Disease Of Central Nervous System Research Articles

Diagnostic and prognostic potential of cell-free RNAs in cerebrospinal fluid and plasma for brain tumors

Systematic assessment of the clinical applicability of cell-free RNAs (cfRNAs), which includes broader RNA categories beyond microRNAs, for patients with brain tumors remains largely unexplored due to the lack of sensitive profiling technologies. Our study endeavors to bridge this gap by utilizing an optimized cell-free transcriptome profiling technique that we have recently developed. We comprehensively profiled the cell-free transcriptome in plasma and cerebrospinal fluid (CSF) samples from a total of 85 patients with glioma, meningioma, or tumor-free central nervous system diseases. We identified 16 cfRNA signatures in CSF with robust performance in brain tumor detection (test set AUC = 0.94; validation set AUC = 1). The integration of CSF and plasma-derived cfRNAs outperformed individual analyses using either CSF or plasma candidates for the classification of glioma (test set AUC = 0.94; validation set AUC = 0.85) and meningioma (test set AUC = 0.92; validation set AUC = 0.83). Additionally, we identified 33 CSF and 3 plasma cfRNAs with prognostic significance for postoperative patient outcomes. Multivariate analysis showed that cfRNA-based risk scores (Hazard ratio=9.9) outperformed traditional risk factors in predicting recurrence-free survival. Importantly, our findings in liquid biopsies are consistent with results from primary tumor tissues. By delving into the diagnostic and prognostic implications of cfRNA signatures in CSF and plasma, our study paves the way for improved diagnostic precision and personalized therapeutic interventions for brain tumor patients.

Targeting autophagy in astrocytes: a potential for neurodegenerative disease intervention

Autophagy contributes to cellular homeostasis by regulating the degradation and recycling of damaged organelles and misfolded proteins. In the central nervous system (CNS), impaired autophagy contributes to inflammation, disrupts cellular metabolism, and leads to the accumulation of toxic protein aggregates that accelerate the progression of neurodegenerative diseases. In addition to its role in protein and organelle turnover, autophagy facilitates the elimination of pathogenic bacteria and viruses, whose infections can also lead to neurological diseases and neuroinflammatory processes. Astrocytes, the most abundant glial cells in the CNS, play a crucial role in maintaining neuronal homeostasis by regulating neurotransmitter balance, ion exchange, and metabolic support. During neurodegeneration, they become reactive, actively participating in neuroinflammatory responses by releasing proinflammatory cytokines, activating microglia, and removing toxic aggregates. Cytokine-mediated responses and metabolic changes in astrocytes influence neuronal viability and neurotransmission. Autophagy in astrocytes plays an important role in tuning the astrocyte-dependent activity of neurons under physiological conditions and in pathological activation of astrocytes by disease, injury or pathogenic stimuli. In this review, we highlight the contribution of astrocytes to neurodegeneration from the perspective of changes in their cytoskeleton, the autophagy process in which the cytoskeleton plays a crucial role, and the metabolic support of neurons. The modulation of autophagy at different stages has the potential to serve as an additional therapeutic target in CNS diseases.

The prospective approach for aptamers applied in the treatment and molecular diagnostics of ischemic stroke

Ischemic stroke is a leading cause of death and disability worldwide. Therefore, there is a critical need to explore the underlying mechanisms and develop effective treatment strategies for ischemic stroke. As small and non-immunogenic nucleic acid molecules, aptamers can be easily chemically modified, break through the blood-brain barrier, and be screened using the classic Systematic Evolution of Ligands by Exponential Enrichment. With the advancements in emerging technologies, aptamer-based strategies have provided diagnostic and therapeutic potential for applications in central nervous system diseases. Aptamers have become a useful tool for targeted therapy and biomarker discovery in ischemic stroke. This review presents recent advances and perspectives on aptamer applications in stroke prevention, treatment, and diagnosis, focusing on targeting pathological blood clotting or thrombosis, inflammatory responses, and specific biomarkers in key cells.

Structure of myelin in the central nervous system and another possible driving force for its formation-myelin compaction.

