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1.
Nucleus ; 13(1): 49-57, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35130129

RESUMO

Lamins are the major constituent of the nuclear lamina, a protein meshwork underlying the inner nuclear membrane. Nuclear lamins are type V intermediate filaments that assemble into ~3.5 nm thick filaments. To date, only the conditions for the in vitro assembly of Caenorhabditis elegans lamin (Ce-lamin) are known. Here, we investigated the assembly of Ce-lamin filaments by cryo-electron microscopy and tomography. We show that Ce-lamin is composed of ~3.5 nm protofilaments that further interact in vitro and are often seen as 6-8 nm thick filaments. We show that the assembly of lamin filaments is undisturbed by the removal of flexible domains, that is, the intrinsically unstructured head and tail domains. In contrast, much of the coiled-coil domains are scaffold elements that are essential for filament assembly. Moreover, our results suggest that Ce-lamin helix 1A has a minor scaffolding role but is important to the lateral assembly regulation of lamin protofilaments.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Microscopia Crioeletrônica , Lamina Tipo A/metabolismo , Laminina , Laminas/metabolismo , Lâmina Nuclear/metabolismo
2.
Methods Enzymol ; 667: 147-181, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35525541

RESUMO

Protein pseudokinases are key regulators of the eukaryotic cell. Understanding their unconventional molecular mechanisms relies on deciphering their putative potential to perform phosphotransfer, their scaffolding properties and the nature of their regulation. Titin pseudokinase (TK) is the defining member of a family of poorly characterized muscle-specific kinases thought to act as sensors and transducers of mechanical signals in the sarcomere. The functional mechanisms of TK remain obscure due to the challenges posed by its production and analysis. Here, we provide guidelines and tailored research approaches for the study of TK, including profiting from its close structure-function relationship to the catalytically active homolog twitchin kinase (TwcK) from C. elegans. We describe a methodological pipeline to produce recombinant TK and TwcK samples; design, prioritize and validate mutated and truncated variants; assess sample stability and perform activity assays. The strategy is exportable to other pseudokinase members of the TK-like kinase family.


Assuntos
Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Conectina/genética
3.
PLoS Genet ; 18(5): e1010178, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35511794

RESUMO

Animals integrate changes in external and internal environments to generate behavior. While neural circuits detecting external cues have been mapped, less is known about how internal states like hunger are integrated into behavioral outputs. Here, we use the nematode C. elegans to examine how changes in internal nutritional status affect chemosensory behaviors. We show that acute food deprivation leads to a reversible decline in repellent, but not attractant, sensitivity. This behavioral change requires two conserved transcription factors MML-1 (MondoA) and HLH-30 (TFEB), both of which translocate from the intestinal nuclei to the cytoplasm during food deprivation. Next, we identify the insulin-like peptide INS-31 as a candidate ligand relaying food-status signals from the intestine to other tissues. Further, we show that neurons likely use the DAF-2 insulin receptor and AGE-1/PI-3 Kinase, but not DAF-16/FOXO to integrate these intestine-released peptides. Altogether, our study shows how internal food status signals are integrated by transcription factors and intestine-neuron signaling to generate flexible behaviors via the gut-brain axis.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead , Insulina , Intestinos , Assunção de Riscos , Fatores de Transcrição/genética
4.
PLoS One ; 17(5): e0267698, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35511952

RESUMO

Ultrasound has been shown to affect the function of both neurons and non-neuronal cells, but, the underlying molecular machinery has been poorly understood. Here, we show that at least two mechanosensitive proteins act together to generate C. elegans behavioral responses to ultrasound stimuli. We first show that these animals generate reversals in response to a single 10 msec pulse from a 2.25 MHz ultrasound transducer. Next, we show that the pore-forming subunit of the mechanosensitive channel TRP-4, and a DEG/ENaC/ASIC ion channel MEC-4, are both required for this ultrasound-evoked reversal response. Further, the trp-4;mec-4 double mutant shows a stronger behavioral deficit compared to either single mutant. Finally, overexpressing TRP-4 in specific chemosensory neurons can rescue the ultrasound-triggered behavioral deficit in the mec-4 null mutant, suggesting that both TRP-4 and MEC-4 act together in affecting behavior. Together, we demonstrate that multiple mechanosensitive proteins likely cooperate to transform ultrasound stimuli into behavioral changes.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Canais Iônicos/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/metabolismo
5.
Cell Mol Life Sci ; 79(5): 274, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35503478

