Search Results (33,064)

Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer’s disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine’s modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine’s effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2–mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials. Full article

Background/Objectives: Autoimmune and immune-mediated adverse events coded in reports listing COVID-19 vaccines as suspect products are rare, heterogeneous, and difficult to evaluate in spontaneous reporting systems. We characterized autoimmune reporting signals using strict case definitions and an active-comparator disproportionality design. Methods: FAERS reports from 2021Q1 to 2023Q4 were deduplicated and harmonized by vaccine product, platform, sex, age group, and MedDRA Preferred Term (PT). COVID-19 vaccine reports recorded as primary or secondary suspect products were compared with traditional non-COVID vaccine reports. Strict autoimmune events were grouped into neurological, endocrine, rheumatological, hematological, dermatological, and cardiac categories. Reporting odds ratios (RORs), proportional reporting ratios (PRRs), PT-level rankings, masking audits, and sensitivity analyses were evaluated. Results: The primary analysis included 4191 COVID-19 vaccine reports, 2817 comparator reports, and 311 strict-autoimmune reports contributing 316 report-category observations. Positive category-level signals were identified for dermatological (ROR 10.49; 95% CI: 2.51–43.86), endocrine (ROR 5.39; 95% CI: 1.24–23.48), hematological (ROR 4.68; 95% CI: 2.32–9.44), and neurological events (ROR 1.63; 95% CI: 1.16–2.29). Rheumatological reporting was lower, strict cardiac events were absent, and hematological signals were most consistent across sensitivity analyses. Among five adjusted-positive finite PT signals, immune thrombocytopenia was more stable, multiple sclerosis intermediate, and acquired hemophilia, myasthenia gravis, and optic neuritis sparse/imprecise. A post hoc audit identified four potential clusters among 20 acquired-hemophilia reports; cluster collapse reduced the ROR to 2.70 (95% CI 0.30–24.18; p = 0.654). Conclusions: These findings are hypothesis-generating and do not establish incidence, absolute risk, or causality. Full article

Although flaviviruses, including DENV, ZIKV and JEV, remain important causes of febrile, congenital, and neurological diseases, treatment options remain largely supportive, with limited availability of virus-specific antiviral therapies. Marine organisms and marine-derived microorganisms produce chemically distinct antiviral materials, including sulfated polysaccharides, terpenoids, alkaloids, peptides, cyclodepsipeptides, and polyketides. However, their activities range from preliminary extract-level inhibition to direct biochemical target validation, making mechanistic comparison difficult. This review critically evaluates marine-derived anti-flaviviral agents using two complementary dimensions, the infection stage implicated by experimental assays and the strength of evidence supporting that assignment. DENV evidence is dominated by sulfated algal macromolecules that interfere with adsorption or internalization, whereas ZIKV studies encompass lipophilic algal metabolites, fungal alkaloids, cyclodepsipeptides, and a few target-oriented candidates. Across the field, most reports remain stage-associated rather than target-validated. Cross-study potency comparisons are constrained by differences in virus strains, cell models, assay formats, and treatment schedules. JEV-specific evidence is particularly sparse. Based on the DENV and ZIKV evidence map, we propose concise priorities for JEV-oriented discovery: early compound-level dereplication, parallel cytotoxicity testing, orthogonal confirmation of productive infection, stage-resolved assays, and biochemical or genetic validation of conserved flaviviral targets. This evidence-based framework can help distinguish promising chemical candidate scaffolds from preliminary antiviral signals and guide mechanism-informed development of marine-derived natural products against flaviviruses. Full article

Zinc is an essential micronutrient involved in many physiological processes in the human body, including immune system regulation, cellular survival, neurologic function, and erythropoiesis. Zinc deficiency can result in a wide range of clinical manifestations, including impaired immune function, dermatologic findings, and decreased growth. Anemia has been reported as a hematologic manifestation of zinc deficiency and may be underrecognized in clinical practice. This narrative review examines the pathophysiology of zinc deficiency-associated anemia, highlighting zinc’s role in erythropoiesis, heme biosynthesis, and red blood cell stability. It also outlines populations at increased risk for zinc deficiency, including patients with chronic kidney disease, sickle cell disease, malabsorptive disorders, chronic proton pump inhibitor use, and older adults. Emerging evidence suggests that zinc deficiency-associated anemia may represent a potentially modifiable contributor to anemia in selected at-risk populations, although the strength of evidence varies across clinical settings and study designs. Assessment of zinc status may be considered in patients with unexplained or refractory anemia and additional risk factors for deficiency. Further prospective studies are needed to clarify the role of zinc deficiency in anemia and define appropriate screening, supplementation, and monitoring strategies. Full article

