Search Results (7,691)

The discovery of ferroptosis and cuproptosis has significantly expanded the landscape of programmed cell death. Artesunate (ART), a semisynthetic derivative of artemisinin, exhibits pleiotropic pharmacological activities beyond its canonical antimalarial role, including anticancer and neuroprotective effects. However, a comprehensive review systematically integrating ART’s roles in modulating both ferroptosis and cuproptosis remains lacking. This review bridges this gap by synthesizing recent advances. The distinct core mechanisms of ferroptosis and cuproptosis are first outlined. Extensive evidence is then summarized regarding ART-induced ferroptosis in cancers, primarily through disrupting iron homeostasis (e.g., stabilizing transferrin receptor (TFRC), promoting ferritinophagy) and impairing antioxidant defenses (e.g., suppressing the System Xc⁻/ glutathione peroxidase 4 (GPX4) axis, targeting peroxiredoxins). In contrast, the anti-cuproptotic effect of ART is currently restricted to Parkinson’s disease (PD) models, mediated by the upregulation of astrocytic metallothionein 2A (MT2A) to chelate excess copper—the only validated cuproptosis-related mechanism of ART to date. The crosstalk between ferroptosis and cuproptosis at shared metabolic nodes, including glutathione depletion, mitochondrial dysfunction, and reactive oxygen species (ROS) amplification, is further delineated as a hypothesis-generating framework. This interplay suggests a theoretical potential for ART—when combined with functional nano-materials—to synchronously engage both death pathways, though direct experimental validation of such dual-pathway synergy for ART as a single agent remains lacking. Finally, translational prospects of ART in cancer therapy, neurodegenerative diseases, and hepatic fibrosis are discussed, together with current challenges and future directions. ART acts as a context-dependent modulator: pro-ferroptotic activity is evident across multiple disease models, whereas anti-cuproptotic activity is currently limited to PD and requires further validation. Systematic characterization of ART’s context-specific effects suggests a preclinical rationale for the future design of ART-based combination strategies targeting metal-dependent cell death, pending further validation. Full article

Parkinson’s disease (PD) involves not only the loss of dopaminergic neurons in the substantia nigra but also spinal cord degeneration. However, the molecular mechanisms of spinal cord degeneration remain unclear. This study investigated the spinal cord transcriptomic characteristics of MPTP-induced PD mice via transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) to identify key gene modules and potential therapeutic targets. An MPTP-induced PD mouse model was established, and spinal cord transcriptome sequencing was conducted to screen differentially expressed genes (DEGs). Functional enrichment analysis, WGCNA for phenotype-correlated modules, and protein–protein interaction analysis were subsequently conducted to identify key genes. In total, 3473 DEGs were identified (1775 upregulated, 1698 downregulated). Downregulated genes were predominantly enriched in pathways related to oxidative phosphorylation and post-transcriptional regulation, whereas upregulated genes were associated with glutamatergic synapses, axonogenesis, and negative regulation of neurogenesis. Among the five co-expression modules, the brown and yellow modules were most strongly correlated with the PD phenotype, enriched in calcium signaling, inflammation, and spliceosome pathways. Key genes like Akt1, Nlrp3, Tgfb1, Lingo1, and Olig2 were upregulated, whereas Vps35 and Omg were downregulated. This study characterizes the spinal transcriptome of PD mice, suggesting that dysregulated post-transcriptional processes, abnormal oxidative phosphorylation, glutamatergic excitotoxicity, and neuroinflammation may be potential candidate mechanisms and vital involved factors in spinal cord degeneration. These findings provide novel insights into the pathological mechanisms of spinal cord degeneration in PD and lay a foundation for targeted therapy, deserving further investigation. Full article

