RÉSUMÉ
4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.
Sujet(s)
Caenorhabditis elegans , Oestrogènes , Nitrophénols , Reproduction , Transduction du signal , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/physiologie , Reproduction/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Nitrophénols/toxicité , Oestrogènes/toxicité , Espèces réactives de l'oxygène/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiquesRÉSUMÉ
Panax ginseng C. A. Meyer (ginseng) is a medicinal plant widely used for promoting longevity. Recently, homogalacturonan (HG) domain-rich pectins purified from some plants have been reported to have anti-aging-related activities, leading us to explore the longevity-promoting activity of the HG pectins from ginseng. In this study, we discovered that two of low methyl-esterified ginseng HG pectins (named as WGPA-2-HG and WGPA-3-HG), whose degree of methyl-esterification (DM) was 16 % and 8 % respectively, promoted longevity in Caenorhabditis elegans. Results showed that WGPA-2-HG/WGPA-3-HG impaired insulin/insulin-like growth factor 1 (IGF-1) signalling (IIS) pathway, thereby increasing the nuclear accumulation of transcription factors SKN-1/Nrf2 and DAF-16/FOXO and enhancing the expression of relevant anti-aging genes. BLI and ITC analysis showed that the insulin-receptor binding, the first step to activate IIS pathway, was impeded by the engagement of WGPA-2-HG/WGPA-3-HG with insulin. By chemical modifications, we found that high methyl-esterification of WGPA-2-HG/WGPA-3-HG was detrimental for their longevity-promoting activity. These findings provided novel insight into the precise molecular mechanism for the longevity-promoting effect of ginseng pectins, and suggested a potential to utilize the ginseng HG pectins with appropriate DM values as natural nutrients for increasing human longevity.
Sujet(s)
Protéines de Caenorhabditis elegans , Caenorhabditis elegans , Facteur de croissance IGF-I , Insuline , Longévité , Panax , Pectine , Transduction du signal , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/métabolisme , Panax/composition chimique , Facteur de croissance IGF-I/métabolisme , Pectine/pharmacologie , Pectine/métabolisme , Pectine/composition chimique , Longévité/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Insuline/métabolisme , Protéines de Caenorhabditis elegans/métabolisme , Protéines de Caenorhabditis elegans/génétique , EstérificationRÉSUMÉ
The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.
Sujet(s)
Antioxydants , Caenorhabditis elegans , Ferroptose , Neurones , Rétinol , Animaux , Ferroptose/effets des médicaments et des substances chimiques , Rétinol/pharmacologie , Rétinol/métabolisme , Caenorhabditis elegans/métabolisme , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , Neurones/métabolisme , Neurones/effets des médicaments et des substances chimiques , Neurones/cytologie , Cyclohexylamines/pharmacologie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Vitamine E/pharmacologie , Récepteurs à l'acide rétinoïque/métabolisme , Récepteurs à l'acide rétinoïque/génétique , Trétinoïne/pharmacologie , Organoïdes/effets des médicaments et des substances chimiques , Organoïdes/métabolisme , Neurogenèse/effets des médicaments et des substances chimiques , Souris , Humains , Protéines de Caenorhabditis elegans/métabolisme , Protéines de Caenorhabditis elegans/génétique , Transduction du signal/effets des médicaments et des substances chimiques , PhénylènediaminesRÉSUMÉ
Drug-Target Interaction (DTI) prediction facilitates acceleration of drug discovery and promotes drug repositioning. Most existing deep learning-based DTI prediction methods can better extract discriminative features for drugs and proteins, but they rarely consider multimodal features of drugs. Moreover, learning the interaction representations between drugs and targets needs further exploration. Here, we proposed a simple Mâ¯ulti-modal Gâ¯ating Nâ¯etwork for DTI prediction, MGNDTI, based on multimodal representation learning and the gating mechanism. MGNDTI first learns the sequence representations of drugs and targets using different retentive networks. Next, it extracts molecular graph features of drugs through a graph convolutional network. Subsequently, it devises a multimodal gating network to obtain the joint representations of drugs and targets. Finally, it builds a fully connected network for computing the interaction probability. MGNDTI was benchmarked against seven state-of-the-art DTI prediction models (CPI-GNN, TransformerCPI, MolTrans, BACPI, CPGL, GIFDTI, and FOTF-CPI) using four data sets (i.e., Human, C. elegans, BioSNAP, and BindingDB) under four different experimental settings. Through evaluation with AUROC, AUPRC, accuracy, F1 score, and MCC, MGNDTI significantly outperformed the above seven methods. MGNDTI is a powerful tool for DTI prediction, showcasing its superior robustness and generalization ability on diverse data sets and different experimental settings. It is freely available at https://github.com/plhhnu/MGNDTI.
