Ischemic stroke is a leading cause of morbidity and mortality worldwide. Resident microglia are the principal immune cells of the brain, and the first to respond to the pathophysiological changes induced by ischemic stroke. Traditionally, it has been thought that microglial activation is deleterious in ischemic stroke, and therapies to suppress it have been intensively explored. However, increasing evidence suggests that microglial activation is also critical for neurogenesis, angiogenesis, and synaptic remodeling, thereby promoting functional recovery after cerebral ischemia. Here, we comprehensively review the dual role of microglia during the different phases of ischemic stroke, and the possible mechanisms controlling the post-ischemic activity of microglia. In addition, we discuss the dynamic interactions between microglia and other cells, such as neurons, astrocytes, oligodendrocytes, and endothelial cells within the brain parenchyma and the neurovascular unit.

Dual Functions of Microglia in Ischemic Stroke

Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there’s a continuum of different intermediate phenotypes between M1 and M2, and microglia can transit from one phenotype to another. M1 microglia release inflammatory mediators and induce inflammation and neurotoxicity, while M2 microglia release anti-inflammatory mediators and induce anti-inflammatory and neuroprotectivity. Microglia-mediated neuroinflammation is considered as a double-edged sword, performing both harmful and helpful effects in neurodegenerative diseases. Previous studies showed that balancing microglia M1/M2 polarization had a promising therapeutic prospect in neurodegenerative diseases. We suggest that shifting microglia from M1 to M2 may be significant and we focus on the modulation of microglia polarization from M1 to M2, especially by important signal pathways, in neurodegenerative diseases.

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

The blood-brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.

Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms.

Ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. As the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. In response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti‑inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. It has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. In addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified.

/pdf/modulators-of-microglia-activation-and-polarization-in-3w3pobi7hr.pdf

Modulators of microglia activation and polarization in ischemic stroke (Review).

Ischemic stroke is a devastating disease with long-term disability. However, the pathogenesis is unclear and treatments are limited. Meisoindigo, a second-generation derivative of indirubin, has general water solubility and is well-tolerated. Previous studies have shown that meisoindigo reduces inflammation by inhibiting leukocyte chemotaxis and migration. In the present study, we investigated the hypothesis that meisoindigo was also protective against ischemic stroke, then evaluated its underlying mechanisms. In vivo, adult male C57BL/6J wild-type mice were used to produce a middle cerebral artery occlusion (MCAO) stroke model. On day three after reperfusion, obvious improvement in neurological scores, infarct volume reduction and cerebral edema amelioration were observed in meisoindigo treatment. Moreover, immunofluorescence staining and western-blot showed that the expression of NLRP3 inflammasome and its associated proteins in neurons and microglia was inhibited by meisoindigo. The effects of Meisoindigo on NLRP3 inflammasome inactivation and increased the M2 phenotype of microglia/macrophage through shifting from a M1 phenotype, which was possibly mediated by inhibition of TLR4/NF-κB. Furthermore, we verified the inhibitory effect of meisoindigo on TLR4/NF-κB signaling pathway, and found that meisoindigo treatment could significantly suppressed the expression of TLR4/NF-κB pathway-associated proteins in a dose-dependent manner, meanwhile, which resulted in downregulation of HMGB1 and IL-1β. Next, we established an in vitro oxygen glucose deprivation/Reperfusion (OGD/R) model in HT-22 and BV2 cells to simulate ischemic conditions. Cytotoxicity assay showed that meisoindigo substantially improved relative cell vitality and in HT-22 and BV2 cells following OGD/R in vitro. After suffering OGD/R, the TLR4/NF-κB pathway was activated, the expression of NLRP3 inflammasome-associated proteins and M1 microglia/macrophage were increased, but meisoindigo could inhibit above changes in both HT-22 and BV2 cells. Additionally, though lipopolysaccharide stimulated the activation of TLR4 signaling in OGD/R models, meisoindigo co-treatment markedly reversed the upregulation of TLR4 and following activation of NLRP3 inflammasome and polarization of M1 microglia/macrophages mediated by TLR4. Overall, we demonstrate for the first time that meisoindigo post-treatment alleviates brain damage induced by ischemic stroke in vivo and in vitro experiments through blocking activation of the NLRP3 inflammasome and regulating the polarization of microglia/macrophages via inhibition of the TLR4/NF-κB signaling pathway.

