Differential impact of diesel exhaust particles on glutamatergic and dopaminergic neurons in Caenorhabditis elegans: A neurodegenerative perspective.

The growing body of evidence links exposure to particulate matter pollutants with an increased risk of neurodegenerative diseases. In the present study, we investigated whether diesel exhaust particles can induce neurobehavioral alterations associated with neurodegenerative effects on glutamatergic and dopaminergic neurons in Caenorhabditis elegans (C. elegans). Exposure to DEP at concentrations of 0.167 µg/cm2 and 1.67 µg/cm2 resulted in significant developmental delays and altered locomotion behaviour. These effects were accompanied by discernible alterations in the expressions of antioxidant genes sod-3 and gst-4 observed in transgenic strains. Behaviour analysis demonstrated a significant reduction in average speed (p < 0.001), altered paths, and decreased swimming activities (p < 0.01), particularly at mid and high doses. Subsequent assessment of neurodegeneration markers in glutamatergic (DA1240) and dopaminergic (BZ555) transgenic worms revealed notable glutamatergic neuron degeneration at 0.167 µg/cm2 (∼30 % moderate, ∼20 % advanced) and 1.67 µg/cm2 (∼28 % moderate, ∼24 % advanced, p < 0.0001), while dopaminergic neurons exhibited structural deformities (∼16 %) without significant degeneration in terms of blebs and breaks. Furthermore, in silico docking simulations suggest the presence of an antagonistic competitive inhibition induced by DEP in the evaluated neuro-targets, stronger for the glutamatergic transporter than for the dopaminergic receptor from the comparative binding affinity point of view. The results underscore DEP's distinctive neurodegenerative effects and suggest a link between locomotion defects and glutamatergic neurodegeneration in C. elegans, providing insights into environmental health risks assessment.

Comparison of intestinal toxicity in enhancing intestinal permeability and in causing ROS production of six PPD quinones in Caenorhabditis elegans.

As the derivatives of p-phenylenediamines (PPDs), PPD quinones (PPDQs) have received increasing attention due to their possible exposure risk. We compared the intestinal toxicity of six PPDQs (6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ and IPPDQ) in Caenorhabditis elegans. In the range of 0.01-10 µg/L, only 77PDQ (10 µg/L) moderately induced the lethality. All the examined PPDQs at 0.01-10 µg/L did not affect intestinal morphology. Different from this, exposure to 6-PPDQ (1-10 µg/L), 77PDQ (0.1-10 µg/L), CPPDQ (1-10 µg/L), DPPDQ (1-10 µg/L), DTPDQ (1-10 µg/L), and IPPDQ (10 µg/L) enhanced intestinal permeability to different degrees. Meanwhile, exposure to 6-PPDQ (0.1-10 µg/L), 77PDQ (0.01-10 µg/L), CPPDQ (0.1-10 µg/L), DPPDQ (0.1-10 µg/L), DTPDQ (1-10 µg/L), and IPPDQ (1-10 µg/L) resulted in intestinal reactive oxygen species (ROS) production and activation of both SOD-3::GFP and GST-4::GFP. In 6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ, and/or IPPDQ exposed nematodes, the ROS production was strengthened by RNAi of genes (acs-22, erm-1, hmp-2, and pkc-3) governing functional state of intestinal barrier. Additionally, expressions of acs-22, erm-1, hmp-2, and pkc-3 were negatively correlated with intestinal ROS production in nematodes exposed to 6-PPDQ, 77PDQ, CPPDQ, DPPDQ, DTPDQ, and/or IPPDQ. Therefore, exposure to different PPDQs differentially induced the intestinal toxicity on nematodes. Our data highlighted potential exposure risk of PPDQs at low concentrations to organisms by inducing intestinal toxicity.

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Generation of environmentally persistent free radicals on photoaged tire wear particles and their neurotoxic effects on neurotransmission in Caenorhabditis elegans.