Sujet(s)
Apprentissage profond , Humains , Découverte de médicament/méthodes , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Préparations pharmaceutiques/composition chimique , Préparations pharmaceutiques/métabolisme , Protéines/métabolisme , Protéines/composition chimiqueRÉSUMÉ
Cisplatin-induced nephrotoxicity restricts its clinical use against solid tumors. The present study elucidated the pharmacological effects of Renogrit, a plant-derived prescription medicine, using cisplatin-induced human renal proximal tubular (HK-2) cells and Caenorhabditis elegans. Quantification of phytochemicals in Renogrit was performed on HPTLC and UHPLC platforms. Renogrit was assessed in vitro in HK-2 cells post-exposure to clinically relevant concentration of cisplatin. It was observed that renoprotective properties of Renogrit against cisplatin-induced injury stem from its ability to regulate renal injury markers (KIM-1, NAG levels; NGAL mRNA expression), redox imbalance (ROS generation; GST levels), and mitochondrial dysfunction (mitochondrial membrane potential; SKN-1, HSP-60 expression). Renogrit was also found to modulate apoptosis (EGL-1 mRNA expression; protein levels of p-ERK, p-JNK, p-p38, c-PARP1), necroptosis (intracellular calcium accumulation; RIPK1, RIPK3, MLKL mRNA expression), mitophagy (lysosome population; mRNA expression of PINK1, PDR1; protein levels of p-PINK1, LC3B), and inflammation (IL-1ß activity; protein levels of LXR-α). More importantly, Renogrit treatment did not hamper normal anti-proliferative effects of cisplatin as observed from cytotoxicity analysis on MCF-7, A549, SiHa, and T24 human cancer cells. Taken together, Renogrit could be a potential clinical candidate to mitigate cisplatin-induced nephrotoxicity without compromising the anti-neoplastic properties of cisplatin.
Sujet(s)
Apoptose , Caenorhabditis elegans , Cisplatine , Mitophagie , Cisplatine/effets indésirables , Cisplatine/toxicité , Animaux , Humains , Mitophagie/effets des médicaments et des substances chimiques , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire , Extraits de plantes/pharmacologie , Tubules rénaux/effets des médicaments et des substances chimiques , Tubules rénaux/métabolisme , Tubules rénaux/anatomopathologie , Antinéoplasiques/pharmacologie , Antinéoplasiques/toxicité , Antinéoplasiques/effets indésirables , Tubules contournés proximaux/effets des médicaments et des substances chimiques , Tubules contournés proximaux/métabolisme , Tubules contournés proximaux/anatomopathologieRÉSUMÉ
BACKGROUND: Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, exhibits promising anti-Alzheimer's disease (AD) effects, but its underlying mechanisms remain inadequately investigated. This paper aims to identify potential targets and molecular mechanisms of DAU in AD treatment. METHODS: Network pharmacology and molecular docking simulation method were used to screen and focus core targets. Various transgenic Caenorhabditis elegans models were chosen to validate the anti-AD efficacy and mechanism of DAU. RESULTS: There are 66 potential DAU-AD target intersections identified from 100 DAU and 3036 AD-related targets. Subsequent protein-protein interaction (PPI) network analysis identified 16 core targets of DAU for anti-AD. PIK3CA, AKT1 and mTOR were predicted to be the central targets with the best connectivity through the analysis of "compound-target-biological process-pathway network". Molecular docking revealed strong binding affinities between DAU and PIK3CA, AKT1, and mTOR. In vivo experiments demonstrated that DAU effectively reduced paralysis in AD nematodes caused by Aß aggregation toxicity, downregulated expression of PIK3CA, AKT1, and mTOR homologues (age-1, akt-1, let-363), and upregulated expression of autophagy genes and the marker protein LGG-1. Simultaneously, DAU increased lysosomal content and enhanced degradation of the autophagy-related substrate protein P62. Thioflavin Tï¼Th-Tï¼staining experiment revealed that DAU decreased Aß accumulation in AD nematodes. Further experiments also confirmed DAU's protein scavenging activity in polyglutamine (polyQ) aggregation nematodes. CONCLUSION: Collectively, the mechanism of DAU against AD may be related to the activation of the autophagy-lysosomal protein clearance pathway, which contributes to the decrease of Aß aggregation and the restoration of protein homeostasis.
