Search Results (1,071)

The neural circuits of the human brain are highly complex (due to the number of neurons and the diversity of synaptic connections), hindering the analysis of the pathological mechanisms of neurodegenerative diseases. Invertebrates with simple yet well-differentiated nervous systems have a natural advantage over mammalian model organisms in the identification of pathogenic genes and functional studies of neurodegenerative diseases. They can provide unique and profound insights into the pathogenesis of complex human neurodegenerative diseases and the formulation of intervention strategies. This article reviews the conserved mechanisms of three neurodegenerative diseases across species, including protein homeostasis imbalance and aggregation toxicity, mitochondrial dysfunction and metabolic abnormalities, axonal transport defects, and loss of synaptic function. Based on research on three invertebrates in the field of neurodegeneration, namely Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D. melanogaster), and Bombyx mori (B. mori), we cover three major types of neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aim is to find important inspirations for the future prevention and treatment of neurodegenerative diseases from the aspects of the material basis and existing treatment strategies. Full article

Cisplatin is an effective platinum-based chemotherapeutic agent used to treat a variety of cancers. However, its clinical utility is limited by dose-dependent neurotoxicity, yet no approved neuroprotective strategy currently exists. Our integrated cellular, metabolic, and in vivo approaches unraveled the neuroprotective potential of Areca catechu ethyl acetate extract (AC-EA) against cisplatin-induced neurotoxicity. Importantly, AC-EA did not reduce cisplatin-induced cytotoxicity in A549 lung cancer cells. In HT22 hippocampal neurons, AC-EA restored cell viability, suppressed reactive oxygen species generation, preserved mitochondrial-associated fluorescence, and attenuated phosphorylated histone H2AX (γH2AX)-marked DNA damage. AC-EA was associated with increased pNRF2 expression, consistent with activation of NRF2-dependent antioxidant signaling, suppressed inducible nitric oxide synthase iNOS (inducible nitric oxide synthase )-mediated neuroinflammation, and prevented the depletion of total AKT (protein kinase B) protein. Untargeted metabolomics and Caenorhabditis elegans survival assays were performed for mechanistic and in vivo validation. Metabolomics data showed restoration of several critical amino acids, including L-tyrosine and β-alanine, disrupted by cisplatin. Moreover, C. elegans studies confirmed in vivo activation of antioxidants via the SKN-1/GST-4 (glutathione S-transferase 4) pathway. While AC-EA shows neuroprotective potential, arecoline’s toxicity demands caution. To our knowledge, this is the first study to demonstrate the neuroprotective activity of A. catechu against cisplatin-induced neurotoxicity, laying the foundation for developing plant-derived adjunct therapies for chemotherapy-associated neuropathy. Full article

Dicyclohexyl phthalate (DCHP) is a widely used plasticizer, but its potential impact on immunity remains largely unexplored. In this study, synchronized L1-stage Caenorhabditis elegans were exposed to 0.0001–0.1 g/L DCHP for 72 h to investigate the effects of chronic early-life exposure on innate immunity; 0.01 and 0.1 g/L were used for subsequent mechanistic analyses. Innate immune function was evaluated using Pseudomonas aeruginosa PA14 survival assays, RT-qPCR, mutant strains, and oxidative-stress-related measurements. Chronic exposure beginning at the L1 stage significantly reduced the survival of C. elegans infected with Pseudomonas aeruginosa PA14. This immunosuppression was associated with increased daf-2 and age-1 transcript levels and reduced daf-16 transcript levels, indicating transcriptional alterations in insulin-like signaling-related genes. Additionally, the expression of pmk-1, nsy-1, and sek-1, key components of the p38 MAPK pathway, was markedly downregulated. Survival assays using different mutants supported the involvement of insulin-like signaling- and p38 MAPK-related genes in the decline in innate immunity following DCHP exposure. Furthermore, DCHP exposure reduced the expression of stress resistance genes, including skn-1, and several antioxidant enzymes. These findings suggest that DCHP may impair innate immune function through transcriptional alterations in immune- and stress-response pathways, although direct pathway activation or inhibition was not demonstrated. Full article

