Sphingoid bases and their involvement in neurodegenerative diseases.

The gut microbiome provides the host access to otherwise indigestible nutrients, which are often further metabolized by the microbiome into bioactive components. The gut microbiome can also shift the balance of host-produced compounds, which may alter host health. One precursor to bioactive metabolites is the essential aromatic amino acid tryptophan. Tryptophan is mostly shunted into the kynurenine pathway but is also the primary metabolite for serotonin production and the bacterial indole pathway. Balance between tryptophan-derived bioactive metabolites is crucial for neurological homeostasis and metabolic imbalance can trigger or exacerbate neurological diseases. Alzheimer's, depression, and schizophrenia have been linked to diverging levels of tryptophan-derived anthranilic, kynurenic, and quinolinic acid. Anthranilic acid from collective microbiome metabolism plays a complex but important role in systemic host health. Although anthranilic acid and its metabolic products are of great importance for host-microbe interaction in neurological health, literature examining the mechanistic relationships between microbial production, host regulation, and neurological diseases is scarce and at times conflicting. This narrative review provides an overview of the current understanding of anthranilic acid's role in neurological health and disease, with particular focus on the contribution of the gut microbiome, the gut-brain axis, and the involvement of the three major tryptophan pathways.

Sphingolipids are ubiquitous in all eukaryotic organisms. Various physiological functions of dietary sphingolipids, such as preventing colon cancer and improving the skin barrier function, have been recently reported. One of the common sphingolipids used as a foodstuff is glucosylceramide from plant sources, which is composed of sphingoid bases distinct from those of mammals. However, the fate of dietary sphingolipids derived from plants is still not understood. In this study, we investigated the absorption of maize glucosylceramide in the rat intestine using a lipid absorption assay of lymph from the thoracic duct. The free and complex forms of trans-4,cis-8-sphingadienine, the predominant sphingoid base of maize glucosylceramide, were found in the lymph after administration of maize glucosylceramide. This plant type of sphingoid base was detected in the ceramide fraction and N-palmitoyl-4,8-sphingadienine (C16:0-d18:2) and N-tricosanoyl-4,8-sphingadienine (C23:0-d18:2) were identified by LC-MS/MS. The cumulative recovery of 4t,8c-sphingadienine in the lymph was very low. These results indicate that dietary glucosylceramide originating from higher plants is slightly absorbed in the intestine and is incorporated into ceramide structures in the intestinal cells. However, it appears that the intact form of sphingoid bases is not reutilized well in the tissues.

Glutamate-induced excito-neurotoxicity likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases. Microglial clearance of dying neurons and associated debris is essential to maintain healthy neural networks in the central nervous system. In fact, the functions of microglia are regulated by various signaling molecules that are produced as neurons degenerate. Here, we show that the soluble CX3C chemokine fractalkine (sFKN), which is secreted from neurons that have been damaged by glutamate, promotes microglial phagocytosis of neuronal debris through release of milk fat globule-EGF factor 8, a mediator of apoptotic cell clearance. In addition, sFKN induces the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in microglia in the absence of neurotoxic molecule production, including NO, TNF, and glutamate. sFKN treatment of primary neuron-microglia co-cultures significantly attenuated glutamate-induced neuronal cell death. Using several specific MAPK inhibitors, we found that sFKN-induced heme oxygenase-1 expression was primarily mediated by activation of JNK and nuclear factor erythroid 2-related factor 2. These results suggest that sFKN secreted from glutamate-damaged neurons provides both phagocytotic and neuroprotective signals.

