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

Q-learning Based Optimal False Data Injection Attack on Probabilistic Boolean Control Networks

In this paper, we present a reinforcement learning (RL) method for solving optimal false data injection attack problems in probabilistic Boolean control networks (PBCNs) where the attacker lacks knowledge of the system model. Specifically, we employ a Q-learning (QL) algorithm to address this problem. We then propose an improved QL algorithm that not only enhances learning efficiency but also obtains optimal attack strategies for large-scale PBCNs that the standard QL algorithm cannot handle. Finally, we verify the effectiveness of our proposed approach by considering two attacked PBCNs, including a 10-node network and a 28-node network

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

Knowledge landscape of tumor-associated macrophage research: A bibliometric and visual analysis

Background and aimsTumor-associated macrophage (TAM) is a highly abundant immune population in tumor microenvironment, which plays an important role in tumor growth and progression. The aim of our study was to explore the development trends and research hotspots of TAM by bibliometric method.MethodsThe publications related to TAM were obtained from the Web of Science Core Collection database. Bibliometric analysis and visualization were conducted using VOSviewer, CiteSpace and R software.ResultsA total of 6,405 articles published between 2001 and 2021 were included. The United States and China received the most citations, whereas the University of Milan, the university of California San Francisco and Sun Yat-sen University were the main research institutions. Mantovani, Alberto from Humanitas University was the most productive authors with the most citations. Cancer Research published the most articles and received the most co-citations. Activation, angiogenesis, breast cancer, NF-κB and endothelial growth factor were important keywords in TAM research. Among them, PD-1/L1, nanoparticle, PI3Kγ, resistance and immune microenvironment have become the focus of attention in more recent research.ConclusionsThe research on TAM is rapidly evolving with active cooperation worldwide. Anticancer therapy targeting TAM is emerging and promising area of future research, especially in translational application. This may provide guidance and new insights for further research in the field of TAM

p47phox-dependent oxidant signalling through ASK1, MKK3/6 and MAPKs in Angiotensin II-induced cardiac hypertrophy and apoptosis

The p47phox is a key regulatory subunit of Nox2-containing NADPH oxidase (Nox2) that by generating reactive oxygen species (ROS) plays an important role in Angiotensin II (AngII)-induced cardiac hypertrophy and heart failure. However, the signalling pathways of p47phox in the heart remains unclear. In this study, we used wild-type (WT) and p47phox knockout (KO) mice (C57BL/6, male, 7-month-old, n = 9) to investigate p47phox-dependent oxidant-signalling in AngII infusion (0.8 mg/kg/day, 14 days)-induced cardiac hypertrophy and cardiomyocyte apoptosis. AngII infusion resulted in remarkable high blood pressure and cardiac hypertrophy in WT mice. However, these AngII-induced pathological changes were significantly reduced in p47phox KO mice. In WT hearts, AngII infusion increased significantly the levels of superoxide production, the expressions of Nox subunits, the expression of PKCα and C-Src and the activation of ASK1 (apoptosis signal-regulating kinase 1), MKK3/6, ERK1/2, p38 MAPK and JNK signalling pathways together with an elevated expression of apoptotic markers, i.e., γH2AX and p53 in the cardiomyocytes. However, in the absence of p47phox, although PKCα expression was increased in the hearts after AngII infusion, there was no significant activation of ASK1, MKK3/6 and MAPKs signalling pathways and no increase in apoptosis biomarker expression in cardiomyocytes. In conclusion, p47phox-dependent redox-signalling through ASK1, MKK3/6 and MAPKs plays a crucial role in AngII-induced cardiac hypertrophy and cardiomyocyte apoptosis

Mapping the Intel Last-Level Cache

Modern Intel processors use an undisclosed hash function to map memory lines into last-level cache slices. In this work we develop a technique for reverse-engineering the hash function. We apply the technique to a 6-core Intel processor and demonstrate that knowledge of this hash function can facilitate cache-based side channel attacks, reducing the amount of work required for profiling the cache by three orders of magnitude. We also show how using the hash function we can double the number of colours used for page-colouring techniques

Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm

Endothelial oxidative stress and inflammation attributable to the activation of a Nox2-NADPH oxidase are key features of many cardiovascular diseases. Here, we report a novel small chemical compound (LMH001, MW=290.079), by blocking phosphorylated p47phox interaction with p22phox, inhibited effectively angiotensin II (AngII)-induced endothelial Nox2 activation and superoxide production at a small dose (IC50=0.25µM) without effect on peripheral leucocyte oxidative response to pathogens. The therapeutic potential of LMH001 was tested using a mouse model (C57BL/6J, 7-month-old) of AngII infusion (0.8mg/kg/d, 14 days)-induced vascular oxidative stress, hypertension and aortic aneurysm. Age-matched littermates of p47phox knockout mice were used as controls of Nox2 inhibition. LMH001 (2.5mg/kg/d, ip. once) showed no effect on control mice, but inhibited completely AngII infusion-induced excess ROS production in vital organs, hypertension, aortic walls inflammation and reduced incidences of aortic aneurysm. LMH001 effects on reducing vascular oxidative stress was due to its inhibition of Nox2 activation and was abrogated by knockout of p47phox. LMH001 has the potential to be developed as a novel drug candidate to treat oxidative stress-related cardiovascular diseases