Biology subjects

Beaudry, F.

Publications and source records attributed to Beaudry, F..

15 recordsLinked to original sources

bioRxiv2026

Structural conservation of the gabapentinoid binding site in human and Caenorhabditis elegans α2δ subunits: a docking and molecular dynamics perspective

Pain is a global health burden, highlighting the need for effective therapeutic strategies. Gabapentin (GBP) and pregabalin (PGB), used for neuropathic pain, act primarily through 2{delta} auxiliary subunits of voltage-gated calcium channels. Caenorhabditis elegans expresses UNC-36, an ortholog of mammalian 2{delta} proteins involved in calcium-channel function and nocifensive behavior. However, whether UNC-36 preserves the molecular features required for gabapentinoid recognition remains unclear. We compared human 2{delta}-1 and UNC-36 using sequence and structural analyses, molecular docking, 500-ns molecular dynamics simulations, interaction profiling, principal component and free-energy landscape analyses, and MM/GBSA calculations. UNC-36 preserved the overall architecture of the mammalian gabapentinoid-binding region despite substantial sequence divergence, and both ligands remained associated with the modeled pockets. However, residue-level interaction networks differed between species. Human 2{delta}-1 showed greater contributions from aromatic interactions, whereas UNC-36 relied more prominently on cationic and hydrogen-bond donor interactions mediated by Arg501 and Arg503. The human 2{delta}-1-PGB complex maintained the most stable ligand pose, whereas 2{delta}-1-GBP showed greater positional variation. In UNC-36, PGB exhibited greater deviation from its initial binding pose than GBP. The first two principal components accounted for more conformational variance in UNC-36 complexes than in human complexes. MM/GBSA estimates showed that PGB was energetically favored over GBP in human 2{delta}-1, whereas GBP was favored over PGB in UNC-36. These findings show that conservation of the gabapentinoid-binding architecture is accompanied by species-specific differences in interaction chemistry, conformational dynamics, and estimated binding energetics, providing a molecular basis for interpreting C. elegans gabapentinoid responses in a translational context.

molecular biology↗

bioRxiv2025

Terpenes as Modulators of Nociceptive Signaling: Behavioral and Molecular Insights from Caenorhabditis elegans

Terpenes such as Limonene and {beta}-Caryophyllene have demonstrated pain-modulating properties, potentially through interactions with TRPV1 receptors. This study examines the antinociceptive effects of four terpenes derived from Cannabis sativa: Limonene, {beta}-Caryophyllene, -Humulene, and -Myrcene using Caenorhabditis elegans (C. elegans). The primary objective was to characterize terpene-induced modulation of nocifensive responses to noxious heat, and to elucidate their influence on molecular pathways via specific receptor targets. Thermotaxis assays quantified the antinociceptive activity of increasing terpene concentrations in wild-type nematodes. To assess receptor-specific mechanisms, assays were performed in mutant strains lacking functional OCR-2 and OSM-9 (TRPV-like vanilloid nociceptors), and NPR-19 and NPR-32 (encoding cannabinoid-like receptors). Proteomic profiling coupled with bioinformatics analysis identified terpene-induced alterations in signaling pathways and biological processes. All four terpenes exhibited significant antinociceptive activity in wild-type C. elegans, with impaired effects observed in vanilloid receptor mutants, implicating TRPV-like channels in their mechanism of action. Proteomic and pathway analyses revealed terpene-specific molecular signatures, highlighting differential modulation of neuronal and stress-responsive signaling cascades. By elucidating the molecular mechanisms underlying terpene-induced nociceptive modulation, this work strengthens the growing body of evidence supporting the therapeutic promise of terpenes in pain management outside the effect referred to as the "entourage effect."

pharmacology and toxicology↗

bioRxiv2025

Fatty Acid Pathways Regulate Thermal Nociception in Caenorhabditis elegans

Chronic pain remains a major unmet medical challenge, and lipid signaling pathways have emerged as key modulators of nociception. Using Caenorhabditis elegans as a genetically tractable model, we investigated how fatty acid composition influences thermal avoidance behavior. Mutant strains lacking functional desaturase enzymes (elo-1, fat-1, fat-2, fat-3, fat-4, fat-6/fat-7), and consequently depleted in polyunsaturated fatty acids (PUFAs) such as arachidonic acid, displayed significantly reduced sensitivity to noxious heat compared to wild-type animals. These findings indicate that intact PUFA biosynthesis is essential for normal thermal nociception in C. elegans. Given that arachidonic acid is a precursor of endocannabinoids (AEA and 2-AG) known to modulate TRPV1-dependent pain signaling, our results suggest that a conserved lipid-based mechanism regulates heat avoidance in nematodes. This study establishes a functional link between fatty acid metabolism and nociceptive behavior, providing a powerful platform to explore metabolic modulation of pain pathways.

