Farrerol Alleviates Cerebral Ischemia-Reperfusion Injury by Promoting Neuronal Survival and Reducing Neuroinflammation.

Ischemia-reperfusion (I/R) injury is a key influencing factor in the outcome of stroke. Inflammatory response, oxidative stress, and neuronal apoptosis are among the main factors that affect the progression of I/R injury. Farrerol (FAR) is a natural compound that can effectively inhibit the inflammatory response and oxidative stress. However, the role of FAR in cerebral I/R injury remains unknown. In this study, we found that FAR reduced brain injury and neuronal viability after cerebral I/R injury. Meanwhile, administration of FAR also reduced the inflammatory response of microglia after brain injury. Mechanistically, FAR treatment directly reduced neuronal death after oxygen glucose deprivation/re-oxygenation (OGD/R) through enhancing cAMP-response element binding protein (CREB) activation to increase the expression of downstream neurotrophic factors and anti-apoptotic genes. Moreover, FAR decreased the activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, inhibited microglia activation, and reduced the production of inflammatory cytokines in microglia after OGD/R treatment or LPS stimulation. The compromised inflammatory response by FAR directly promoted the survival of neurons after OGD/R. In conclusion, FAR exerted a protective effect on cerebral I/R injury by directly decreasing neuronal death through upregulating CREB expression and attenuating neuroinflammation. Therefore, FAR could be a potentially effective drug for the treatment of cerebral I/R injury.

Chromatin target of protein arginine methyltransferases alleviates cerebral ischemia/reperfusion-induced injury by regulating RNA alternative splicing.

RNA splicing is a post-transcriptional event that regulates many physiological and pathological events. However, whether RNA splicing regulates cerebral I/R-induced brain injury remains largely unknown. In this study, we found that the chromatin target of Prmts (CHTOP) was highly expressed in neurons, and anti-inflammatory cytokine interleukin-10 (IL-10) upregulates its expression after ischemia. In addition, overexpression or knockdown of CHTOP alleviated or exacerbated neuronal death in both experimental stroke mice and cultured neurons. Mechanistically, RNA alternative splicing is altered early after oxygen and glucose deprivation/reoxygenation (OGD/R). CHTOP interacted with nuclear speckle-related proteins to regulate alternative mRNA splicing of neuronal survival-related genes after OGD/R. In addition, I/R injury-induced cytokines IL-10 regulate CHTOP-mediated RNA splicing to alleviate ischemic brain injury. Taken together, this study reveals the alteration of RNA splicing after OGD/R and identifies the IL-10-CHTOP-RNA splicing axis as a modulator of brain injury, which may be promising therapeutic targets for ischemic stroke.

CHTOP Promotes Microglia-Mediated Inflammation by Regulating Cell Metabolism and Inflammatory Gene Expression.

During the initiation of the inflammatory response of microglia, the expression of many inflammation- and cell metabolism-related genes alters. However, how the transcription of inflammation- and metabolism-related genes are coordinately regulated during inflammation initiation is poorly understood. In this study, we found that LPS stimulation induced the expression of the chromatin target of PRMT1 (protein arginine methyltransferase 1) (CHTOP) in microglia. Knocking down CHTOP in microglia decreased proinflammatory cytokine expression. In addition, CHTOP knockdown altered cell metabolism, as both the upregulated genes were enriched in cell metabolism-related pathways and the metabolites profile was greatly altered based on untargeted metabolomics analysis. Mechanistically, CHTOP could directly bind the regulatory elements of inflammation and cell metabolism-related genes to regulate their transcription. In addition, knocking down CHTOP increased neuronal viability in vitro and alleviated microglia-mediated neuroinflammation in a systemic LPS treatment mouse model. Collectively, these data revealed CHTOP as a novel regulator to promote microglia-mediated neuroinflammation by coordinately regulating the transcription of inflammation and cell metabolism-related genes.

Perovskite-based photodetector for real-time and quantitative monitoring of sports motion.

Reliable monitoring the movement amplitude and dynamics during sports exercise is significant for improving training results and preventing training wound. Here, we present a printed perovskite-based photodetector for real-time and quantitative monitoring of sports motion. The ordered nucleation and growth of perovskite crystals are regulated by the 4-acetamidothiophenol (AMTP) at the interface, which promotes the size of perovskite crystals into the micrometer. Benefiting from the uniformity of the AMTP-regulated MAPbI3, the as-prepared photodetector gives great photocurrent response under indoor light or outdoor light. During the exercise, real-time monitoring sports motion is achieved through detecting the illumination changing of photodetectors attaching on the wrist and ankles. Moreover, twelve kinds of common sports can be quantitatively analyzed with the detection of illumination changing on the photodetector. Such photodetector provides an efficient measurement method of wearable electronics for sports monitoring.

Unconventional T cells in brain homeostasis, injury and neurodegeneration.

The interaction between peripheral immune cells and the brain is an important component of the neuroimmune axis. Unconventional T cells, which include natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and other poorly defined subsets, are a special group of T lymphocytes that recognize a wide range of nonpolymorphic ligands and are the connection between adaptive and innate immunity. Recently, an increasing number of complex functions of these unconventional T cells in brain homeostasis and various brain disorders have been revealed. In this review, we describe the classification and effector function of unconventional T cells, review the evidence for the involvement of unconventional T cells in the regulation of brain homeostasis, summarize the roles and mechanisms of unconventional T cells in the regulation of brain injury and neurodegeneration, and discuss immunotherapeutic potential as well as future research goals. Insight of these processes can shed light on the regulation of T cell immunity on brain homeostasis and diseases and provide new clues for therapeutic approaches targeting brain injury and neurodegeneration.

ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression.

Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme in polyunsaturated fatty acid (PUFA) metabolism. The role of ACSL4 in the lipopolysaccharide (LPS)-induced inflammation of microglia, and the effects of ACSL4-mediated inflammation on the progression of Parkinson's disease (PD) are unknown. In this study, we found that ACSL4 expression was increased after LPS stimulation. Knocking down ACSL4 in microglia decreased proinflammatory cytokine production. Mechanistically, ACSL4 reduced vestigial-like family member 4(VGLL4) expression to promote NF-κB signal transduction; and ACSL4 regulated lipid composition after LPS stimulation. In addition, knocking down ACSL4 alleviated neuroinflammation in a systemic LPS model and acute l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) model. These data revealed ACSL4 to be a novel regulator that promotes microglia-mediated neuroinflammation by regulating VGLL4 expression and lipid metabolism.

Roles of peripheral immune cells in the recovery of neurological function after ischemic stroke.

Stroke is a leading cause of mortality and long-term disability worldwide, with limited spontaneous repair processes occurring after injury. Immune cells are involved in multiple aspects of ischemic stroke, from early damage processes to late recovery-related events. Compared with the substantial advances that have been made in elucidating how immune cells modulate acute ischemic injury, the understanding of the impact of the immune system on functional recovery is limited. In this review, we summarized the mechanisms of brain repair after ischemic stroke from both the neuronal and non-neuronal perspectives, and we review advances in understanding of the effects on functional recovery after ischemic stroke mediated by infiltrated peripheral innate and adaptive immune cells, immune cell-released cytokines and cell-cell interactions. We also highlight studies that advance our understanding of the mechanisms underlying functional recovery mediated by peripheral immune cells after ischemia. Insights into these processes will shed light on the double-edged role of infiltrated peripheral immune cells in functional recovery after ischemic stroke and provide clues for new therapies for improving neurological function.