Long-term Outcome for Wilson Disease: 85% Good

Activation of RAW264.7 cells with a lipopolysaccharide specific for the TLR4 receptor, Kdo2-lipid A (KLA), causes a large increase in cellular sphingolipids, from 1.5 to 2.6 × 109 molecules per cell in 24 h, based on the sum of subspecies analyzed by “lipidomic” mass spectrometry. Thus, this study asked the following question. What is the cause of this increase and is there a cell function connected with it? The sphingolipids arise primarily from de novo biosynthesis based on [U-13C]palmitate labeling, inhibition by ISP1 (myriocin), and an apparent induction of many steps of the pathway (according to the distribution of metabolites and microarray analysis), with the exception of ceramide, which is also produced from pre-existing sources. Nonetheless, the activated RAW264.7 cells have a higher number of sphingolipids per cell because KLA inhibits cell division; thus, the cells are larger and contain increased numbers of membrane vacuoles termed autophagosomes, which were detected by the protein marker GFP-LC3. Indeed, de novo biosynthesis of sphingolipids performs an essential structural and/or signaling function in autophagy because autophagosome formation was eliminated by ISP1 in KLA-stimulated RAW264.7 cells (and mutation of serine palmitoyltransferase in CHO-LYB cells); furthermore, an anti-ceramide antibody co-localizes with autophagosomes in activated RAW264.7 cells versus the Golgi in unstimulated or ISP1-inhibited cells. These findings establish that KLA induces profound changes in sphingolipid metabolism and content in this macrophage-like cell line, apparently to produce sphingolipids that are necessary for formation of autophagosomes, which are thought to play important roles in the mechanisms of innate immunity.

Progressive functional deterioration and loss of neurons underlies neurological diseases and constitutes an important cause of disability and death worldwide. The causes of various types of neurological diseases often share several critical nerve-related cellular mechanisms and pathological features, particularly the neuroinflammatory response in the nervous system. A rapidly growing body of evidence indicates that various microRNAs play pivotal roles in these processes in neurological diseases and might be viable therapeutic targets. Among these microRNAs, microRNA-146a (miR-146a) stands out due to the rapid increase in recent literature on its mechanistic involvement in neurological diseases. In this review, we summarize and highlight the critical role of miR-146a in neurological diseases. MiR-146a polymorphisms are associated with the risk of neurological disease. Alterations in miR-146a expression levels are crucial events in the pathogenesis of numerous neurological diseases that are spatially and temporally diverse. Additionally, the target genes of miR-146a are involved in the regulation of pathophysiological processes in neurological diseases, particularly the neuroinflammatory response. In summary, miR-146a mainly plays a critical role in neuroinflammation during the progression of neurological diseases and might be a prospective biomarker and therapeutic target. Understanding the mechanisms by which miR-146a affects the neuroinflammatory response in different neurological injuries, different cell types, and even different stages of certain neurological diseases will pave the way for its use as a therapeutic target in neurodegenerative diseases.

Autoimmune diseases have a broad spectrum of clinical manifestations. Among them, neurologic involvement, both from the central nervous system as well as from the peripheral nervous system, is among the most challenging manifestations, regarding diagnosis and treatment [1]. Neurologic involvement in systemic lupus erythematosus and antiphospholipid syndrome is frequently observed, and reported and several etiological factors are involved including immunomediated damage and thrombosis [1, 2]. In this issue, we focused on less frequently described neurologic manifestations. One of the papers describes complex regional pain syndrome (CRPS) in a patient with adult onset Still's disease. CRPS is a chronic neuropathic pain disorder characterized by neuropathic pain and associated with local edema and changes suggestive of autonomic involvement such as altered sweating, skin color, and skin temperature of the affected region. Although it has been described in patients following trauma, psychiatric conditions, and malignancy, the association of CRPS with other autoimmune diseases is rare. The paper entitled “Sensory neuronopathy and autoimmune diseases” describes the importance of recognizing this clinical entity, frequently characterized by ataxia and often associated with systemic autoimmune diseases. The authors discuss not only the epidemiologicy and pathophysiology of this syndrome, but also emphasize clinical findings and discuss specific autoimmune diseases where sensory neuronopathy is frequently observed. Broad aspects of the involvement of the nervous system in Sjogren's disease are described in the paper entitled “Neurological disorders in primary Sjogren's syndrome.” The authors not only discuss the clinical aspects and physiopathology of central and peripheral nervous system involvement, but also emphasize biological markers for neurologic involvement in this disease. In the practical aspect of the paper, the authors discuss treatment, including immunosupressive drugs, anti-TNF drugs, and other biological therapies such as rituximab. Localized scleroderma is a rare disease, characterized by sclerotic lesions. A variety of presentations have been described, with different clinical characteristics and specific prognosis. Once considered an exclusive cutaneous disorder, the neurologic involvement present in localized scleroderma has been described in several case reports. Seizures are most frequently observed, but focal neurologic deficits, movement disorders, trigeminal neuralgia, and mimics of hemiplegic migraines have been reported. In the paper “Neurologic involvement in scleroderma en coup de sabre” the authors describe clinical and radiologic aspects of neurologic involvement in localized scleroderma. Although no randomized controlled trials exist for treatment of neurologic manifestations in scleroderma en coup de sabre, the authors describe the current literature findings. In the paper “Significant changes in the levels of secreted cytokines in brains of experimental antiphospholipid syndrome mice” the authors examined the role of proinflammatory and anti-inflammatory cytokines in experimental APS (eAPS) mice brains. The authors showed that other immune mediators, apart from autoantibodies, are important in the inflammatory and degenerative processes in the APS brain. These results are encouraging and endeavor clinical studies in APS patients with neurologic symptoms with immunomodulatory drugs. Simone Appenzeller Yehuda Shoenfeld Jozelio Freire de Carvalho

