Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging

Microglia express constitutively a Nox2 enzyme that is involved in neuroinflammation by the generation of reactive oxygen species (ROS). Amyloid β (Aβ) plays a crucial role in Alzheimer’s disease. However, the mechanism of Aβ-induced microglial dysfunction and redox-regulation of microgliosis in aging remains unclear. In this study, we examined Nox2-derived ROS in mediating microglial response to Aβ peptide 1–42 (Aβ42) stimulation in vitro, in aging-associated microgliosis in vivo and in post-mortem human samples. Compared to controls, Aβ42 markedly induced BV2 cell ROS production, Nox2 expression, p47phox and ERK1/2 phosphorylation, cell proliferation and IL-1β secretion. All these changes could be inhibited to the control levels in the presence of Nox2 inhibitor or superoxide scavenger. Compared to young (3–4 months) controls, midbrain tissues from wild-type aging mice (20– 22 months) had significantly higher levels of Nox2-derived ROS production, Aβ deposition, microgliosis and IL-1β production. However, these aging-related changes were reduced or absent in Nox2 knockout aging mice. Clinical significance of aging-associated Nox2 activation, microgliosis and IL-1β production was investigated using post-mortem midbrain tissues of humans at young (25–38 years) and old age (61–85 years). In conclusion, Nox2-dependent redox-signalling is crucial in microglial response to Aβ42 stimulation and in aging-associated microgliosis and brain inflammation

Preparation and In Vitro Evaluation of Tacrolimus-Loaded Ethosomes

The main objective of the present work was to prepare and assess dermal delivery of tacrolimus-loaded ethosomes versus classic liposomes. Both delivery systems were characterized for particle size, polydispersity index, and entrapment efficiency (EE), by dynamic laser diffraction and ultrafiltration or dialysis methods, respectively. The results indicated that presence of ethanol in the formulations affected the particle size. In addition, ultrafiltration method was selected to determine EE due to relatively short period as compared with dialysis method. Ethosomes exhibited a significant higher EE and amount of drug in dermis in contrast to classic liposomes suggesting that ethosomes with higher entrapment capacity prompted more amount of tacrolimus to permeate through stratum corneum and reach the target of atopic dermatitis (AD). Physical stability was very well for tacrolimus-loaded ethosomes under storage condition (4°C). Our results demonstrated that the ethosomal system might be a promising candidate for dermal delivery of tacrolimus for AD

Effect of sodium hyaluronate in treating fungal corneal ulcer

AIM: To retrospectively analyze the effects of sodium hyaluronate in treating fungal corneal ulcer.<p>METHODS: Since June, 2006, there were 178 patients(178 eyes)with fungal corneal ulcer receiving medical treatment in our hospital. Among them, 81 patients(81 eyes)as the control group received the traditional antifungal treatment with the natamycin and fluconazole being the major medicine, from June 2006 to June 2008. While, 97 patients(97 eyes)as the treatment group received sodium hyaluronate treatment based on traditional antifungal treatment during the period of June 2008 to March 2010. Effects of two therapeutic methods were compared and analyzed. <p>RESULTS: Of the 97 cases in the treatment group, the average hospital stay was: 14.15±4.23d, with 90 cases(92.8%)cured, 5 cases(5.2%)improved, 2 cases(2.1%)ineffective, the final visual acuity of 51.6% patients better than 0.3. Of the 81 cases in the control group, average hospital stay was: 17.26±6.23d, with 69 cases(85.2%)cured, 7 cases(8.6%)improved, 5 cases(6.2%)ineffective, the final visual acuity of 39.5% patients better than 0.3. After statistical analysis, the average hospital stay, the cure rate, the effective rate and the final visual acuity in both groups showed statistically significant difference(<i>P</i><0.05). The average hospital stay of the treatment group was shorter than that of the control group, while the cure rate and effective rate and the final visual acuity was better than that of the control group.<p>CONCLUSION: Sodium hyaluronate can promote fungal corneal ulcer healing, improve the cure rate and reduce the formation of corneal scar

In vivo and in silico characterization of apocynin in reducing organ oxidative stress: a pharmacokinetic and pharmacodynamic study

Apocynin has been widely used in vivo as a Nox2-contaninig NADPH oxidase inhibitor. However, its time-dependent tissue distribution and inhibition on organ reactive oxygen species (ROS) production remained unclear. In this study, we examined apocynin pharmacokinetics and pharmacodynamics (PKPD) after iv injection (bolus, 5 mg/kg) of mice (CD1, 12-week). Apocynin was detected using a HPLC coupled to a linear ion-trap tandem mass spectrometer. Apocynin peak concentrations were detected in plasma at 1 min (5494±400 ng/mL) (t1/2=0.05 h, clearance=7.76 L/h/kg), in urine at 15 min (14942±5977 ng/mL), in liver at 5 min (2853±35 ng/g), in heart at 5 min (3161±309 ng/g) and in brain at 1 min (4603±208 ng/g) after iv injection. These were accompanied with reduction of ROS production in the liver, heart and brain homogenates. Diapocynin was not detected in these samples. Therapeutic effect of apocynin was examined using a mouse model (C57BL/6J) of high-fat diet (HFD, 16 weeks)-induced obesity and accelerated aging. Apocynin (5 mM) was supplied in drinking water during the HFD period and was detected at the end of treatment in the brain (5369±1612 ng/g), liver (4818±1340 ng/g) and heart (1795±1487 ng/g) along with significant reductions of ROS production in these organs. In conclusion, apocynin PKPD is characterized by a short half-life, rapid clearance, good distribution and inhibition of ROS production in major organs. Diapocynin is not a metabolite of apocynin in vivo. Apocynin crosses easily the blood-brain barrier and reduces brain oxidative stress associated with metabolic disorders and aging

