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JOURNAL/nrgr/04.03/01300535-202508000-00026/figure1/v/2024-09-30T120553Z/r/image-tiff Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202507000-00031/figure1/v/2024-09-09T124005Z/r/image-tiff FK506 (Tacrolimus) is a systemic immunosuppressant approved by the U.S. Food and Drug Administration. FK506 has been shown to promote peripheral nerve regeneration, however, its precise mechanism of action and its pathways remain unclear. In this study, we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve, increased the numbers of motor and sensory neurons, reduced inflammatory responses, markedly improved the conduction function of the injured nerve, and promoted motor function recovery. These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.

Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events. Currently, there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with and without post-traumatic stress disorder. In addition, the heterogeneity of clinical presentations of post-traumatic stress disorder and the overlap of symptoms with other conditions can lead to misdiagnosis and inappropriate treatment. Evidence suggests that this condition is a multisystem disorder that affects many biological systems, raising the possibility that peripheral markers of disease may be used to diagnose post-traumatic stress disorder. We performed a PubMed search for microRNAs (miRNAs) in post-traumatic stress disorder (PTSD) that could serve as diagnostic biomarkers and found 18 original research articles on studies performed with human patients and published January 2012 to December 2023. These included four studies with whole blood, seven with peripheral blood mononuclear cells, four with plasma extracellular vesicles/exosomes, and one with serum exosomes. One of these studies had also used whole plasma. Two studies were excluded as they did not involve microRNA biomarkers. Most of the studies had collected samples from adult male Veterans who had returned from deployment and been exposed to combat, and only two were from recently traumatized adult subjects. In measuring miRNA expression levels, many of the studies had used microarray miRNA analysis, miRNA Seq analysis, or NanoString panels. Only six studies had used real time polymerase chain reaction assay to determine/validate miRNA expression in PTSD subjects compared to controls. The miRNAs that were found/validated in these studies may be considered as potential candidate biomarkers for PTSD and include miR-3130-5p in whole blood; miR-193a-5p, -7113-5p, -125a, -181c, and -671-5p in peripheral blood mononuclear cells; miR-10b-5p, -203a-3p, -4488, -502-3p, -874-3p, -5100, and -7641 in plasma extracellular vesicles/exosomes; and miR-18a-3p and -7-1-5p in blood plasma. Several important limitations identified in the studies need to be taken into account in future studies. Further studies are warranted with war veterans and recently traumatized children, adolescents, and adults having PTSD and use of animal models subjected to various stressors and the effects of suppressing or overexpressing specific microRNAs.

The oral cavity is a complex physiological community encompassing a wide range of microorganisms. Dysbiosis of oral microbiota can lead to various oral infectious diseases, such as periodontitis and tooth decay, and even affect systemic health, including brain aging and neurodegenerative diseases. Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration, indicating potential avenues for intervention strategies. In this review, we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases, and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration. We also highlight advances in therapeutic development grounded in the realm of oral microbes, with the goal of advancing brain health and promoting healthy aging.

JOURNAL/nrgr/04.03/01300535-202507000-00025/figure1/v/2024-09-09T124005Z/r/image-tiff To investigate the mechanisms underlying the onset and progression of ischemic stroke, some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex. However, these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied, although ischemic stroke is strongly age-related. In this study, we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser. We observed the molding process in mice of different ages and presented age-dependent vascular embolism differentiation. Moreover, we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a stroke. Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages, thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.

JOURNAL/nrgr/04.03/01300535-202507000-00032/figure1/v/2024-09-09T124005Z/r/image-tiff A microgravity environment has been shown to cause ocular damage and affect visual acuity, but the underlying mechanisms remain unclear. Therefore, we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity. After 4 weeks of tail suspension, there were no notable alterations in retinal function and morphology, while after 8 weeks of tail suspension, significant reductions in retinal function were observed, and the outer nuclear layer was thinner, with abundant apoptotic cells. To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina, proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension. The results showed that the expression levels of fibroblast growth factor 2 (also known as basic fibroblast growth factor) and glial fibrillary acidic protein, which are closely related to Müller cell activation, were significantly upregulated. In addition, Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks, respectively, of simulated weightlessness. These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.

The cGAS-STING pathway plays an important role in ischemia-reperfusion injury in the heart, liver, brain, and kidney, but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed. Here, we outline the components of the cGAS-STING pathway and then analyze its role in autophagy, ferroptosis, cellular pyroptosis, disequilibrium of calcium homeostasis, inflammatory responses, disruption of the blood-brain barrier, microglia transformation, and complement system activation following cerebral ischemia-reperfusion injury. We further analyze the value of cGAS-STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms. Inhibition of the cGAS-STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.

Subarachnoid hemorrhage leads to a series of pathological changes, including vascular spasm, cellular apoptosis, blood-brain barrier damage, cerebral edema, and white matter injury. Microglia, which are the key immune cells in the central nervous system, maintain homeostasis in the neural environment, support neurons, mediate apoptosis, participate in immune regulation, and have neuroprotective effects. Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage. Moreover, microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage. Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury. This provides new targets and ideas for the treatment of subarachnoid hemorrhage. However, an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking. This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm, neuroinflammation, neuronal apoptosis, blood-brain barrier disruption, cerebral edema, and cerebral white matter lesions. It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage. Currently, microglia in subarachnoid hemorrhage are targeted with TLR inhibitors, nuclear factor-κB and STAT3 pathway inhibitors, glycine/tyrosine kinases, NLRP3 signaling pathway inhibitors, Gasdermin D inhibitors, vincristine receptor α receptor agonists, ferroptosis inhibitors, genetic modification techniques, stem cell therapies, and traditional Chinese medicine. However, most of these are still being evaluated at the laboratory stage. More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage.

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca 2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca 2+ mainly via N-methyl-D-aspartate receptors, particularly of those at the extrasynaptic site. This Ca 2+ -evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca 2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic, but gradually set off deteriorating Ca 2+ -dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca 2+ hypothesis of Alzheimer's disease and recent advances, this Ca 2+ -activated "silent" degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer's disease, therefore, share an N-methyl-D-aspartate receptor- and Ca 2+ -mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca 2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

JOURNAL/nrgr/04.03/01300535-202507000-00026/figure1/v/2024-09-09T124005Z/r/image-tiff Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta. Ferroptosis, a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation, plays a vital role in the death of dopaminergic neurons. However, the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated. NADPH oxidase 4 is related to oxidative stress, however, whether it regulates dopaminergic neuronal ferroptosis remains unknown. The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis, and if so, by what mechanism. We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model. NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons. Moreover, NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals. Mechanistically, we found that NADPH oxidase 4 interacted with activated protein kinase C α to prevent ferroptosis of dopaminergic neurons. Furthermore, by lowering the astrocytic lipocalin-2 expression, NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation. These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation, which contribute to dopaminergic neuron death, suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.