Dysregulation of the microbiota–gut–brain axis has been implicated in Parkinson’s disease (PD), and modulation of the intestinal microbiota may offer a complementary nutritional approach. This study evaluated the preventive attenuation of MPTP-induced PD-like abnormalities by Lactiplantibacillus plantarum SHOU LAC-1 and examined associated microbiota–gut–brain axis-related changes. Forty male C57BL/6J mice were allocated to Control, MPTP, L-DOPA, and SHOU LAC-1 groups (n = 10 per group). SHOU LAC-1 was orally administered at 1 × 10⁹ CFU per mouse per day for 42 days, with MPTP administered during the final 14 days; L-DOPA was administered during the MPTP-treatment period as a positive control. Motor performance and defecatory parameters, nigrostriatal TH and α-SYN immunoreactivity, neurotrophic-support-related gene expression, inflammatory markers, glial-cell-related gene expression, Nrf2-related antioxidant gene expression, colonic histopathology and tight-junction-related gene expression, gut microbiota composition, and serum metabolic profiles were assessed. Compared with MPTP-treated mice, SHOU LAC-1-treated mice showed better motor and defecatory performance, partial preservation of nigrostriatal TH immunoreactivity, reduced α-SYN immunoreactivity, increased neurotrophic-support-related gene expression, lower central and colonic inflammatory markers and glial-cell-related gene expression, increased Nrf2/HO-1/NQO1-related antioxidant gene expression, and comparatively better-preserved colonic morphology with higher tight-junction-related gene expression. 16S rRNA sequencing and untargeted serum metabolomics further showed that SHOU LAC-1 administration was accompanied by changes in gut microbial diversity and composition and serum metabolic profiles. Overall, under this preventive experimental design, SHOU LAC-1 administration was associated with attenuation of multiple MPTP-induced PD-like abnormalities, accompanied by changes in gut microbial and serum metabolic profiles. These preclinical findings are predominantly associative; causal relationships among microbial, metabolic, intestinal, and neurological changes remain to be established, and the translational relevance of SHOU LAC-1 requires further validation. Full article

Valerian (Valeriana officinalis L.), passionflower (Passiflora incarnata L.), and ginkgo (Ginkgo biloba L.) are among the most widely used medicinal plants in European phytotherapy, with well-documented traditional use for anxiety, insomnia, cognitive decline, attention-deficit/hyperactivity disorder (ADHD), and Parkinson’s disease. This narrative review critically analyses available clinical, pharmacological, toxicological, and regulatory data on these three species in the context of central nervous system (CNS) disorders. A comprehensive literature search was conducted in PubMed, Scopus, and the Cochrane Library; regulatory documents from the European Medicines Agency (EMA), the European Scientific Cooperative on Phytotherapy (ESCOP), and the World Health Organization (WHO) were also included. Valerian showed the most consistent clinical evidence for an improvement in sleep quality and reduction in anxiety. Passionflower demonstrated anxiolytic and mild sedative effects in several controlled trials. Ginkgo showed clinically relevant benefits in mild cognitive impairment, dementia, and vertigo. All three plants exhibited acceptable safety profiles at the recommended doses; however, significant drug interactions were identified, notably ginkgo’s inhibition of CYP2C19 and antiplatelet effects, and valerian’s potentiation of CNS depressants. Regulatory frameworks across EU member states remain inconsistent. Further high-quality randomized controlled trials with standardized extract characterization are needed. Full article

Cervical dystonia (CD) is a hyperkinetic movement disorder characterized by involuntary muscle contractions leading to abnormal postures of the head and neck. The injection of botulinum neurotoxin type A (BoNT-A) into the muscles involved is the treatment of choice for CD. BoNT-A therapy of CD requires appropriate training, which has not been standardized in Germany. To address the key challenges in BoNT-A education, an expert panel developed a simplified step-by-step treatment guideline for beginners, adapted from the established Col-Cap-Concept (“Dystonia 3×3”). Based on expert consensus, recommendations were developed for the core clinical elements of BoNT-A treatment in CD—recognition of the movement pattern, identification of target muscles, development of an injection plan, ultrasound-guided injection, and dosing, taking into account the target audience of the guideline. As such, Dystonia 3×3 provides a user-friendly beginner’s guidebook, enhancing accessibility and standardization of CD treatment training. Further research is required to evaluate its clinical efficacy and suitability for training. Full article

Gut microbial metabolism links intestinal ecology with systemic physiology and neural pathology, but its effects vary across disease stage, tissue compartment, and host background. This review uses Alzheimer’s disease (AD) as the principal model and compares selected features with Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Across the AD continuum, fermentation-related changes appear in prodromal cohorts, whereas broader alterations in amino acid products, host–microbial co-metabolites, bile acids, and lipids accompany mild cognitive impairment and dementia. These group-level patterns do not constitute a fixed patient trajectory. Microbial production, intestinal absorption, hepatic conversion, renal clearance, barrier integrity, and tissue-specific receptors jointly determine biological exposure. Experimental studies connect short-chain fatty acids and indole derivatives with epithelial and neuroimmune homeostasis, while imidazole propionate, trimethylamine N-oxide, selected kynurenine products, and remodeled bile acid pools engage vascular, inflammatory, amyloid, or tau-related pathways. Cerebral pathology can also remodel the intestinal ecosystem, creating reciprocal feedback. Apolipoprotein E4 modifies lipid handling, vascular permeability, and immune responses, helping to explain why comparable metabolic profiles may carry different consequences among individuals. Translation therefore requires more than a change in community composition. Trials must verify microbial function, metabolite target engagement, AD biomarker response, and clinical benefit in appropriately stratified participants. Shared pathways in PD and ALS provide comparison points, but disease-specific cells, proteinopathies, and treatment exposures constrain direct transfer of AD-derived targets. Full article

Gait and balance impairments in Parkinson’s disease (PD) severely compromise mobility and independence. This exploratory randomized pilot study evaluated a multimodal Adapted Physical Activity (APA) protocol, a tango-based program (Riabilitango^®, RT), and standard care regarding walking distance, static postural stability, joint range of motion, and plantar-load redistribution. Twenty-seven participants with PD (Hoehn and Yahr 1–3) were allocated to APA (n = 10), RT (n = 10), or Control (n = 7). The active groups completed 24 supervised sessions over 12 weeks. Static postural stability and treadmill-based walking distance were evaluated at baseline and post-intervention. Both active interventions showed favorable static sway profiles compared to Control, though between-group differences were non-significant. Crucially, APA demonstrated a significantly greater post-intervention improvement in walking distance than RT and Control. Exploratory analyses linked APA walking gains to adaptations in joint mobility and plantar-load redistribution. In conclusion, multimodal APA showed the clearest functional signal for improving walking distance in PD, whereas Riabilitango^® offered a complementary profile focused on sensorimotor integration and balance. These preliminary pilot findings warrant confirmation in larger prospective trials. Full article

Background/Objectives: Intranasal delivery is a promising noninvasive approach to enhance central nervous system drug delivery in Parkinson’s disease (PD), potentially bypassing the blood–brain barrier and minimizing gastrointestinal side effects. This review summarizes clinical trials and translational evidence for intranasal PD therapies by treatment options and intent, highlighting key challenges in efficacy, pharmacokinetics, and safety. Methods: We reviewed human clinical trials, preclinical and pilot studies, and pharmacokinetic investigations of intranasal therapies for PD. Comparisons to established treatments were included in context. Only PD-specific clinical studies were analyzed. Therapies were grouped by rescue, antioxidant/metabolic/hormonal, and biologic or cell-based approaches, with continuous-delivery systems reviewed separately. Results: Intranasal rescue therapies, such as apomorphine, provide rapid improvement during OFF episodes (periods when the effects of PD medications fade and symptoms reappear), but tolerability issues and nasal irritation limit usage. Early-phase studies suggest intranasal delivery enables quick symptom relief and favorable pharmacokinetics, though most trials are small and focus on feasibility. New approaches include antioxidants, neurotrophic factors, gene therapy, and cell-based methods, with advanced formulations enhancing nasal retention and brain uptake. However, more translational evidence and long-term safety data are needed. Conclusions: Intranasal therapies for PD offer rapid rescue and expand options beyond standard drugs. Large, well-designed trials are needed to confirm efficacy, long-term safety, and optimal formulations. Intranasal delivery remains an emerging but potentially transformative strategy requiring further clinical research. Full article

Neurological disorders like Alzheimer’s disease, Parkinson’s disease, and epilepsy are becoming major causes of disability and mortality worldwide, and their prevalence is expected to rapidly increase with the aging of the population. These diseases develop silently, with irreversible neuronal damage often occurring decades before any clinical signs of illness are noticed, making early diagnosis and treatment difficult. The presymptomatic period greatly restricts the effectiveness of therapeutic interventions and reduces the possibility of disease-modifying interventions. Traditional diagnostic methods based on clinical assessment, neuroimaging, and invasive biomarkers are not sensitive enough to identify the disease at an early stage and are expensive to the healthcare system. The latest artificial intelligence (AI) technology and machine learning (ML) approaches, together with digital biomarkers obtained from eye tracking, facial expressions, speech analysis, motor dynamics, electrophysiology, wearable devices, and passive sensing, offer promising non-invasive alternatives for early detection of diseases. However, most reported performance metrics are derived from retrospective or pre-validated datasets, and prospective external validation remains limited. This narrative review synthesizes current evidence on AI-driven digital biomarkers for early detection of neurological diseases, examining disease-specific applications, methodological approaches, and challenges in clinical practices. We emphasize that clinical utility is task specific and dependent on disease stage, validation design, clinical endpoints, cost, workflow integration, and availability of disease-modifying therapies. We also note that much of the evidence summarized here derives from retrospective, case-control, or internally validated datasets and that prospective, patient-independent, and external validation with clinically meaningful endpoints remains limited. Reported performance figures should be read as proof-of-concept evidence rather than as evidence of demonstrated clinical readiness. We highlight promising future directions, including federated learning, explainable AI, and precision neurology approaches, while acknowledging that most applications remain investigational and require prospective validation before broad clinical deployment. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing disabling motor dysfunction and substantial socioeconomic burden. Photobiomodulation (PBM), a noninvasive red/near-infrared light therapy, has shown preclinical promise, but its clinical efficacy and safety in PD remain uncertain. Objectives: To systematically evaluate the efficacy and safety of PBM on motor outcomes in PD. Methods: This PRISMA-compliant systematic review was prospectively registered in PROSPERO (CRD420261411269). Databases were searched through May 2026. Randomized and non-randomized trials in adults with PD were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias (RoB 2.0; ROBINS-I). Where data permitted, random-effects meta-analyses used mean difference (MD) with REML estimation and Hartung–Knapp–Sidik–Jonkman confidence intervals. Results: Eight trials (n = 279) were included, exhibiting substantial heterogeneity in wavelength, device type, stimulation sites, and dosimetry. PBM was safe and well tolerated, with only minor adverse effects. Meta-analysis of four RCTs found no significant effect on MDS-UPDRS-III (MD = −1.37 points, 95% CI: −5.55 to 2.80; I² = 20.6%) or TUG (MD = −0.52 s, 95% CI: −5.03 to 3.99; I² = 55.1%). An exploratory TMWT meta-analysis (k = 2) yielded MD = −0.65 s (95% CI: −1.78 to 0.49; I² = 0.0%), with direction consistently favoring PBM. Individual effect sizes ranged from negligible (d = 0.03–0.06) to small-to-moderate (d = 0.41). Conclusions: PBM appears safe, feasible, and acceptable in PD, but current evidence does not support clinically meaningful motor benefits. Heterogeneous protocols, small samples, and absent target-engagement biomarkers limit definitive interpretation. Well-powered standardized trials with mechanistic endpoints are needed. Full article

Background: The most effective pharmacological treatment for Parkinson’s disease (PD) remains levodopa, whose responsiveness is distinguished into two temporally and mechanistically distinct components: the short-duration response (SDR), which lasts hours, closely paralleling drug plasma concentration, and the long-duration response (LDR), which derives from prolonged administration of levodopa and persists for days to weeks after drug discontinuation. The mechanisms underlying the LDR and, in particular, the behavior in early PD patients are incompletely understood. This review aims to gather current evidence on the pharmacodynamics, neurobiological substrate, natural history, and clinical implications of the LDR, with a specific focus on early PD patients. Methods: A narrative review was conducted based on a selection of original research articles, clinical studies, and reviews identified through PubMed/MEDLINE, covering the period from January 1995 to July 2026. Studies were selected for their methodological relevance to the characterization of LDR in drug-naive or early-stage PD patients, including pharmacodynamic studies, neuroimaging investigations, and neurophysiological assessments. Results: Evidence consistently demonstrates that the LDR is a pharmacodynamically distinct component of levodopa response, present from the earliest stages of dopaminergic therapy. In drug-naive patients, the LDR represents a quantitatively substantial fraction of total levodopa benefit, and it is linked to modifications in cortical excitability, dopaminergic neuroplasticity, and motor learning. Structural neuroimaging identifies predisposing gray matter features in motor cortex regions. Whether LDR magnitude declines with disease and treatment duration, and thereby underlies the emergence of motor fluctuations, remains disputed across studies. This discrepancy appears attributable, at least in part, to differences in how the LDR is measured (direct washout assessment versus inference against a projected untreated trajectory) rather than necessarily to divergent underlying biology. Conclusions: The LDR to levodopa represents a neurobiologically and clinically significant dimension of levodopa response. Its characterization in early PD patients may refine therapeutic strategies, inform the design of neuroprotection trials, and open new possibilities for precision medicine approaches. Full article

Objectives: Adults exposed to the Bacillus Calmette–Guérin (BCG) vaccine demonstrate a reduced incidence of Parkinson’s disease (PD). This retrospective study evaluated whether early-life BCG vaccination predicts a long-term reduction in PD incidence during aging. Methods: Published age-adjusted incidence rates (AAIRs) of PD (2002–2021) were structured into single-age birth cohorts. Missing values were calculated via interpolation and shuffling simulations. Cohorts were categorized into three historical BCG policy periods: unvaccinated controls (born 1945–1949), vaccinated at age 12 (born 1950–1954), and vaccinated as newborns (born 1955–1959). AAIRs were compared at identical cross-sectional ages (57 and 62 years), applying an environmental drift penalty to control for temporal improvements. Results: In men, the age 12 policy showed a 21.8% AAIR reduction at age 57, which attenuated to 4.4% by age 62; the newborn policy showed a sustained reduction (25.8% at age 57; 20.4% at age 62). In women, the age 12 policy yielded a 67.5% reduction at age 57 (33.1% at age 62), while the newborn policy showed a 56.8% reduction at age 57 (44.0% at age 62). Conclusions: Early-life BCG vaccination is associated with reduced later-life PD incidence, displaying a profound sex-dependent effect favoring females. Newborn vaccination provides long-term resistance as well. Full article

Parkinsonian syndromes comprise overlapping neurodegenerative and non-degenerative disorders, making aetiological diagnosis difficult, while existing procedural guidance does not fully integrate tracer-specific biology with clinical decision-making, multimodal strategies, and emerging quantitative and pathology-directed biomarkers. This review synthesises evidence on the molecular targets, radiopharmaceutical characteristics, biological interpretation, and clinical applications of dopaminergic single-photon emission computed tomography (SPECT) and positron emission tomography (PET), focusing on the dopamine transporter (DAT), aromatic L-amino acid decarboxylase (AADC), vesicular monoamine transporter type 2 (VMAT2), dopamine D₂/D₃ receptors, differential diagnosis, semiquantification, kinetic modelling, and artificial intelligence-assisted interpretation. The evidence confirms that DAT SPECT with [¹²³I]ioflupane ([¹²³I]FP-CIT) remains the most established method for demonstrating or arguing against presynaptic nigrostriatal dysfunction, but an abnormal result cannot establish aetiology, and a normal result can redirect evaluation towards non-degenerative mimics; target-specific PET provides complementary biological information, although availability, standardisation, and prospective validation remain limiting. By additionally integrating genetic and prodromal applications, question-driven multimodal imaging, emerging acquisition approaches, α-synuclein imaging and seed amplification assays, and contemporary biological staging frameworks, this review extends procedural guidance and positions dopaminergic imaging as a targeted functional biomarker selected according to the unresolved clinical question rather than as a stand-alone disease label. Full article