RESUMO

Polyglutamine (PolyQ) diseases include a group of inherited neurodegenerative disorders caused by unstable expansions of CAG trinucleotide repeats in the coding region of specific genes. Such genetic alterations produce abnormal proteins containing an unusually long PolyQ tract that renders them more prone to aggregate and cause toxicity. Although research in the field in the last years has contributed significantly to the knowledge of the biological mechanisms implicated in these diseases, effective treatments are still lacking. In this review, we revisit work performed in models of PolyQ diseases, namely the yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster, and provide a critical overview of the high-throughput unbiased genetic screens that have been performed using these systems to identify novel genetic modifiers of PolyQ diseases. These approaches have revealed a wide variety of cellular processes that modulate the toxicity and aggregation of mutant PolyQ proteins, reflecting the complexity of these disorders and demonstrating how challenging the development of therapeutic strategies can be. In addition to the unbiased large-scale genetic screenings in non-vertebrate models, complementary studies in mammalian systems, closer to humans, have contributed with novel genetic modifiers of PolyQ diseases, revealing neuronal function and inflammation as key disease modulators. A pathway enrichment analysis, using the human orthologues of genetic modifiers of PolyQ diseases clustered modifier genes into major themes translatable to the human disease context, such as protein folding and transport as well as transcription regulation. Innovative genetic strategies of genetic manipulation, together with significant advances in genomics and bioinformatics, are taking modifier genetic studies to more realistic disease contexts. The characterization of PolyQ disease modifier pathways is of extreme relevance to reveal novel therapeutic possibilities to delay disease onset and progression in patients.


Assuntos
Drosophila melanogaster , Peptídeos , Animais , Caenorhabditis elegans/metabolismo , Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Testes Genéticos , Humanos , Mamíferos/genética , Proteínas Mutantes/metabolismo , Peptídeos/metabolismo , Saccharomyces cerevisiae/metabolismo
6.
STAR Protoc ; 3(2): 101344, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35509971

RESUMO

Reciprocal exchanges between genetically identical sister chromatids (sister chromatid exchanges or SCEs) have been challenging to study. Here, we describe a protocol that utilizes a pulse/chase of the thymidine analog 5-ethyl-3'-deoxyuridine (EdU) in combination with click chemistry and antibody labeling to selectively label sister chromatids in the C. elegans germline. Labeling has no discernable effects on meiosis, allowing for cytological quantification of SCEs. This protocol can be combined with a variety of imaging approaches, including STED, confocal and super-resolution. For complete details on the use and execution of this protocol, please refer to Almanzar et al. (2021).


Assuntos
Caenorhabditis elegans , Desoxiuridina/química , Troca de Cromátide Irmã , Animais , Caenorhabditis elegans/genética , Células Germinativas , Meiose , Nucleotídeos
7.
Exp Suppl ; 114: 115-136, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35544001

RESUMO

Microsporidia are poorly understood, ubiquitous eukaryotic parasites that are completely dependent on their hosts for replication. With the discovery of microsporidia species naturally infecting the genetically tractable transparent nematode C. elegans, this host has been used to explore multiple areas of microsporidia biology. Here we review results about microsporidia infections in C. elegans, which began with the discovery of the intestinal-infecting species Nematocida parisii. Recent findings include new species identification in the Nematocida genus, with more intestinal-infecting species, and also a species with broader tissue tropism, the epidermal and muscle-infecting species Nematocida displodere. This species has a longer polar tube infection apparatus, which may enable its wider tissue range. After invasion, multiple Nematocida species appear to fuse host cells, which likely promotes their dissemination within host organs. Localized proteomics identified Nematocida proteins that have direct contact with the C. elegans intestinal cytosol and nucleus, and many of these host-exposed proteins belong to expanded, species-specific gene families. On the host side, forward genetic screens have identified regulators of the Intracellular Pathogen Response (IPR), which is a transcriptional response induced by both microsporidia and the Orsay virus, which is also a natural, obligate intracellular pathogen of the C. elegans intestine. The IPR constitutes a novel immune/stress response that promotes resistance against microsporidia, virus, and heat shock. Overall, the Nematocida/C. elegans system has provided insights about strategies for microsporidia pathogenesis, as well as innate defense pathways against these parasites.