Tire wear particles (TWP) are a prevalent form of microplastics (MPs) extensively distributed in the environment, raising concerns about their environmental behaviors and risks. However, knowledge regarding the properties and toxicity of these particles at environmentally relevant concentrations, specifically regarding the role of environmentally persistent free radicals (EPFRs) generated during TWP photoaging, remains limited. In this study, the evolution of EPFRs on TWP under different photoaging times and their adverse effects on Caenorhabditis elegans were systematically investigated. The photoaging process primarily resulted in the formation of EPFRs and reactive oxygen species (O2•-, ⋅OH, and 1O2), altering the physicochemical properties of TWP. The exposure of nematodes to 100 µg/L of TWP-50 (TWP with a photoaging time of 50 d) led to a significant decrease in locomotory behaviors (e.g., head thrashes, body bends, and wavelength) and neurotransmitter contents (e.g., dopamine, glutamate, and serotonin). Similarly, the expression of neurotransmission-related genes was reduced in nematodes exposed to TWP-50. Furthermore, the addition of free-radical inhibitors significantly suppressed TWP-induced neurotoxicity. Notably, correlation analysis revealed a significantly negative correlation between EPFRs levels and the locomotory behaviors and neurotransmitter contents of nematodes. Thus, it was concluded that EPFRs on photoaged TWP induce neurotoxicity by affecting neurotransmission. These findings elucidate the toxicity effects and mechanisms of EPFRs, emphasizing the importance of considering their contributions when evaluating the environmental risks associated with TWP.

Natural flavonoid hesperetin blocks amyloid ß-protein fibrillogenesis, depolymerizes preformed fibrils and alleviates cytotoxicity caused by amyloids.

The aggregation of ß-amyloid (Aß) peptides to form amyloid plaques is one of the primary hallmarks for Alzheimer's disease (AD). Dietary flavonoid supplements containing hesperetin have an ability to decline the risk of developing AD, but the molecular mechanism is still unclear. In this work, hesperetin, a flavanone abundant in citrus fruits, has been proven to prevent the formation of Aß aggregates and depolymerized preformed fibrils in a concentration-dependent fashion. Hesperetin inhibited the conformational conversion from the natural structure to a ß-sheet-rich conformation. It was found that hesperetin significantly reduced the cytotoxicity and relieved oxidative stress eventuated by Aß aggregates in a concentration-dependent manner. Additionally, the beneficial effects of hesperetin were confirmed in Caenorhabditis elegans, including the inhibition of the formation and deposition of Aß aggregates and extension of their lifespan. Finally, the results of molecular dynamics simulations showed that hesperetin directly interacted with an Aß42 pentamer mainly through strong non-polar and electrostatic interactions, which destroyed the structural stability of the preformed pentamer. To summarize, hesperetin exhibits great potential as a prospective dietary supplement for preventing and improving AD.

C. elegans: a prominent platform for modeling and drug screening in neurological disorders.

INTRODUCTION: Human neurodevelopmental and neurodegenerative diseases (NDevDs and NDegDs, respectively) encompass a broad spectrum of disorders affecting the nervous system with an increasing incidence. In this context, the nematode C. elegans, has emerged as a benchmark model for biological research, especially in the field of neuroscience. AREAS COVERED: The authors highlight the numerous advantages of this tiny worm as a model for exploring nervous system pathologies and as a platform for drug discovery. There is a particular focus given to describing the existing models of C. elegans for the study of NDevDs and NDegDs. Specifically, the authors underscore their strong applicability in preclinical drug development. Furthermore, they place particular emphasis on detailing the common techniques employed to explore the nervous system in both healthy and diseased states. EXPERT OPINION: Drug discovery constitutes a long and expensive process. The incorporation of invertebrate models, such as C. elegans, stands as an exemplary strategy for mitigating costs and expediting timelines. The utilization of C. elegans as a platform to replicate nervous system pathologies and conduct high-throughput automated assays in the initial phases of drug discovery is pivotal for rendering therapeutic options more attainable and cost-effective.

Exposure to 6-PPD Quinone at Environmentally Relevant Concentrations Inhibits Both Lifespan and Healthspan in C. elegans.

