Maternal Polyunsaturated Fatty Acid Status And Offspring Allergic Disease Up To The Age of 18 Months

Master'sMASTER OF SCIENC

Probucol reduces the cerebral edema area and infarction volume in rat cerebral infarction model via PI3K/Akt pathway

Purpose: To study the effects of probucol on rats with cerebral infarction through the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (Akt) pathway.Methods: Sprague-Dawley (SD) rats were divided into sham group (SO group, n = 7), model group (MO group, n = 7) and probucol group (PR group, n = 7). Infarction volume, messenger ribonucleic acid (mRNA), protein expressions of PI3K/Akt, neurological score, brain water content, degree of brain tissue lesions and neurological function score were determined.Results: Neurological score was 0, 2.54 ± 0.67 and 1.34 ± 0.21 points, in SO, O and PR groups, respectively. In turning angle test, neurological function score gradually rose at 24 h after cerebral infarction in PR and MO groups, compared with that in the SO group (p < 0.05), but significantly declined at 48 h in PR group compared with that in MO group (p < 0.05). Brain water content was lowest in the SO group but highest in MO group; it was significantly lower in PR group than that in MO group (p < 0.05). The mRNA and protein expressions of PI3K/Akt were highest in SO group and lowest in MO group; the expressions were higher in PR group than those in the MO group (p < 0.05).Conclusion: Probucol reduces the cerebral edema area and infarction volume by activating PI3K/Akt pathway, thereby exerting a significant therapeutic effect on rat model with cerebral infarction. Thus, this agent has the potential for use in the management of cerebral infarction

Breviscapine alleviates MPP+-induced damage and apoptosis of SH-SY5Y cells by activating Nrf2 pathway

Purpose: To investigate the role and mechanism of action of breviscapine (Brp) in 1-methyl-4- phenylpyridinium ion (MPP+)-induced cell injury in human neuroblastoma cell line, SH-SY5Y.Methods: The injury on SH-SY5Y cells was induced using MPP+. Cell viability and apoptotic ability were determined by CCK8 assay and Annexin V/PI staining, respectively. Protein expressions of nuclear factor E2-related factor 2 (Nrf2) and its related downstream proteins - hemeoxygenase 1(HO-1) and NAD(P)H-quinoneoxido reductase 1(NQO1), were determined using Western blotting.Results: Brp dose-dependently attenuated MPP+ induced reduction in the viability of SH SY5Y cells, but alleviated MPP+-induced oxidative stress (OS) and cell injury, as evidenced by the levels of reactive oxygen species (ROS), tyrosine hydroxylase (TH), lactic dehydrogenase (LDH), and dopaminetransporter (DAT) (p < 0.05). Brp decreased the amount of apoptotic cells induced by MPP+, as well as the protein levels of Bax and cleaved-caspase 3, and also induced the activation of Nrf2 signaling pathway (p < 0.05).Conclusion: Brp alleviates MPP+-induced cellular damage and cell apoptosis in SH-SY5Y cells by activating Nrf2 pathway. Thus, Brp is a potential therapeutic candidate for the treatment of PD

Structural specializations of α4β7\alpha_4 \beta_7, an integrin that mediates rolling adhesion

The lymphocyte homing receptor integrin $\alpha_4 \beta_7$ is unusual for its ability to mediate both rolling and firm adhesion. $\alpha_4 \beta_1$ and $\alpha_4 \beta_7$ are targeted by therapeutics approved for multiple sclerosis and Crohn’s disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind α4β7. A long binding groove at the $\alpha_4 -\beta_7$interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in $\alpha_4$ ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion–dependent adhesion site in $\alpha_4 \beta_7$ is essential for binding to MAdCAM-1 in $Mg^{2+}$ yet swings away when RO0505376 binds. A novel intermediate conformation of the $\alpha_4 \beta_7$ headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled

Dialysate glucose response phenotypes during peritoneal equilibration test and their association with cardiovascular death : a cohort study

Different measures of rates of transfer of glucose during the peritoneal equilibrium test (PET), undertaken during peritoneal dialysis (PD) might provide additional information regarding a patient's risk of future cardiovascular mortality. This study aimed to characterize the heterogeneity of dialysate glucose (DG) response phenotypes during the PET and compare the cardiovascular mortality rates associated with the different phenotypes. Our cohort was derived from Henan peritoneal dialysis registry. A total of 3477 patients initiating PD in 2007 to 2014 had the DG measured at 0, 2-hour and 4-hour (D0, D2, and D4 respectively) during the PET for estimation of D2/D0 and D4/D0. Deaths mainly due to CVD within 2 years since the initiation of PD were defined as the outcome. Latent class mixed-effect models were fitted to identify distinct phenotypes of the DG response during the PET. Multivariable unconditional Logistic regression models with adjustment for cardiometabolic risk factors were used to compare the 2-year risk of cardiovascular mortality among patients in the different latent classes. Three distinct DG response phenotypes during the PET were identified. Those with consistently high D2/D0 and D4/D0 ratios had a 1.22 [95% confidence interval: 1.02, 1.35] excess risk of a cardiovascular death within 2 years of commencing PD compared with patients with the lowest D2/D0 ratio and decreased D4/D0 ratio after adjustment for cardiometabolic risk factors. Consistently elevated D2/D0 and D4/D0 ratios during the PET are associated with an increased risk of 2-year cardiovascular mortality independent of other cardiometabolic risk factors. In view of the potential bias due to unmeasured confounders (eg, Family history of cardiovascular diseases, and dietary patterns), this association should be further validated in other external cohorts