Introduction. Statins’ established cardiovascular benefits are often undermined by hepatic adverse effects in obese diabetic patients with suspected non-alcoholic fatty liver disease. We evaluated whether cannabis plant treatment is a safe and effective alternative to atorvastatin in a metabolically challenged rodent model. Methods. Fourteen obese and diabetic Wistar rats received either atorvastatin for 30 days or cannabis plant extract for 30 days. Main outcome: lipid profile; secondary outcomes: renal function, glycemia and endothelial health assessed through atherogenic indices. Safety was assessed using plasma liver enzyme concentrations. Results. Baseline biochemical profiles were similar between groups. Atorvastatin increased HDL-Col more than cannabis plant (MD: 44.3; IQR [33, 57.5] mg/dL, Hedges’ g 2.713 vs. MD: 14.3; IQR [14, 17] mg/dL, Hedges’ g 5.049), and cannabis plant did not change LDL-Col. Atherogenic index of plasma and Castelli Risk Index 1 improved with both interventions, more so with atorvastatin. Liver enzymes increased with atorvastatin (ALAT, MD: 15.9; IQR [12.5, 19.5] U/L; ASAT, MD: 33; IQR [26.5, 38] U/L) but remained virtually unchanged with cannabis. Serum creatinine increased with cannabis plant, with moderate effect size (Hedges’ g 0.798), but negligibly with statins (Hedges’ g 0.122). Conclusions. Cannabis plant extract modestly improved the lipid profile and atherogenic indices, with differences often not exceeding the change in control groups. Despite apparent liver safety, the undesired renal and neurological consequences limit applicability in humans. Further studies should prioritize addiction development and renal function. Full article

Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease increasingly recognized for extra-motor manifestations, including cognitive dysfunction involving frontal cortical systems. Conventional clinical assessments are primarily behavioral and may not capture subtle alterations in the neural systems that support cognitive performance. This pilot study examined whether wearable functional near-infrared spectroscopy (fNIRS) could detect task-evoked prefrontal hemodynamic differences during the King-Devick Task (KDT), a rapid oculomotor number-naming task that engages visual scanning, attention, processing speed, and verbal response production. Methods: Sixteen participants, including seven individuals with ALS and nine age-matched healthy controls (HC), completed four progressively difficult KDT conditions while prefrontal cortical activity was recorded. Results: As task difficulty increased, response times became slower across participants, while accuracy remained preserved and behavioral performance did not differ significantly between groups. Prefrontal oxygenated hemoglobin (HbO) responses increased with task difficulty across all prefrontal optodes, supporting task-evoked cortical engagement. In contrast, deoxygenated hemoglobin (HbR) responses showed a group-specific pattern in the left dorsolateral prefrontal cortex: individuals with ALS demonstrated progressively increasing HbR responses across difficulty conditions, whereas HC showed relatively stable responses, with group differences emerging at higher difficulty levels. Conclusions: These findings suggest a dissociation between preserved behavioral performance and altered prefrontal hemodynamic regulation in ALS. The observed HbR pattern may reflect differences in cortical recruitment, neurovascular coupling, oxygen extraction, vascular responsiveness, or the efficiency of cortical resource allocation during increasing cognitive-motor demands. Wearable fNIRS may therefore complement behavioral assessments by revealing task-evoked neural alterations that are not evident from performance measures alone. Full article

