Search Results (3,493)

Gaucher disease is a prototypical lysosomal sphingolipid storage disorder caused by pathogenic variants in GBA1, resulting in glucocerebrosidase deficiency and accumulation of bioactive lipids, including glucosylceramide and glucosylsphingosine (lyso-Gb1). While non-neuronopathic Gaucher disease is effectively managed with enzyme replacement and substrate reduction therapies, neuronopathic forms remain largely refractory to treatment due to progressive central nervous system (CNS) involvement and limited penetration of current therapies across the blood–brain barrier. Disease pathobiology extends beyond lysosomal substrate accumulation to encompass dysregulated sphingolipid signaling, particularly sphingosine-1-phosphate (S1P)-mediated “inside-out” signaling, alongside neuroinflammation, oxidative stress, and glial activation, which collectively drive neurodegeneration. In this review, we synthesize current knowledge on sphingolipid metabolism and signaling in neuronopathic Gaucher disease and integrate these mechanisms into a three-tier, CNS-focused biomarker framework. The first tier comprises substrate-proximal markers of lysosomal burden (lyso-Gb1), which reflect GCase deficiency and correlate with systemic disease severity but incompletely capture CNS pathology. The second tier comprises markers of glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], glycoprotein non-metastatic melanoma protein B [GPNMB]), which reflect the downstream neuroimmune response to sphingolipid accumulation. The third tier comprises markers of neuroaxonal injury (neurofilament light chain [NfL]), which index irreversible neuronal damage as the terminal consequence of uncontrolled CNS disease. Together, these tiers map distinct but mechanistically interconnected stages of disease progression, from lysosomal dysfunction through glial activation to neuroaxonal loss, enabling stage-specific interpretation of biomarker signals that single-analyte approaches cannot provide. We further examine how S1P-mediated inside-out signaling links intracellular lipid dysregulation to extracellular neuroimmune and neurovascular responses and how the blood–brain barrier shapes compartment-dependent biomarker behavior across cerebrospinal fluid and blood. By grounding biomarker selection in this mechanistic cascade, the framework provides explicit criteria for pairing analytes across tiers, interpreting discordance between peripheral and CNS compartments, and designing multi-modal endpoints for clinical trials of CNS-penetrant therapies. Despite these advances, significant challenges remain, including limited longitudinal datasets, variability in assay methodologies, and incomplete validation of biomarkers as surrogates of CNS disease progression. Addressing these gaps will require harmonized, multi-modal approaches integrating biochemical, functional, and imaging measures. By positioning neuronopathic Gaucher disease as a model of sphingolipid-driven neurodegeneration, this review highlights opportunities for biomarker-guided therapeutic development relevant to Gaucher disease and the broader spectrum of sphingolipid-associated neurological disorders. Full article

Neuroscience is a rapidly advancing field; however, a comprehensive understanding of brain function at the molecular, cellular, and systems levels remains incomplete. Neurological and psychiatric disorders represent a major global health burden, highlighting the need for improved diagnostic and therapeutic strategies. Cerebrospinal fluid (CSF) is one of the most informative biofluids for investigating central nervous system (CNS) pathology due to its close biochemical relationship with brain tissue. Recent advances in neurometabolomics, defined as the comprehensive analysis of small-molecule metabolites in CSF, have been driven by the development of highly sensitive and informative mass spectrometry-based techniques. These approaches enable the identification of disease-associated metabolic signatures. This review summarizes current chromatography–mass spectrometry-based methods used in both untargeted and targeted CSF metabolomics, with particular emphasis on their analytical performance, reproducibility, and limitations. Special attention is given to method standardization and validation, as well as to the identification of reliable metabolic biomarkers for the diagnosis and monitoring of neurological disorders, including neurodegenerative, psychiatric, oncological, and neuroinflammatory diseases. Full article