A Novel Role of Dma1 in Regulating Forespore Membrane Assembly and Sporulation in Fission Yeast

By characterizing the fission yeast Dma1's function during meiosis, we revealed that Dma1 is required for spore formation, while it is dispensable for fidelity of nuclear divisions. We also found that Dma1 is functionally related to SIN pathway and meiosis-specific kinase Slk1 during sporulation

Mechanistic evaluation of the inhibitory effect of four SGLT-2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches

Sodium-glucose co-transporter type 2 (SGLT 2, gliflozins) inhibitors are potent orally active drugs approved for managing type 2 diabetes. SGLT 2 inhibitors exert a glucose-lowering effect by suppressing sodium-glucose co-transporters 1 and 2 in the intestinal and kidney proximal tubules. In this study, we developed a physiologically based pharmacokinetic (PBPK) model and simulated the concentrations of ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin in target tissues. We used the perfusion-limited model to illustrate the disposition of SGLT 2 inhibitors in vivo. The modeling parameters were obtained from the references. Simulated steady-state plasma concentration-time curves of the ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin are similar to the clinically observed curves. The 90% prediction interval of simulated excretion of drugs in urine captured the observed data well. Furthermore, all corresponding model-predicted pharmacokinetic parameters fell within a 2-fold prediction error. At the approved doses, we estimated the effective concentrations in intestinal and kidney proximal tubules and calculated the inhibition ratio of SGLT transporters to differentiate the relative inhibition capacities of SGLT1 and 2 in each gliflozin. According to simulation results, four SGLT 2 inhibitors can nearly completely inhibit SGLT 2 transporter at the approved dosages. Sotagliflozin exhibited the highest inhibition activity on SGLT1, followed by ertugliflozin, empagliflozin, and henagliflozin, which showed a lower SGLT 1 inhibitory effect. The PBPK model successfully simulates the specific target tissue concentration that cannot be measured directly and quantifies the relative contribution toward SGLT 1 and 2 for each gliflozin

Human cytomegalovirus exploits interferon-induced transmembrane proteins to facilitate morphogenesis of the virion assembly compartment

Recently, interferon-induced transmembrane proteins (IFITMs) have been identified to be key effector molecules in the host type I interferon defense system. The invasion of host cells by a large range of RNA viruses is inhibited by IFITMs during the entry step. However, the roles of IFITMs in DNA virus infections have not been studied in detail. In this study, we report that human cytomegalovirus (HCMV), a large human DNA virus, exploits IFITMs to facilitate the formation of the virion assembly compartment (vAC) during infection of human fibroblasts. We found that IFITMs were expressed constitutively in human embryonic lung fibroblasts (MRC5 cells). HCMV infection inhibited IFITM protein accumulation in the later stages of infection. Overexpression of an IFITM protein in MRC5 cells slightly enhanced HCMV production and knockdown of IFITMs by RNA interference reduced the virus titer by about 100-fold on day 8 postinfection, according to the findings of a virus yield assay at a low multiplicity of infection. Virus gene expression and DNA synthesis were not affected, but the typical round structure of the vAC was not formed after the suppression of IFITMs, thereby resulting in defective virion assembly and the production of less infectious virion particles. Interestingly, the replication of herpes simplex virus, a human herpesvirus that is closely related to HCMV, was not affected by the suppression of IFITMs in MRC5 cells. These results indicate that IFITMs are involved in a specific pathway required for HCMV replication. IMPORTANCE HCMV is known to repurpose the interferon-stimulated genes (ISGs) viperin and tetherin to facilitate its replication. Our results expand the range of ISGs that can be exploited by HCMV for its replication. This is also the first report of a proviral function of IFITMs in DNA virus replication. In addition, whereas previous studies showed that IFITMs modulate virus entry, which is a very early stage in the virus life cycle, we identified a new function of IFITMs during the very late stage of virus replication, i.e., virion assembly. Virus entry and assembly both involve vesicle transport and membrane fusion; thus, a common biochemical activity of IFITMs is likely to be involved. Therefore, our findings may provide a new platform for dissecting the molecular mechanism of action of IFITMs during the blocking or enhancement of virus infection, which are under intense investigation in this field

Surface properties of novel wood-based reinforced composites manufactured from crushed veneers and phenolic resins

This study was performed to determine the surface properties of novel wood-based reinforced composites made from poplar veneers and phenolic resins. The veneers with different thickness (1.8, 4, 6, 8 mm) were finely crushed and then were impregnated with phenolic resins to achieve different resin loading (12, 14, 18%). Finally, they were laminated or random paved to manufacture novel wood-based reinforced composites with different target densities (0.8-1.1 g cm-3). With increased veneer thickness or resin content, the hardness of novel wood-based reinforced composites decreased and their roughness increased. The increase of density contributed to the increased hardness and decreased roughness. The surface wettability of novel wood-based reinforced composites appeared to be closely related to their surface roughness. There was a negative correlation between contact angle and roughness. The novel wood-based reinforced composites prepared by laminated mat formation showed higher hardness, lower roughness than those by random mat formation. Such data of surface properties can be applied to design the novel wood-based reinforced composites products with desired quality and provide basic information for further panel processing