Assuntos
Proteínas de Caenorhabditis elegans , Microsporídios , Animais , Biologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Interações Hospedeiro-Patógeno/genética , Microsporídios/genética
8.
Proc Jpn Acad Ser B Phys Biol Sci ; 98(5): 207-221, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35545527

RESUMO

Fertilization is the starting point for creating new progeny. At this time, the highly differentiated oocyte and sperm fuse to form one zygote, which is then converted into a pluripotent early embryo. Recent studies have shown that the lysosomal degradation system via autophagy and endocytosis plays important roles in the remodeling of intracellular components during oocyte-to-embryo transition. For example, in Caenorhabditis elegans, zygotes show high endocytic activity, and some populations of maternal membrane proteins are selectively internalized and delivered to lysosomes for degradation. Furthermore, fertilization triggers selective autophagy of sperm-derived paternal mitochondria, which establishes maternal inheritance of mitochondrial DNA. In addition, it has been shown that autophagy via liquid-liquid phase separation results in the selective degradation of some germ granule components, which are distributed to somatic cells of early embryos. This review outlines the physiological functions of the lysosomal degradation system and its molecular mechanisms in C. elegans and mouse embryos.


Assuntos
Caenorhabditis elegans , Fertilização , Animais , Autofagia/genética , Caenorhabditis elegans/genética , Embrião não Mamífero/metabolismo , Endocitose , Fertilização/fisiologia , Camundongos , Oócitos
9.
Parasit Vectors ; 15(1): 158, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513885

RESUMO

BACKGROUND: The nematode Parascaris univalens is one of the most prevalent parasitic pathogens infecting horses but anthelmintic resistance undermines treatment approaches. The molecular mechanisms underlying drug activity and resistance remain poorly understood in this parasite since experimental in vitro models are lacking. The aim of this study was to evaluate the use of Caenorhabditis elegans as a model for P. univalens drug metabolism/resistance studies by a comparative gene expression approach after in vitro exposure to the anthelmintic drug ivermectin (IVM). METHODS: Twelve adult P. univalens worms in groups of three were exposed to ivermectin (IVM, 10-13 M, 10-11 M, 10-9 M) or left unexposed for 24 h at 37 °C, and total RNA, extracted from the anterior end of the worms, was sequenced using Illumina NovaSeq. Differentially expressed genes (DEGs) involved in metabolism, transportation, or gene expression with annotated Caernorhabditis elegans orthologues were identified as candidate genes to be involved in IVM metabolism/resistance. Similarly, groups of 300 adult C. elegans worms were exposed to IVM (10-9 M, 10-8 M and 10-7 M) or left unexposed for 4 h at 20 °C. Quantitative RT-PCR of RNA extracted from the C. elegans worm pools was used to compare against the expression of selected P. univalens candidate genes after drug treatment. RESULTS: After IVM exposure, 1085 DEGs were found in adult P. univalens worms but the relative gene expression changes were small and large variabilities were found between different worms. Fifteen of the DEGs were chosen for further characterization in C. elegans after comparative bioinformatics analyses. Candidate genes, including the putative drug target lgc-37, responded to IVM in P. univalens, but marginal to no responses were observed in C. elegans despite dose-dependent behavioral effects observed in C. elegans after IVM exposure. Thus, the overlap in IVM-induced gene expression in this small set of genes was minor in adult worms of the two nematode species. CONCLUSION: This is the first time to our knowledge that a comparative gene expression approach has evaluated C. elegans as a model to understand IVM metabolism/resistance in P. univalens. Genes in P. univalens adults that responded to IVM treatment were identified. However, identifying conserved genes in P. univalens and C. elegans involved in IVM metabolism/resistance by comparing gene expression of candidate genes proved challenging. The approach appears promising but was limited by the number of genes studied (n = 15). Future studies comparing a larger number of genes between the two species may result in identification of additional candidate genes involved in drug metabolism and/or resistance.


Assuntos
Anti-Helmínticos , Ascaridoidea , Animais , Anti-Helmínticos/uso terapêutico , Caenorhabditis elegans , Resistência a Medicamentos/genética , Expressão Gênica , Cavalos , Ivermectina/uso terapêutico , RNA/metabolismo
11.
Sci Rep ; 12(1): 7133, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504914

RESUMO

microRNAs (miRNAs) are crucial for normal development and physiology. To identify factors that might coordinate with miRNAs to regulate gene expression, we used 2'O-methylated oligonucleotides to precipitate Caenorhabditis elegans let-7, miR-58, and miR-2 miRNAs and the associated proteins. A total of 211 proteins were identified through mass-spectrometry analysis of miRNA co-precipitates, which included previously identified interactors of key miRNA pathway components. Gene ontology analysis of the identified interactors revealed an enrichment for RNA binding proteins, suggesting that we captured proteins that may be involved in mRNA lifecycle. To determine which miRNA interactors are important for miRNA activity, we used RNAi to deplete putative miRNA co-factors in animals with compromised miRNA activity and looked for alterations of the miRNA mutant phenotypes. Depletion of 25 of 39 tested genes modified the miRNA mutant phenotypes in three sensitized backgrounds. Modulators of miRNA phenotypes ranged from RNA binding proteins RBD-1 and CEY-1 to metabolic factors such as DLST-1 and ECH-5, among others. The observed functional interactions suggest widespread coordination of these proteins with miRNAs to ultimately regulate gene expression. This study provides a foundation for future investigations aimed at deciphering the molecular mechanisms of miRNA-mediated gene regulation.


Assuntos
Proteínas de Caenorhabditis elegans , MicroRNAs , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , MicroRNAs/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
12.
Proc Natl Acad Sci U S A ; 119(21): e2015576119, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35576466

RESUMO

SignificanceAging animals, particularly females, suffer from diminished reproductive ability, likely due to high costs of germline maintenance. Potential remedies may be found in signals exchanged by members of opposite sexes to promote reproductive success. We show that in the nematode Caenorhabditis elegans, male pheromone facilitates healthy oocyte aging. This pheromone increases germline proliferation and physiological cell death, which is required to maintain oocyte quality. We show that young adults that have not yet commenced reproduction are particularly sensitive to signals from mates and nutrients, likely because during this narrow time window, they set an environment-appropriate balance between germline and soma investment. We advocate the study of social signals as a productive avenue for identifying regulators of physiology and aging.


Assuntos
Caenorhabditis elegans , Senescência Celular , Oócitos , Oogênese , Atrativos Sexuais , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Feminino , Masculino , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Oogênese/efeitos dos fármacos , Oogênese/fisiologia , Atrativos Sexuais/farmacologia , Atrativos Sexuais/fisiologia
13.
Nat Commun ; 13(1): 2403, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504873

RESUMO

C. elegans react to metabolic distress caused by mismatches in oxygen and energy status via distinct behavioral responses. At the molecular level, these responses are coordinated by under-characterized, redox-sensitive processes, thought to initiate in mitochondria. Complex I of the electron transport chain is a major site of reactive oxygen species (ROS) production and is canonically associated with oxidative damage following hypoxic exposure. Here, we use a combination of optogenetics and CRISPR/Cas9-mediated genome editing to exert spatiotemporal control over ROS production. We demonstrate a photo-locomotory remodeling of avoidance behavior by local ROS production due to the reversible oxidation of a single thiol on the complex I subunit NDUF-2.1. Reversible thiol oxidation at this site is necessary and sufficient for the behavioral response to hypoxia, does not respond to ROS produced at more distal sites, and protects against lethal hypoxic exposure. Molecular modeling suggests that oxidation at this thiol residue alters the ability for NDUF-2.1 to coordinate electron transfer to coenzyme Q by destabilizing the Q-binding pocket, causing decreased complex I activity. Overall, site-specific ROS production regulates behavioral responses and these findings provide a mechanistic target to suppress the detrimental effects of hypoxia.


Assuntos
Caenorhabditis elegans , Compostos de Sulfidrila , Animais , Aprendizagem da Esquiva , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Hipóxia , Espécies Reativas de Oxigênio/metabolismo
14.
Sci Rep ; 12(1): 7652, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538106

RESUMO

Autophagy is an essential cellular pathway that ensures degradation of a wide range of substrates including damaged organelles or large protein aggregates. Understanding how this proteolytic pathway is regulated would increase our comprehension on its role in cellular physiology and contribute to identify biomarkers or potential drug targets to develop more specific treatments for disease in which autophagy is dysregulated. Here, we report the development of molecular traps based in the tandem disposition of LC3-interacting regions (LIR). The estimated affinity of LC3-traps for distinct recombinant LC3/GABARAP proteins is in the low nanomolar range and allows the capture of these proteins from distinct mammalian cell lines, S. cerevisiae and C. elegans. LC3-traps show preferences for GABARAP/LGG1 or LC3/LGG2 and pull-down substrates targeted to proteaphagy and mitophagy. Therefore, LC3-traps are versatile tools that can be adapted to multiple applications to monitor selective autophagy events in distinct physiologic and pathologic circumstances.


Assuntos
Caenorhabditis elegans , Macroautofagia , Animais , Autofagia , Caenorhabditis elegans/metabolismo , Mamíferos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Biológicos , Ligação Proteica , Saccharomyces cerevisiae/metabolismo
15.
Commun Biol ; 5(1): 422, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513700

RESUMO

Innate immune surveillance, which monitors the presence of potentially harmful microorganisms and the perturbations of host physiology that occur in response to infections, is critical to distinguish pathogens from beneficial microbes. Here, we show that multidrug resistance-associated protein-1 (MRP-1) functions in the basolateral membrane of intestinal cells to transport byproducts of cellular redox reactions to control both molecular and behavioral immunity in Caenorhabditis elegans. Pseudomonas aeruginosa infection disrupts glutathione homeostasis, leading to the excess production of the MRP-1 substrate, oxidized glutathione (GSSG). Extracellular GSSG triggers pathogen avoidance behavior and primes naïve C. elegans to induce aversive learning behavior via neural NMDA class glutamate receptor-1 (NMR-1). Our results indicate that MRP-1 transports GSSG, which acts as a danger signal capable of warning C. elegans of changes in intestinal homeostasis, thereby initiating a gut neural signal that elicits an appropriate host defense response.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Aprendizagem da Esquiva , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Dissulfeto de Glutationa , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Oxirredução
16.
Commun Biol ; 5(1): 417, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513705

RESUMO

Amyloid-ß (Aß) and semen-derived enhancer of viral infection (SEVI) are considered as the two causative proteins for central pathogenic cause of Alzheimer's disease (AD) and HIV/AIDS, respectively. Separately, Aß-AD and SEVI-HIV/AIDS systems have been studied extensively both in fundamental research and in clinical trials. Despite significant differences between Aß-AD and SEVI-HIV/AIDS systems, they share some commonalities on amyloid and antimicrobial characteristics between Aß and SEVI, there are apparent overlaps in dysfunctional neurological symptoms between AD and HIV/AIDS. Few studies have reported a potential pathological link between Aß-AD and SEVI-HIV/AIDS at a protein level. Here, we demonstrate the cross-seeding interactions between Aß and SEVI proteins using in vitro and in vivo approaches. Cross-seeding of SEVI with Aß enabled to completely prevent Aß aggregation at sub-stoichiometric concentrations, disaggregate preformed Aß fibrils, reduce Aß-induced cell toxicity, and attenuate Aß-accumulated paralysis in transgenic AD C. elegans. This work describes a potential crosstalk between AD and HIV/AIDS via the cross-seeding between Aß and SEVI, identifies SEVI as Aß inhibitor for possible treatment or prevention of AD, and explains the role of SEVI in the gender difference in AD.


Assuntos
Síndrome de Imunodeficiência Adquirida , Doença de Alzheimer , Infecções por HIV , Viroses , Doença de Alzheimer/genética , Amiloide/metabolismo , Peptídeos beta-Amiloides , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Infecções por HIV/metabolismo , Sementes , Fatores Sexuais
17.
Sci Rep ; 12(1): 7161, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504961

RESUMO

Lipofuscin is a representative biomarker of aging that is generated naturally over time. Remofuscin (soraprazan) improves age-related eye diseases by removing lipofuscin from retinal pigment epithelium (RPE) cells. In this study, the effect of remofuscin on longevity in Caenorhabditis elegans and the underlying mechanism were investigated. The results showed that remofuscin significantly (p < 0.05) extended the lifespan of C. elegans (N2) compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms. The expression levels of genes related to lysosomes (lipl-1 and lbp-8), a nuclear hormone receptor (nhr-234), fatty acid beta-oxidation (ech-9), and xenobiotic detoxification (cyp-34A1, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. elegans with loss-of-function mutations (lipl-1, lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), suggesting that these genes are associated with lifespan extension in remofuscin-treated C. elegans. In conclusion, remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Imidazóis , Lipofuscina/metabolismo , Longevidade/fisiologia , Lisossomos/metabolismo , Chaperonas Moleculares/metabolismo , Naftiridinas , Transdução de Sinais , Xenobióticos/metabolismo , Xenobióticos/farmacologia
18.
Elife ; 112022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35510610

RESUMO

While screening our in-house 1072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic, and anti-aging effects, and could further lead to promising application prospects.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Longevidade/genética , Proteínas do Tecido Nervoso , Pressão Osmótica , Estresse Oxidativo , Canais de Cátion TRPV , Toluidinas
19.
ACS Chem Neurosci ; 13(8): 1165-1177, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35385645

RESUMO

Cannabidiol is a nonpsychoactive phytocannabinoid produced by the Cannabis sativa plant and possesses a wide range of pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective activities. Cannabidiol functions in a neuroprotective manner, in part through the activation of cellular antioxidant pathways. The glyoxalase pathway detoxifies methylglyoxal, a highly reactive metabolic byproduct that can accumulate in the brain, and contributes to the severity of neurodegenerative diseases, including Alzheimer's disease. While cannabidiol's antioxidant properties have been investigated, it is currently unknown how it may modulate the glyoxalase pathway. In this research paper, we examine the effects of Cannabidiol on cerebellar neurons and in several Caenorhabditis elegans strains. We determined that a limited amount of Cannabidiol can prevent methylglyoxal-mediated cellular damage through enhancement of the neural glyoxalase pathway and extend the lifespan and survival of C. elegans, including a transgenic C. elegans strain modeling Alzheimer's disease.


Assuntos
Doença de Alzheimer , Proteínas de Caenorhabditis elegans , Canabidiol , Lactoilglutationa Liase , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/farmacologia , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/farmacologia , Canabidiol/farmacologia , Lactoilglutationa Liase/metabolismo , Longevidade , Aldeído Pirúvico/metabolismo
20.
Open Biol ; 12(4): 210308, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35472285

RESUMO

Translation machinery is responsible for the production of cellular proteins; thus, cells devote the majority of their resources to ribosome biogenesis and protein synthesis. Single-copy loss of function in the translation machinery components results in rare ribosomopathy disorders, such as Diamond-Blackfan anaemia in humans and similar developmental defects in various model organisms. Somatic copy number alterations of translation machinery components are also observed in specific tumours. The organism-wide response to haploinsufficient loss-of-function mutations in ribosomal proteins or translation machinery components is complex: variations in translation machinery lead to reduced ribosome biogenesis, protein translation and altered protein homeostasis and cellular signalling pathways. Cells are affected both autonomously and non-autonomously by changes in translation machinery or ribosome biogenesis through cell-cell interactions and secreted hormones. We first briefly introduce the model organisms where mutants or knockdowns of protein synthesis and ribosome biogenesis are characterized. Next, we specifically describe observations in Caenorhabditis elegans and Drosophila melanogaster, where insufficient protein synthesis in a subset of cells triggers cell non-autonomous growth or apoptosis responses that affect nearby cells and tissues. We then cover the characterized signalling pathways that interact with ribosome biogenesis/protein synthesis machinery with an emphasis on their respective functions during organism development.


Assuntos
Drosophila melanogaster , Ribossomos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas Ribossômicas/genética , Ribossomos/genética , Ribossomos/metabolismo , Transdução de Sinais
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