Dementia, including Alzheimer’s disease (AD), represents one of the most pressing public health challenges of the 21st century, affecting more than 55 million individuals worldwide, with projections reaching 139 million by 2050. Current pharmacological treatments offer limited efficacy and significant side effects, driving intense interest in plant-derived natural products as both preventive and therapeutic agents. This review synthesizes preclinical and clinical evidence for key phytochemical classes, including polyphenols, phenolic acids, flavonoids, terpenoids, and alkaloids, in the context of dementia and age-related cognitive decline. Molecular mechanisms are examined in detail, including effects on antioxidant defense and redox homeostasis, suppression of neuroinflammation, and enhancement of synaptic plasticity and neurotransmission. Despite promising preclinical and epidemiological evidence, most clinical trials remain limited in scale and duration and provide mixed results on the efficacy of using phytochemicals for cognitive health. Among the compounds with the most consistent clinical support are the ginkgo diterpene extract EGb 761, saffron carotenoids, curcumin, and rosmarinic acid. A dedicated section addresses the emerging evidence for aromatherapy as a non-pharmacological intervention for behavioral and cognitive symptoms of dementia. Future directions include strategies to improve bioavailability of phytochemicals, the utilization of aromatherapy together with oral supplements, and the need for larger randomized controlled trials using well-characterized and reproducibly manufactured formulations and purified active compounds. Priority areas for future investigation include resolving pharmacokinetic barriers to central nervous system (CNS) delivery, standardizing herbal product composition, and conducting adequately designed clinical trials in well-defined patient populations. Full article

Major depressive disorder (MDD) is a mental illness with high mortality, suicide, and relapse rates that could become the leading cause of health problems worldwide by 2030. The microbiota–gut–brain axis involves bidirectional communication between the human gut microbiota and the central nervous system (CNS). The gut microbiome is a complex ecosystem of approximately 100 trillion microorganisms, including viruses, bacteria, and fungi. The gut microbiota has recently been recognized for its impact on various diseases and health concerns. Several factors influence the composition and structure of gut microbes, ultimately affecting human physiology, with the nervous system being particularly vulnerable. The gut–brain–microbiota axis influences several important brain functions through numerous pathways, including vagus nerve signaling, gut microbial synthesis of metabolites, and immune-related chemicals. These factors can influence neurotransmitter activity, neuroinflammation, behavior, and mental health. Despite increased interest, the possibility of modifying the gut microbiota as a therapeutic approach remains unclear. Although numerous studies suggest that microbiota play an important role in many illnesses, the precise mechanisms are yet to be elucidated, and there are currently no evidence-based, microbiota-focused treatments for these illnesses. Recent research indicates that gut dysbiosis (GD) causes increased intestinal permeability (leaky gut), initiates systemic inflammation, and contaminates the blood. Opportunistic microbial metabolites cross the blood–brain barrier, triggering a neuroinflammatory cascade and apoptotic pathways while affecting neurogenesis and neurotransmitters, ultimately resulting in the development of MDD and anxiety. This review examined the factors influencing normal gut microbiota and GD-mediated MDD, as well as possible therapeutic options. The study outlines its objectives and methodological approaches, including the screening and filtering of research on GD-induced depression. Furthermore, it explored the daily use of dietary supplements, revealing new paths for clinical and preclinical research. Full article

Background: The blood–brain barrier (BBB) separates the circulation from the central nervous system (CNS) and serves to maintain brain homeostasis. The BBB comprises highly specialized brain endothelial cells (BECs) with unique properties that allow the BBB to maintain strict regulation of molecules entering and exiting the CNS. These characteristics include tight junctions, low endocytosis rates, and efflux and nutrient transporters. Breast cancer resistance protein (BCRP) is an efflux transporter found at the BBB that plays a key role in protecting the CNS. Together with other efflux transporters, BCRP contributes to multidrug-resistant cancers and difficulty delivering drugs and therapeutics to the brain and other organs. Methods: Using the hCMEC/D3 line, we utilized BCRP substrate rosuvastatin to effectively select for cells expressing high amounts of BCRP, thus generating hCMEC/D3-BCRP. To assess protein abundance, we utilized flow cytometry and confirmed expression via qPCR. To investigate BCRP efflux function in evolved hCMEC/D3-BCRP, we performed substrate accumulation assays with BCRP and P-gp substrates. Results: We found hCMEC/D3-BCRP had increased BCRP abundance and expression relative to parent hCMEC/D3. We also observed an increase in BCRP function via substrate accumulation of two BCRP substrates compared to parent hCMEC/D3. Conclusions: BCRP serves a protective role within the BBB and is a major hurdle in drug delivery. We generated a BCRP overexpression BEC cell line (hCMEC/D3-BCRP) under the influence of endogenous promoters. This cell line can be used to further investigate the role of BCRP in BECs and utilized in efflux transport studies. Full article