neuroscience↗

bioRxiv2025

Cannabivarin and Tetrahydrocannabivarin Modulate Nociception via Vanilloid Channels and Cannabinoid-Like Receptors in Caenorhabditis elegans

Cannabis has attracted growing interest for its therapeutic potential, especially in pain management. This study explores the antinociceptive effects of two promising non-psychoactive cannabinoids, cannabivarin (CBV) and tetrahydrocannabivarin (THCV), using Caenorhabditis elegans (C. elegans), a nematode model that expresses homologs of mammalian cannabinoid and vanilloid receptors. Thermotaxis assays were employed to quantify the antinociceptive effects of CBV and THCV in C. elegans. Wild-type animals were exposed to increasing concentrations of each compound to establish dose-response relationships. To investigate potential molecular targets, additional experiments were performed using mutant strains deficient in vanilloid receptor homologs (OCR-2 and OSM-9) and cannabinoid receptor homologs (NPR-19 and NPR-32). Mass spectrometry-based proteomics combined with network biology analyses were used to identify the biological pathways associated with drug response. Results confirmed that both compounds elicit dose-dependent antinociceptive effects. Mutant analyses support the involvement of vanilloid and cannabinoid signaling pathways in mediating these responses. These findings highlight the potential of CBV and THCV as non-psychoactive analgesic agents and support further research into their mechanisms of action and translational relevance for mammalian pain management.

pharmacology and toxicology↗

bioRxiv2024

Translational control in the spinal cord regulates gene expression and pain hypersensitivity in the chronic phase of neuropathic pain

Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell-type-specific profiling revealed that spinal inhibitory and excitatory neurons exhibited substantial changes in translation after peripheral nerve injury. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV+) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV+ neurons decreased their intrinsic excitability and spiking activity. Conversely, reducing translation in spinal PV neurons prevented the nerve injury-induced decrease in excitability but did not alleviate mechanical hypersensitivity. Together, these findings advance our understanding of translational control mechanisms in the spinal cord during neuropathic pain and highlight their cell-type- and phase-specific contributions to gene expression and pain hypersensitivity.

neuroscience↗

bioRxiv2022

Deletion of Tac1 gene impact kinase phosphorylation involved in signaling pathways associated with pain

Pain in elderly persons is often not adequately treated, and current treatments may lead to poor outcomes. Therefore, new treatment strategies need to be developed based on a better understanding of the mechanisms underlying the development of chronic pain. Recent studies have shown that Tac1-/- mice display a significant decrease in nociceptive pain responses to moderate or intense stimuli but present no phenotypic changes following light or nonpainful stimuli. Moreover, the deletion of the Tac1 gene led to a deficit of opioid peptides, which are essential to endogenous pain control mechanisms. Thus, we investigated whether Tac1-/- mice show defective pain modulatory pathways by specifically profiling protein kinases in mice spinal cord using phosphoproteomics and bioinformatics. Protein phosphorylation is a key feature of the cellular regulatory mechanism, and phosphorylation status is related to the regulation and modulation of protein-protein binding. Bioinformatics analysis revealed that MAPK, tyrosine kinase, senescence, interleukin signaling, and TCR signaling are modulated in Tac1-/- mice. Interestingly, these processes are intimately linked with inflammatory responses leading to the release of cytokines and chemokines implicated in the interactions and communications between cells. They are key players involved in the initiation and persistence of pathologic pain. The absence of the Tac1 gene products may trigger a much wider cell response to compensate for the lack of important components of the nociceptive pain transmission system.

neuroscience↗

bioRxiv2022

Unbiased proteomic analysis detects painful systemic inflammatory profile in the serum of nerve injured mice