Myelin formation is considered the last true "invention" in the evolution of vertebrate nervous system cell structure. The rapid jumping pulse propagation achieved by myelin enables the high conduction speed that is the basis of human movement, sensation, and cognitive function. As a key structure in the brain, white matter is the gathering place of myelin. However, with age, white matter-associated functions become abnormal and a large number of myelin sheaths undergo degenerative changes, causing serious neurological and cognitive disorders. Despite the extensive time and effort invested in exploring myelination and its functions, numerous unresolved issues and challenges persist. In-depth exploration of the functional role of myelin may bring new inspiration for the treatment of central nervous system (CNS) diseases and even mental illnesses. In this study, we conducted a comprehensive examination of the structure and key molecules of the myelin in the CNS, delving into its formation process. Specifically, we propose a new hypothesis regarding the source of power for myelin expansion in which membrane compaction may serve as a driving force for myelin extension. The implications of this hypothesis could provide valuable insights into the pathophysiology of diseases involving myelin malfunction and open new avenues for therapeutic intervention in myelin-related disorders.

Clinical and Radiological Advances in Autoimmune GFAP Astrocytopathy: Analysis of 387 Patients in Japan

ABSTRACTAutoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP‐A) is an autoimmune inflammatory central nervous system disease. Recent neuropathological findings indicate that GFAP‐specific cluster of differentiation (CD)8+ T cells are likely the effectors of GFAP‐A. Of 387 individuals in Japan identified as having GFAP‐A, most presented with headache and/or fever followed by neurological symptoms including consciousness disturbance, urinary dysfunction, hyperreflexia, movement disorders, and papilledema. Sixteen (5.9%) of the 270 GFAP‐A patients tested had coexisting antibodies. Cerebrospinal fluid (CSF) examination revealed lymphocytic pleocytosis and increased protein levels. Moreover, transiently increased CSF adenosine deaminase, decreased glucose, and positive oligoclonal band results were sometimes observed. Brain magnetic resonance imaging (MRI) occasionally showed T2‐hyperintensity lesions. Linear perivascular radial gadolinium‐enhancement patterns were observed and may be an imaging hallmark of GFAP‐A. Spinal cord MRI sometimes exhibited T2‐hyperintensity spinal cord lesions, most of which were longitudinally extensive. Most patients were treated with immunotherapies, including intravenous methylprednisolone pulse therapy with or without intravenous immunoglobulin therapy and/or plasma exchange; this was followed by oral corticosteroid therapy, which was gradually tapered. Some refractory patients received second‐line immunotherapies including rituximab or cyclophosphamide. In 203 patients with follow‐up ≥ 6 months, the median modified Rankin scale score at last follow‐up was 1 (range: 0–6); however, 44 patients (21.7%) had scores of 3 or greater, and six patients died. The most common neurological finding at last follow‐up was cognitive dysfunction, followed by urinary dysfunction; the recurrence rate was 10.5%. CSF GFAP‐immunoglobulin G should be examined in patients who present with these characteristic clinical and radiological features.Trial Registration: Autoimmune GFAP astrocytopathy registry (UMIN: 000054387).

A No-Brainer! The Therapeutic Potential of TRIM Proteins in Viral and Central Nervous System Diseases.

Tripartite motif (TRIM) proteins comprise an important class of E3 ubiquitin ligases that regulate numerous biological processes including protein expression, cellular signaling pathways, and innate immunity. This ubiquitous participation in fundamental aspects of biology has made TRIM proteins a focus of study in many fields and has illuminated the negative impact they exert when functioning improperly. Disruption of TRIM function has been linked to the success of various pathogens and separately to the occurrence and development of several neurodegenerative diseases, making TRIM proteins an appealing candidate to study for novel therapeutic approaches. Here, we review the current findings on TRIM proteins that demonstrate their analogous properties in the distinct fields of viral infection and central nervous system (CNS) disorders. We also examine recent advancements in drug development and targeted protein degradation as potential strategies for TRIM-mediated therapeutic treatments and discuss the implications these technologies have on future research directions.

Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunity.

In chronic inflammatory disorders of the central nervous system (CNS), tissue-resident self-reactive T cells perpetuate disease. The specific tissue factors governing the persistence and continuous differentiation of these cells remain undefined but could represent attractive therapeutic targets. In a model of chronic CNS autoimmunity, we find that oligodendrocyte-derived IL-33, an alarmin, is key for locally regulating the pathogenicity of self-reactive CD8+ T cells. The selective ablation of IL-33 from neo-self-antigen-expressing oligodendrocytes mitigates CNS disease. In this context, fewer self-reactive CD8+ T cells persist in the inflamed CNS, and the remaining cells are impaired in generating TCF-1low effector cells. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. Our study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cells in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases.

