Multi-loaded PLGA microspheres as neuroretinal therapy in a chronic glaucoma animal model.

This work focused on the co-encapsulation and simultaneous co-delivery of three different neuroprotective drugs in PLGA (poly(lactic-co-glycolic acid) microspheres for the treatment of glaucoma. For formulation optimization, dexamethasone (anti-inflammatory) and ursodeoxycholic acid (anti-apoptotic) were co-loaded by the solid-in-oil-in-water emulsion solvent extraction-evaporation technique as a first step. The incorporation of a water-soluble co-solvent (ethanol) and different amounts of dexamethasone resulted critical for the encapsulation of the neuroprotective agents and their initial release. The optimized formulation was obtained with 60 mg of dexamethasone and using an 80:20 dichloromethane:ethanol ratio. In the second step in the microencapsulation process, the incorporation of the glial cell line-derived neurotrophic factor (GDNF) was performed. The final prototype showed encapsulation efficiencies for each component above 50% with suitable properties for long-term application for at least 3 months. Physicochemical studies were performed by SEM, TEM, DSC, XRD, and gas chromatography. The evaluation of the kinetic release by the Gallagher-Corrigan analysis with Gorrasi correction helped to understand the influence of the co-microencapsulation on the delivery of the different actives from the optimized formulation. The final prototype was tested in a chronic glaucoma animal model. Rats received two intravitreal injections of the neuroprotective treatment within a 24-week follow-up study. The proposed formulation improved retinal ganglion cell (RGC) functionality examined by electroretinography. Also, it was able to maintain a neuroretinal thickness similar to that of healthy animals scanned by in vivo optical coherence tomography, and a higher RGC count on histology compared to glaucomatous animals at the end of the study.

Precision Targeting of BET Proteins - Navigating Disease Pathways, Inhibitor Insights, and Shaping Therapeutic Frontiers: A Comprehensive Review.

The family of proteins known as Bromodomain and Extra-Terminal (BET) proteins has become a key participant in the control of gene expression, having a significant impact on numerous physiological and pathological mechanisms. This review offers a thorough investigation of the BET protein family, clarifying its various roles in essential cellular processes and its connection to a variety of illnesses, from inflammatory disorders to cancer. The article explores the structural and functional features of BET proteins, emphasizing their special bromodomain modules that control chromatin dynamics by identifying acetylated histones. BET proteins' complex roles in the development of cardiovascular, neurodegenerative, and cancer diseases are carefully investigated, providing insight into possible treatment avenues. In addition, the review carefully examines the history and relevance of BET inhibitors, demonstrating their capacity to modify gene expression profiles and specifically target BET proteins. The encouraging outcomes of preclinical and clinical research highlight BET inhibitors' therapeutic potential across a range of disease contexts. The article summarizes the state of BET inhibitors today and makes predictions about the challenges and future directions of the field. This article provides insights into the changing field of BET protein-targeted interventions by discussing the potential of personalized medicine and combination therapies involving BET inhibitors. This thorough analysis combines many aspects of BET proteins, such as their physiological roles and their roles in pathophysiological conditions. As such, it is an invaluable tool for scientists and medical professionals who are trying to figure out how to treat patients by using this fascinating protein family.

Characterization of sub-micrometre-sized voids in fixed human brain tissue using scanning X-ray microdiffraction.

Using a 5 µm-diameter X-ray beam, we collected scanning X-ray microdiffraction in both the small-angle (SAXS) and the wide-angle (WAXS) regimes from thin sections of fixed human brain tissue from Alzheimer's subjects. The intensity of scattering in the SAXS regime of these patterns exhibits essentially no correlation with the observed intensity in the WAXS regime, indicating that the structures responsible for these two portions of the diffraction patterns, which reflect different length scales, are distinct. SAXS scattering exhibits a power-law behavior in which the log of intensity decreases linearly with the log of the scattering angle. The slope of the log-log curve is roughly proportional to the intensity in the SAXS regime and, surprisingly, inversely proportional to the intensity in the WAXS regime. We interpret these observations as being due to the presence of sub-micrometre-sized voids formed during dehydration of the fixed tissue. The SAXS intensity is due largely to scattering from these voids, while the WAXS intensity derives from the secondary structures of macromolecular material surrounding the voids. The ability to detect and map the presence of voids within thin sections of fixed tissue has the potential to provide novel information on the degradation of human brain tissue in neurodegenerative diseases.

