Metalloproteins and metalloproteomics in health and disease.

Metalloproteins represents more than one third of human proteome, with huge variation in physiological functions and pathological implications, depending on the metal/metals involved and tissue context. Their functions range from catalysis, bioenergetics, redox, to DNA repair, cell proliferation, signaling, transport of vital elements, and immunity. The human metalloproteomic studies revealed that many families of metalloproteins along with individual metalloproteins are dysregulated under several clinical conditions. Also, several sorts of interaction between redox- active or redox- inert metalloproteins are observed in health and disease. Metalloproteins profiling shows distinct alterations in neurodegenerative diseases, cancer, inflammation, infection, diabetes mellitus, among other diseases. This makes metalloproteins -either individually or as families- a promising target for several therapeutic approaches. Inhibitors and activators of metalloenzymes, metal chelators, along with artificial metalloproteins could be versatile in diagnosis and treatment of several diseases, in addition to other biomedical and industrial applications.

Exploring regulatory mechanisms on miRNAs and their implications in inflammation-related diseases.

This comprehensive exploration delves into the pivotal role of microRNAs (miRNAs) within the intricate tapestry of cellular regulation. As potent orchestrators of gene expression, miRNAs exhibit diverse functions in cellular processes, extending their influence from the nucleus to the cytoplasm. The complex journey of miRNA biogenesis, involving transcription, processing, and integration into the RNA-induced silencing complex, showcases their versatility. In the cytoplasm, mature miRNAs finely tune cellular functions by modulating target mRNA expression, while their reach extends into the nucleus, influencing transcriptional regulation and epigenetic modifications. Dysregulation of miRNAs becomes apparent in various pathologies, such as cancer, autoimmune diseases, and inflammatory conditions. The adaptability of miRNAs to environmental signals, interactions with transcription factors, and involvement in intricate regulatory networks underscore their significance. DNA methylation and histone modifications adds depth to understanding the dynamic regulation of miRNAs. Mechanisms like competition with RNA-binding proteins, sponging, and the control of miRNA levels through degradation and editing contribute to this complex regulation process. In this review, we mainly focus on how dysregulation of miRNA expression can be related with skin-related autoimmune and autoinflammatory diseases, arthritis, cardiovascular diseases, inflammatory bowel disease, autoimmune and autoinflammatory diseases, and neurodegenerative disorders. We also emphasize the multifaceted roles of miRNAs, urging continued research to unravel their complexities. The mechanisms governing miRNA functions promise advancements in therapeutic interventions and enhanced insights into cellular dynamics in health and disease.

Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration.

Aggregation of the microtubule-associated protein tau (MAPT) is the hallmark pathology in a spectrum of neurodegenerative disorders collectively called tauopathies. Physiologically, tau is an inherent neuronal protein that plays an important role in the assembly of microtubules and axonal transport. However, disease-associated mutations of this protein reduce its binding to the microtubule components and promote self-aggregation, leading to formation of tangles in neurons. Tau is also expressed in oligodendrocytes, where it has significant developmental roles in oligodendrocyte maturation and myelin synthesis. Oligodendrocyte-specific tau pathology, in the form of fibrils and coiled coils, is evident in major tauopathies including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Multiple animal models of tauopathy expressing mutant forms of MAPT recapitulate oligodendroglial tau inclusions with potential to cause degeneration/malfunction of oligodendrocytes and affecting the neuronal myelin sheath. Till now, mechanistic studies heavily concentrated on elucidating neuronal tau pathology. Therefore, more investigations are warranted to comprehensively address tau-induced pathologies in oligodendrocytes. The present review provides the current knowledge available in the literature about the intricate relations between tau and oligodendrocytes in health and diseases.

The Role of miR-137 in Neurodegenerative Disorders.

Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.

Extracellular Vesicles: The Next Generation of Biomarkers and Treatment for Central Nervous System Diseases.