Curcumin and natural curcuminoids possess numerous beneficial properties, including antioxidant, antitumor, and anti-inflammatory effects. However, their application is challenging because of instability and rapid metabolism. Cyclic C₅-curcuminoids, a subgroup of curcuminoids, are chemically more stable and less susceptible to hydrolysis or metabolism. In our study, seven synthetic compounds—five cyclic C₅-curcuminoids (compounds 8, 9, 11, 12, and 13) and two cyclic chalcones (compounds 4 and 5)—were examined using an in vitro 6-hydroxydopamine-induced neuronal damage model established with all-trans retinoic acid-differentiated SH-SY5Y and BV-2 microglial cells. The antioxidant, anti-apoptotic (including ferroptosis markers (iron, GSH/GSSG, and malondialdehyde)), apoptotic (PARP, cytochrome c, caspase 9, active caspase-3, and oligonucleosome release), and anti-inflammatory effects of these compounds were also investigated. Compounds 5, 9, 12, and 13 significantly decreased reactive oxygen species production (percentage changes: 5: 28.9%; 9: 32%; 12: 29.8%; 13: 49.2%) and increased antioxidant capacity (percentage changes: 5: 63.4%; 9: 85.8%; 12: 31.2%; 13: 85.9%) and antioxidant enzyme activity (catalase, superoxide dismutase, and glutathione peroxidase) in SH-SY5Y cells. Compounds 5, 9, and 12 decreased microglial activation by downregulating Iba1 expression (fold changes: 5: 0.73; 9: 0.39; 12: 0.33) and decreasing glutamate concentration (percentage changes: 5: 26.5%; 9: 41.2%; 12: 27.3%). Together with compound 13, they reduced pro-inflammatory cytokine (IL-6, TNFα) secretion and induced anti-inflammatory cytokine (IL-10) release in SH-SY5Y and BV-2 cells. Based on these results, the blood–brain barrier penetrations of compounds 5, 9, 12, and 13 were also investigated. The highest blood–brain barrier penetration was observed for compound 12 (P_app value 13.6 × 10⁻⁶ cm/s). Synthetic cyclic C₅-curcuminoids derived from curcumin overcome the limitations of stability and bioavailability and exhibit strong antioxidant, anti-inflammatory, and anti-apoptotic effects, making them promising candidates for treating neurodegenerative diseases. Full article

Both RIT1 and RIT2 are members of the RAS superfamily of small GTPases, which regulate various cellular processes. RIT1 is widely expressed, whereas RIT2 is primarily found in neuronal tissues. Dysregulation of these proteins has been associated with several human diseases, including Noonan syndrome, cancer, Parkinson’s disease, autism, and schizophrenia. Although RIT1 and RIT2 are often compared to classical RAS proteins, they exhibit distinct regulatory and biochemical properties. Here, we demonstrate that RIT1 differs from classical RAS in GTPase cycling. Unlike classical RAS proteins, RIT1 did not respond to SOS1-mediated nucleotide exchange or p120GAP-stimulated GTP hydrolysis under cell-free conditions. These results imply that RIT1 may depend on regulatory mechanisms that differ from those of classical RAS proteins. However, the relevant physiological regulators remain unknown. Disease-associated RIT1 mutations cluster around the P-loop and Switch II regions. In this transient overexpression screening system, however, these mutations had only a modest effect on the canonical MAPK, PI3K/AKT, and JNK signaling pathways in HEK293T overexpression experiments. This suggests the existence of additional context-specific effectors and regulatory factors. We demonstrate that RIT1 and RIT2 interact with membrane lipids via a basic C-terminal extension. The KRLK-containing region contributes to the binding of phosphatidylserine and phosphoinositides. Charge-reversal mutations disrupt lipid interactions and liposome binding, supporting the functional importance of this region. In a reconstituted liposome system, galectin-3 and LZTR1, but not galectin-1, reduced the interaction of GDP-loaded RIT1 and RIT2 with liposomes. These results suggest that accessory proteins may influence RIT membrane interactions. However, their cellular relevance requires further validation. Together, our findings provide biochemical insights into RIT GTPase regulation and its interactions with membrane lipids under cell-free conditions. Full article