Mitochondrial unfolded protein response (UPR^mt) is crucial in preserving mitochondrial health and, consequently, in prolonging healthspan. Natural bioactive polysaccharides have emerged as a central focus for delaying senescence, although their links to mitochondrial stress responses remain incompletely understood. In this study, a purified fraction of Lycii Fructus polysaccharide (FSP) significantly extended lifespan, improved healthspan-related phenotypes, and enhanced resistance to heat, oxidative, and ultraviolet stress in C. elegans. FSP also preserved mitochondrial abundance and morphology, increased adenosine triphosphate (ATP) levels and mitochondrial membrane potential, and reduced reactive oxygen species. Transcriptomic and qPCR analyses, together with hsp-60 and hsp-6 reporter assays, showed an enhanced UPR^mt-associated response after FSP treatment. FSP-mediated lifespan extension was not observed in the atfs-1 and ubl-5 mutant strains, supporting pathway involvement of ATFS-1/UBL-5-dependent UPR^mt signaling. FSP reduced senescence-associated β-galactosidase positivity and improved mitochondrial function in human dermal fibroblasts. Our findings provide a vision of regulating UPR^mt for anti-aging interventions with plant polysaccharides and highlight the anti-aging potential of FSP by improving mitochondrial health. Full article

Pseudomonas aeruginosa is a predominant spoilage organism in meat products. The extensive use of antimicrobial preservatives has, however, led to the emergence of resistant strains. Mitigating the resistance of foodborne P. aeruginosa to conventional preservatives has become a critical challenge in food safety. Piperonylpiperazine (Pip), a piperazine derivative sourced from Piper nigrum, was first examined in this work as a novel agent capable of both suppressing virulence and enhancing preservative efficacy against P. aeruginosa, with its mode of action elucidated. At sub-inhibitory concentrations, Pip strongly suppressed the production of virulence factors and potentiated the susceptibility of P. aeruginosa to the common preservative EDTA. Mechanistically, a multi-pronged approach involving pull-down assay, transcriptomic profiling, isothermal titration calorimetry (ITC) analysis, and gene knockout models demonstrated that Pip binds specifically to the LYS-164 and ASP-35 residues of the RhlI synthase, blocking the quorum sensing (QS) signaling cascade. This QS disruption led to reduced virulence factor production and attenuated pathogenicity in a Caenorhabditis elegans model. The compromised QS system subsequently induced oxidative stress, which disrupted cell membrane integrity and permeability, thereby potentiating EDTA’s antibacterial action. These findings suggest that Pip is a promising natural additive that can be used in combination with existing preservatives to enhance food safety. Full article

FOXO/DAF-16 is involved in stress resistance and metabolic regulation, but the molecular mechanisms of its interaction with hypoxia remain unclear. This study aimed to evaluate the anti-hypoxic effects of Poecilobdella manillensis bioactive peptide (PMP) and to investigate whether IIS/FOXO acts as a key node in mediating the regulation of oxidative stress and metabolic reprogramming. In the chemical hypoxia model of Caenorhabditis elegans (C. elegans) induced by sodium sulfite, PMP treatment improved the survival status and movement, feeding, and reproductive ability of hypoxic C. elegans, and significantly increased their survival rate. It also reduced reactive oxygen species (ROS) and lipofuscin levels in C. elegans, enhancing their tolerance to oxidative and heat stress. In the terminal normobaric hypoxia mice model, PMP intervention prolonged the survival time of hypoxic mice, alleviated the damage of heart, lung, and brain tissues, and increased superoxide dismutase (SOD) activity and glutathione (GSH) levels, and decreased malondialdehyde (MDA) concentrations and lactate dehydrogenase (LDH) activity in serum and tissues of mice. ¹H-NMR metabolomics analysis showed that PMP treatment reversed hypoxia-induced abnormalities in key metabolites such as glucose, lactic acid, glutamic acid, and taurine. Next, we utilized C. elegans mutants deficient in daf-2, age-1, akt-1, daf-16, and hsp-16.2, and further observed the nuclear translocation of DAF-16 in DAF-16::GFP C. elegans. The results showed PMP induced DAF-16 nuclear translocation and upregulated the expression of downstream SOD-3. Key metabolites representing antioxidant and energy metabolism were measured in the daf-16 mutant C. elegans. The results showed that PMP intervention failed to restore the levels of glucose, lactic acid, glutamic acid, and taurine in the mutant. Finally, 12 peptides containing antioxidant-related bioactive amino acid residues in PMP were screened by UPLC-Q-Exactive-MS and peptide biological activity prediction. Among them, molecular docking showed that KPPGP had a good binding with FOXO1. In conclusion, in C. elegans, PMP activated DAF-16/FOXO by inhibiting the Insulin/insulin-like growth factor-1 signaling (IIS) pathway and regulated redox homeostasis and metabolic reprogramming to resist hypoxia injury, and this protective effect was also observed in mouse models. IIS/FOXO can be used as a key node to regulate oxidative stress and energy metabolism under hypoxic conditions, and the identification of KPPGP provides insights into the screening and study of bioactive peptides in natural products. Full article