Neuropathic pain is a complex, debilitating disease that results from injury to the somatosensory nervous system. The presence of systemic chronic inflammation has been observed in chronic pain patients, but whether it plays a causative role remains unclear. This study aims to determine the perturbation of systemic homeostasis by an injury to peripheral nerve and its involvement in neuropathic pain. We assessed the proteomic profile in the serum of mice at 1-day and 1-month following partial sciatic nerve injury (PSNL) or sham surgery. We also assessed mouse mechanical and cold sensitivity in naive mice after receiving intravenous administration of serum from PSNL or sham mice. Mass spectrometry-based proteomic analysis revealed that PSNL resulted in a long-lasting alteration of serum proteome, where the majority of differentially expressed proteins were in inflammation related pathways, involving cytokines/chemokines, autoantibodies and complement factors. While transferring sham serum to naive mice did not change their pain sensitivity, PSNL serum significantly lowered mechanical thresholds and induced cold hypersensitivity in naive mice. With broad anti-inflammatory properties, bone marrow cell extracts (BMCE) not only partially restored serum proteomic homeostasis, but also significantly ameliorated PSNL-induced mechanical allodynia, and serum from BMCE-treated PSNL mice no longer induced hypersensitivity in naive mice. These findings clearly demonstrate that nerve injury has a long-lasting impact on systemic homeostasis, and nerve injury associated systemic inflammation contributes to the development of neuropathic pain.

neuroscience↗

bioRxiv2022

Janus Kinase 3 phosphorylation and the JAK/STAT pathway are positively modulated by follicle-stimulating hormone (FSH) in bovine granulosa cells.

JAK3 is a member of the JAK family of tyrosine kinase proteins involved in cytokine receptor-mediated intracellular signal transduction through the JAK/STAT signaling pathway. JAK3 was shown as differentially expressed in granulosa cells (GC) of bovine pre-ovulatory follicles suggesting that JAK3 could modulate GC function and activation/inhibition of downstream targets. We used JANEX-1, a JAK3 inhibitor, and FSH treatments and analyzed proliferation markers, steroidogenic enzymes and phosphorylation of target proteins including STAT3, CDKN1B/p27Kip1 and MAPK8IP3/JIP3. GC were treated with or without FSH in the presence or not of JANEX-1. Expression of steroidogenic enzyme CYP11A1, but not CYP19A1, was upregulated in GC treated with FSH and both were significantly decreased when JAK3 was inhibited. Proliferation markers CCND2 and PCNA were reduced in JANEX-1-treated GC and upregulated by FSH. Western blots analyses showed that JANEX-1 treatment reduced pSTAT3 amounts while JAK3 overexpression increased pSTAT3. Similarly, FSH treatment increased pSTAT3 even in JANEX-1-treated GC. UHPLC-MS/MS analyses revealed phosphorylation of specific amino acid residues within JAK3 as well as CDKN1B and MAPK8IP3 suggesting possible activation or inhibition post-FSH or JANEX-1 treatments. We show that FSH activates JAK3 in GC, which could phosphorylate target proteins and likely modulate other signaling pathways involving CDKN1B and MAPK8IP3.

molecular biology↗

bioRxiv2021

Resiniferatoxin hampers the nocifensive response of Caenorhabditis elegans to noxious heat, and pathway analysis revealed that the Wnt signaling pathway is involved

Resiniferatoxin (RTX) is a metabolite extracted from Euphorbia resinifera. RTX is a potent capsaicin analog with specific biological activities resulting from its agonist activity with the transient receptor potential channel vanilloid subfamily member 1 (TRPV1). RTX has been examined as a pain reliever, and more recently, investigated for its ability to desensitize cardiac sensory fibers expressing TRPV1 to improve chronic heart failure (CHF) outcomes using validated animal models. Caenorhabditis elegans (C. elegans) expresses orthologs of vanilloid receptors activated by capsaicin, producing antinociceptive effects. Thus, we used C. elegans to characterize the antinociceptive properties and performed proteomic profiling to uncover specific signaling networks. After exposure to RTX, wild-type (N2) and mutant C. elegans were placed on petri dishes divided into quadrants for heat stimulation. The thermal avoidance index was used to phenotype each tested C. elegans experimental group. The data revealed for the first time that RTX can hamper the nocifensive response of C. elegans to noxious heat (32{degrees}C - 35{degrees}C). The effect was reversed 6 h after RTX exposure. Additionally, we identified the RTX target, the C. elegans transient receptor potential channel OCR-3. The proteomics and pathway enrichment analysis results suggest that Wnt signaling is triggered by the agonistic effects of RTX on C. elegans vanilloid receptors.