Sujet(s)
Peptides bêta-amyloïdes , Benzylisoquinoléines , Caenorhabditis elegans , Animaux , Maladie d'Alzheimer/traitement médicamenteux , Peptides bêta-amyloïdes/métabolisme , Animal génétiquement modifié , Benzylisoquinoléines/pharmacologie , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Simulation de docking moléculaire , Pharmacologie des réseaux , TétrahydroisoquinoléinesRÉSUMÉ
As the areca nut market is expanding, there is a growing concern regarding areca nut toxicity. Areca nut alkaloids are the major risky components in betel nuts, and their toxic effects are not fully understood. Here, we investigated the parental and transgenerational toxicity of varied doses of areca nut alkaloids in Caenorhabditis elegans. The results showed that the minimal effective concentration of arecoline is 0.2-0.4 mM. First, arecoline exhibited transgenerational toxicity on the worms' longevity, oviposition, and reproduction. Second, the redox homeostasis of C. elegans was markedly altered under exposure to 0.2-0.4 mM arecoline. The mitochondrial membrane potential was thereafter impaired, which was also associated with the induction of apoptosis. Moreover, antioxidant treatments such as lycopene could significantly ameliorate the toxic effects caused by arecoline. In conclusion, arecoline enhances the ROS levels, inducing neurotoxicity, developmental toxicity, and reproductive toxicity in C. elegans through dysregulated oxidative stress, cell apoptosis, and DNA damage-related gene expression. Therefore, the drug-induced production of reactive oxygen species (ROS) may be crucial for its toxic effects, which could be mitigated by antioxidants.
Sujet(s)
Antioxydants , Apoptose , Arécoline , Caenorhabditis elegans , Stress oxydatif , Espèces réactives de l'oxygène , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Arécoline/toxicité , Apoptose/effets des médicaments et des substances chimiques , Stress oxydatif/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolisme , Antioxydants/pharmacologie , Altération de l'ADN , Reproduction/effets des médicaments et des substances chimiques , Longévité/effets des médicaments et des substances chimiques , Potentiel de membrane mitochondriale/effets des médicaments et des substances chimiques , Oviposition/effets des médicaments et des substances chimiquesRÉSUMÉ
Pharmacological inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway with rapamycin can extend lifespan in several organisms. Although this includes the nematode Caenorhabditis elegans, effects in this species are relatively weak and sometimes difficult to reproduce. Here we test effects of drug dosage and timing of delivery to establish the upper limits of its capacity to extend life, and investigate drug effects on age-related pathology and causes of mortality. Liposome-mediated rapamycin treatment throughout adulthood showed a dose-dependent effect, causing a maximal 21.9% increase in mean lifespan, but shortening of lifespan at the highest dose, suggesting drug toxicity. Rapamycin treatment of larvae delayed development, weakly reduced fertility and modestly extended lifespan. By contrast, treatment initiated later in life robustly increased lifespan, even from Day 16 (or ~70 years in human terms). The rapalog temsirolimus extended lifespan similarly to rapamycin, but effects of everolimus were weaker. As in mouse, rapamycin had mixed effects on age-related pathologies, inhibiting one (uterine tumor growth) but not several others, suggesting a segmental antigeroid effect. These findings should usefully inform future experimental studies with rapamycin and rapalogs in C. elegans.