N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD), one of the most common additives used in rubber, enters the environment due to significant emissions of tire wear particles. 6-PPD quinone (6-PPDQ) is an important derivative of 6-PPD after ozonization. With concentrations ranging from nanograms per liter to µg/L, 6-PPDQ has so far been identified in a series of water samples. Acute lethality of 6-PPDQ in coho salmon (LC50 < 1 µg/L) was lower than environmental concentrations of 6-PPDQ, highlighting the environment exposure risks of 6-PPDQ. It is becoming increasingly necessary to investigate the potential toxicity of 6-PPDQ at environmental concentrations. Here, we examined the effect of 6-PPDQ exposure on lifespan and healthspan and the underlying mechanism in Caenorhabditis elegans. Exposure to 6-PPDQ (1 and 10 µg/L) shortened the lifespan. Meanwhile, during the aging process, 6-PPDQ (0.1-10 µg/L) could decrease both pumping rate and locomotion behavior, suggesting the 6-PPDQ toxicity on healthspan. For the underlying molecular mechanism, the dysregulation in the insulin signaling pathway was linked to toxicity of 6-PPDQ on lifespan and healthspan. In the insulin signaling pathway, DAF-2 restricted the function of DAF-16 to activate downstream targets (SOD-3 and HSP-6), which in turn controlled the toxicity of 6-PPDQ on lifespan and healthspan. Additionally, in response to 6-PPDQ toxicity, insulin peptides (INS-6, INS-7, and DAF-28) could activate the corresponding receptor DAF-2. Therefore, exposure to 6-PPDQ at environmentally relevant concentrations potentially causes damage to both lifespan and healthspan by activating insulin signaling in organisms.

Disruption of dopamine metabolism by exposure to 6-PPD quinone in Caenorhabditis elegans.

Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) on dopamine metabolism and underling molecular basis in nematodes. The dopamine content was reduced by 6-PPDQ (1 and 10 µg/L). Meanwhile, dopamine related behaviors (basal slowing response and area restricted searching) were changed by 6-PPDQ (1 and 10 µg/L). Exposure to 6-PPDQ (1 and 10 µg/L) decreased expressions of genes (cat-2 and bas-1) encoding enzymes governing dopamine synthesis and cat-1 encoding dopamine transporter. Development of dopaminergic neurons was also affected by 10 µg/L 6-PPDQ as reflected by decrease in fluorescence intensity, neuronal loss, and defect in dendrite development. Exposure to 6-PPDQ (1 and 10 µg/L) altered expressions of ast-1 and rcat-1 encoding upregulators of cat-2 and bas-1. The dopamine content and expressions of cat-2 and bas-1 were inhibited by RNAi of ast-1 and increased by RNAi of rcat-1 in 6-PPDQ exposed nematodes. Using endpoints of locomotion behavior and brood size, in 6-PPDQ exposed nematodes, the susceptibility to toxicity was caused by RNAi of ast-1, cat-2, bas-1, and cat-1, and the resistance to toxicity was induced by RNAi of rcat-1. Therefore, 6-PPDQ exposure disrupted dopamine metabolism and the altered molecular basis for dopamine metabolism was associated with 6-PPDQ toxicity induction. Moreover, the defects in dopamine related behaviors and toxicity on locomotion and reproduction could be rescued by treatment with 0.1 mM dopamine.

Predicting lifespan-extending chemical compounds for C. elegans with machine learning and biologically interpretable features.

Recently, there has been a growing interest in the development of pharmacological interventions targeting ageing, as well as in the use of machine learning for analysing ageing-related data. In this work, we use machine learning methods to analyse data from DrugAge, a database of chemical compounds (including drugs) modulating lifespan in model organisms. To this end, we created four types of datasets for predicting whether or not a compound extends the lifespan of C. elegans (the most frequent model organism in DrugAge), using four different types of predictive biological features, based on: compound-protein interactions, interactions between compounds and proteins encoded by ageing-related genes, and two types of terms annotated for proteins targeted by the compounds, namely Gene Ontology (GO) terms and physiology terms from the WormBase's Phenotype Ontology. To analyse these datasets, we used a combination of feature selection methods in a data pre-processing phase and the well-established random forest algorithm for learning predictive models from the selected features. In addition, we interpreted the most important features in the two best models in light of the biology of ageing. One noteworthy feature was the GO term "Glutathione metabolic process", which plays an important role in cellular redox homeostasis and detoxification. We also predicted the most promising novel compounds for extending lifespan from a list of previously unlabelled compounds. These include nitroprusside, which is used as an antihypertensive medication. Overall, our work opens avenues for future work in employing machine learning to predict novel life-extending compounds.