Impairment in blood supply to the brain deprives its cells of the much-needed nutrients and molecules such as oxygen and glucose necessary for its development, growth and survival. This will set up a host of pathological processes such as impaired homeostasis, energy failure, excitotoxicity, oxidative stress, impaired protein synthesis, inflammation, cytokine-mediated toxicity and impairment of blood–brain barrier. These pathological processes will result in the damage or death of the cells depending on the extent of the deprivation. Similarly, they will impair synthesis of acetylcholine (Ach) and norepinephrine (NE), which are important neurotransmitters in the cholinergic and adrenergic systems responsible for cellular communication and functions. Thus, interventions to help arrest and/or modulate the initial and subsequent pathological states and help recover the functions of the brain are needed. One of such interventions is vagus nerve stimulation, which helps activate the cholinergic and the adrenergic systems via projections of the afferent fibers of the vagus nerve to the nucleus of the solitary tract (NTS). Activation of the cholinergic and the adrenergic systems results in reduction in pro-inflammatory factors such as tumor necrosis α, increase in pro-angiogenic factors and increase in firing of adrenergic neurons in the central nervous system (CNS). Full article

Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia–reperfusion (RIR) injury, and Alzheimer’s disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood–retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β–driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders. Full article

Background: Central nervous system (CNS) involvement in multiple myeloma (MM) represents an extramedullary manifestation of the disease, which is often really challenging for clinicians, as the neurological symptoms could easily overlap with those related to hypercalcemia, uremia, high viscosity of the blood, or treatment-related neuropathy. Objectives: this retrospective study was conducted at Fundeni Clinical Institute in Bucharest, aiming to identify and systematically analyze a series of clinical cases diagnosed with extramedullary disease. Methods: We have identified 6 out of 583 patients with CNS involvement in our centre between 2019 and 2025. The diagnosis of meningeal myelomatosis was established through cerebrospinal fluid analysis, whereas CNS plasmacytomas were confirmed by CT-guided biopsy followed by immunohistochemistry evaluation. Results: All cases of CNS involvement occurred at relapse, with intervals from initial MM diagnosis to CNS involvement ranging from 9 months to 10 years. CNS-MM was linked to particular features, such as high-risk cytogenetics (four out of six patients), elevated lactate dehydrogenase, and the presence of extramedullary disease, highlighting its association with aggressive disease behaviour. Discussions: Although CNS-MM is correlated with poor prognosis, prolonged survival in one of our patients resulted from multimodal treatment, which included craniospinal radiotherapy, DPd systemic treatment, and intrathecal therapy (over 39 months). This aggressive approach effectively controlled both systemic disease and high-risk CNS involvement. Immunoglobulin isotype switching is a rare form of clonal evolution in MM, illustrated by the same patient whose disease evolved from IgA kappa at diagnosis to IgA lambda at CNS relapse, showing clonal heterogeneity and providing clinical evidence of clonal evolution. Conclusions: CNS involvement in MM usually occurs in a relapsed/refractory setting in patients with advanced, high-risk disease, and it is usually associated with extramedullary disease. Despite using multimodal therapies, outcomes remain poor, highlighting the need for novel and tailored agents. Full article

Background: The prognostic significance of histological transformation (HT) in treatment-naive diffuse large B-cell lymphoma (DLBCL) remains controversial. This study aimed to evaluate the clinical outcomes and failure patterns of treatment-naive transformed DLBCL (trDLBCL) compared with de novo DLBCL using a large-scale cohort. Methods: We retrospectively analyzed 1735 consecutively enrolled treatment-naive DLBCL patients (118 trDLBCL and 1617 de novo). Propensity score matching (PSM) was performed to balance baseline characteristics. Survival outcomes were assessed using Kaplan–Meier and Cox proportional hazards models. Subgroups were defined by pathology (t-FL vs. t-MZL) and pattern: concurrent (synchronous indolent lymphoma and DLBCL components at diagnosis) vs. pure transformation (DLBCL occurring as the sole histology in patients with a prior history of untreated indolent lymphoma). Results: In the overall cohort, trDLBCL was associated with significantly inferior progression-free survival (PFS) compared with de novo disease and remained an independent adverse prognostic factor in multivariable analysis (HR 1.754, p < 0.001). These findings were confirmed in a 1:1 propensity score-matched cohort (108 pairs), where trDLBCL continued to show worse PFS (p < 0.01), while overall survival (OS) was comparable (p = 0.99). Within trDLBCL patients, the underlying indolent subtype (t-FL vs. t-MZL) did not significantly affect survival (PFS p = 0.17, OS p = 0.35), whereas “pure transformation” was associated with markedly inferior PFS (p = 0.005) and OS (HR 2.56, p = 0.02) compared with concurrent transformation. Failure pattern analysis revealed a higher risk of early progression in trDLBCL (POD24: 30.56% vs. 18.52%; OR 1.94, 95% CI: 1.05–3.56), whereas central nervous system (CNS) involvement was low and comparable between groups (2.78% vs. 0.93%, p = 0.62). Conclusions: Treatment-naive trDLBCL is associated with inferior PFS driven by early progression, whereas OS is comparable due to effective salvage therapies. Pure transformation appeared to define a higher-risk subgroup with inferior disease control, supporting the need for future prospective studies to evaluate risk-adapted frontline, consolidation, or maintenance strategies. Full article