Sujet(s)
Vieillissement , Caenorhabditis elegans , Longévité , Inhibiteurs de mTOR , Sirolimus , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Sirolimus/pharmacologie , Sirolimus/analogues et dérivés , Vieillissement/effets des médicaments et des substances chimiques , Vieillissement/physiologie , Longévité/effets des médicaments et des substances chimiques , Inhibiteurs de mTOR/pharmacologie , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Sérine-thréonine kinases TOR/métabolisme , Relation dose-effet des médicaments , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Cryptococcosis is a fungal infection that is becoming increasingly prevalent worldwide, particularly among individuals with compromised immune systems, such as HIV patients. Amphotericin B (AmB) is the first-line treatment mainly combined with flucytosine. The scarcity and the prohibitive cost of this regimen urge the use of fluconazole as an alternative, leading to increased rates of treatment failure and relapses. Therefore, there is a critical need for efficient and cost-effective therapy to enhance the efficacy of AmB. In this study, we evaluated the efficacy of the HIV protease inhibitors (PIs) to synergize the activity of AmB in the treatment of cryptococcosis. Five PIs (ritonavir, atazanavir, saquinavir, lopinavir, and nelfinavir) were found to synergistically potentiate the killing activity of AmB against Cryptococcus strains with Æ©FICI ranging between 0.09 and 0.5 against 20 clinical isolates. This synergistic activity was further confirmed in a time-kill assay, where different AmB/PIs combinations exhibited fungicidal activity within 24 hrs. Additionally, PIs in combination with AmB exhibited an extended post-antifungal effect on treated cryptococcal cells for approximately 10 hrs compared to 4 hours with AmB alone. This promising activity against cryptococcal cells did not exhibit increased cytotoxicity towards treated kidney cells, ruling out the risk of drug combination-induced nephrotoxicity. Finally, we evaluated the efficacy of AmB/PIs combinations in the Caenorhabditis elegans model of cryptococcosis, where these combinations significantly reduced the fungal burden of the treated nematodes by approximately 2.44 Log10 CFU (92.4%) compared to the untreated worms and 1.40 Log10 ((39.4%) compared to AmB alone. The cost-effectiveness and accessibility of PIs in resource-limited geographical areas compared to other antifungal agents, such as flucytosine, make them an appealing choice for combination therapy.
Sujet(s)
Amphotéricine B , Antifongiques , Cryptococcose , Synergie des médicaments , Inhibiteurs de protéase du VIH , Amphotéricine B/pharmacologie , Amphotéricine B/usage thérapeutique , Antifongiques/pharmacologie , Antifongiques/usage thérapeutique , Inhibiteurs de protéase du VIH/usage thérapeutique , Inhibiteurs de protéase du VIH/pharmacologie , Animaux , Cryptococcose/traitement médicamenteux , Humains , Caenorhabditis elegans/microbiologie , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Tests de sensibilité microbienne , Cryptococcus neoformans/effets des médicaments et des substances chimiques , Association de médicaments , Ritonavir/usage thérapeutique , Ritonavir/pharmacologie , Cryptococcus/effets des médicaments et des substances chimiquesRÉSUMÉ
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bge. (SMB) is an herbal medicine extensively used for improving metabolic disorders, including Nonalcoholic fatty liver disease (NAFLD). However, the potential material basis and working mechanism still remained to be elucidated. AIM OF THE STUDY: To find potential ingredients for therapy of NAFLD by high content screening and further verify the efficacy on restoring hepatic steatosis and insulin resistance, and clarify the potential working mechanism. MATERIALS AND METHODS: The mouse transcription factor EB (Tfeb) in preadipocytes was knocked out by CRISPR-Cas9 gene editing. High content screening of TFEB nuclear translocation was performed to identify TFEB activators. The effect of candidate compounds on reducing lipid accumulation was evaluated using Caenorhabditis elegans (C. elegans). Then the role of Salvia miltiorrhiza extract (SMB) containing Tanshinone IIA and the derivatives were further investigated on high-fat diet (HFD) fed mice. RNA-seq was performed to explore potential molecular mechanism of SMB. Finally, the gut microbiota diversity was evaluated using 16S rRNA sequencing to investigate the protective role of SMB on regulating gut microbiota homeostasis. RESULTS: Knockout of Tfeb led to excessive lipid accumulation in adipocytes while expression of TFEB homolog HLH-30 in C. elegans (MAH240) attenuated lipid deposition. Screening of TFEB activators identified multiple candidates from Salvia miltiorrhiza, all of them markedly induced lysosome biogenesis in HepG2 cells. One of the candidate compounds Tanshinone IIA significantly decreased lipid droplet deposition in HFD fed C. elegans. Administration of SMB on C57BL/6J mice via gastric irrigation at the dose of 15 g/kg/d markedly alleviated hepatic steatosis, restored serum lipid profile, and glucose tolerance. RNA-seq showed that gene expression profile was altered and the genes related to lipid metabolism were restored. The disordered microbiome was remodeled by SMB, Firmicutes and Actinobacteriotawere notably reduced, Bacteroidota and Verrucomicrobiota were significantly increased. CONCLUSION: Taken together, the observations presented here help address the question concerning what were the main active ingredients in SMB for alleviating NAFLD, and established that targeting TFEB was key molecular basis for the efficacy of SMB.
Sujet(s)
Abiétanes , Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines , Caenorhabditis elegans , Insulinorésistance , Souris de lignée C57BL , Salvia miltiorrhiza , Animaux , Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines/métabolisme , Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines/génétique , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Abiétanes/pharmacologie , Souris , Mâle , Stéatose hépatique non alcoolique/traitement médicamenteux , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Extraits de plantes/pharmacologie , Métabolisme lipidique/effets des médicaments et des substances chimiques , Alimentation riche en graisse , Cellules 3T3-L1RÉSUMÉ
Diazepam (DZP) is a sedative medication prescribed to treat anxiety and as a sleep inducer, although its residual effects are unfavorable to patients. Nanotechnology represents a tool to improve the pharmacological characteristics of drugs, reducing their side effects. This study aimed to develop and characterize DZP nanocapsules and to evaluate their toxicity in alternative models and the hypnotic-sedative effect in mice. Nanocapsules were prepared by the nanoprecipitation method and properly characterized. Long-term and accelerated stability studies were performed. The in vitro release profile was determined by diffusion in Franz cells. The safety of the formulation was evaluated in the Caenorhabditis elegans (C. elegans) and the oral acute toxicity in mice. Pharmacological evaluation was performed using thiopental-induced sleeping time. DZP was successfully incorporated into Poly-(É-caprolactone) (PCL) nanocapsules, with high entrapment efficiency. The nanocapsule did not affect the development or survival of C. elegans, different from the free drug, which affected the nematode development at the higher tested dose. No signs of toxicity, nor body mass or feed consumption changes were observed during the 14 days evaluated. Finally, this innovative formulation carrying DZP can produce a hypnotic-effect at a reduced dose compared to the free drug, with no toxicity in alternative models.
Sujet(s)
Caenorhabditis elegans , Diazépam , Hypnotiques et sédatifs , Nanocapsules , Sommeil , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Nanocapsules/toxicité , Nanocapsules/composition chimique , Hypnotiques et sédatifs/toxicité , Hypnotiques et sédatifs/pharmacologie , Souris , Diazépam/toxicité , Diazépam/pharmacologie , Sommeil/effets des médicaments et des substances chimiques , Mâle , FemelleRÉSUMÉ
Alcohol tolerance is a neuroadaptive response that leads to a reduction in the effects of alcohol caused by previous exposure. Tolerance plays a critical role in the development of alcohol use disorder (AUD) because it leads to the escalation of drinking and dependence. Understanding the molecular mechanisms underlying alcohol tolerance is therefore important for the development of effective therapeutics and for understanding addiction in general. This review explores the molecular basis of alcohol tolerance in invertebrate models, Drosophila and C. elegans, focusing on synaptic transmission. Both organisms exhibit biphasic responses to ethanol and develop tolerance similar to that of mammals. Furthermore, the availability of several genetic tools makes them a great candidate to study the molecular basis of ethanol response. Studies in invertebrate models show that tolerance involves conserved changes in the neurotransmitter systems, ion channels, and synaptic proteins. These neuroadaptive changes lead to a change in neuronal excitability, most likely to compensate for the enhanced inhibition by ethanol.
Sujet(s)
Caenorhabditis elegans , Éthanol , Plasticité neuronale , Transmission synaptique , Animaux , Plasticité neuronale/effets des médicaments et des substances chimiques , Éthanol/pharmacologie , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/physiologie , Caenorhabditis elegans/métabolisme , Transmission synaptique/effets des médicaments et des substances chimiques , Tolérance aux médicaments , Synapses/métabolisme , Synapses/effets des médicaments et des substances chimiques , Synapses/physiologie , Alcoolisme/métabolisme , Drosophila/physiologie , Humains , Invertébrés/physiologieRÉSUMÉ
AREAS COVERED: This paper outlines the selection of NAMs, including in vitro assays using primary rat cortical neurons, zebrafish embryos, and Caenorhabditis elegans. These assays aim to assess neurotoxic endpoints such as neuronal activity and behavioral responses. Microelectrode array recordings of rat cortical neurons provide insights into the impact of botanical extracts on neuronal function, while the zebrafish embryos and C. elegans assays evaluate neurobehavioral responses. The paper also provides an account of the selection of botanical case studies based on expert judgment and existing neuroactivity/toxicity information. The proposed battery of assays will be tested with these case studies to evaluate their utility for neurotoxicity screening. EXPERT OPINION: The complexity of botanicals necessitates the use of multiple NAMs for effective neurotoxicity screening. This paper discusses the evaluation of methodologies to develop a robust framework for evaluating botanical safety, including complex neuronal models and key neurodevelopmental process assays. It aims to establish a comprehensive screening framework.
Sujet(s)
Caenorhabditis elegans , Neurones , Syndromes neurotoxiques , Tests de toxicité , Danio zébré , Animaux , Neurones/effets des médicaments et des substances chimiques , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Rats , Syndromes neurotoxiques/diagnostic , Syndromes neurotoxiques/étiologie , Humains , Tests de toxicité/méthodes , Extraits de plantes/effets indésirables , Extraits de plantes/pharmacologie , Extraits de plantes/administration et posologie , Évaluation préclinique de médicament/méthodes , Préparations à base de plantes/effets indésirables , Préparations à base de plantes/toxicité , Préparations à base de plantes/pharmacologie , Embryon non mammalien/effets des médicaments et des substances chimiquesRÉSUMÉ
The natural antimicrobial properties of essential oils (EOs) have contributed to the battle against multidrug-resistant microorganisms by providing new ways to develop more effective antibiotic agents. In this study, we investigated the chemical composition of Ocotea diospyrifolia essential oil (OdOE) and its antimicrobial properties combined with amikacin (AMK). Through gas chromatography-mass spectrometry (GCMS) analysis, the primary constituents of OdOE were identified as α-bisabolol (45.8 %), ß-bisabolene (9.4 %), γ-elemene (7.6 %), (Z)- ß-farnesene (5.2 %), spathulenol (3.5 %), (Z)-caryophyllene (3.3 %), and (E)-caryophyllene (3.1 %). In vitro assessments showed that the combined administration of OdOE and AMK exerted a synergistic antibacterial effect on the multidrug-resistant K. pneumoniae strain. This synergistic effect demonstrated bacteriostatic action. OdEO combined with amikacin showed protein extravasation within 2 h of treatment, leading to bacterial death, which was determined by a reduction in viable cell count. The effective concentrations showed hemocompatibility. In vivo assessments using Caenorhabditis elegans as a model showed the survival of 85 % of infected nematodes. Therefore, the combination OdEO combined with amikacin exhibited antimicrobial activity against a multidrug-resistant K. pneumoniae strain. Thus, OdOE is a promising agent that may be considered for development of antimicrobial treatment.
Sujet(s)
Amikacine , Antibactériens , Multirésistance bactérienne aux médicaments , Synergie des médicaments , Klebsiella pneumoniae , Tests de sensibilité microbienne , Huile essentielle , Amikacine/pharmacologie , Huile essentielle/pharmacologie , Huile essentielle/composition chimique , Animaux , Multirésistance bactérienne aux médicaments/effets des médicaments et des substances chimiques , Antibactériens/pharmacologie , Klebsiella pneumoniae/effets des médicaments et des substances chimiques , Chromatographie gazeuse-spectrométrie de masse , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Infections à Klebsiella/traitement médicamenteux , Infections à Klebsiella/microbiologie , Sesquiterpènes monocycliques/pharmacologie , Sesquiterpènes polycycliques/pharmacologie , Sesquiterpènes polycycliques/composition chimique , Sesquiterpènes/pharmacologieRÉSUMÉ
Two concentrations (6.25 and 1.25 mg/L) were used for two Parkinson's disease medications, Benserazide, and Trihexyphenidyl, to test their effects on the meiobenthic nematofauna. It is predicted that these highly hydrosoluble drugs will end up in marine environments. The results showed that both medications when added alone, induced (i) important changes in the numbers and (ii) taxonomic composition. The impact of Benserazide and Trihexyphenidyl was also reflected in the (iii) functional traits of nematofauna, with the most affected categories following exposure being the trophic group 1B, the clavate tails, the circular amphids, the c-p2 life history, and the body length of 1-2 mm. These results were supported by the molecular interactions of the studied drugs with both GLD-3 and SDP proteins of Caenorhabditis elegans. (iv) The mixtures of both drugs did not show any changes in the nematode communities, suggesting that no synergistic or antagonistic interactions exist between them.
Sujet(s)
Antiparkinsoniens , Bensérazide , Caenorhabditis elegans , Trihexyphénidyle , Animaux , Antiparkinsoniens/pharmacologie , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/physiologie , Polluants chimiques de l'eau , Nematoda/effets des médicaments et des substances chimiquesRÉSUMÉ
Pseudomonas aeruginosa (P. aeruginosa) biofilm formation is a crucial cause of enhanced antibiotic resistance. Quorum sensing (QS) is involved in regulating biofilm formation; QS inhibitors block the QS signaling pathway as a new strategy to address bacterial resistance. This study investigated the potential and mechanism of L-HSL (N-(3-cyclic butyrolactone)-4-trifluorophenylacetamide) as a QS inhibitor for P. aeruginosa. The results showed that L-HSL effectively inhibited the biofilm formation and dispersed the pre-formed biofilm of P. aeruginosa. The production of extracellular polysaccharides and the motility ability of P. aeruginosa were suppressed by L-HSL. C. elegans infection experiment showed that L-HSL was non-toxic and provided protection to C. elegans against P. aeruginosa infection. Transcriptomic analysis revealed that L-HSL downregulated genes related to QS pathways and biofilm formation. L-HSL exhibits a promising potential as a therapeutic drug for P. aeruginosa infection. KEY POINTS: ⢠Chemical synthesis of N-(3-cyclic butyrolactone)-4-trifluorophenylacetamide, named L-HSL. ⢠L-HSL does not generate survival pressure on the growth of P. aeruginosa and can inhibit the QS system. ⢠KEGG enrichment analysis found that after L-HSL treatment, QS-related genes were downregulated.
Sujet(s)
4-Butyrolactone , Biofilms , Caenorhabditis elegans , Pseudomonas aeruginosa , Détection du quorum , Pseudomonas aeruginosa/effets des médicaments et des substances chimiques , Pseudomonas aeruginosa/physiologie , Pseudomonas aeruginosa/génétique , Biofilms/effets des médicaments et des substances chimiques , Biofilms/croissance et développement , Détection du quorum/effets des médicaments et des substances chimiques , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/microbiologie , Animaux , 4-Butyrolactone/analogues et dérivés , 4-Butyrolactone/pharmacologie , 4-Butyrolactone/métabolisme , Antibactériens/pharmacologie , Analyse de profil d'expression de gènes , Homosérine/analogues et dérivés , Homosérine/métabolisme , Homosérine/pharmacologie , Régulation de l'expression des gènes bactériens/effets des médicaments et des substances chimiquesRÉSUMÉ
Micro-nano plastics have been reported as important carriers of polycyclic aromatic hydrocarbons (PAHs) for long-distance migration in the environment. However, the combined toxicity from long-term chronic exposure beyond the vehicle-release mechanism remains elusive. In this study, we investigated the synergistic action of Benzo[a]pyrene (BaP) and Polystyrene nanoparticles (PS) in Caenorhabditis elegans (C. elegans) as a combined exposure model with environmental concentrations. We found that the combined exposure to BaP and PS, as opposed to single exposures at low concentrations, significantly shortened the lifespan of C. elegans, leading to the occurrence of multiple senescence phenotypes. Multi-omics data indicated that the combined exposure to BaP and PS is associated with the disruption of glutathione homeostasis. Consequently, the accumulated reactive oxygen species (ROS) cannot be effectively cleared, which is highly correlated with mitochondrial dysfunction. Moreover, the increase in ROS promoted lipid peroxidation in C. elegans and downregulated Ferritin-1 (Ftn-1), resulting in ferroptosis and ultimately accelerating the aging process of C. elegans. Collectively, our study provides a new perspective to explain the long-term compound toxicity caused by BaP and PS at real-world exposure concentrations.