Background: Juvenile-onset Huntington disease (JoHD) is a rare form of Huntington disease characterized by symptom onset at or before 20 years of age. Early manifestations are often non-choreic and may be attributed to developmental, psychiatric, movement, metabolic, or epileptic disorders. We described three molecularly confirmed cases and examined early manifestations, diagnostic pathways, and epilepsy. Methods: We conducted a retrospective case series and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 systematic review of PubMed, Scopus, and Web of Science Core Collection through 5 July 2026. The strict patient-level synthesis required attributable onset at or before 20 years, patient-specific molecular confirmation of a pathogenic HTT repeat expansion, and extractable clinical data. Complementary aggregate or linked reports using closely aligned JoHD criteria were retained for context but excluded from patient-level calculations. Results: The cases included childhood-onset JoHD with drug-resistant epilepsy, adolescent-onset JoHD with progressive motor-cognitive decline and epilepsy in a known Huntington disease pedigree, and childhood-onset JoHD without available family history, in whom status epilepticus prompted renewed diagnostic evaluation. Ninety-three reports were included; of these, 81 contributed 228 unique patients and 12 provided complementary data. Early manifestations were heterogeneous and broadly consistent with previously described childhood-onset JoHD phenotypes. Diagnostic delay was extractable in 180/228 patients; among 172 with point estimates, the median was 4.0 years. Definite epilepsy was reported in 60/145 patients with ascertainable seizure status and was descriptively more frequent in childhood-onset (<10 years) than adolescent-onset (10–20 years) JoHD (49/84 [58.3%] vs. 11/57 [19.3%]). Conclusions: JoHD should be considered in children and adolescents with progressive multisystem neurological involvement, particularly when epilepsy occurs with developmental regression, gait or speech deterioration, pyramidal or extrapyramidal signs, basal-ganglia abnormalities, or a compatible family history. Full article

In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered “foreign”. For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, may render normally functional deoxyribonucleic acid (DNA) and RNA persistently available and aberrantly structured ligands for innate immunity. Z-DNA-binding protein 1 (ZBP1), recently identified as an important component of this innate immune system, recognizes both left-handed DNA (Z-DNA) and left-handed RNA (Z-RNA) using its tandem Z-alpha (Zα) domains and couples recognition of these conformational states to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-, receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-, and mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent inflammatory and cell-death pathways. More recent studies have also shown that ZBP1 plays a role in recognizing damaged self-nucleic acids associated with tauopathies, Alzheimer’s disease (AD), traumatic brain injury (TBI), and amyloid-associated neuroinflammation. The nucleic-acid forms associated with these conditions include transposable-element activation, extended repeat-containing transcripts, RNA–RNA duplexes or RNA:DNA hybrids, oxidized mitochondrial DNA (mtDNA), and intercellularly transferred nucleic acids, all of which may exhibit substrate structures compatible with Z-form formation. Signaling by ZBP1 does not occur simply based upon nucleic-acid abundance; rather, signaling occurs after prolonged exposure to a nucleic acid when it persists in a structurally competent state, sufficient receptors are present to bind its exposed regions, the receptor proteoforms are competent to participate in signaling, receptor-interacting protein homotypic interaction motif (RHIM)-dependent assembly occurs, and the appropriate adaptor molecules are present. Furthermore, the identity of the cell type expressing ZBP1 determines whether the response produces RIPK3–MLKL-dependent neuronal injury, microglia-mediated inflammation, apoptosis, or mixed cell death. Finally, competition with adenosine deaminase acting on RNA 1 (ADAR1), melanoma differentiation-associated protein 5 (MDA5), double-stranded RNA-dependent protein kinase (PKR), the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway, and other nucleic-acid-sensing proteins divides the available pool of endogenous nucleic acids among the outcomes of immune tolerance, type I interferon (IFN-I) signaling, translational inhibition, neuroinflammation, and necroptosis. Full article

Background/Objectives: Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, and elucidating the molecular determinants of its malignant progression is essential for improving patient outcomes. NTAN1 encodes N-terminal asparagine amidase 1, a component of the N-degron pathway involved in selective protein turnover; however, its role in GBM remains unclear. This study aimed to investigate the clinical significance and biological function of NTAN1 in GBM. Methods: Integrated analyses of The Cancer Genome Atlas (TCGA) transcriptomic and clinical data were performed, together with tissue microarray validation, to assess the association between NTAN1 expression and prognosis in GBM. Immunohistochemical analysis of GBM specimens was conducted to evaluate NTAN1 protein expression. Functional studies, including NTAN1 knockdown and overexpression experiments, were used to examine its effects on GBM cell proliferation, clonogenic growth, migration, and invasion. An orthotopic GBM model was established to assess the effect of NTAN1 inhibition on tumor growth. Transcriptomic analysis was further performed to explore the molecular changes associated with NTAN1 knockdown. Results: Elevated NTAN1 expression was associated with poor survival in GBM. Immunohistochemical analysis further demonstrated that high NTAN1 protein expression predicted unfavorable prognosis. Functional studies showed that NTAN1 knockdown inhibited GBM cell proliferation, clonogenic growth, migration, and invasion, whereas NTAN1 overexpression promoted these malignant phenotypes. In an orthotopic GBM model, NTAN1 inhibition significantly reduced tumor volume. Transcriptomic analysis showed that NTAN1 knockdown was associated with reduced expression of invasion-related genes, including SPINK1, MMP1, and LIF, and with enrichment changes in inflammation-associated pathways, suggesting that NTAN1 may promote GBM progression through pro-invasive molecular programs. Conclusions: Collectively, these findings identify NTAN1 as a potential promoter of GBM malignant progression and a prognostic biomarker of poor outcome. Full article