Background/Objectives: The blood–brain barrier (BBB) presents a major challenge for delivering therapeutics to the central nervous system (CNS) due to its highly selective permeability. Human brain microvascular endothelial cells (hBMECs), the principal cellular component of the BBB, tightly regulate molecular transport and restrict the entry of many CNS-targeted therapies. Lipid-based nanoparticles have emerged as promising carriers for BBB transport because of their biocompatibility, tunable surface properties, and cargo encapsulation capabilities. One strategy to enhance nanoparticle transport involves surface functionalization with ligands that exploit endogenous transcytosis pathways. Mannose-6-phosphate (M6P), a glycan implicated in the brain entry of certain proteins and viruses, represents a potential targeting ligand for this purpose. Methods: In this study, we established a physiologically relevant in vitro BBB model using human-induced pluripotent stem cell-derived brain microvascular endothelial cells (hiPSC-BMECs) to evaluate M6P-functionalized liposomes for BBB transport. Fluorophore-labeled liposomes were used to monitor nanoparticle uptake and transcytosis. Results: M6P-functionalized liposomes exhibited significantly enhanced uptake in hiPSC-BMECs compared with non-functionalized control liposomes. Pharmacological inhibition studies supported the involvement of a clathrin-sensitive endocytic pathway. Transcytosis assays demonstrated enhanced BBB crossing of M6P-functionalized liposomes, with transport increasing according to ligand density and reaching approximately 55% of the transport observed for transferrin under the same experimental conditions. Following transcytosis, intact M6P-functionalized liposomes showed significantly higher uptake by downstream hiPSC-derived neurons and astrocytoma cells compared with control formulations. Conclusions: Together, these findings support M6P-functionalization as a promising strategy to enhance liposome uptake and transcytosis across a human-relevant in vitro BBB model. This work provides a proof-of-concept framework for the development and optimization of glycan-functionalized nanocarriers for CNS-directed delivery. Full article

Control of resistant mosquito populations may be approached by the development of novel synergists to improve the performance of already commercialized compounds. Extracts of black pepper (Piper nigrum), Cha Plu (Piper sarmentosum), and Sichuan pepper (Zanthoxylum spp.) synergized natural pyrethrins applied topically to Aedes aegypti females. Both black pepper and Sichuan pepper extracts synergized natural pyrethrins over 13-fold. Synergism was also observed directly on the mosquito larval central nervous system (CNS), suggesting this effect is an important contributing factor distinct from that of reduced metabolism. Piperine, from black pepper, and α-hydroxysanshool (α-HS) from Sichuan pepper, synergized natural pyrethrins on susceptible CNS, but only piperine was capable of synergizing natural pyrethrins on the CNS of a pyrethroid-resistant strain of Ae. aegypti, indicating that these molecules may possess slightly different mechanisms of action or binding sensitivities. These results demonstrate that pepper alkamides are capable of enhancing select insecticidal chemistries via target-site synergism, a novel mechanism of synergism that might be important for enhancing future insecticidal formulations. Full article