A Directed Content Analysis for Greatest Problems Among People With and Without Traumatic Brain Injury

The prevalence of neurodegenerative, cerebrovascular, and psychiatric diseases and other neurological disorders has increased dramatically worldwide. Fucoxanthin is an algal pigment with many biological functions, and there is rising evidence that fucoxanthin plays a preventive and therapeutic role in neurological disorders. This review focuses on the metabolism, bioavailability, and blood-brain barrier penetration of fucoxanthin. Furthermore, the neuroprotective potential of fucoxanthin in neurodegenerative diseases, cerebrovascular diseases, and psychiatric diseases as well as other neurological disorders such as epilepsy, neuropathic pain, and brain tumors by acting on multiple targets will be summarized. The multiple targets include regulating apoptosis, reducing oxidative stress, activating the autophagy pathway, inhibiting Aβ aggregation, improving dopamine secretion, reducing α-synuclein aggregation, attenuating neuroinflammation, modulating gut microbiota, and activating brain-derived neurotrophic factor, etc. Additionally, we look forward to brain-targeted oral transport systems due to the low bioavailability and blood-brain barrier permeability of fucoxanthin. We also propose exploring the systemic mechanisms of fucoxanthin metabolism and transport through the gut-brain process and envision new therapeutic targets for fucoxanthin to act on the central nervous system. Finally, we propose dietary fucoxanthin delivery interventions to achieve preventive effects on neurological disorders. This review provides a reference for the application of fucoxanthin in the neural field.

Glucose utilization is reduced in vulnerable brain regions affected by neurological disorders, especially Alzheimer's disease (AD), but the basis for abnormal glucose homeostasis is unknown. Studies of brain-bank human tissue have made major contributions to understanding complex aspects of neurological, psychiatric, and neurodegenerative diseases, but they are not appropriate for metabolomic analysis of labile metabolites because postmortem intervals between death and tissue freezing are much too long. Recent reports of postmortem brain glucose levels led to suggestions that AD patients may be hyperglycemic and that elevated brain glucose levels along with reduced glycolytic activity reveal abnormal glucose homeostasis before clinical symptoms become manifest. These conclusions are, however, questioned because virtually all brain glucose is consumed within minutes after death, followed by progressive increases in glucose and amino acid levels, presumably due to autolytic changes. To illustrate pitfalls in use of autopsy material for metabolomic assays of labile metabolites, data from living human brain are compared with those from autopsy samples, and metabolism at the onset of postmortem ischemia is compared with calculated glycolytic enzyme activities. Postmortem glucose levels range from extremely low to unrealistically high, precluding their extrapolation to living brain. Indirect evaluation of glycolytic enzyme activities in postmortem AD brain is not valid because the glucose and amino acid concentrations used in the calculations are not stable after death, and reported values are unrealistically high. Specific recommendations are provided for non-invasive longitudinal monitoring of brain metabolism and metabolite levels in patients with neurological diseases.

Adropin, a peptide hormone has role in various various physiological processes, including metabolic regulation and cardiovascular health. This systematic review aimed to synthesize findings from observational studies on the involvement of adropin in neurological disorders and cognitive performance. An extensive literature search was conducted across PubMed, Scopus, Web of Science, Embase, CORE, and Google Scholar using terms such as "adropin," "Neurological Disorders," "cognitive function," "Alzheimer's disease," "Parkinson's disease," "cognition," and "brain function." Studies published from 2020 to 2024 were selected and reviewed. The search and selection process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Out of 127 screened articles, 5 met the inclusion criteria for this review. The combined research findings suggest a consistent link between decreased adropin levels and a range of neurological disorders and cognitive impairments. In particular, reduced adropin levels were seen in individuals with dementia, cognitive impairment, bipolar disorder, Parkinson's disease, and multiple sclerosis. These findings highlight adropin's potential role in modulating neurological health and cognitive function. This systematic review underscores the importance of adropin in neurological health and its potential as a therapeutic agent. Based on the observed connections, adropin might serve as a new focus for treating neurological disorders, prompting the need for more research and trials.