The Impact of Comorbidities on the Treatment Outcome in Patients With Severe Covid-19-Associated Pneumonia

BACKGROUND. A significant role in the course and outcome of COVID-19, alongside other clinical and laboratory factors, is played by comorbidities.THE AIM OF THE STUDY. We studied the impact of comorbidities on the course and outcomes of severe COVID-19-associated pneumonia.MATERIAL AND METHODS. The study was conducted at the Yakut Republican Clinical Hospital. We analyzed treatment outcomes of 450 patients with severe COVID-19-associated pneumonia who were hospitalized in the intensive care unit. An observational case-control study was conducted, in accordance with the research objective, comorbidities were analyzed in detail in two groups of patients: survivors — 144 (32.0%) and deceased — 306 (68.0%). The endpoint of the study was a fatal outcome. The modified Charlson comorbidity index was used to assess the patients’ comorbidity status.RESULTS. The study revealed the presence of concomitant pathology in 446 (99.1%) patients. 57 (12.7%) patients had two concomitant diseases, 369 (82%) patients had three or more pathologies. A statistically significant impact on the risk of death for the following combinations of comorbid conditions were found: chronic central nervous system diseases with chronic kidney disease; hypertension with chronic kidney disease; coronary heart disease with chronic kidney disease; severe obesity (class III) with coronary heart disease and chronic kidney disease; severe obesity (class III) with type 2 diabetes mellitus. The mortality rate of patients increases linearly with the growth of the Charlson comorbidity index (p<0.001).CONCLUSION. The obtained data indicate a significant increase in the risk of death in patients with severe COVID-19-associated pneumonia in the presence of comorbidities. Therefore, when predicting the outcome and improving the treatment results of this category of patients, one should take into account the patient’s comorbidity.

Central Nervous System Involvement in Patients with Endogenous Endophthalmitis: A Retrospective Study

ABSTRACT Purpose The detrimental effects of endogenous endophthalmitis on visual acuity have been well studied; however, other complications of the central nervous system have not been robustly investigated. Our objective was to investigate central nervous system involvement associated with endogenous endophthalmitis. Methods We analyzed hospitalized patients with endogenous endophthalmitis in two hospitals from January 2010 to November 2020. We documented patient characteristics and outcomes related to endogenous endophthalmitis, including relevant neurologic complications. A neuroradiologist reviewed any available central nervous system imaging. Results A total of 62 patients were included (42 [68%] males and 20 [32%] female). Of those included, 14 patients (23%) had at least one neurologic complication associated with the central nervous system. Of those 14 patients, 8 (57%) had ischemic/embolic brain infarction(s), 7 (50%) had encephalopathy, 4 (29%) had cerebral hemorrhage(s), 2 (14%) had meningitis, 1 (7%) had a brain abscess, and 1 (7%) had an anoxic brain injury. Of the patients who had central nervous system complications, a majority of eight patients (57%) had positive blood cultures, two (14%) had positive intraocular cultures, while two (14%) were positive in both. There was no statistically significant difference in demographics, comorbidities, source of infection, or organism between patients with and without central nervous system complications. Conclusion The incidence of comorbid central nervous system disease in our cohort was higher than previously reported in the literature. Although we identified no specific risk factors for the development of central nervous system disease in endogenous endophthalmitis, we found that cases with more severe central nervous system complications were associated with culture positivity.

Preliminary exploration of endoplasmic reticulum stress transmission in astrocytes and neurons, and its mediators.

Unfolded protein response (UPR) signaling in cells stimulates UPR signaling in adjacent cells, facilitating the progression of disease (such as diabetes)by upregulating UPR target genes; however, whether this dissemination occurs between nerve cells, and its molecular basis, is currently unclear. In the present study, the supernatant of endoplasmic reticulum (ER) stress‑induced rat astrocytes was prepared and used to treat rat adrenal pheochromocytoma cell to simulate the propagation of ER stress between nerve cells. Reverse transcription‑quantitative PCR and western blotting were performed to detect the expression levels of mRNAs and protein levels associated with ER stress in cells. The results revealed that ER stress may propagate between rat nerve cells, ultimately leading to apoptosis. Analysis also revealed that the mediators of ER stress transmission were non‑vesicular, oxidative molecules with molecular weights >100 kDa. In conclusion, ER stress propagation may have a role in neuronal death following ER stress in central nervous system diseases, presenting potential novel therapeutic targets for these conditions.