/pdf/meisoindigo-protects-against-focal-cerebral-ischemia-2jldcpp8i6.pdf

Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway.

Treatment targets for M2 microglia polarization in ischemic stroke.

Previous studies on the association between thyroid hormones and prognosis of acute ischemic stroke (AIS) reported conflicting results. We conducted a meta-analysis to assess the prognostic value of thyroid hormones in AIS. The PubMed, EMBASE, and Cochrane library databases were searched through May 12, 2017 to identify eligible studies on this subject. Out of 2,181 studies retrieved, 11 studies were finally included with a total number of 3,936 acute stroke patients for analysis. Odds ratio (OR) for predicting poor outcome or standardized mean difference (SMD) of thyroid hormone levels with 95% confidence intervals (95% CI) obtained from the studies were pooled using Review Manager 5.3. From the results, in AIS, patients with a poor outcome had lower levels of triiodothyronine (T3) and higher thyroxine (T4). Pooled OR confirmed the same association. Our study provides statistical evidence supporting the utility of thyroid hormone levels in prognosis of acute stroke.

/pdf/prognostic-value-of-thyroid-hormones-in-acute-ischemic-4finebgi6e.pdf

Prognostic value of thyroid hormones in acute ischemic stroke – a meta analysis

Betulinic acid mitigates zearalenone-induced liver injury by ERS/MAPK/Nrf2 signaling pathways in mice.

Citrinin (CTN) is a mycotoxin found in crops and agricultural products and poses a serious threat to human and animal health. The aim of this study is to investigate the hepatotoxicity of CTN in mice and analyze its mechanisms from Ca2+-dependent endoplasmic reticulum (ER) stress perspective. We showed that CTN induced histopathological damage, caused ultrastructural changes in liver cells, and induced abnormal values of biochemical laboratory tests of some liver functions in mice. Treatment with CTN could induce nitric oxide (NO), malondialdehyde (MDA), and reactive oxygen species (ROS) accumulation in mice, accompanied with losses of activities of superoxide dismutase (SOD) and catalase (CAT), levels of glutathione (GSH), and capacities of total antioxidant (T-AOC), resulting in oxidative stress in mice. Furthermore, CTN treatment significantly increased Ca2+ accumulation, upregulated protein expressions of ER stress-mediated apoptosis signal protein (glucose regulated protein 78 (GRP78/BIP), C/EBP-homologous protein (CHOP), Caspase-12, and Caspase-3), and induced hepatocyte apoptosis. These adverse effects were counteracted by 4-phenylbutyric acid (4-PBA), an ER stress inhibitor. In summary, our results showed a possible underlying molecular mechanism for CTN that induced hepatocyte apoptosis in mice by the regulation of the Ca2+/ER stress signaling pathway.

/pdf/citrinin-induced-hepatotoxicity-in-mice-is-regulated-by-the-eapyrun2.pdf

Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

To separate the long-lived minor actinides (MA = Am, Cm) from high-level liquid waste (HLLW), we have been studying an advanced separation process via selective adsorption that uses minimal amounts of organic solvent and compact equipment. The process consists of two separation columns packed with a CMPO (octyl(phenyl)-N,N-diisobutylcarbamoyl-methyl phosphine oxide) adsorbent for elemental group separation and a soft-donor named the R-BTP (2,6-bis-(5,6-dialkyl-1,2,4-triazine-3-yl) pyridine) adsorbent for the isolation of MA from lanthanides (Ln). In this work, the effects of nitrate ion (NO3−) on the adsorption behavior of Am(III) and a typical fission product Ln(III) onto the isoBu-BTP/SiO2-P adsorbent were studied experimentally. Then, the desorption properties of the adsorbed element were examined using different eluting agents. A hot test for the separation of MA from the fission product Ln in a genuine MA containing effluent from the irradiated MOX-fuel treatment process was carried out using a nBu-BTP/SiO2-P packed column. It was found that the separation factor between Am(III) and Ln(III)-FP is over 100 in the measured 0.5–4 M NO3−. The adsorbed elements could be effectively eluted off using a complexing agent such as DTPA or pure water. Complete separation between MA and Ln was achieved in the column results, indicating that the proposed MA separation process is feasible in principle.

https://www.mdpi.com/2305-6304/10/12/741/pdf?version=1670313771

Separation of Minor Actinides from High-Level Liquid Waste Using Novel Silica-Based Butyl-BTP Adsorbents

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