Exposure to 6-PPD quinone enhances lipid accumulation through activating metabolic sensors of SBP-1 and MDT-15 in Caenorhabditis elegans.

Although it has been shown that exposure to 6-PPDQ can cause toxicity on environmental organisms, its possible effects on metabolic state remain largely unclear. We here determined the effect of 6-PPDQ exposure on lipid accumulation in Caenorhabditis elegans. We observed increase in triglyceride content, enhancement in lipid accumulation, and increase in size of lipid droplets in 6-PPDQ (1-10 µg/L) exposed nematodes. This detected lipid accumulation was associated with both increase in fatty acid synthesis reflected by increased expressions of fasn-1 and pod-2 and inhibition in mitochondrial and peroxisomal fatty acid ß-oxidation indicated by decreased expressions of acs-2, ech-2, acs-1, and ech-3. The observed lipid accumulation in 6-PPDQ (1-10 µg/L) exposed nematodes was also related to the increase in synthesis of monounsaturated fatty acylCoAs reflected by altered expressions of fat-5, fat-6, and fat-7. Exposure to 6-PPDQ (1-10 µg/L) further increased expressions of sbp-1 and mdt-15 encoding two metabolic sensors to initiate the lipid accumulation and to regulate the lipid metabolism. Moreover, the observed increase in triglyceride content, enhancement in lipid accumulation, and alterations in fasn-1, pod-2, acs-2, and fat-5 expressions in 6-PPDQ exposed nematodes were obviously inhibited by sbp-1 and mdt-15 RNAi. Our observations demonstrated the risk of 6-PPDQ at environmentally relevant concentration in affecting lipid metabolic state in organisms.

Selective control of parasitic nematodes using bioactivated nematicides.

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land1-4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4-12. Here we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

Long-term exposure to 6-PPD quinone reduces reproductive capacity by enhancing germline apoptosis associated with activation of both DNA damage and cell corpse engulfment in Caenorhabditis elegans.

Recently, 6-PPD quinone (6-PPDQ), a derivative of tire antioxidant 6-PPD, was reported to have acute toxicity for organisms. However, the possible reproductive toxicity of 6-PPDQ is still largely unclear. In this study, the reproductive toxicity of 6-PPDQ after long-term exposure was further investigated in Caenorhabditis elegans. Exposure to 1 and 10 µg/L 6-PPDQ reduced the reproductive capacity. Meanwhile, exposure to 1 and 10 µg/L 6-PPDQ enhanced the germline apoptosis, which was accompanied by upregulation of ced-3, ced-4, and egl-1 expressions and downregulation of ced-9 expression. The observed increase in germline apoptosis in 1 and 10 µg/L 6-PPDQ exposed nematodes was associated with the enhancement in DNA damage and increase in expressions of related genes of cep-1, clk-2, hus-1, and mrt-2. The detected enhancement in germline apoptosis in 1 and 10 µg/L 6-PPDQ exposed nematodes was further associated with the increase in expressions of ced-1 and ced-6 governing the cell corpse engulfment process. Molecular docking analysis indicated the binding potentials of 6-PPDQ with three DNA damage checkpoints (CLK-2, HUS-1, and MRT-2) and corpse-recognizing phagocytic receptor CED-1. Therefore, our data suggested the toxicity on reproductive capacity by 6-PPDQ at environmentally relevant concentrations by enhancing DNA damage- and cell corpse engulfment-induced germline apoptosis in organisms.

Exposure to 6-PPD Quinone at Environmentally Relevant Concentrations Causes Abnormal Locomotion Behaviors and Neurodegeneration in Caenorhabditis elegans.