neuroscience↗

bioRxiv2020

Vanilloids Hamper Caenorhabditis elegans Response to Noxious Heat

Eugenol, a known vanilloid, was frequently used in dentistry as a local analgesic in addition, antibacterial and neuroprotective effects were also reported. Eugenol, capsaicin and many vanilloids are interacting with the transient receptor potential vanilloid 1 (TRPV1) in mammals and are activated by noxious heat. The pharmacological manipulation of the TRPV1 has been shown to have therapeutic value. Caenorhabditis elegans (C. elegans) express TRPV orthologs (e.g. OCR-2, OSM-9) and it is a commonly used animal model system to study nociception as it displays a well-defined and reproducible nocifensive behavior. After exposure to vanilloid solutions, C. elegans wild type (N2) and mutants were placed on petri dishes divided in quadrants for heat stimulation. Thermal avoidance index was used to phenotype each tested C. elegans experimental groups. The results showed that eugenol, vanillin and zingerone can hamper nocifensive response of C. elegans to noxious heat (32{degrees}C - 35{degrees}C) following a sustained exposition. Also, the effect was reversed 6h post exposition. Furthermore, eugenol and vanillin did not target specifically the OCR-2 or OSM-9 but zingerone did specifically target the OCR-2 similarly to capsaicin. Further structural and physicochemical analyses were performed. Key parameters for quantitative structure-property relationships (QSPR), quantitative structure-activity relationships (QSAR) and frontier orbital analyses suggest similarities and dissimilarities amongst the tested vanilloids and capsaicin in accordance with the relative anti-nociceptive effects observed.

pharmacology and toxicology↗

bioRxiv2020

Capsaicin and its analogues impede nocifensive response of Caenorhabditis elegans to noxious heat

Capsaicin is the most abundant pungent molecule identified in red chili peppers, and it is widely used for food flavoring, in pepper spray for self-defense devices and recently in ointments for the relief of neuropathic pain. Capsaicin and several other related vanilloid compounds are secondary plant metabolites. Capsaicin is a selective agonist of the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). After exposition to vanilloid solution, C. elegans wild type (N2) and mutants were placed on petri dishes divided in quadrants for heat stimulation. Thermal avoidance index was used to phenotype each tested C. elegans experimental groups. The data revealed for the first-time that capsaicin can impede nocifensive response of C. elegans to noxious heat (32{degrees}C - 35{degrees}C) following a sustained exposition. The effect was reversed 6h post capsaicin exposition. Additionally, we identified the capsaicin target, the C. elegans transient receptor potential channel OCR-2. Further experiments also undoubtedly revealed anti-nociceptive effect for capsaicin analogues, including ginger (Zingiber officinale) and turmeric (Curcuma longa) secondary metabolites.

neuroscience↗

bioRxiv2019

Evaluation of Upconverting nanoparticles towards heart theranostics

Restricted and controlled drug delivery to the heart remains a challenge giving frequent off-target effects as well as limited retention of drugs in the heart. There is a need to develop and optimize tools to allow for improved design of drug candidates for treatment of heart diseases. Over the last decade, novel drug platforms and nanomaterials were designed to confine bioactive materials to the heart. Yet, the research remains in its infancy, not only in the development of tools but also in the understanding of effects of these materials on cardiac function and tissue integrity. Upconverting nanoparticles are nanomaterials that recently accelerated interest in theranostic nanomedicine technologies. Their unique photophysical properties allow for sensitive in vivo imaging that can be combined with spatio-temporal control for targeted release of encapsulated drugs.\n\nHere we synthesized upconverting NaYF4:Yb,Tm nanoparticles and show for the first time their innocuity in the heart, when injected in the myocardium or in the pericardial space in mice. Nanoparticle retention and upconversion in the cardiac region did not alter heart rate variability, nor cardiac function as determined over a 15-day time course ensuing the sole injection. Altogether, our nanoparticles show innocuity primarily in the pericardial region and can be safely used for controlled spatiotemporal drug delivery.\n\nOur results support the use of upconverting nanoparticles as potential theranostics tools overcoming some of the key limitations associated with conventional experimental cardiology.

biophysics↗

bioRxiv2019

Impaired EAT-4 Vesicular Glutamate Transporter Leads to Defective Nocifensive Response of Caenorhabditis elegans to Noxious Heat