A Biomimetic Human Multi-Cellular In Vitro Model of the Blood-Brain Barrier.

Current in vitro models fail to recapitulate specific physiological properties of the human blood-brain barrier (BBB); hence the need for a reliable platform to study central nervous system diseases and drug permeability. To mimic the normally tight blood-brain interface, primary human endothelial cells (HAECs) and primary human astrocytes (A) were grown in a confined space of the physical scaffold created by gelatin methacrylate (GelMA) hydrogel to allow optimal astrocyte-endothelial cell direct/indirect interaction. Evidence for a physiologically relevant BBB was established by assessing the expression of tight junction markers conferring the barrier function, and by measuring biophysical attributes using the trans-endothelial electrical resistance (TEER) and the Evans blue albumin (EBA) permeability assay. An HAEC+A three-dimensional (3D) co-culture was associated with 12-fold higher claudin-5 (CLDN5) and cadherin-1 (CDH1 or Epithelial [E]-cadherin) transcriptional levels than two-dimensional (2D) models. This model conferred the highest TEER (45 Ω·cm2) in 3D HAEC+A, which value was 30 Ω·cm2 in 2D (p < 0.01) and 25 Ω·cm2 in 3D HAEC cultures (p < 0.001). Functionally, in 3D HAEC+A co-cultures, higher TEER resulted in 10-fold and 7-fold lower EBA permeability at 120 min, in HAECs alone or in to 2D co-cultures (p < 0.01). The established human primary cell model has acquired features mimicking the human BBB in vitro, and is now poised to be tested for the permeability of the BBB to pharmacological agents, parasites, cells (such as brain-tropic cancer cell metastasis) and any mechanisms that might involve traversing the BBB.

Neuroprotective effects of ghrelin in cuprizone-induced rat model of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory central nervous system disease characterized by demyelination and axonal loss and is the main cause of non-traumatic neurological disability in young adults. Although there are several treatment approaches to manage the disease, there is no definitive cure for multiple sclerosis. Inflammation and oxidative stress are known to play important roles in the pathophysiology of MS. Ghrelin, a peptide secreted by the stomach, is reported to have neuroprotective properties through several pathways, including attenuating oxidative stress and inflammation. In the present study cuprizone (CPZ)-induced model of MS was used in Wistar albino rats to study the possible anti-inflammatory, antioxidant and neuroprotective effects of ghrelin. Rats were randomly divided into six groups: Control groups (Control35 and Control-S42), demyelination group, remyelination group, remyelination + ghrelin (20 µg/kg) group and remyelination + ghrelin (40 µg/kg) group. Y maze test was performed on the rats on their last day of the experiment. Oxidative stress and inflammatory parameters were investigated in brain using commercial kits by enzyme-linked immunosorbent assay (ELISA). Luxol fast blue (LFB) and hematoxylen&eosin (H&E) staining were performed in brain tissues. CPZ leads to a significant decrease in glutathione peroxidase (GSH-Px) levels and myelin content and a significant increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-ɑ), interleukin- 6 (IL- 6) levels, the number of lymphatic cells and inflammatory cells. A significant increase in the antioxidant parameter levels and a significant decrease in MDA levels were found in the ghrelin treated groups (p < 0.05). CPZ leads to irregular, fragmented, demyelinating nerve fibers. A more significant remyelination was observed in the ghrelin treated groups compared to the other groups (p < 0.05). In conclusion, ghrelin treatment showed neuroprotective and antioxidant properties and reduced demyelination in the CPZ-induced rat model of multiple sclerosis.Graphical

Breaking down barriers with sensory science-improving accessibility to neuroimmunology for the blind and low-vision communities.

Scientific public engagement activities and participation in bioscience discussions need to be open to everyone, as they play a significant role in connecting the general public to research and breaking down barriers of scientific skepticism. In a society increasingly shaped by scientific progress, it is crucial that everyone, regardless of their background or ability, feels empowered to participate in these conversations. However, this is not usually the case for blind or low-vision communities who are often excluded, in part due to scientific outreach events being historically limited to visual imagery. To break down such barriers, we organized a multisensory exhibition as part of the Cambridge Festival 2024. The initiative was inspired by Monash Sensory Science, a targeted outreach program designed to engage individuals who are blind, have low vision or diverse needs. Our aim was to use novel, tactile and informative models to explore the role of the immune system in the central nervous system health and disease, focusing on two inflammation models: traumatic brain injury and multiple sclerosis. In Sensory Science, we fostered the involvement of the blind and low-vision community through tactile scientific posters, resin and plaster brain models, and interactive experiences involving heat, sound, tactile poetry and photography. The Sensory Science exhibition held during March 2024 not only promoted equality but also reminded us that true innovation lies in the collective efforts of a diverse and inclusive community.

Glial fibrillary acidic protein: a potential biomarker for small fiber neuropathy?

Abstract Background Objective and easily applicable biomarkers for diabetic polyneuropathy (DPN) are warranted. Circulating nerve-specific proteins have emerged as valuable biomarkers for central nervous system disease but few of these have been tested in peripheral neuropathy. Glial Fibrillary Acidic Protein (GFAP) is highly expressed in non-myelinating Schwann cells while UCH-L1 is a neuron expressed stress protein not previous analyzed in DPN. In this pilot study, we explore serum GFAP and UCH-L1 levels in patients with/without DPN and controls. Methods Persons with DPN (n = 28), without DPN (n = 31), and controls (n = 30) were evaluated in a cross-sectional design. Sural nerve conduction (velocity and amplitude) was evaluated by NC-stat DPNCheck™ and quantitative sensory testing of cold detection and pain was performed. GFAP and UCH-L1 levels were compared across study groups and the unadjusted correlation with nerve assessments evaluated. Results Serum GFAP were lower in persons with DPN (20.9 ± 10.9 pg/ml) than in persons without DPN (26.2 ± 14.1 pg/ml) (p = 0.04) or controls (31.7 ± 26.0 pg/ml) (p = 0.02). GFAP levels were not different in persons without DPN and controls (p = 0.61). UCH-L1 levels were not different between study groups (p = 0.48). GFAP levels correlated with cold pain threshold (Rho= − 0.320, p = 0.02) but failed to reach significance for cold detection (Rho= − 0.236, p = 0.09). No correlation was observed between GFAP and nerve amplitude (p = 0.58) or conductivity (p = 0.86). Conclusion Serum GFAP levels are reduced in persons with DPN compared to persons without DPN and controls. Reduced serum GFAP levels may be associated with reduced markers of small nerve fiber damage obtained from quantitative sensory testing in people with diabetes.

CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer's disease: progress and prospects.

CRISPR/Cas9 technology has revolutionized genetic and biomedical research in recent years. It enables editing and modulation of gene function with an unparalleled precision and effectiveness. Among the various applications and prospects of this technology, the opportunities it offers in unraveling the molecular underpinnings of a myriad of central nervous system diseases, including neurodegenerative disorders, psychiatric conditions, and developmental abnormalities, are unprecedented. In this review, we highlight the applications of CRISPR/Cas9-based therapeutics as a promising strategy for management of Alzheimer's disease and transformative impact of this technology on AD research. Further, we emphasize the role of CRISPR/Cas9 in generating accurate AD models for identification of novel therapeutic targets, besides the role of CRISPR-based therapies aimed at correcting AD-associated mutations and modulating the neurodegenerative processes. Furthermore, various delivery systems are reviewed and potential of the non-viral nanotechnology-based carriers for overcoming the critical limitations of effective delivery systems for CRISPR/Cas9 is discussed. Overall, this review highlights the promise and prospects of CRISPR/Cas9 technology for unraveling the intricate molecular processes underlying the development of AD, discusses its limitations, ethical concerns and several challenges including efficient delivery across the BBB, ensuring specificity, avoiding off-target effects. This article can be helpful in better understanding the applications of CRISPR/Cas9 based therapeutic approaches and the way forward utilizing enormous potential of this technology in targeted, gene-specific treatments that could change the trajectory of this debilitating and incurable illness.

Human neural stem cell-derived exosomes activate PINK1/Parkin pathway to protect against oxidative stress-induced neuronal injury in ischemic stroke

BackgroundMitochondria play a critical role in oxidative stress (OS)-induced neuronal injury during ischemic stroke (IS), making them promising therapeutic targets. Mounting evidence underscores the extraordinary therapeutic promise of exosomes derived from human neural stem cells (hNSCs) in the management of central nervous system (CNS) diseases. Nonetheless, the precise mechanisms by which these exosomes target mitochondria to ameliorate the effects of IS remain only partially elucidated. This study investigates the protective effects of hNSC derived exosomes (hNSC-Exos) on neuronal damage.MethodsUsing a rat model of middle cerebral artery occlusion (MCAO) in vivo and OS-induced HT22 cells in vitro. Firstly, our research group independently isolated human neural stem cells (hNSCs) and subsequently prepared hNSC-Exos. In vivo, MCAO rats were restored to blood flow perfusion to simulate ischemia–reperfusion injury, and hNSC-Exos were injected through stereotaxic injection into the brain. Subsequently, the protective effects of hNSC-Exos on MCAO rats were evaluated, including histological studies, behavioral assessments. In vivo, H2O2 was used in HT22 cells to simulate the OS environment in MCAO, and then its protective effects on HT22 were evaluated by co-culturing with hNSC-Exos, including immunofluorescence staining, western blotting (WB), quantitative real time PCR (qRT-PCR). In the process of exploring specific mechanisms, we utilized RNA sequencing (RNA-seq) to detect the potential induction of mitophagy in OS-induced HT22 cells. Afterwards, we employed a series of mitochondrial function assessments and autophagy related detection techniques, including measuring mitochondrial membrane potential, reactive oxygen species (ROS) levels, transmission electron microscopy (TEM) imaging, monodansylcadaverine (MDC) staining, and mCherry-GFP-LC3B staining. In addition, we further investigated the regulatory pathway of hNSC-Exos by using autophagy inhibitor mdivi-1 and knocking out PTEN induced kinase 1 (PINK1) in HT22 cells.ResultsAdministration of hNSC-Exos significantly ameliorated brain tissue damage and enhanced behavioral outcomes in MCAO rats. This treatment led to a reduction in brain tissue apoptosis and facilitated the normalization of impaired neurogenesis and neuroplasticity. Notably, the application of hNSC-Exos in vitro resulted in an upregulation of mitophagy in HT22 cells, thereby remedying mitochondrial dysfunction. We demonstrate that hNSC-Exos activate mitophagy via the PINK1/Parkin pathway, improving mitochondrial function and reducing neuronal apoptosis.ConclusionsThese findings suggest that hNSC-Exos alleviate OS-induced neuronal damage by regulating the PINK1/Parkin pathway. These reveals a novel role of stem cell-derived mitochondrial therapy in promoting neuroprotection and suggest their potential as a therapeutic approach for OS-associated CNS diseases, including IS.Graphical

A Bright Future for Photopharmaceuticals Addressing Central Nervous System Disorders: State of the Art and Challenges Toward Clinical Translation

ABSTRACTPhotopharmacology is an innovative approach that uses light to activate drugs. This method offers the potential for highly localized and precise drug activation, making it particularly promising for the treatment of neurological disorders. Despite the enticing prospects of photopharmacology, its application to treat human central nervous system (CNS) diseases remains to be demonstrated. In this review, we provide an overview of prominent strategies for the design and activation of photopharmaceutical agents in the field of neuroscience. Photocaged and photoswitchable drugs and bioactive molecules are discussed, and an instructive list of examples is provided to highlight compound design strategies. Special emphasis is placed on photoactivatable compounds for the modulation of glutamatergic, GABAergic, dopaminergic, and serotonergic neurotransmission for the treatment of neurological conditions, as well as various photoresponsive molecules with potential for improved pain management. Compounds holding promise for clinical translation are discussed in‐depth and their potential for future applications is assessed. Neurophotopharmaceuticals have yet to achieve breakthrough in the clinic, as both light delivery and drug design have not reached full maturity. However, by describing the current state of the art and providing illustrative case studies, we offer a perspective on future opportunities in the field of neurophotopharmacology focused on addressing CNS disorders.

Engineered endoplasmic reticulum-targeting nanodrugs with Piezo1 inhibition and promotion of cell uptake for subarachnoid hemorrhage inflammation repair

Subarachnoid hemorrhage (SAH) is a life-threatening acute hemorrhagic cerebrovascular condition, often presenting with severe headaches caused by intracranial hypertension, which in severe cases can lead to brain herniation. Piezo1 is a mechanosensitive ion channel protein whose mechanical properties are closely linked to central nervous system diseases. In this study, we developed an engineered endoplasmic reticulum membrane-based nanomedicine (CAQKERM@GsMTx4) using HEK293T cells, aimed at targeted delivery to acute hemorrhagic regions, rapid absorption, and precise inhibition of Piezo1 therapy. To ensure optimal targeting and therapeutic efficacy, we fused the CAQK peptide gene to the N-terminus of TRP-PK1, presenting the CAQK peptide on the endoplasmic reticulum membrane, and loaded GsMTx4 into engineered vesicles (EVs) derived from this engineered membrane. Through in vivo and in vitro experiments and multi-omics analysis, we have demonstrated the marked advantages of endoplasmic reticulum membrane vesicles over cell membrane-based vesicles. CAQKERM@GsMTx4 successfully inhibits Piezo1 in SAH, helps microglia change from the M1 phenotype to the M2 phenotype, and inhibits inflammatory responses and neuronal damage. Overall, this novel engineered endoplasmic reticulum membrane nanomedicine provides a potential effective strategy for the clinical treatment of subarachnoid hemorrhage.Graphical Engineered endoplasmic reticulum membrane-based nanomedicine, CAQKERM@GsMTx4, specifically targets hemorrhagic regions in subarachnoid hemorrhage (SAH). By inhibiting the Piezo1 ion channel, it promotes M2 microglial transformation, reducing inflammation and neuronal damage. This innovative approach leverages targeted delivery and precise modulation, offering a promising strategy for SAH treatment in both in vitro and in vivo models.

Air Pollution-Induced Neurotoxicity: The Relationship Between Air Pollution, Epigenetic Changes, and Neurological Disorders.

Air pollution is a major global health threat, responsible for over 8 million deaths in 2021, including 700,000 fatalities among children under the age of five. It is currently the second leading risk factor for mortality worldwide. Key pollutants, such as particulate matter (PM2.5, PM10), ozone, sulfur dioxide, nitrogen oxides, and carbon monoxide, have significant adverse effects on human health, contributing to respiratory and cardiovascular diseases, as well as neurodevelopmental and neurodegenerative disorders. Among these, particulate matter poses the most significant threat due to its highly complex mixture of organic and inorganic compounds with diverse sizes, compositions, and origins. Additionally, it can penetrate deeply into tissues and cross the blood-brain barrier, causing neurotoxicity which contributes to the development of neurodegenerative diseases. Although the link between air pollution and neurological disorders is well documented, the precise mechanisms and their sequence remain unclear. Beyond causing oxidative stress, inflammation, and excitotoxicity, studies suggest that air pollution induces epigenetic changes. These epigenetic alterations may affect the expression of genes involved in stress responses, neuroprotection, and synaptic plasticity. Understanding the relationship between neurological disorders and epigenetic changes induced by specific air pollutants could aid in the early detection and monitoring of central nervous system diseases.

Exome sequencing reveals low-frequency and rare variant contributions to multiple sclerosis susceptibility in Turkish families

Multiple sclerosis (MS) is characterized as an immune-mediated central nervous system disease marked by chronic inflammation, demyelination, and progressive neurodegeneration. In this study, we evaluated the contribution of low-frequency and rare genetic variants to MS susceptibility within one of the largest family-based MS cohorts to date, comprising 215 individuals from 59 Turkish multiplex MS families. Whole exome sequencing was conducted on all samples including affected and unaffected members, followed by investigation of the effect of well-established human leukocyte antigen loci for MS on the elevated MS risk observed in our families. Subsequently, a gene-based burden analysis was performed on candidate genes identified through both our segregation analysis and existing literature. To prioritize the genes and pathways that are potentially associated with MS, a segregation-based analysis of the variants was conducted and complemented by gene-based pathway enrichment analysis. Our results highlighted the significance of the extracellular matrix in MS pathogenesis, as we identified laminin-related genes including LAMA5 and LAMB1 from both the segregation analysis and gene-based burden test. Hemidesmosome assembly emerged as a key pathway in our analysis, primarily driven by the identification of DST and PLEC as significant genes in the gene-based segregation analysis. Finally, we identified two rare coding variants passing our allele frequency and deleteriousness score-based filters, rs41266745 (C> T) in the CD109 gene with CADD phred score 24 and rs143093165 (T> G) in the ITPR1 gene with CADD phred score 22 and LOEUF 0.325, segregating within more than one family. Overall, this is one of the first and largest family-based MS studies from Turkey that features a unique cohort from an admixed population that enabled the detection of novel low-frequency and rare variants associated with MS. The findings from this study offer valuable insights that could guide future research aimed at further exploring and understanding the factors contributing to MS risk.