6-PPD quinone (6-PPDQ) can be transformed from 6-PPD through ozonation. Nevertheless, the potential neurotoxicity of 6-PPDQ after long-term exposure and the underlying mechanism are largely unclear. In Caenorhabditis elegans, we here observed that 0.1-10 µg/L of 6-PPDQ caused several forms of abnormal locomotion behaviors. Meanwhile, the neurodegeneration of D-type motor neurons was observed in 10 µg/L of 6-PPDQ-exposed nematodes. The observed neurodegeneration was associated with the activation of the Ca2+ channel DEG-3-mediated signaling cascade. In this signaling cascade, expressions of deg-3, unc-68, itr-1, crt-1, clp-1, and tra-3 were increased by 10 µg/L of 6-PPDQ. Moreover, among genes encoding neuronal signals required for the control of stress response, expressions of jnk-1 and dbl-1 were decreased by 0.1-10 µg/L of 6-PPDQ, and expressions of daf-7 and glb-10 were decreased by 10 µg/L of 6-PPDQ. RNAi of jnk-1, dbl-1, daf-7, and glb-10 resulted in the susceptibility to 6-PPDQ toxicity in decreasing locomotory ability and in inducing neurodegeneration, suggesting that JNK-1, DBL-1, DAF-7, and GLB-10 were also required for the induction of 6-PPDQ neurotoxicity. Molecular docking analysis further demonstrated the binding potential of 6-PPDQ to DEG-3, JNK-1, DBL-1, DAF-7, and GLB-10. Together, our data suggested the exposure risk of 6-PPDQ at environmentally relevant concentrations in causing neurotoxicity in organisms.

The impact of glucose on mitochondria and life span is determined by the integrity of proline catabolism in Caenorhabditis elegans.

Mutations in genes involved in mitochondrial proline catabolism lead to the rare genetic disorder hyperprolinemia in humans. We have previously reported that mutations of proline catabolic genes in Caenorhabditis elegans impair mitochondrial homeostasis and shorten life span, and that these effects surprisingly occur in a diet type-dependent manner. Therefore, we speculated that a specific dietary component may mitigate the adverse effects of defective proline catabolism. Here, we discovered that high dietary glucose, which is generally detrimental to health, actually improves mitochondrial homeostasis and life span in C. elegans with faulty proline catabolism. Mechanistically, defective proline catabolism results in a shift of glucose catabolism toward the pentose phosphate pathway, which is crucial for cellular redox balance. This shift helps to maintain mitochondrial reactive oxygen species homeostasis and to extend life span, as suppression of the pentose phosphate pathway enzyme GSPD-1 prevents the favorable effects of high glucose. In addition, we demonstrate that this crosstalk between proline and glucose catabolism is mediated by the transcription factor DAF-16. Altogether, these findings suggest that a glucose-rich diet may be advantageous in certain situations and might represent a potentially viable treatment strategy for disorders involving impaired proline catabolism.

Long-term exposure to tire-derived 6-PPD quinone causes intestinal toxicity by affecting functional state of intestinal barrier in Caenorhabditis elegans.

2-((4-Methylpentan-2-yl)amino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione (6-PPDQ) is the ozonation product of 6-PPD, a commonly used tire preservative. Although the 6-PPDQ has been frequently detected in different environmental ecosystems, its long-term effects on organisms remain still largely unknown. We here used Caenorhabditis elegans as an experimental animal to investigate the toxic effect of prolonged exposure to 6-PPDQ (0.1-100 µg/L). After the exposure, we found that 100 µg/L 6-PPDQ caused the lethality. We further selected concentrations of 0.1-10 µg/L to examine the possible intestinal toxicity induced by 6-PPDQ. Although 0.1-10 µg/L 6-PPDQ could not influence intestinal morphology, the intestinal permeability was significantly enhanced by 1-10 µg/L 6-PPDQ as indicated by erioglaucine disodium staining. In addition, the expression of intestinal fatty acid transporter ACS-22 governing functional state of intestinal barrier was decreased by exposure to 1-10 µg/L 6-PPDQ. Meanwhile, intestinal reactive oxygen species (ROS) production was induced by 0.1-10 µg/L 6-PPDQ and lipofuscin accumulation reflected by intestinal autofluorescence was activated by 1-10 µg/L 6-PPDQ. Accompanied with activation of intestinal oxidative stress, expressions of some anti-oxidation related genes (ctl-2, sod-2, sod-3, and sod-4) were significantly increased by 0.1-10 µg/L 6-PPDQ. Moreover, intestinal RNAi of acs-22 strengthened the susceptibility of nematodes to intestinal toxicity of 6-PPDQ. Therefore, considering that the environmentally relevant concentrations of 6-PPDQ were ≤10 µg/L, our data suggested that long-term exposure to 6-PPDQ at environmentally relevant concentrations potentially results in intestinal toxicity by disrupting functional state of intestinal barrier in organisms.

