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Background: After an acute stroke, highly reactive oxygen and nitrogen species (ROS/RNS) lead to microvessel injury and inhibit endogenous mediators to prevent the repair process of endothelial dysfunction and tissue injury. Among them, the peroxynitrite (ONOO−) generation as a result of nitric oxide (NO) and superoxide anion (O2·−) reaction contributes to ischemic brain injury. Purpose: To validate the targeted inhibition of ischemic injury's markers with the delivery of potent antioxidants such as β-carotene (BC) in lipid nanoparticles (LNPs) directly acting with ONOO− compound to prevent the breakdown of blood-brain barrier (BBB). Study design: In the current work, BC in polyethylene glycol (PEG) lipid nanoparticles (PEG-LNPs) with or without attached anti-nitrotyrosine antibody (3-NT) inhibits ONOO− generation in the transient middle cerebral artery occlusion (tMCAO) model. Transmission electron microscopy (TEM) was used to examine structural change in LNPs with or without 3-NT antibody attachment. Fluorescence imaging was employed to study drug encapsulated PEG-LNPs accumulation in mice brain following MCAO and spectrophotometry for the in-vitro drug release profile. Immunoblotting using antibodies specific for spectrin and calcineurin, occludin and ZO-1 and other targets was utilized. The NP3 fluorescent probe was used for the detection of ONOO−generation. Evans Blue was injected 24 h after tMCAO in vehicle and BC PEG-LNPs with 3-NT antibody treated animal groups to observe the tight junction breakdown. Results: The fluorescence's data reveals that attachment of 3-NT antibody has directed the delivery of BC to the ischemic ipsilateral region. BC, as well, is found effective to improve infarct volume and neurological deficit by neuronal protection by inhibiting spectrin and calcineurin (CaN) breakdown. Furthermore, inhibition of ONOO−generation is observed in NP3 probe incubation of brain slices and protects BBB from breakdown in Evans blue extravasation. Conclusion: The current work suggests that inhibiting ONOO−at ischemic site protects the brain microvessels from injury. 3-NT/BC/LNPs carrier system is potentially efficient in delivering BC at the site of ONOO−generation, and possibly suitable for ischemic region-targeted therapy.

Abstract Accumulating evidence indicates that epilepsy has a higher risk of inducing memory impairment and dementia. However, the underlying onset mechanism remains unclear. Here, we found that mice with spontaneous epilepsy induced by endothelial CDK5 deficiency exhibited hippocampal‐dependent memory impairment at 6 months of age, but not at 2 months of age. Moreover, the persistent epileptic seizures induce aberrant changes in phosphorylation of CaMKII protein in the hippocampus of spontaneous epileptic mice. Using genome‐wide RNA sequencing and intergenic interaction analysis of STRING, we found that in addition to epilepsy‐related genes, there are changes in synaptic organization pathway node genes, such as Bdnf and Grin1. The synapse‐related proteins by Western blot analysis, such as NMDA receptors (NR1 and NR2B), PSD95, and the phosphorylation of synapsin1, are progressively decreased during epileptic seizures in Cdh5‐CreERT2;CDK5f/f mice. Notably, we found that valproate (VPA) and phenytoin (PHT) augment mRNA expression and protein levels of synapse‐related genes and ameliorate memory impairment in Cdh5‐CreERT2;CDK5f/f mice. Our study elucidates a potential mechanism of memory deficits in epilepsy, and pharmacological reversal of synaptic pathology targeting might provide a new therapeutic intervention for epileptic memory deficits.

