD3 McAb and low concentration IL-2 were used to activate CD3AK. Flow cytometry was used to assay the phenotype change of CD3AK to analyze the proportional change of CD34(+) cells in normal bone marrow mononuclear cells (BMMNC) cocultured with autologous or allogeneic CD3AK. The effect of CD3AK on normal hematopoietic progenitor cells was also assayed by methylcellulose clonogenic culture of CFU-GM. It was found that 3 - 5 micro g/ml immobilized anti-CD3 McAb and 100 U/ml IL-2 could activate CD3AK effectively. There were 99.51% CD3(+) cells in CD3AK groups. When BMMNCs from healthy volunteers were cocultured with allogeneic CD3AK for six hours, the percentage of CD34(+) cells was decreased 32.37%. CD3AK had no significant influence on autologous BMMNC. Allogeneic and autologous CD3AK were cultured with BMMNC from healthy volunteers for six hours, and then CFU-GM was evaluated. Allogeneic CD3AK inhibited 20.44% CFU-GM formation, but autologous CD3AK had no inhibition on CFU-GM. It is concluded that CD3AK has no inhibition to autologous normal hematopoietic progenitor cells after cocultured with them from these results, while allogeneic CD3AK inhibits the normal hematopoietic progenitor cells significantly.