DNA methylation 6 mA and histone methylation involved in multi-/trans-generational reproductive effects in Caenorhabditis elegans induced by Atrazine.

Atrazine (ATR), a widely used triazine herbicide, is an environmental endocrine disruptor that can cause health problems. However, whether there are multi/trans-generational reproductive impacts of ATR have not been studied. Therefore, in this study, Caenorhabditis elegans was used as a preferable model organism to identify the multi/trans-generational reproductive toxicity of ATR. Only parental C.elegans (P0) were exposed to different concentrations (0.0004-40 mg/L) for 48 h and the subsequent offspring (F1-F5) were grown under ATR-free conditions and ATR conditions.The results showed that ATR exposure during P0 decreased fecundity, including a reduction in fertilized eggs, oocytes, and ovulation rate, delayed gonadal development, and decreased the relative area of gonad arm and germ cell number. Furthermore, continuous ATR exposure (P0-F5) causes a significant increase in reproductive toxicity in subsequent generations, although no significant toxicity occurred in the P0 generation after exposure to environmental-related concentrations, suggesting that ATR exposure might have cumulative effects. Likewise, parental exposure to ATR caused transgenerational toxicity impairments. Interestingly, only reproductive toxicity, not development toxicity, was transmitted to several generations (F1-F4), and the F2 generation showed the most notable changes. QRT-PCR results showed that genes expression related to DNA methylation 6 mA (damt-1, nmad-1) and histone H3 methylation (mes-4, met-2, set-25, set-2, and utx-1) can also be passed on to offspring. The function of H3K4 and H3K9 methylation were explored by using loss-of-function mutants for set-2, set-25, and met-2. Transmissible reproductive toxicity was absent in met-2(n4256), set-2(ok952), and set-25(n5021) mutants, which suggests that the histone methyltransferases H3K4 and H3K9 activity are indispensable for the transgenerational effect of ATR. Finally, the downstream genes of DNA methylation and histone H3 methylation were determined. ATR upregulated the expression of ZC317.7, hsp-6, and hsp-60. Mitochondrial stress in parental generation dependent transcription 6 mA modifiers may establish these epigenetic marks in progeny.

Per- and polyfluoroalkyl substances enhance Staphylococcus aureus pathogenicity and impair host immune response.

Per- and Poly-fluoroalkyl substances (PFAS) are major persistent environmental contaminants. Epidemiological studies have linked PFAS exposures to altered immunity and increased occurrence of infections in children. However, the mechanisms leading to immune susceptibility to bacterial infections remains unclear. To elucidate the mechanism, transcriptional alteration in the Caenorhabditis elegans model caused by a PFAS contaminated environmental water and two reconstituted PFAS solutions were evaluated using RNA-sequencing. PFAS affected the expression of several genes involved in C. elegans immune surveillance to Gram-positive bacteria (cpr-2, tag-38, spp-1, spp-5, clec-7, clec-172). The combined exposure to PFAS and Staphylococcus aureus significantly reduced C. elegans survival and increased intestinal membrane permeability. Furthermore, the growth of S. aureus in the presence of PFAS increased the expression of virulence genes, specifically, the virulence gene regulator saeR and α-hemolysin, hla, which resulted in increased hemolytic activity. The present study demonstrated that PFAS exposure not only increased C. elegans susceptibility to pathogens by reducing host immunity and increasing intestinal membrane permeability, but also increased bacteria virulence. This presents a broader implication for humans and other animals, where environmental contaminants simultaneously reduce host resilience, while, increasing microbial pathogenicity.

Aquilaria crassna Leaf Extract Ameliorates Glucose-Induced Neurotoxicity In Vitro and Improves Lifespan in Caenorhabditis elegans.