Selective neuron loss in discrete brain regions is a hallmark of various neurodegenerative disorders, although the mechanisms responsible for this regional vulnerability of neurons remain largely unknown. Earlier studies attributed neuron dysfunction and eventual loss during neurodegenerative diseases as exclusively cell autonomous. Although cell-intrinsic factors are one critical aspect in dictating neuron death, recent evidence also supports the involvement of other central nervous system cell types in propagating non-cell autonomous neuronal injury during neurodegenerative diseases. One such example is astrocytes, which support neuronal and synaptic function, but can also contribute to neuroinflammatory processes through robust chemokine secretion. Indeed, aberrations in astrocyte function have been shown to negatively impact neuronal integrity in several neurological diseases. The present review focuses on neuroinflammatory paradigms influenced by neuron-astrocyte cross-talk in the context of select neurodegenerative diseases.

The sialylation pathway is uniquely partitioned in Drosophila between glia and neurons and mediates a novel mechanism of glia-neuron coupling that regulates neural functions, promotes tolerance to heat and oxidative stress, and maintains the normal level of voltage-gated sodium channels.

BackgroundFine particulate matter (PM2.5) has been significantly linked to the progression of various neurological and neurodegenerative diseases.ObjectiveThis review aims to elucidate the molecular and pathophysiological effects induced by chronic exposure to PM2.5 in neurological and neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis, and epilepsy.IntroductionPM2.5 penetrates the central nervous system (CNS) via the olfactory nerve or by disrupting the blood–brain barrier (BBB), triggering oxidative stress, neuroinflammation, mitochondrial dysfunction, and epigenetic alterations.DiscussionIn Alzheimer’s and Parkinson’s diseases, PM2.5 exacerbates the accumulation of β‐amyloid, hyperphosphorylated tau, and α‐synuclein, while in Huntington’s disease, it worsens toxicity mediated by mutant huntingtin. In multiple sclerosis, these particles intensify neuroinflammation and axonal damage, whereas in epilepsy, they promote neuronal hyperexcitability and recurrent seizures. These mechanisms contribute to neuronal damage, symptom progression, and functional decline.ConclusionThis evidence highlights the urgent need for strict environmental policies to reduce PM2.5 exposure and further research to develop therapeutic strategies that mitigate its effects on neurological diseases, thereby improving the health of vulnerable populations.

The molecular basis of programmed cell death and neuroinflammation in neurodegenerative diseases The pathogenesis of neurodegenerative diseases is closely linked to the occurrence of programmed cell death, also known as apoptosis and neuroinflammation. Despite the presence of a distinct mode of cell death exhibiting unique morphological characteristics, the identification and implications of this phenomenon in neurological diseases remain unknown. Current scientific investigations are diligently striving to identify and understand distinct cellular and molecular targets that can be selectively engaged in therapeutic intervention for Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This special edition is dedicated to a diverse array of original research, comprehensive literature reviews, and expert opinions that its aim is to provide a deeper understanding of the intricate molecular mechanisms underlying programmed cell death in the context of neurodegenerative disorders. The perspective article from Zhang et al. presents a comprehensive analysis of the landscape of necroptosis research spanning the period from 2012 to 2021. The investigation of necroptosis has exhibited a sustained and consistent expansion throughout the previous decade. The current focus of research revolves around the phenomenon of synergistic interactions with ferroptosis, with an increasing emphasis on the exploration of RIPK1/ RIPK3/MLKL pathways. This line of investigation aims to elucidate the intricate connections between ferroptosis, inflammation, and oxidative stress while also exploring the translational applications and therapeutic prospects for combating cancer and neurological disorders. The seminal study conducted by Lee et al. introduced a chronic constriction injury (CCI) model as an effective animal model for investigating neuropathic pain. Their research Frontiers in Immunology frontiersin.org 01