Theranostics advances in the treatment and diagnosis of neurological and neurosurgical diseases.

Theranostics represents a significant advance in the fields of neurology and neurosurgery, offering innovative approaches that combine the diagnosis and treatment of various neurological disorders. This innovation serves as a cornerstone of personalized medicine, where therapeutic strategies are closely integrated with diagnostic tools to enable precise and targeted interventions. Primary research results emphasize the profound impact of theranostics in Neuro Oncol. In this context, it has provided valuable insights into the complexity of the tumor microenvironment and mechanisms of resistance. In addition, in the field of neurodegenerative diseases (NDs), theranostics has facilitated the identification of distinct disease subtypes and novel therapeutic targets. It has also unravelled the intricate pathophysiology underlying conditions such as cerebrovascular disease (CVD) and epilepsy, setting the stage for more refined treatment approaches. As theranostics continues to evolve through ongoing research and refinement, its goals include further advancing the field of precision medicine, developing practical biomarkers for clinical use, and opening doors to new therapeutic opportunities. Nevertheless, the integration of these approaches into clinical settings presents challenges, including ethical considerations, the need for advanced data interpretation, standardization of procedures, and ensuring cost-effectiveness. Despite these obstacles, the promise of theranostics to significantly improve patient outcomes in the fields of neurology and neurosurgery remains a source of optimism for the future of healthcare.

Multimorbidity in neurodegenerative diseases: a network analysis.

The socioeconomic costs of neurodegenerative diseases (NDs) are highly affected by comorbidities. This study aims to enhance our understanding of the prevalent complications of NDs through the lens of network analysis. A multimorbidity network (MN) was constructed based on a longitudinal EHR dataset of 93,647,498 diagnoses of 824,847 patients. The association between the conditions was measured by two metrics, i.e. Phi-correlation and Cosine Index (CI). Based on multiple network centrality measures, a fused ranking list of the prevalent multimorbidities was provided. Finally, class-level networks depicting the prevalence and strength of diseases in different classes were constructed. The general MN included 928 diseases and 337,253 associations. Considering a 99% confidence level, two networks of 575 relationships were constructed based on Phi-correlations (73 diseases) and CI (102 diseases). Five out of 19 ICD-9 categories did not appear in either of the networks. Also, ND's immediate MNs for the top 50% of the significant associations included 42 relationships, whereas the Phi-correlation and CI networks included 36 and 34 diseases, respectively. Thirteen diseases were identified as the most notable multimorbidities based on various centrality measures. The analysis framework helps practitioners toward better resource allocations, more effective preventive screenings, and improved quality of life for ND patients and caregivers.

Metagenomic symphony of the intestinal ecosystem: How the composition affects the mind.

Mental health disorders and neurodegenerative diseases place a heavy burden on patients and societies, and, although great strides have been made to understand the pathophysiology of these conditions, advancement in drug development is lagging. The importance of gastrointestinal health in maintaining overall health and preventing disease is not a new concept. Hundreds of years ago, healers from various cultures and civilizations recognized the crucial role of the gut in sustaining health. More than a century ago, scientists began exploring the restorative effects of probiotics, marking the early recognition of the importance of gut microbes. The omics era brought more enlightenment and enabled researchers to identify the complexity of the microbial ecosystems we harbour, encompassing bacteria, eukaryotes (including fungi), archaea, viruses, and other microorganisms. The extensive genetic capacity of the microbiota is dynamic and influenced by the environment. The microbiota therefore serves as a significant entity within us, with evolutionarily preserved functions in host metabolism, immunity, development, and behavior. The significant role of the bacterial gut microbiome in mental health and neurodegenerative disorders has been realized and described within the framework of the microbiota-gut-brain axis. However, the bacterial members do not function unaccompanied, but rather in concert, and there is a substantial knowledge gap regarding the involvement of non-bacterial microbiome members in these disorders. In this review, we will explore the current literature that implicates a role for the entire metagenomic ensemble, and how their complex interkingdom relationships could influence CNS functioning in mental health disorders and neurodegenerative diseases.