Background/Objectives: The apelin/APJ system has demonstrated neuroprotective effects in experimental studies by regulating key pathogenic mechanisms of ischemic stroke, including oxidative stress, apoptosis, cerebral edema, and inflammation. This study aimed to investigate the role of serum apelin levels measured within the first 24 h in predicting 28-day and long-term mortality in patients with ischemic cerebrovascular disease. Methods: This prospective cohort study included 44 patients hospitalized with a diagnosis of acute ischemic stroke due to large artery atherosclerosis. Serum apelin levels were measured using the ELISA method from blood samples obtained within the first 24 h after symptom onset. Patients were prospectively followed for 28-day and long-term mortality. Results: During the follow-up period, 32.6% of the patients died. The median serum apelin level was significantly higher in the deceased group compared to the survivors [105.0 pg/mL vs. 55.8 pg/mL]. In ROC analysis, the area under the curve (AUC) for apelin in predicting mortality was 0.727 (95% CI: 0.550–0.903). The optimal cut-off value was determined as ≥70.47 pg/mL (sensitivity: 85.71%, specificity: 62.07%). In Kaplan–Meier analysis, the 28-day mortality rate was 52.2% in the high-apelin group (≥70.47 pg/mL), whereas it was 10.0% in the low-apelin group (<70.47 pg/mL) (p = 0.004). In multivariate Cox regression analysis, an apelin level <70.47 pg/mL was identified as an independent prognostic factor (HR: 0.16; 95% CI: 0.03–0.94). The cumulative survival rates at days 28, 56, and 180 were 56.1%, 46.7%, and 11.7%, respectively, in the high-apelin group, while these rates were 100%, 100%, and 81.8%, respectively, in the low-apelin group. The mean NIHSS score was significantly higher in the high-apelin group, and a strong, positive, and highly significant correlation was found between serum apelin level and NIHSS score (r = 0.703, p < 0.001). Conclusions: High serum apelin levels measured within the first 24 h in acute ischemic stroke are associated with increased 28-day and long-term mortality. The association of high endogenous apelin levels with poor prognosis in the clinical setting suggests that apelin is mobilized as a stress response during ischemia, and that elevated circulating levels may actually reflect the severity of the ischemic insult. Full article

Neurologic manifestations of long COVID, also called neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC: NP) include persistent alteration of cognitive functions. We investigated whether these could be driven by immune perturbations. We combined flow cytometry (FC), sleep profiling, and single-cell RNA sequencing of peripheral blood immune cells from older adult (>55 years) individuals with and without NP to evaluate relationships with objective cognitive performance. NP participants showed reduced numbers of blood monocytes with increased mitochondrial superoxide, indicating an altered monocyte mitochondrial redox state. Higher peripheral capillary oxygen saturation (SpO₂) was associated with better processing speed in NP participants. Monocyte transcriptional analyses identified mitochondrial adenosine triphosphate (ATP) synthase/Complex V (Complex V) pathway associated with cognitive performance in people without NP; this coupling was abrogated in NP patients, in whom cognitive performance instead showed an opposite relationship with Complex V. Shared leading-edge genes defined a 13-gene monocyte anchor representing this cognition-associated NP phenotype. Higher anchor scores were associated with coordinated oxidative phosphorylation and cytotoxic programs across CD3⁺ T-cell subsets in individuals without NP, but not in NP participants. T-cell receptor stratified analyses showed that this altered relationship occurred in both expanded and unexpanded T-cell populations. FC correlations also supported reduced monocyte-to-lymphocyte mitochondrial coordination in NP. These exploratory findings identify a sleep and cognition-linked monocyte mitochondrial phenotype characterized by altered myeloid–lymphoid immune coordination in NP. Full article