It has been widely established that the characterization of extracellular vesicles (EVs), particularly small EVs (sEVs), shed by different cell types into biofluids, helps to identify biomarkers and therapeutic targets in neurological and neurodegenerative diseases. Recent studies are also exploring the efficacy of mesenchymal stem cell-derived extracellular vesicles naturally enriched with therapeutic microRNAs and proteins for treating various diseases. In addition, EVs released by various neural cells play a crucial function in the modulation of signal transmission in the brain in physiological conditions. However, in pathological conditions, such EVs can facilitate the spread of pathological proteins from one brain region to the other. On the other hand, the analysis of EVs in biofluids can identify sensitive biomarkers for diagnosis, prognosis, and disease progression. This review discusses the potential therapeutic use of stem cell-derived EVs in several central nervous system diseases. It lists their differences and similarities and confers various studies exploring EVs as biomarkers. Further advances in EV research in the coming years will likely lead to the routine use of EVs in therapeutic settings.

Exploring the Regulation of Cytochrome P450 in SH-SY5Y Cells: Implications for the Onset of Neurodegenerative Diseases.

Human individual differences in brain cytochrome P450 (CYP) metabolism, including induction, inhibition, and genetic variation, may influence brain sensitivity to neurotoxins and thus participate in the onset of neurodegenerative diseases. The aim of this study was to explore the modulation of CYPs in neuronal cells. The experimental approach was focused on differentiating human neuroblastoma SH-SY5Y cells into a phenotype resembling mature dopamine neurons and investigating the effects of specific CYP isoform induction. The results demonstrated that the differentiation protocols using retinoic acid followed by phorbol esters or brain-derived neurotrophic factor successfully generated SH-SY5Y cells with morphological neuronal characteristics and increased neuronal markers (NeuN, synaptophysin, ß-tubulin III, and MAO-B). qRT-PCR and Western blot analysis showed that expression of the CYP 1A1, 3A4, 2D6, and 2E1 isoforms was detectable in undifferentiated cells, with subsequent increases in CYP 2E1, 2D6, and 1A1 following differentiation. Further increases in the 1A1, 2D6, and 2E1 isoforms following ß-naphthoflavone treatment and 1A1 and 2D6 isoforms following ethanol treatment were evident. These results demonstrate that CYP isoforms can be modulated in SH-SY5Y cells and suggest their potential as an experimental model to investigate the role of CYPs in neuronal processes involved in the development of neurodegenerative diseases.

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders.

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral Aß amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis-Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10-3), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10-5) and plasma tau concentration (0.06 log2(ng l-1) 95%CI 0.03; 0.08, p = 4.55 × 10-6). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases.

BACKGROUND: Maintaining the structural and functional integrity of the blood-brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. MAIN BODY: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. CONCLUSIONS: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Metabolic Endotoxemia: From the Gut to Neurodegeneration.

Metabolic endotoxemia is a severe health problem for residents in developed countries who follow a Western diet, disrupting intestinal microbiota and the whole organism's homeostasis. Although the effect of endotoxin on the human immune system is well known, its long-term impact on the human body, lasting many months or even years, is unknown. This is due to the difficulty of conducting in vitro and in vivo studies on the prolonged effect of endotoxin on the central nervous system. In this article, based on the available literature, we traced the path of endotoxin from the intestines to the blood through the intestinal epithelium and factors promoting the development of metabolic endotoxemia. The presence of endotoxin in the bloodstream and the inflammation it induces may contribute to lowering the blood-brain barrier, potentially allowing its penetration into the central nervous system; although, the theory is still controversial. Microglia, guarding the central nervous system, are the first line of defense and respond to endotoxin with activation, which may contribute to the development of neurodegenerative diseases. We traced the pro-inflammatory role of endotoxin in neurodegenerative diseases and its impact on the epigenetic regulation of microglial phenotypes.

Pills of Multi-Target H2S Donating Molecules for Complex Diseases.

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs) able to modulate multiple targets of interest, including the pathways where hydrogen sulfide (H2S) is involved. By incorporating an H2S donor moiety into a native drug, researchers have been able to simultaneously target multiple therapeutic pathways, resulting in improved treatment outcomes. This review gives the reader some pills of successful multi-target H2S-donating molecules as worthwhile tools to combat the multifactorial nature of complex disorders, such as inflammatory-based diseases and cancer, as well as cardiovascular, metabolic, and neurodegenerative disorders.

14-3-3 Family of Proteins: Biological Implications, Molecular Interactions, and Potential Intervention in Cancer, Virus and Neurodegeneration Disorders.