Nano- (NPs, <1 µm) and microplastics (MPs, 1 µm–5 mm) are ubiquitous contaminants whose toxicity to invertebrates carries implications at the individual scale and (although not yet quantitatively validated) at the population scale. This semi-systematic narrative review organizes available evidence within an adverse outcome pathway (AOP) framework, linking primary molecular initiating events (MIEs) to adverse outcomes while flagging evidence strength at each step. It involves a structured synthesis that applies selected PRISMA 2020 transparency principles, namely disclosed databases, a priori eligibility criteria, and explicit harvest and de-duplication counts, but does not attempt the exhaustive paired screening, formal risk-of-bias scoring, or quantitative meta-analysis of a full systematic review; this design was chosen because the marked heterogeneity of particle physicochemistry, exposure regimes, and endpoint metrics across the available literature makes pooled statistical synthesis premature. Evidence is appraised across Daphnia, Artemia, Chironomus, Caenorhabditis elegans, Eisenia, marine mollusks, and crustaceans. Polymer chemistry, size, surface charge, weathering, biofilm formation, additives, and adsorbed co-contaminants shape uptake and downstream toxicity. Reactive oxygen species, mitochondrial dysfunction, lysosomal destabilization, and ER stress recur as coupled key events downstream of four MIEs (direct membrane interaction, protein corona formation, surface-catalyzed redox chemistry, and Trojan horse delivery). Multi-omics datasets converge on dysregulated stress, repair, apoptotic, immune, and inflammatory programs; epigenetic marks are increasingly considered as substrates for persistent and potentially heritable toxicity, although stable transgenerational transmission remains poorly demonstrated. The review delivers (i) an AOP map with evidence-strength annotations (strong, moderate, emerging), (ii) a structured cross-study synthesis comparing NP and MP effect profiles, and (iii) a critical layer that reinterprets biphasic and apparently contradictory data as mechanistically informative once particle physicochemistry and tissue context are resolved. Progress will depend on standardized characterization, environmentally realistic mixtures, and AOP-anchored designs that distinguish experimentally demonstrated mechanisms from inferred mechanisms and theoretical extrapolations. Full article

Alzheimer’s disease (AD) is a major neurodegenerative condition with limited treatment options. Applications of food-derived products rich in bioactive compounds have emerged as promising strategies, yet comparative evidence across different matrices remains scarce. Here, we present an integrative metabolomic analysis of eleven food extracts previously tested in Caenorhabditis elegans models of AD. By combining chemical fingerprints and functional bioassay data—including oxidative stress resistance, β-amyloid-induced paralysis, and tau-associated locomotion—we employed multivariate statistics to uncover common patterns and correlations. Principal Component Analysis, PLS-DA, and hierarchical clustering revealed distinct groupings of extracts based on metabolite profiles and neuroprotective effects. Polyphenols, flavonoids, and iridoids were consistently associated with beneficial outcomes, while antioxidant capacity and acetylcholinesterase inhibition emerged as key functional traits. Correlation heatmaps highlighted extract-specific strengths, suggesting potential for rational combinations targeting complementary bioactivities. This work underscores the value of integrating metabolomics and functional biology to inform the design of food-based interventions for neurodegenerative diseases, paving the way for evidence-based innovation in brain health. Full article