RNA modification of m6A/m5C/m1A contributes to the occurrence and development of cancer. Consequently, this study aimed to investigate the functions of m6A/m5C/m1A regulated genes in the prognosis and immune microenvironment of hepatocellular carcinoma (HCC). The expression levels of 45 m6A/m5C/m1A regulated genes in HCC tissues were determined. The functional mechanisms and protein–protein interaction network of m6A/m5C/m1A regulated genes were investigated. The Cancer Genome Atlas (TCGA) HCC gene set was categorized based on 45 m6A/m5C/m1A regulated genes, and survival analysis was used to determine the relationship between the overall survival of HCC patients in subgroups. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct the risk model and nomogram for m6A/m5C/m1A regulated genes. The relationships between m6A/m5C/m1A regulated gene subsets and risk model and immune cell infiltration were analyzed using CIBERSORT. m6A/m5C/m1A regulated genes were involved in mRNA and RNA modifications, mRNA and RNA methylation, mRNA and RNA stability, and other processes. There was a statistically significant difference between cluster1 and cluster2 groups of genes regulated by m6A/m5C/m1A. The prognosis of cluster1 patients was significantly better than that of cluster2 patients. There were statistically significant differences between the two cluster groups in terms of fustat status, grade, clinical stage, and T stage of HCC patients. The risk model comprised the overexpression of YBX1, ZC3H13, YTHDF1, TRMT10C, YTHDF2, RRP8, TRMT6, LRPPRC, and IGF2BP3, which contributed to the poor prognosis of HCC patients. The high-risk score was associated with prognosis, fustat status, grade, clinical stage, T stage, and M stage and was an independent risk factor for poor prognosis in HCC patients. High-risk score mechanisms included spliceosome, RNA degradation, and DNA replication, among others, and high-risk was closely related to stromal score, CD4 memory resting T cells, M0 macrophages, M1 macrophages, resting mast cells, CD4 memory activated T cells, and follicular helper T cells. In conclusion, the cluster subgroup and risk model of m6A/m5C/m1A regulated genes were associated with the poor prognosis and immune microenvironment in HCC and are expected to be the new tools for assessing the prognosis of HCC patients.

Background & Aims Metformin is currently the most widely used first-line hypoglycemic agent for diabetes mellitus. Besides glucose-lowering action, there is increasingly interest in the potential anti-inflammatory action of this drug. In the present study, we investigated the actions of metformin on experimental insulitis using STZ-induced diabetic mice. Methods Mice with acute diabetes induced by STZ were administered metformin by gavage. Changes of blood glucose and body weight, and the daily amount of food and water intake were measured. Pancreatic tissues were collected for histologic analyses. Pathological assessment and immunohistochemistry analysis were used to determine the effect of metformin on insulitis. Inflammatory cytokines in the pancreas and insulin levels were measured through ELISA analysis. Results Metformin significantly reduced blood glucose levels and improved aberrant water intake behavior in experimental diabetic mice. No significant differences were observed in terms of body weight and food intake behavior in metformin-treated animals. In the STZ-induced model of diabetes, we found the appearance of pronounced insulitis. However, metformin administration reduced the severity of insulitis assessed by blind pathological scoring. In addition, metformin treatment improved insulin levels in experimental diabetic mice. ELISA assay revealed decreased levels of inflammatory response marker IL-1β and TNF-α in the pancreatic tissues following metformin treatment. Conclusion Metformin attenuated insulitis in the STZ-induced mice model of diabetes. This islet-protective effect might be partly correlated with the anti-inflammatory action of metformin.

C6H6(SiF2)3 has a very unique spatial geometry shape, electronic structure, and hetero‐chain structure. The addition of external electric field makes C6H6(SiF2)3 become a strong candidate for the research and development of new functional materials. Based on quantum chemical calculation, we studied the influence of external electric field on C6H6(SiF2)3 and came to the conclusion that the addition of external electric field makes the molecular structure of C6H6(SiF2)3 occur obvious deformation. The essence of structural deformation is energy change and atomic force. But if the external electric field is removed, C6H6(SiF2)3 will return to its original configuration; that is, C6H6(SiF2)3 has obvious elastic characteristics. The existence of strong external electric field will lead to the charge polarization distribution of C6H6(SiF2)3. With the increase of external electric field intensity, C6H6(SiF2)3 shows color in the visible light range, and it can be controlled to show different color by changing the intensity of external electric field. In addition, applying external electric field to C6H6(SiF2)3 in invisible solvent benzene can save more electricity than that without solvent, and the absorption band in the visible light range is more significant. Therefore, invisible solvent can be added to enhance its color display under different external electric field intensity. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice. Methods: Streptozotocin (STZ, 60 mg/kg/d × 5 d, i.p.) was injected to induce type 1 diabetes in male C57BL/6 mice. Mice were treated with metformin (250 mg/kg/d, i.g.) for consecutive 14 days. Wound closure was evaluated by wound area and number of CD31 stained capillaries. Functions of bone marrow-endothelial progenitor cells (BMEPCs) were assessed by tube formation and migration assays, and expression of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) was determined by western blot analysis. Results: Metformin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in metformin treated diabetic mice. Abilities of tube formation and migration of BM-EPCs were impaired in diabetic mice, which were improved by metformin. Expression of both phosphorylated-AMPK and phosphorylated-eNOS was significantly increased, and nitric oxide (NO) production was enhanced by metformin in BM-EPCs of diabetic mice. In vitro, metformin improved impaired BM-EPC functions, and increased phosphorylated-eNOS expression and NO production in cultured BM-EPCs caused by high glucose, which was prevented by the AMPK inhibitor compound C. Conclusions: Our results suggest that metformin could improve BM-EPC functions in STZ-induced diabetic mice, which was possibly dependent on the AMPK/eNOS pathway. [ABSTRACT FROM AUTHOR]