The 14-3-3 family of proteins are highly conserved acidic eukaryotic proteins (25-32 kDa) abundantly present in the body. Through numerous binding partners, the 14-3-3 is responsible for many essential cellular pathways, such as cell cycle regulation and gene transcription control. Hence, its dysregulation has been linked to the onset of critical illnesses such as cancers, neurodegenerative diseases and viral infections. Interestingly, explorative studies have revealed an inverse correlation of 14-3-3 protein in cancer and neurodegenerative diseases, and the direct manipulation of 14-3-3 by virus to enhance infection capacity has dramatically extended its significance. Of these, COVID-19 has been linked to the 14-3-3 proteins by the interference of the SARS-CoV-2 nucleocapsid (N) protein during virion assembly. Given its predisposition towards multiple essential host signalling pathways, it is vital to understand the holistic interactions between the 14-3-3 protein to unravel its potential therapeutic unit in the future. As such, the general structure and properties of the 14-3-3 family of proteins, as well as their known biological functions and implications in cancer, neurodegeneration, and viruses, were covered in this review. Furthermore, the potential therapeutic target of 14-3-3 proteins in the associated diseases was discussed.

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases.

Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.

Blood-Brain Barrier Permeability Is Associated With Cognitive Functioning in Normal Aging and Neurodegenerative Diseases.

BACKGROUND: The purpose of this study was to investigate the relationship between blood-brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. METHODS AND RESULTS: A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix Alzheimer's and cerebrovascular diseases and 55 controlparticipants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast-enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion-tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning. Vascular risk burden predicted BBB permeability (r=0.24, P<0.05) and white matter injury (r=0.38, P<0.001). BBB permeability predicted increased white matter injury (r=0.34, P<0.001) and increased white matter injury predicted lower cognitive functioning (r=-0.51, P<0.001). CONCLUSIONS: The study provides empirical support for a vascular contribution to white matter injury and cognitive impairment, directly or indirectly via BBB permeability. This highlights the importance of targeting modifiable vascular risk factors to help mitigate future cognitive decline.

Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders.

Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss of genome integrity, is a common feature among both neurodegenerative (mayo-trophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) and psychiatric (schizophrenia, autism, bipolar depression) disorders. Genomic instability is associated with the accumulation of persistent DNA damage and the activation of DNA damage response (DDR) pathways, as well as pathologic neuronal cell loss or senescence. Typically, DDR signaling ensures that genomic and proteomic homeostasis are maintained in both dividing cells, including neural progenitors, and post-mitotic neurons. However, dysregulation of these protective responses, in part due to aging or environmental insults, contributes to the progressive development of neurodegenerative and/or psychiatric disorders. In this Special Issue, we introduce and highlight the overlap between neurodegenerative diseases and neuropsychiatric disorders, as well as the emerging clinical, genomic, and molecular evidence for the contributions of DNA damage and aberrant DNA repair. Our goal is to illuminate the importance of this subject to uncover possible treatment and prevention strategies for relevant devastating brain diseases.

Brain microvascular endothelial cell metabolism and its ties to barrier function.

Brain microvascular endothelial cells, which lie at the interface between blood and brain, are critical to brain energetics. These cells must precisely balance metabolizing nutrients for their own demands with transporting nutrients into the brain to sustain parenchymal cells. It is essential to understand this integrated metabolism and transport so that we can develop better diagnostics and therapeutics for neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, and traumatic brain injury. In this chapter, we first describe brain microvascular endothelial cell metabolism and how these cells regulate both blood flow and nutrient transport. We then explain the impact of brain microvascular endothelial cell metabolism on the integrity of the blood-brain barrier, as well as how metabolites produced by the endothelial cells impact other brain cells. We detail some ways that cell metabolism is typically measured experimentally and modeled computationally. Finally, we describe changes in brain microvascular endothelial cell metabolism in aging and neurodegenerative diseases. At the end of the chapter, we highlight areas for future research in brain microvascular endothelial cell metabolism. The goal of this chapter is to underscore the importance of nutrient metabolism and transport at the brain endothelium for cerebral health and neurovascular disease treatment.

Protein Tyrosine Phosphatase 1B (PTP1B): A Comprehensive Review of Its Role in Pathogenesis of Human Diseases.