Frontiers of Neurodegenerative Disease Treatment: Targeting Immune Cells in Brain Border Regions.

Neurodegenerative diseases (NDs) demonstrate a complex interaction with the immune system, challenging the traditional view of the brain as an "immune-privileged" organ. Microglia were once considered the sole guardians of the brain's immune response. However, recent research has revealed the critical role of peripheral immune cells located in key brain regions like the meninges, choroid plexus, and perivascular spaces. These previously overlooked cells are now recognized as contributors to the development and progression of NDs. This newfound understanding opens doors for pioneering therapeutic strategies. By targeting these peripheral immune cells, we may be able to modulate the brain's immune environment, offering an alternative approach to treat NDs and circumvent the challenges posed by the blood-brain barrier. This comprehensive review will scrutinize the latest findings on the complex interactions between these peripheral immune cells and NDs. It will also critically assess the prospects of targeting these cells as a ground-breaking therapeutic avenue for these debilitating disorders.

Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.

The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.

Specific iron binding to natural sphingomyelin membrane induced by non-specific co-solutes.

HYPOTHESIS: Sphingomyelin (SPM), a crucial phospholipid in the myelin sheath, plays a vital role in insulating nerve fibers. We hypothesize that iron ions selectively bind to the phosphatidylcholine (PC) template within the SPM membrane under near-physiological conditions, resulting in disruptions to membrane organization. These interactions could potentially contribute to the degradation of the myelin sheath, thereby playing a role in the development of neurodegenerative diseases. EXPERIMENTS: We utilized synchrotron-based X-ray spectroscopy and diffraction techniques to study the interaction of iron ions with a bovine spinal-cord SPM monolayer (ML) at the liquid-vapor interface under physiological conditions. The SPM ML serves as a model system, representing localized patches of lipids within a more complex membrane structure. The experiments assessed iron binding to the SPM membrane both in the presence of salts and with additional evaluation of the effects of various ion species on membrane behavior. Grazing incidence X-ray diffraction was employed to analyze the impact of iron binding on the structural integrity of the SPM membrane. FINDINGS: Our results demonstrate that iron ions in dilute solution selectively bind to the PC template of the SPM membrane exclusively at near-physiological salt concentrations (e.g., NaCl, KCl, KI, or CaCl2) and are pH-dependent. In-significant binding was detected in the absence of these salts or at near-neutral pH with salts. The surface adsorption of iron ions is correlated with salt concentration, reaching saturation at physiological levels. In contrast, multivalent ions such as La3+ and Ca2+ do not bind to SPM under similar conditions. Notably, iron binding to the SPM membrane disrupts its in-plane organization, suggesting that these interactions may compromise membrane integrity and contribute to myelin sheath damage associated with neurological disorders.

Rejuvenation factor PF4: a potential gatekeeper for neurodegenerative diseases.

Recently, it is discovered PF4 is a cognitive enhancer that improved the cognitive abilities of younger mice and gave older animals their middle-aged acuity back. PF4 works by reducing inflammation during the aging process. As we all known, aging is undoubtedly the main risk factor of neurodegenerative diseases. Furthermore, inflammation has been extensively investigated and attracted even more interest. Therefore, the aim of the proposal is to highlight the worth of PF4 in inflammaging of neurodegenerative diseases, which might provide a potential therapeutic strategy.

Hidden in the white matter: Current views on interstitial white matter neurons.