Sujet(s)
Benzo[a]pyrène , Caenorhabditis elegans , Ferroptose , Mitochondries , Espèces réactives de l'oxygène , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/physiologie , Benzo[a]pyrène/toxicité , Mitochondries/effets des médicaments et des substances chimiques , Ferroptose/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolisme , Nanoparticules/toxicité , Microplastiques/toxicité , VieillissementRÉSUMÉ
2K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L displayed improved and broad-spectrum antibacterial activity than temporin-1CEc in vitro. Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, C. elegans and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant Acinetobacter baumannii strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-κB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against A. baumannii uptake into C. elegans, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by A. baumannii. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-κB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.
Sujet(s)
Acinetobacter baumannii , Caenorhabditis elegans , Lipopolysaccharides , Macrophages , Choc septique , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Souris , Acinetobacter baumannii/effets des médicaments et des substances chimiques , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Choc septique/traitement médicamenteux , Choc septique/induit chimiquement , Choc septique/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Peptides antimicrobiens/pharmacologie , Peptides antimicrobiens/composition chimique , Humains , p38 Mitogen-Activated Protein Kinases/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Inflammation/traitement médicamenteux , Inflammation/métabolisme , Antibactériens/pharmacologie , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/composition chimique , Stress oxydatif/effets des médicaments et des substances chimiques , Mitogen-Activated Protein Kinases , Protéines de Caenorhabditis elegansRÉSUMÉ
Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is a stress-responsive hub that inhibits the translation elongation factor eEF2, and consequently mRNA translation elongation, in response to hypoxia and nutrient deprivation. EEF2K is also involved in the response to DNA damage but its role in response to DNA crosslinks, as induced by cisplatin, is not known. Here we found that eEF2K is critical to mediate the cellular response to cisplatin. We uncovered that eEF2K deficient cells are more resistant to cisplatin treatment. Mechanistically, eEF2K deficiency blunts the activation of the DNA damage response associated ATM and ATR pathways, in turn preventing p53 activation and therefore compromising induction of cisplatin-induced apoptosis. We also report that loss of eEF2K delays the resolution of DNA damage triggered by cisplatin, suggesting that eEF2K contributes to DNA damage repair in response to cisplatin. In support of this, our data shows that eEF2K promotes the expression of the DNA repair protein ERCC1, critical for the repair of cisplatin-caused DNA damage. Finally, using Caenorhabditis elegans as an in vivo model, we find that deletion of efk-1, the worm eEF2K ortholog, mitigates the induction of germ cell death in response to cisplatin. Together, our data highlight that eEF2K represents an evolutionary conserved mediator of the DNA damage response to cisplatin which promotes p53 activation to induce cell death, or alternatively facilitates DNA repair, depending on the extent of DNA damage.
Sujet(s)
Caenorhabditis elegans , Cisplatine , Altération de l'ADN , Elongation Factor 2 Kinase , Protéine p53 suppresseur de tumeur , Cisplatine/pharmacologie , Protéine p53 suppresseur de tumeur/métabolisme , Protéine p53 suppresseur de tumeur/génétique , Elongation Factor 2 Kinase/métabolisme , Elongation Factor 2 Kinase/génétique , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/génétique , Caenorhabditis elegans/métabolisme , Humains , Réparation de l'ADN/effets des médicaments et des substances chimiques , Protéines mutées dans l'ataxie-télangiectasie/métabolisme , Apoptose/effets des médicaments et des substances chimiquesRÉSUMÉ
Milk-derived peptides and milk fat globule membrane (MFGM) have gained interest as health-promoting food ingredients. However, the mechanisms by which these nutraceuticals modulate the function of biological systems often remain unclear. We utilized Caenorhabditis elegans to elucidate how MFGM-containing protein powder (MProPow), previously used in a clinical trial, affect the physiology of this model organism. Our results demonstrate that MProPow does not affect lifespan but promotes the fitness of the animals. Surprisingly, gene expression analysis revealed that MProPow decreases the expression of genes functioning on innate immunity, which also translates into reduced survival on pathogenic bacteria. One of the innate immunity-associated genes showing reduced expression upon MProPow supplementation is cpr-3, the homolog of human cathepsin B. Interestingly, knockdown of cpr-3 enhances fitness, but not in MProPow-treated animals, suggesting that MProPow contributes to fitness by downregulating the expression of this gene. In summary, this research highlights the value of C. elegans in testing the biological activity of food supplements and nutraceuticals. Furthermore, this study should encourage investigations into whether milk-derived peptides and MFGM mediate their beneficial effects through the modulation of cathepsin B expression in humans.