Mitochondrial dysfunction is increasingly recognized as a major contributor to central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Animal models are essential for elucidating disease mechanisms and supporting the development of new therapeutic strategies. Among these models, non-mammalian organisms offer distinct advantages, including low cost, rapid life cycles, genetic tractability, and suitability for large-scale, high-throughput studies. Organisms such as Saccharomyces cerevisiae, Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio have substantially advanced the understanding of mitochondrial processes relevant to CNS pathology. Studies using these models have revealed conserved mechanisms involving mitophagy, mitochondrial quality control, respiratory function, bioenergetic signaling, and neurodegenerative pathways. Their strengths, including scalability, live imaging capacity, and efficient genetic manipulation, have accelerated disease modeling and therapeutic discovery. However, simplified physiology, evolutionary distance from humans, and the incomplete representation of complex CNS organization limit their translational relevance and often require validation in higher-order organisms. Nevertheless, integrating these models into CNS research, particularly alongside emerging technologies, provides a powerful strategy for linking fundamental mitochondrial biology with translational neuroscience. This review summarizes the use of non-mammalian models in neuroscience research, with an emphasis on mitochondrial dysfunction in CNS disorders and their potential to support future therapeutic advances. Full article

Kombucha is a functional beverage produced through the fermentation of Camellia sinensis by a symbiotic culture of bacteria and yeast (SCOBY). Incorporating cashew (Anacardium occidentale L.) and Cajá (Spondias mombin L.) pulps represents a value-addition strategy to mitigate the post-harvest perishability of native Cerrado fruits. This study evaluated physicochemical kinetics, 21-day refrigerated shelf life, consumer acceptance, and biological effects in Caenorhabditis elegans of flavored kombuchas. During a 9-day primary fermentation, the pH decreased to 2.95 while total acidity reached 5.38%. Following flavoring (10% v/v pulp/juice), cashew kombucha exhibited the highest total phenolic content (4.19 mg GAE/mL) and ferric reducing power (FRAP), whereas Cajá kombucha showed superior DPPH scavenging activity (1236 µM TroloxE/mL). Refrigerated storage (4 °C) maintained high counts of viable microorganisms (>10⁵ CFU/mL), though active residual fermentation induced ongoing sugar cleavage and a transient yeast proliferation peak on day 7 (8.15 log CFU/mL in Cajá kombucha). Toxicity assays using C. elegans revealed the initial mortality (31.5–62.5%); however, adjusting the pH to near-neutrality restored high organism viability (<10% mortality), confirming that mortality was acidity-driven. In pH-adjusted media, cashew kombucha promoted a modest extension of nematode lifespan, whereas Cajá kombucha reduced lipid accumulation. Sensory testing revealed moderate consumer acceptance, with cashew kombucha achieving a higher Acceptance Index (72.92%) than Cajá (67.26%). Overall, fruit supplementation enriches the bioactive potential of green tea kombucha, provided that post-fermentation acidity is appropriately managed. Full article