Untargeted Black-box Attacks for Social Recommendations

The rise of online social networks has facilitated the evolution of social recommender systems, which incorporate social relations to enhance users' decision-making process. With the great success of Graph Neural Networks in learning node representations, GNN-based social recommendations have been widely studied to model user-item interactions and user-user social relations simultaneously. Despite their great successes, recent studies have shown that these advanced recommender systems are highly vulnerable to adversarial attacks, in which attackers can inject well-designed fake user profiles to disrupt recommendation performances. While most existing studies mainly focus on targeted attacks to promote target items on vanilla recommender systems, untargeted attacks to degrade the overall prediction performance are less explored on social recommendations under a black-box scenario. To perform untargeted attacks on social recommender systems, attackers can construct malicious social relationships for fake users to enhance the attack performance. However, the coordination of social relations and item profiles is challenging for attacking black-box social recommendations. To address this limitation, we first conduct several preliminary studies to demonstrate the effectiveness of cross-community connections and cold-start items in degrading recommendations performance. Specifically, we propose a novel framework Multiattack based on multi-agent reinforcement learning to coordinate the generation of cold-start item profiles and cross-community social relations for conducting untargeted attacks on black-box social recommendations. Comprehensive experiments on various real-world datasets demonstrate the effectiveness of our proposed attacking framework under the black-box setting.Comment: Preprint. Under revie

Analysis of corrections to the eikonal approximation

Various corrections to the eikonal approximations are studied for two- and three-body nuclear collisions with the goal to extend the range of validity of this approximation to beam energies of 10 MeV/nucleon. Wallace's correction does not improve much the elastic-scattering cross sections obtained at the usual eikonal approximation. On the contrary, a semiclassical approximation that substitutes the impact parameter by a complex distance of closest approach computed with the projectile-target optical potential efficiently corrects the eikonal approximation. This opens the possibility to analyze data measured down to 10 MeV/nucleon within eikonal-like reaction models.Comment: 10 pages, 8 figure

catena-Poly[[bis­[2-(2-pyrid­yl)-1-H-imidazole-κ2 N 2,N 3]cadmium]-μ-benzene-1,3-dicarboxyl­ato-κ2 O 1:O 3]

In the title coordinaltion polymer, [Cd(C8H4O4)(C8H7N3)2]n, the CdII atom, lying on a twofold rotation axis, is six-coordinated by two carboxyl­ate O atoms from two benzene-1,3-dicarboxyl­ate (m-BDC) ligands and four N atoms from two chelating 2-(2-pyrid­yl)imidazole mol­ecules, forming a slightly distorted octa­hedral geometry. The m-BDC ligand is located over a twofold rotation axis. The CdII atoms are bridged by the m-BDC ligands, leading to a wave-shaped chain structure along [010]. N—H⋯O hydrogen bonds connect the chains

4-(2-Nitro­benzene­sulfonamido)pyri­dinium trifluoro­acetate

In the title compound, C11H10N3O4S+·C2F3O2 −, the dihedral angle between the benzene ring and the pyridinium ring is 88.7 (4)°. In the crystal structure, a network of N—H⋯O, C—H⋯O and C—H⋯F hydrogen bonds links the constituent ions. One O atom of the nitro group is disordered over two positions, with site-occupancy factors of 0.57 (2) and 0.43 (2)

Aging-associated metabolic disorder induces Nox2 activation and oxidative damage of endothelial function

Oxidative stress attributable to the activation of a Nox2-containing NADPH oxidase is involved in the development of vascular diseases and in aging. However, the mechanism of Nox2 activation in normal aging remains unclear. In this study, we used age-matched wild-type (WT) and Nox2 knockout (KO) mice at 3–4 months (young); 11–12 months (middle-aged) and 21–22 months (aging) to investigate age-related metabolic disorders, Nox2 activation and endothelial dysfunction. Compared to young mice, middle-aged and aging WT mice had significant hyperglycaemia, hyperinsulinaemia, increased systemic oxidative stress and higher blood pressure. Endothelium-dependent vessel relaxation to acetylcholine was significantly impaired in WT aging aortas, and this was accompanied by increased Nox2 and ICAM-1 expressions, MAPK activation and decreased insulin receptor expression and signaling. However, these aging-associated disorders were significantly reduced or absent in Nox2KO aging mice. The effect of metabolic disorder on Nox2 activation and endothelial dysfunction was further confirmed using high-fat diet-induced obesity and insulin resistance in middle-aged WT mice treated with apocynin (a Nox2 inhibitor). In vitro experiments showed that in response to high glucose plus high insulin challenge, WT coronary microvascular endothelial cells increased significantly the levels of Nox2 expression, activation of stress signaling pathways and the cells were senescent, e.g. increased p53 and β–galactosidase activity. However,these changes were absent in Nox2KO cells. In conclusion, Nox2 activation in response to aging-associated hyperglycaemia and hyperinsulinaemia plays a key role in the oxidative damage of vascular function. Inhibition or knockout of Nox2 preserves endothelial function and improves global metabolism in old age