Thepotential energy surface (PES) for reaction C2H4+ HO2was examined by using the quantum chemicalmethods. All rates were determined computationally using the CBS-QB3composite method combined with conventional transition state theory(TST),variational transition-state theory (VTST) and Rice–Ramsberger–Kassel–Marcus/master-equation(RRKM/ME) theory. The geometries optimization and the vibrationalfrequency analysis of reactants, transition states, and products wereperformed at the B3LYP/CBSB7 level. The composite CBS-QB3 method wasapplied for energy calculations. The major product channel of reactionC2H4+ HO2is the formation C2H4O2H via an OH···π complex with 3.7 kcal/mol binding energy which exhibits negative-temperaturedependence. We further investigated the reactions related to thiscomplex, which were ignored in previous studies. Thermochemical propertiesof the species involved in the reactions were determined using theCBS-QB3 method, and enthalpies of formation of species were comparedwith literature values. The calculated rate constants are in goodagreement with those available from literature and given in modifiedArrhenius equation form, which are serviceable in combustion modelingof hydrocarbons. Finally, in order to illustrate the effect for low-temperatureignition of our new rate constants, we have implemented them intothe existing mechanisms, which can predict ethylene ignition in ashock tube with better performance. [ABSTRACT FROM AUTHOR]

Sepsis is a common disease that continues to increase in incidence in the world. Diseases, such as diabetes, may make the situation worse. Diabetic patients are at increased risk for common infections. This study was designed to investigate the role of glibenclamide on myocardial injury by lipopolysaccharides (LPS) in streptozotocin induced diabetic mice (STZ-mice). Methods LPS was used to induce endotoxemia in STZ-mice. Heart rate and mean arterial pressure were measured by MPA-HBBS. Serum epinephrine level was measured by enzyme-linked immunosorbent assays (ELISA). Myocardial injury was examined by light and transmission electron microscope and TUNEL staining. Macrophage infiltration was measured by immunohistochemistry. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in myocardial tissue and serum in STZ-mice, and in conditional medium of primary cultured peritoneal macrophages were determined by ELISA. Nalp3 and Caspase-1 protein levels were measured by Western blotting analysis. Results STZ administration decreased body weight and increased blood glucose in C57BL/6 mice. LPS injection caused decreases of heart rate and mean arterial pressure, and elevated serum epinephrine level in C57BL/6 mice. Compared with control mice without STZ treatment, LPS induced more severe myocardial injury and macrophage infiltration in STZ-mice, which was attenuated by pretreatment of glibenclamide. LPS stimulation enhanced the levels of IL- 1β and TNF-α in both cardiac tissue and serum. Glibenclamide pretreatment significantly inhibited the serum levels of pro-inflammatory cytokines. Either high glucose or LPS increased the levels of IL-1β and TNF-α in the conditional medium of peritoneal macrophages. Glibenclamide treatment suppressed the increase of IL-1β level induced by high glucose and LPS. Furthermore, Nalp3 and Caspase-1 levels were markedly increased by high glucose plus LPS, and both proteins were significantly inhibited by glibenclamide treatment. Conclusions We conclude that glibenclamide could attenuate myocardial injury induced by LPS challenge in STZ-mice, which was possibly related to inhibiting inflammation through Nalp3 inflammasomes. [ABSTRACT FROM AUTHOR]

Background: Cardiac dysfunction is well-described in endotoxemia and diagnosed in up to 60% of patients with endotoxic shock. ATP-sensitive potassium (KATP) channels are critical to cardiac function. This study investigates the role of Kir6.2 subunits of KATP channels on cardiac dysfunction in lipopolysaccharide (LPS)-induced endotoxemia. Methods: Kir6.2 subunits knockout (Kir6.2-/-) and wild-type (WT) mice were injected with LPS to induce endotoxemia. Cardiac function was monitored by echocardiography. Left ventricles were taken for microscopy (both light and electron) and TUNEL examination. Serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities, and tumor necrosis factor-α (TNF-α) levels in both serum and left ventricular tissues were determined. Results: Compared to WT, Kir6.2-/- mice showed significantly declined cardiac function 360 min after LPS administration, aggravated myocardial damage and elevated serum LDH and CK activities. Apoptotic cells were obviously increased in heart tissues from Kir6.2-/- mice at 90, 180 and 360 min. TNF-α expression in both serum and heart tissues of Kir6.2-/- mice was significantly increased. Conclusions: We conclude that Kir6.2 subunits are critical in resistance to endotoxemia-induced cardiac dysfunction through reducing myocardial damage by inhibition of apoptosis and inflammation. KATP channels blockers are extensively used in the treatment of diabetes, their potential role should therefore be considered in the clinic when patients treated with antidiabetic sulfonylureas are complicated by endotoxemia. [ABSTRACT FROM AUTHOR]