Hyperglycemia is one of the important causes of neurodegenerative disorders and aging. Aquilaria crassna Pierre ex Lec (AC) has been widely used to relieve various health ailments. However, the neuroprotective and anti-aging effects against high glucose induction have not been investigated. This study aimed to investigate the effects of hexane extract of AC leaves (ACH) in vitro using human neuroblastoma SH-SY5Y cells and in vivo using nematode Caenorhabditis elegans. SH-SY5Y cells and C. elegans were pre-exposed with high glucose, followed by ACH treatment. To investigate neuroprotective activities, neurite outgrowth and cell cycle progression were determined in SH-SY5Y cells. In addition, C. elegans was used to determine ACH effects on antioxidant activity, longevity, and healthspan. In addition, ACH phytochemicals were analyzed and the possible active compounds were identified using a molecular docking study. ACH exerted neuroprotective effects by inducing neurite outgrowth via upregulating growth-associated protein 43 and teneurin-4 expression and normalizing cell cycle progression through the regulation of cyclin D1 and SIRT1 expression. Furthermore, ACH prolonged lifespan, improved body size, body length, and brood size, and reduced intracellular ROS accumulation in high glucose-induced C. elegans via the activation of gene expression in the DAF-16/FoxO pathway. Finally, phytochemicals of ACH were analyzed and revealed that ß-sitosterol and stigmasterol were the possible active constituents in inhibiting insulin-like growth factor 1 receptor (IGFR). The results of this study establish ACH as an alternative medicine to defend against high glucose effects on neurotoxicity and aging.

An extracellular scaffolding complex confers unusual rectification upon an ionotropic acetylcholine receptor in C. elegans.

Biophysical properties of ligand-gated receptors can be profoundly modified by auxiliary subunits or by the lipid microenvironment of the membrane. Hence, it is sometimes challenging to relate the properties of receptors reconstituted in heterologous expression systems to those of their native counterparts. Here we show that the properties of Caenorhabditis elegans levamisole-sensitive acetylcholine receptors (L-AChRs), the ionotropic acetylcholine receptors targeted by the cholinergic anthelmintic levamisole at neuromuscular junctions, can be profoundly modified by their clustering machinery. We uncovered that L-AChRs exhibit a strong outward rectification in vivo, which was not previously described in heterologous systems. This unusual feature for an ionotropic AChR is abolished by disrupting the interaction of the receptors with the extracellular complex required for their synaptic clustering. When recorded at -60 mV, levamisole-induced currents are similar in the wild type and in L-AChR-clustering-defective mutants, while they are halved in these mutants at more depolarized physiological membrane potentials. Consequently, levamisole causes a strong muscle depolarization in the wild type, which leads to complete inactivation of the voltage-gated calcium channels and to an irreversible flaccid paralysis. In mutants defective for L-AChR clustering, the levamisole-induced depolarization is weaker, allowing voltage-gated calcium channels to remain partially active, which eventually leads to adaptation and survival of the worms. This explains why historical screens for C. elegans mutants resistant to levamisole identified the components of the L-AChR clustering machinery, in addition to proteins required for receptor biosynthesis or efficacy. This work further emphasizes the importance of pursuing ligand-gated channel characterization in their native environment.

Hydroalcoholic extract of Haematoxylum brasiletto protects Caenorhabditis elegans from cadmium-induced toxicity.

BACKGROUND: H. brasiletto is used in popular culture due to its therapeutic properties, including antioxidant, anti-inflammatory and antiproliferative properties, although little is known about its role as a protector against metal toxicity. This study aimed to investigate the chemical composition and efficacy of the hydroalcoholic extract from H. brasiletto (HAE-Hbrasiletto) collected in northern Colombia to defend against cadmium (Cd)-induced toxicity. METHODS: Phytochemical characterization was performed using HPLC-ESI-QTOF. Caenorhabditis elegans was employed to assess the shielding effect of HAE-Hbrasiletto against Cd toxicity in vivo, and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was utilized to measure radical scavenging activity. RESULTS: The main secondary metabolites identified by HPLC-ESI-QTOF in the extracts were hematoxylins (brazilein and hematein) and protosappanins (protosappanin A, B and C, 10-O-methylprotosappanin B, and protosappanin A dimethyl acetal). The HAE-Hbrasiletto elicited low lethality in N2 worms and significantly reduced the Cd-induced death of the nematodes. It also improved Cd-induced motility inhibition, as well as body length and reproduction reduction provoked by the heavy metal. The extract displayed a good capacity to halt Cd-induced DAF-16 translocation. As this last process was associated with lethality (r = 0.962, p < 0.01), the antioxidant properties of the extract may contribute to ameliorating tissue damage induced by oxidative stress from Cd exposure. CONCLUSION: HAE-Hbrasiletto has remarkable properties to protect against Cd-induced toxicity.