The mammalian brain comprises two structurally and functionally distinct compartments: the gray matter (GM) and the white matter (WM). In humans, the WM constitutes approximately half of the brain volume, yet it remains significantly less investigated than the GM. The major cellular elements of the WM are neuronal axons and glial cells. However, the WM also contains cell bodies of the interstitial neurons, estimated to number 10 to 28 million in the adult bat brain, 67 million in Lar gibbon brain, and 450 to 670 million in the adult human brain, representing as much as 1.3%, 2.25%, and 3.5% of all neurons in the cerebral cortex, respectively. Many studies investigated the interstitial WM neurons (IWMNs) using immunohistochemistry, and some information is available regarding their electrophysiological properties. However, the functional role of IWMNs in physiologic and pathologic conditions largely remains unknown. This review aims to provide a concise update regarding the distribution and properties of interstitial WM neurons, highlight possible functions of these cells as debated in the literature, and speculate about other possible functions of the IWMNs and their interactions with glial cells. We hope that our review will inspire new research on IWMNs, which represent an intriguing cell population in the brain.

Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?

Neurodegenerative diseases encompass a spectrum of conditions characterized by the gradual deterioration of neurons in the central and peripheral nervous system. While their origins are multifaceted, emerging data underscore the pivotal role of impaired mitochondrial functions and endolysosomal homeostasis to the onset and progression of pathology. This article explores whether mitochondrial dysfunctions act as causal factors or are intricately linked to the decline in endolysosomal function. As research delves deeper into the genetics of neurodegenerative diseases, an increasing number of risk loci and genes associated with the regulation of endolysosomal and autophagy functions are being identified, arguing for a downstream impact on mitochondrial health. Our hypothesis centers on the notion that disturbances in endolysosomal processes may propagate to other organelles, including mitochondria, through disrupted inter-organellar communication. We discuss these views in the context of major neurodegenerative diseases including Alzheimer's and Parkinson's diseases, and their relevance to potential therapeutic avenues.

3D light-sheet fluorescence microscopy in preclinical and clinical drug discovery.

Light-sheet fluorescence microscopy (LSFM) combined with tissue clearing has emerged as a powerful technology in drug discovery. LSFM is applicable to a variety of samples, from rodent organs to clinical tissue biopsies, and has been used for characterizing drug targets in tissues, demonstrating the biodistribution of pharmaceuticals and determining their efficacy and mode of action. LSFM is scalable to high-throughput analysis and provides resolution down to the single cell level. In this review, we describe the advantages of implementing LSFM into the drug discovery pipeline and highlight recent advances in this field.

Nanosystems for targeted drug Delivery: Innovations and challenges in overcoming the Blood-Brain barrier for neurodegenerative disease and cancer therapy.

The evolution of sophisticated nanosystems has revolutionized biomedicine, notably in treating neurodegenerative diseases and cancer. These systems show potential in delivering medication precisely to affected tissues, improving treatment effectiveness while minimizing side effects. Nevertheless, a major hurdle in targeted drug delivery is breaching the blood-brain barrier (BBB), a selective shield separating the bloodstream from the brain and spinal cord. The tight junctions between endothelial cells in brain capillaries create a formidable physical barrier, alongside efflux transporters that expel harmful molecules. This presents a notable challenge for brain drug delivery. Nanosystems present distinct advantages in overcoming BBB challenges, offering enhanced drug efficacy, reduced side effects, improved stability, and controlled release. Despite their promise, challenges persist, such as the BBB's regional variability hindering uniform drug distribution. Efflux transporters can also limit therapeutic agent efficacy, while nanosystem toxicity necessitates rigorous safety evaluations. Understanding the long-term impact of nanomaterials on the brain remains crucial. Additionally, addressing nanosystem scalability, cost-effectiveness, and safety profiles is vital for widespread clinical implementation. This review delves into the advancements and obstacles of advanced nanosystems in targeted drug delivery for neurodegenerative diseases and cancer therapy, with a focus on overcoming the BBB.

Protein aggregation and its affecting mechanisms in neurodegenerative diseases.

Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid ß (Aß) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aß, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.

Uric Acid: A Biomarker and Pathogenic Factor of Affective Disorders and Neurodegenerative Diseases.