C6H6(SiF2)3 has a very unique spatial geometry shape, electronic structure, and hetero‐chain structure. The addition of external electric field makes C6H6(SiF2)3 become a strong candidate for the research and development of new functional materials. Based on quantum chemical calculation, we studied the influence of external electric field on C6H6(SiF2)3 and came to the conclusion that the addition of external electric field makes the molecular structure of C6H6(SiF2)3 occur obvious deformation. The essence of structural deformation is energy change and atomic force. But if the external electric field is removed, C6H6(SiF2)3 will return to its original configuration; that is, C6H6(SiF2)3 has obvious elastic characteristics. The existence of strong external electric field will lead to the charge polarization distribution of C6H6(SiF2)3. With the increase of external electric field intensity, C6H6(SiF2)3 shows color in the visible light range, and it can be controlled to show different color by changing the intensity of external electric field. In addition, applying external electric field to C6H6(SiF2)3 in invisible solvent benzene can save more electricity than that without solvent, and the absorption band in the visible light range is more significant. Therefore, invisible solvent can be added to enhance its color display under different external electric field intensity. [ABSTRACT FROM AUTHOR]

In this paper, we construct a Si x F y ( x ≤ 6, y ≤ 12) series optimised at the B3LYP/6-31G(d,p) level. At the same level, we perform frontline molecular orbital (FMO), Mayer bond order (MBO), molecular surface electrostatic potential (MS-EPS) and natural population analysis (NPA) calculations to study the chemical structure stabilities of these Si x F y molecules. The FMO and MBO results demonstrate that the chemical structure stabilities of the Si x F y ( x ≤ 6, y ≤ 12) series are ranked (from strong to weak) as SiF 4 > Si 2 F 6 > Si 3 F 8 > Si 4 F 10 > SiF 2 > Si 5 F 12 > Si 3 F 6 (ring) > Si 5 F 10 (ring) > Si 6 F 12 (ring) > Si 4 F 8 (ring). Furthermore, the chemical structure stabilities of the chains are stronger than those of the rings, while the number of silicon atoms is the same. In addition, infrared spectroscopy analysis shows that SiF 4 is the most stable among the Si x F y ( x ≤ 6, y ≤ 12) series, followed by Si 2 F 6 , and SiF 2 is unstable. The experimental results are consistent with theoretical calculations. Finally, the MS-EPS and NPA results indicate that compounds in the Si x F y ( x ≤ 6, y ≤ 12) series tend to be attacked by nucleophiles rather than by electrophiles; also, they show poor chemical structure stability when encountering nucleophiles., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Hydrogen abstraction from toluene by OH, H, O, CH3, and HO2 radicals are important reactions in oxidation process of toluene. Geometries and corresponding harmonic frequencies of the reactants, transition states as well as products involved in these reactions are determined at the B3LYP/6-31G(2df,p) level. To achieve highly accurate thermochemical data for these stationary points on the potential energy surfaces, the Gaussian-4(G4) composite method was employed. Torsional motions are treated either as free rotors or hindered rotors in calculating partion functions to determine thermodynamic properties. The obtained standard enthalpies of formation for reactants and some prodcuts are shown to be in excellent agreement with experimental data with the largest error of 0.5 kcal mol(-1). The conventional transition state theory (TST) with tunneling effects was adopted to determine rate constants of these hydrogen abstraction reactions based on results from quantum chemistry calculations. To faciliate its application in kinetic modeling, the obtained rate constants are given in Arrhenius expression: k(T) = AT(n) exp(-EaR/T). The obtained reaction rate constants also agree reasonably well with available expermiental data and previous theoretical values. Branching ratios of these reactions have been determined. The present reaction rates for these reactions have been used in a toluene combustion mechanism, and their effects on some combustion properties are demonstrated.