As an emergent contaminant, 6-PPD quinone (6-PPDQ) causes toxic effects in organisms, including induction of immunosuppression. Thiamine pyrophosphate (TPP) serves as an important cofactor for some metabolisms. We aimed to examine the role of thiamine pyrophosphokinase TPK-1 in modulating 6-PPD-induced immunosuppression. Using Caenorhabditis elegans as the animal model, 6-PPDQ-exposure treatment was applied to nematodes from the L1 larval stage to adult day 3, and innate immune response was assessed by the expression of antimicrobial genes. In nematodes, 6-PPDQ (1–10 μg/L) elevated TPP content, which was due to an increase in the expression of tpk-1, and RNAi of tpk-1 could block 6-PPDQ-induced immunosuppression. Meanwhile, RNAi of tpk-1 strengthened expressions of mitochondrial UPR (mt UPR) marker genes (hsp-6 and hsp-60) by activating three transcription factor (TF) genes (atfs-1, ubl-5, and dve-1) in 6-PPDQ-exposed nematodes. RNAi of mitochondrial UPR marker genes and three TF genes aggravated 6-PPDQ-induced immunosuppression. TPK-1 acted upstream of these three TF genes to modulate 6-PPDQ-induced immunosuppression. Moreover, RNAi of tpk-1 inhibited the expression of complex III/IV subunit genes, and RNAi of these complex III/IV subunit genes conferred resistance to 6-PPDQ-induced immunosuppression. Additionally, these complex III/IV subunit genes functioned upstream of TF genes (atfs-1, ubl-5, and dve-1) to regulate 6-PPDQ-induced immunosuppression. Therefore, our data provide a novel basis for 6-PPDQ-induced immunosuppression mediated by activation of TPK-1 and the following mt UPR suppression. Full article

Aberrant self-assembly of ataxin-3 (ATX3) into amyloid aggregates is a key pathological event in spinocerebellar ataxia type 3 (SCA3). Bioactive nutraceutical compounds, particularly polyphenols, have emerged as promising candidates for targeting protein aggregation and cellular stress responses associated with neurodegenerative disorders. Here, we investigated cinnamon bud extract as a natural source of neuroprotective molecules, focusing on its total extract (Etot) and two bioactive fractions: a polyphenol-enriched fraction (Fr. B) and a cinnamaldehyde-rich fraction (Fr. C). By integrating biochemical and biophysical techniques, we demonstrate that cinnamon-derived compounds modulate ATX3 aggregation by reducing the formation of β-sheet-rich amyloid assemblies and promoting the generation of SDS-resistant, soluble, structurally distinct, non-fibrillar species. NMR profiling identified flavonoids, cinnamaldehyde, and cinnamic acid as key ATX3-interacting molecules, supporting their contribution to the anti-amyloidogenic activity of the extract. Moreover, in a Caenorhabditis elegans SCA3 model, Etot and Fr. B improved locomotor defects and enhanced resistance to oxidative and thermal stress, indicating broader cytoprotective effects beyond direct aggregation modulation. Overall, these findings highlight cinnamon bud extract, particularly its polyphenol-rich fraction, as a promising nutraceutical source of bioactive compounds with potential neuroprotective properties and provide a basis for further investigation of nutraceutical strategies targeting polyglutamine-related neurodegenerative diseases. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. Oxidative stress, neuroinflammation, and α-synuclein aggregation are central pathological features of PD. Zanthoxylum piperitum DC, commonly known as Korean pepper or chopi, is a traditional dietary spice in Eastern Asia and has been reported to possess antioxidant and anti-inflammatory properties. This study investigated the neuroprotective and motor function–enhancing effects of distilled extract of Z. piperitum (deZP) in 1-Methyl-4-phenylpyridinium (MPP⁺)-treated Caenorhabditis elegans and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models of PD. Methods: In the C. elegans model, dopaminergic neurotoxicity was induced by MPP⁺, and deZP was tested at 0.25, 0.5, and 1% (v/v) to evaluate neuronal preservation through GFP-labeled dopaminergic neurons and α-synuclein expression. Concurrently, in the MPTP-induced mouse model, deZP was administered intranasally at a fixed dose of 20 μL/mouse, equivalent to 5 mg/mouse. Motor function was assessed using the rota-rod test, pole test, and grip strength test, while dopaminergic neuronal survival was evaluated by tyrosine hydroxylase (TH) immunostaining. Results: In MPP⁺-treated C. elegans, deZP significantly restored green fluorescent protein (GFP) fluorescence in dopaminergic neurons and reduced α-synuclein expression, with the most pronounced effects observed at 1% (v/v). In the MPTP-induced mouse model, deZP at this fixed intranasal dose significantly improved motor performance and preserved TH-positive neurons in the substantia nigra. Conclusions: These findings suggest that deZP may represent a promising preclinical candidate for further investigation in PD-related neurodegeneration. Full article