In mammals, glutamate is an important excitatory neurotransmitter. Glutamate and glutamate receptors are found in areas specifically involved in pain sensation, transmission and transduction such as peripheral nervous system, spinal cord and brain. In C. elegans, several studies have suggested glutamate pathways are associated with withdrawal responses to mechanical stimuli and to chemical repellents. However, few evidences demonstrate that glutamate pathways are important to mediate nocifensive response to noxious heat. The thermal avoidance behavior of C. elegans was studied and results illustrated that mutants of glutamate receptors (glr-1, glr-2, nmr-1, nmr-2) behaviors was not affected. However, results revealed that all strains of eat-4 mutants, C. elegans vesicular glutamate transporters, displayed defective thermal avoidance behaviors. Due to the interplay between the glutamate and the FLP-18/FLP-21/NPR-1 pathways, we analyzed the effectors FLP-18 and FLP-21 at the protein level, we did not observebiologically significant differences compared to N2 (WT) strain (fold-change < 2) except for the IK602 strain. The data presented in this manuscript reveals that glutamate signaling pathways are essential to elicit a nocifensive response to noxious heat in C. elegans.

neuroscience↗

bioRxiv2019

Ancestral and neo-sex chromosomes contribute to population divergence in a dioecious plant

Empirical evidence from several animal groups suggests that sex chromosomes may disproportionately contribute to reproductive isolation. This occurs particularly when sex chromosomes are associated with turnover of sex determination systems resulting from structural rearrangements to the sex chromosomes. We investigated these predictions in the dioecious plant Rumex hastatulus, which is comprised of populations of two sex chromosome cytotypes. Using population genomic analyses, we investigated the demographic history of R. hastatulus and explored the contributions of ancestral and neo-sex chromosomes to population genetic divergence. Our study revealed that the cytotypes represented genetically divergent populations with evidence for historical but not contemporary gene flow between them. In agreement with classical predictions, we found that the ancestral X chromosome was disproportionately divergent compared with the rest of the genome. Excess differentiation was also observed on the Y chromosome, even when using measures of differentiation that control for differences in effective population size. Our estimates of the timing of the origin of the neo-sex chromosomes in R. hastatulus are coincident with cessation of gene flow, suggesting that the chromosomal fusion event that gave rise to the origin of the XYY cytotype may have also been a key driver of reproductive isolation.

plant biology↗

bioRxiv2019

Escherichia coli O157:H7 responds to phosphate starvation by modifying LPS involved in biofilm formation

In open environments such as water, enterohemorrhagic Escherichia coli O157:H7 responds to inorganic phosphate (Pi) starvation by inducing the Pho regulon controlled by PhoB. The phosphate-specific transport (Pst) system is the high-affinity Pi transporter. In the {Delta}pst mutant, PhoB is constitutively activated and regulates the expression of genes from the Pho regulon. In E. coli O157:H7, the {Delta}pst mutant, biofilm, and autoagglutination were increased. In the double-deletion mutant {Delta}pst {Delta}phoB, biofilm and autoagglutination were similar to the wild-type strain, suggesting that PhoB is involved. We investigated the relationship between PhoB activation and enhanced biofilm formation by screening a transposon mutant library derived from {Delta}pst mutant for decreased autoagglutination and biofilms mutants. Lipopolysaccharide (LPS) genes involved in the synthesis of the LPS core were identified. Transcriptomic studies indicate the influence of Pi-starvation and pst mutation on LPS biosynthetic gene expression. LPS analysis indicated that the O-antigen was deficient in the {Delta}pst mutant. Interestingly, waaH, encoding a glycosyltransferase associated with LPS modifications in E. coli K-12, was highly expressed in the {Delta}pst mutant of E. coli O157:H7. Deletion of waaH from the {Delta}pst mutant and from the wild-type strain grown in Pi-starvation conditions decreased the biofilm formation but without affecting LPS. Our findings suggest that LPS core is involved in the autoagglutination and biofilm phenotypes of the {Delta}pst mutant and that WaaH plays a role in biofilm in response to Pi-starvation. This study highlights the importance of Pi-starvation in biofilm formation of E. coli O157:H7, which may affect its transmission and persistence. IMPORTANCEEnterohemorrhagic Escherichia coli O157:H7 is a human pathogen responsible for bloody diarrhea and renal failures. In the environment, O157:H7 can survive for prolonged periods of time under nutrient-deprived conditions. Biofilms are thought to participate in this environmental lifestyle. Previous reports have shown that the availability of extracellular inorganic phosphate (Pi) affected bacterial biofilm formation; however, nothing was known about O157:H7 biofilm formation. Our results show that O157:H7 membrane undergoes modifications upon PhoB activation leading to increased biofilm formation. A mutation in the Pst system results in reduced amount of the smooth type LPS and that this could influence the biofilm composition. This demonstrates how the E. coli O157:H7 adapts to Pi starvation increasing its ability to occupy different ecological niches.

microbiology↗