Uric acid (UA), the end-product of purine metabolism, has a complicated physiological role in the body, showing the combination of regulating inflammatory response, promoting oxidation/anti-oxidation, and modifying autophagy activity in vivo. Meanwhile, various research and theories support that inflammation, oxidative stress, and other risk factors promote the onset and progression of affective disorders and neurodegenerative diseases. Existing studies suggest that UA may be involved in the pathophysiological processes of affective disorders in various ways, and there has been a gradual advance in the understanding of the interplay between UA levels and affective disorders and neurodegenerative diseases. This review summarized the role of UA in the process of inflammation, oxidative stress, and autophagy. On this basis, we discussed the correlation between UA and affective disorders and several neurodegenerative diseases, and simultaneously analyzed the possible mechanism of its influence on affective disorders and neurodegenerative diseases, to provide a theoretical basis for UA as a biomarker or therapeutic target for the diagnosis of these diseases.

Hypoxia Pathways in Parkinson's Disease: From Pathogenesis to Therapeutic Targets.

The human brain is highly dependent on oxygen, utilizing approximately 20% of the body's oxygen at rest. Oxygen deprivation to the brain can lead to loss of consciousness within seconds and death within minutes. Recent studies have identified regions of the brain with spontaneous episodic hypoxia, referred to as "hypoxic pockets". Hypoxia can also result from impaired blood flow due to conditions such as heart disease, blood clots, stroke, or hemorrhage, as well as from reduced oxygen intake or excessive oxygen consumption caused by factors like low ambient oxygen, pulmonary diseases, infections, inflammation, and cancer. Severe hypoxia in the brain can manifest symptoms similar to Parkinson's disease (PD), including cerebral edema, mood disturbances, and cognitive impairments. Additionally, the development of PD appears to be closely associated with hypoxia and hypoxic pathways. This review seeks to investigate the molecular interactions between hypoxia and PD, emphasizing the pathological role of hypoxic pathways in PD and exploring their potential as therapeutic targets.

Intrathecal Immunoselective Nanopheresis for Alzheimer's Disease: What and How? Why and When?

Nanotechnology is transforming therapeutics for brain disorders, especially in developing drug delivery systems. Intrathecal immunoselective nanopheresis with soluble monoclonal antibodies represents an innovative approach in the realm of drug delivery systems for Central Nervous System conditions, especially for targeting soluble beta-amyloid in Alzheimer's disease. This review delves into the concept of intrathecal immunoselective nanopheresis. It provides an overall description of devices to perform this technique while discussing the nanotechnology behind its mechanism of action, its potential advantages, and clinical implications. By exploring current research and advancements, we aim to provide a comprehensive understanding of this novel method, addressing the critical questions of what it is, how it works, why it is needed, and when it should be applied. Special attention is given to patient selection and the optimal timing for therapy initiation in Alzheimer's, coinciding with the peak accumulation of amyloid oligomers in the early stages. Potential limitations and alternative targets beyond beta-amyloid and future perspectives for immunoselective nanopheresis are also described.

Effects of Leaf Extracts from Genetic Resource of Capsicum spp. on Neuroprotection and Anti-Neuroinflammation in HT22 and in BV2 Cells.

To develop functional varieties of Capsicum spp. leaves, 40 genetic resources were collected and extracted with 30% aqueous-fermented ethanol. We investigated the protective effects of extracts from 40 genetic resources of Capsicum spp. on glutamate-induced HT22 and LPS-induced BV2 cells. The results showed that the five extracts exhibited cell-protective activities. We also investigated the anti-inflammatory effects of these five extracts on LPS-induced BV2 cell neuroinflammation and found that 23OM18 exhibited superior anti-inflammatory effects. We further investigated the protective activity and anti-inflammatory mechanisms of 23OM18 in these two cell models. In addition, the profiles of 16 metabolites were compared between the representative accessions and among the five genetic resources using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). The results showed that 23OM18 protected HT22 cells by inhibiting reactive oxygen species generation and regulating the MAPK-JNK signaling pathway, thereby reducing LPS-induced BV2 cell neuroinflammation by regulating the NF-κB and MAPK signaling pathways. Based on these results, 23OM18 has the potential to be developed as a functional food for the treatment of neurodegenerative diseases.