HIV-associated neurocognitive disorders (HAND) arise from HIV infection of the central nervous system, resulting in chronic neuroinflammation and progressive neuronal damage that impair cognitive, motor, and behavioral functions. Clinically, HAND encompasses a spectrum of neurological impairments ranging from asymptomatic neurocognitive impairment to severe HIV-associated dementia. Despite the widespread use of combination antiretroviral therapy (cART) and significant improvements in the life expectancy of people living with HIV, HAND remains prevalent and continues to pose a major clinical challenge. One of the primary limitations of cART is the limited penetration of many antiretroviral drugs across the blood–brain barrier (BBB), thereby allowing the persistence of viral reservoirs within the CNS and contributing to sustained neuroinflammation and neuronal damage. To address these challenges, novel nanotherapeutic strategies have been developed to enhance the delivery of antiretroviral agents to the brain. These approaches include targeted delivery systems and the co-delivery of therapeutics across the BBB through mechanisms such as receptor-mediated transcytosis and other transport pathways. In this review, we discuss the pathophysiological challenges associated with HAND and recent advances in nanotherapeutic approaches designed to improve treatment efficacy. We also discuss the current state of the art in vitro and in vivo models used to test the efficacy of these advanced therapeutics. Finally, we outline the remaining challenges and future prospects for the development of nanotherapeutics to improve the treatment of HAND. Full article

Prenatal alcohol exposure (PAE) can cause fetal alcohol spectrum disorder (FASD). The FASD continuum encompasses facial dysmorphism, growth failure, and central nervous system (CNS) abnormalities/dysfunctions. Because some of these features may not be apparent in newborns, detecting PAE in the neonatal period is challenging, while early diagnosis may improve neurodevelopmental outcomes. Maternal self-reported alcohol consumption is limited by recall bias and denial, leading to misdiagnosis. Currently, there is a lack of universally implemented and standardized tools for identifying PAE/FASD in children across clinical settings. We aimed to review the existing literature on PAE assessment methods. Analysis of alcohol metabolites in neonatal meconium is the most widely studied and appears to be feasible for routine use, but it has some limitations. Recent advances in understanding the effects of alcohol on neurotransmitters, growth factors, and gene activity have contributed to the development of novel diagnostic strategies and have brought us closer to effective PAE detection. Some laboratory assays appear to be feasible for implementation in routine clinical practice, i.e., testing for pro- and anti-inflammatory cytokines, including interleukins (IL): IL-6, IL-1β, IL-10, and tumor necrosis factor-alpha (TNF-α) and Insulin-like Growth Factor 1(IGF1). These molecular approaches hold promise but require replication and validation before becoming the standard in clinical practice. Further research on biomarkers and other screening tools should continue to determine their feasibility and availability. Full article

Background: Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) central nervous system (CNS) infections represent a major therapeutic challenge in neurosurgical patients. Intraventricular or intrathecal polymyxin B sulfate (PMB) is commonly used as salvage therapy but is limited by substantial neurotoxicity. Ceftazidime–avibactam (CZA) exhibits potent in vitro activity against KPC-Kp; however, prospective clinical and pharmacokinetic evidence supporting its use in CNS infections remains limited. Methods: In this prospective, single-centre observational study, adult neurosurgical patients with culture-confirmed KPC-Kp CNS infections admitted to the neurointensive care unit of Huashan Hospital were enrolled. Patients received either intravenous CZA (CZA group, n = 15) or intrathecal/intraventricular PMB-based therapy (PMB group, n = 10). Primary outcomes included clinical cure, microbiological eradication, 28-day mortality, and safety. Therapeutic drug monitoring was performed to determine steady-state plasma and cerebrospinal fluid (CSF) concentrations of ceftazidime, avibactam, and polymyxin B, enabling assessment of CSF penetration and exposure–toxicity relationships. Results: Overall clinical cure and microbiological eradication rates were 68.0% and 84.0%, respectively, with a 28-day mortality of 20.0%. Compared with PMB, CZA was associated with a significantly higher clinical cure rate (86.7% vs. 40.0%, p = 0.024) and a numerically higher eradication rate (93.3% vs. 70.0%). No neurological adverse events occurred in the CZA group, whereas neurological toxicity was observed in 60.0% of PMB-treated patients (p < 0.001). Functional outcomes favoured the CZA group, with lower modified Rankin Scale scores at discharge and at 6 months. Pharmacokinetic analyses demonstrated that steady-state CSF concentrations of ceftazidime and avibactam exceeded commonly accepted pharmacodynamic targets, while markedly elevated PMB CSF concentrations were observed in patients with neurological toxicity. Conclusions: While intravenous CZA showed potentially favourable efficacy and safety compared with local PMB in this cohort, these preliminary findings should be interpreted as hypothesis-generating given the small sample size and non-randomised design. These results provide a rationale for further validation in larger multicentre, randomised controlled trials. Full article