In 2024, we published a paper which described the identification of the fusion DNAJB1::PRKACA kinase in young patients with aggressive hepatoblastoma (HBL) and with biliary atresia (BA). In our study, we used sensitive molecular and cellular techniques and found that about 70% of our analyzed HBL samples showed varying levels of DNAJB1::PRKACA expression. In total, 15–20% of those fusion-positive HBL samples had DNAJB1::PRKACA levels comparable to those observed in FLC, whereas the remaining samples exhibited lower kinase levels. Palaz et al. analyzed five HBL datasets and one BA RNA-Seq dataset with Arriba and found no DNAJB1::PRKACA fusion transcript. Based on their analysis, the authors concluded that DNAJB1::PRKACA is not expressed in HBL patients. They further stated that the identification of DNAJB1::PRKACA fusion in either HBL or BA requires orthogonal molecular validation to confirm the fusion event at the DNA or RNA level. Therefore, we conducted Sanger sequencing on RT-PCR products from several fusion-positive HBL samples and three BA samples. Both HBL and BA cases showed the presence of the DNAJB1::PRKACA fusion transcript, identical to that detected in FLC. These results verify that DNAJB1::PRKACA is present in some HBL and BA patients, as has already been demonstrated using sensitive molecular and cellular techniques. Arriba analysis of current RNA-Seq data may not be sensitive enough for detecting low DNAJB1::PRKACA levels in HBL cases, especially if they are mixed with fusion-negative HBL specimens. Thus, we found that several independent methods, such as immunoanalysis and RT-PCR sequencing, effectively detect DNAJB1::PRKACA in HBL and BA cases. Our study also highlights that detecting low levels of DNAJB1::PRKACA requires individual analysis of HBL and BA patients within the same study, using FLC as the control. Full article

Background: Given the rising global prevalence of dementia and its complex etiology, involving genetic and environmental risk factors, the aim of the present exploratory study was to investigate how offspring of individuals with dementia perceive genetic risk and the role of diet in dementia prevention. Methods: A mixed-methods study was conducted in Greece. Overall, 118 offspring completed an online questionnaire assessing demographics, risk perceptions, and dietary beliefs and practices in dementia risk reduction. Additionally, 22 semi-structured interviews explored dietary beliefs, practices, and influencing factors using framework analysis. Results: Most participants (76.3%) recognized diet’s role in dementia prevention, while 52.5% perceived offspring as having increased genetic risk; 40.7% reported making dietary changes to reduce disease risk. Healthcare professional consultation was the factor most strongly associated with dietary modification (OR = 26.61, 95% CI 7.47–94.76, p < 0.001). Qualitative findings showed that, while dementia was viewed as severe, personal susceptibility was often perceived as uncertain or distant. Key barriers, facilitators, and the role of self-efficacy in adopting healthier dietary practices were also explored. Conclusions: Our findings identify personalized dietary counselling and risk communication as priorities for evaluation in future intervention studies, aimed at supporting the implementation of dietary modifications and reducing the gap between knowledge and behavior in dementia risk reduction. Full article

Raccoon dog and fox amdoparvovirus (RFAV) has been reported in raccoon dogs and foxes, but natural infection in domestic dogs has not previously been documented. During March–April 2026, samples from four affected Dobermann dogs from a kennel near Novi Sad, Serbia, were submitted for laboratory investigation. After negative testing for canine adenovirus, canine coronavirus, herpesvirus, parvovirus, distemper virus, influenza A virus, and leptospirosis, metagenomic sequencing was performed on selected tissues, followed by bioinformatic analysis and targeted RFAV PCR screening of additional outbreak-associated samples. Affected dogs had prolonged illness characterized by conjunctivitis with ocular and nasal discharge, occasional blue eye appearance, progressive weight loss, poor coat quality, jaundice and biochemical evidence of hepatic injury, and neurologic signs including paraplegia in advanced cases. Sequencing generated 434,220 reads and identified multiple RFAV hits; pooled assembly produced a 4799 bp consensus genome with approximately 97% similarity to known RFAV strains and genome organization consistent with the genus Amdoparvovirus. RFAV DNA was subsequently detected by virus-specific PCR in an epidemiologically linked dog and across diverse specimen types including blood, urine, kidney, spleen, brain, lung, testicle, ileocecal lymph node, and throat swabs, whereas clinically healthy unrelated dogs were PCR-negative. Full article