Polyphenols are natural compounds with antioxidant properties that help prevent chronic diseases. Red onion (Allium cepa) peels are an underutilized source of polyphenols, offering a sustainable opportunity for the valorization of agricultural by-products. Polyphenol-rich extracts were obtained from red onion peels using subcritical water extraction and adsorption resin chromatography. Their biological effects were evaluated in Caenorhabditis elegans under oxidative stress conditions. A multi-omics approach integrating transcriptomics, metabolomics, and lipidomics was applied to assess molecular responses. The extract exhibited a high total phenolic content (>400 mg GAE/g) and strong antioxidant capacity, supporting a highly enriched polyphenolic profile. Survival assays confirmed the absence of toxicity at 100 µg/mL GAE. Transcriptomic analysis revealed 158 differentially expressed genes associated with stress response and metabolic regulation. Metabolomic profiling indicated a systematic reduction in amino acid levels alongside an increase in betaine in treated worms, suggesting adaptive metabolic reprogramming. Lipidomic analysis revealed significant lipid remodeling, characterized by decreased triglycerides, increased diacylglycerols, and changes in membrane phospholipids, indicating alterations in membrane composition and cellular responses associated with oxidative stress adaptation. Together, these results support a model in which red onion peel extracts induce coordinated transcriptional and metabolic adaptations associated with cellular resilience and stress adaptation. This study highlights the potential of agro-industrial by-products as functional bioactive ingredients and demonstrates the value of multi-omics approaches for uncovering system-level responses. Full article

Background/Objectives: The N-NOSE test is a non-invasive, urine-based multi-cancer screening assay that uses Caenorhabditis elegans chemotaxis toward cancer-associated volatile organic compounds in human urine. Scaling the test from a manual research-grade workflow to a high-throughput clinical service has required automation, and the central question this raises, centering around whether mechanization alters the analytical performance of the test, must be answered with operational, not bench-top, data. Methods: Here, we present a nine-month (January–September 2023) real-world, side-by-side comparison of the two workflows operating under their actual routine clinical laboratory conditions: the manual chemotaxis assay performed by trained technicians at the Fukuoka Research and Development Center (R&D) and the fully automated Chemotaxis Scoring Apparatus (CSA) running continuously at the Tokyo Testing Center. Results: The manual workflow generated 551 paired chemotaxis index (CI) measurements from positive-control (PC) and negative-control (NC) synthetic urine/volatile organic compound (VOC)-mimic reference materials at each of two standard urine dilutions (10⁻¹ and 10⁻²); over the same period, the CSA processed 2448 quality control samples (612 per control type) with both biobank-derived urine-based comparison materials and synthetic volatile organic compound reference standards. Both workflows produced large, highly significant, and quantitatively comparable PC-versus-NC separation under genuine operating conditions (manual: Δ_CI = 0.096 and 0.103; Welch’s t = 19.83 and 21.95; p < 0.0001; Cohen’s d = 1.19 and 1.32; CSA risk scale Δ_P–N = 14.47 with biobank-derived urine-based materials and 10.17 with synthetic VOC standards). The CSA risk score is a linear, monotonic transformation of the CI. Standardized separation is directly comparable across workflows and is concordant (Cohen’s d: manual 1.19–1.32; CSA 0.80–1.44, all large); the manual and automated processes therefore show no meaningful difference in discriminative performance. Because the CSA mechanizes only the handling of worms, samples, and machine-vision counting around an unchanged biological transducer, the live nematode, analytical equivalence is the predicted outcome, and these data confirm it at scale in a real clinical laboratory setting. Conclusions: Automation of the N-NOSE process does not compromise its ability to discriminate cancer from non-cancer urine. These results provide real-world evidence supporting the validity, reproducibility, and reliability of the N-NOSE testing process and large-scale validation studies. Full article