Overexpression of protein tyrosine phosphatase 1B (PTP1B) disrupts signaling pathways and results in numerous human diseases. In particular, its involvement has been well documented in the pathogenesis of metabolic disorders (diabetes mellitus type I and type II, fatty liver disease, and obesity); neurodegenerative diseases (Alzheimer's disease, Parkinson's disease); major depressive disorder; calcific aortic valve disease; as well as several cancer types. Given this multitude of therapeutic applications, shortly after identification of PTP1B and its role, the pursuit to introduce safe and selective enzyme inhibitors began. Regrettably, efforts undertaken so far have proved unsuccessful, since all proposed PTP1B inhibitors failed, or are yet to complete, clinical trials. Intending to aid introduction of the new generation of PTP1B inhibitors, this work collects and organizes the current state of the art. In particular, this review intends to elucidate intricate relations between numerous diseases associated with the overexpression of PTP1B, as we believe that it is of the utmost significance to establish and follow a brand-new holistic approach in the treatment of interconnected conditions. With this in mind, this comprehensive review aims to validate the PTP1B enzyme as a promising molecular target, and to reinforce future research in this direction.

Transgenerational hormesis in healthy aging and antiaging medicine from bench to clinics: Role of food components.

Neurodegenerative diseases have multifactorial pathogenesis, mainly involving neuroinflammatory processes. Finding drugs able to treat these diseases, expecially because for most of these diseases there are no effective drugs, and the current drugs cause undesired side effects, represent a crucial point. Most in vivo and in vitro studies have been concentrated on various aspects related to neurons (e.g. neuroprotection), however, there has not been focus on the prevention of early stages involving glial cell activation and neuroinflammation. Recently, it has been demonstrated that nutritional phytochemicals including polyphenols, the main active constituents of the Mediterranean diet, maintain redox balance and neuroprotection through the activation of hormetic vitagene pathway. Recent lipidomics data from our laboratory indicate mushrooms as strong nutritional neuronutrients with strongly activity against neuroinflammation in Meniere' diseaseas, a model of cochleovestibular neural degeneration, as well as in animal model of traumatic brain injury, or rotenone induced parkinson's disease. Moreover, Hidrox®, an aqueous extract of olive containing hydroxytyrosol, and Boswellia, acting as Nrf2 activators, promote resilience by enhancing the redox potential, and thus, regulate through hormetic mechanisms, cellular stress response mechanisms., Thus, modulation of cellular stress pathways, in particular vitagenes system, may be an innovative approach for therapeutic intervention in neurodegenerative disorders.

Drp1 and neuroinflammation: Deciphering the interplay between mitochondrial dynamics imbalance and inflammation in neurodegenerative diseases.

Neuroinflammation and mitochondrial dysfunction are closely intertwined with the pathophysiology of neurological disorders. Recent studies have elucidated profound alterations in mitochondrial dynamics across a spectrum of neurological disorders. Dynamin-related protein 1 (DRP1) emerges as a pivotal regulator of mitochondrial fission, with its dysregulation disrupting mitochondrial homeostasis and fueling neuroinflammation, thereby exacerbating disease severity. In addition to its role in mitochondrial dynamics, DRP1 plays a crucial role in modulating inflammation-related pathways. This review synthesizes important functions of DRP1 in the central nervous system (CNS) and the impact of epigenetic modification on the progression of neurodegenerative diseases. The intricate interplay between neuroinflammation and DRP1 in microglia and astrocytes, central contributors to neuroinflammation, is expounded upon. Furthermore, the use of DRP1 inhibitors to influence the activation of microglia and astrocytes, as well as their involvement in processes such as mitophagy, mitochondrial oxidative stress, and calcium ion transport in CNS-mediated neuroinflammation, is scrutinized. The modulation of microglia to astrocyte crosstalk by DRP1 and its role in inflammatory neurodegeneration is also highlighted. Overall, targeting DRP1 presents a promising avenue for ameliorating neuroinflammation and enhancing the therapeutic management of neurological disorders.

Neuropeptide FF (NPFF)-positive nerve cells of the human cerebral cortex and white matter in controls, selected neurodegenerative diseases, and schizophrenia.

We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles.