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1.
J Environ Sci (China) ; 145: 97-106, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38844327

RESUMO

Sediment is the ultimate sink of environmental pollutants. A total of 128 surface sediment samples were collected from 8 rivers and 3 reservoirs in Maoming City, Guangdong Province. This study assessed the content and distribution of brominated flame retardants in sediments. The acute toxicity effects of tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDs) in sediments were evaluated using Caenorhabditis elegans as model organisms. The concentration of TBBPA in sediments ranged from not detected (ND) to 12.59 µg/kg and was mainly distributed in the central area, which was affected by the emission of TBBPA from residential and factory. The concentration of HBCDs ranged from ND to 6.31 µg/kg, and the diastereoisomer distribution was consistent, showing a trend close to the South China Sea. The composition pattern of HBCDs in the surface sediments from rivers were 41.73%-62.33%, 7.89%-25.54%, and 18.76%-40.65% for α-, ß-, and γ-HBCD, respectively, and in the sediments from reservoirs were 26.15%-45.52%, 7.44%-19.23%, and 47.04%-61.89% for α-, ß-, and γ-HBCD, respectively. When the sum of concentrations of TBBPA and HBCD in sediments were above high levels, reactive oxygen species in nematodes significantly increased, resulting in an oxidative stress response. Intestinal permeability was also enhanced, causing intestinal damage. In addition, in terms of this study, TBBPA had a greater impact on biotoxicity compared to HBCDs, and more attention should be paid to the toxic effects of the river ecosystem organisms in Maoming City, Guangdong Province. This study can complement the pollution database in the study area and provide basic data for pollution control.


Assuntos
Caenorhabditis elegans , Monitoramento Ambiental , Retardadores de Chama , Sedimentos Geológicos , Hidrocarbonetos Bromados , Poluentes Químicos da Água , Animais , Retardadores de Chama/toxicidade , Retardadores de Chama/análise , China , Caenorhabditis elegans/efeitos dos fármacos , Sedimentos Geológicos/química , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , Hidrocarbonetos Bromados/análise , Hidrocarbonetos Bromados/toxicidade , Bifenil Polibromatos/toxicidade , Bifenil Polibromatos/análise
2.
Sci Rep ; 14(1): 12756, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38830930

RESUMO

Caenorhabditis elegans is an appealing tool for experimental evolution and for working with antiparasitic drugs, from understanding the molecular mechanisms of drug action and resistance to uncover new drug targets. We present a new methodology for studying the impact of antiparasitic drugs in C. elegans. Viscous medium was initially designed for C. elegans maintenance during long-term evolution experiments. Viscous medium provides a less structured environment than the standard nematode growth media agar, yet the bacteria food source remains suspended. Further, the Viscous medium offers the worm population enough support to move freely, mate, and reproduce at a rate comparable to standard agar cultures. Here, the Viscous medium was adapted for use in antiparasitic research. We observed a similar sensitivity of C. elegans to anthelmintic drugs as in standard liquid media and statistical difference to the standard agar media through a larval development assay. Using Viscous medium in C. elegans studies will considerably improve antiparasitic resistance research, and this medium could be used in studies aimed at understanding long-term multigenerational drug activity.


Assuntos
Anti-Helmínticos , Caenorhabditis elegans , Meios de Cultura , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/crescimento & desenvolvimento , Animais , Anti-Helmínticos/farmacologia , Meios de Cultura/química , Viscosidade , Ágar , Resistência a Medicamentos/efeitos dos fármacos , Larva/efeitos dos fármacos
3.
Crit Rev Toxicol ; 54(5): 330-343, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38832580

RESUMO

Despite the growing epidemiological evidence of an association between toxin exposure and developmental neurotoxicity (DNT), systematic testing of DNT is not mandatory in international regulations for admission of pharmaceuticals or industrial chemicals. However, to date around 200 compounds, ranging from pesticides, pharmaceuticals and industrial chemicals, have been tested for DNT in the current OECD test guidelines (TG-443 or TG-426). There are calls for the development of new approach methodologies (NAMs) for DNT, which has resulted in a DNT testing battery using in vitro human cell-based assays. These assays provide a means to elucidate the molecular mechanisms of toxicity in humans which is lacking in animal-based toxicity tests. However, cell-based assays do not represent all steps of the complex process leading to DNT. Validated models with a multi-organ network of pathways that interact at the molecular, cellular and tissue level at very specific timepoints in a life cycle are currently missing. Consequently, whole model organisms are being developed to screen for, and causally link, new molecular targets of DNT compounds and how they affect whole brain development and neurobehavioral endpoints. Given the practical and ethical restraints associated with vertebrate testing, lower animal models that qualify as 3 R (reduce, refine and replace) models, including the nematode (Caenorhabditis elegans) and the zebrafish (Danio rerio) will prove particularly valuable for unravelling toxicity pathways leading to DNT. Although not as complex as the human brain, these 3 R-models develop a complete functioning brain with numerous neurodevelopmental processes overlapping with human brain development. Importantly, the main signalling pathways relating to (neuro)development, metabolism and growth are highly conserved in these models. We propose the use of whole model organisms specifically zebrafish and C. elegans for DNT relevant endpoints.


Assuntos
Caenorhabditis elegans , Síndromes Neurotóxicas , Testes de Toxicidade , Peixe-Zebra , Animais , Caenorhabditis elegans/efeitos dos fármacos , Modelos Animais , Testes de Toxicidade/métodos
4.
Elife ; 122024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38857169

RESUMO

Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable challenge to decipher the genetic underpinnings that dictate the specific connections formed between neuronal types. To address this, we propose a novel bilinear modeling approach that leverages the architecture similar to that of recommendation systems. Our model transforms the gene expressions of presynaptic and postsynaptic neuronal types, obtained from single-cell transcriptomics, into a covariance matrix. The objective is to construct this covariance matrix that closely mirrors a connectivity matrix, derived from connectomic data, reflecting the known anatomical connections between these neuronal types. When tested on a dataset of Caenorhabditis elegans, our model achieved a performance comparable to, if slightly better than, the previously proposed spatial connectome model (SCM) in reconstructing electrical synaptic connectivity based on gene expressions. Through a comparative analysis, our model not only captured all genetic interactions identified by the SCM but also inferred additional ones. Applied to a mouse retinal neuronal dataset, the bilinear model successfully recapitulated recognized connectivity motifs between bipolar cells and retinal ganglion cells, and provided interpretable insights into genetic interactions shaping the connectivity. Specifically, it identified unique genetic signatures associated with different connectivity motifs, including genes important to cell-cell adhesion and synapse formation, highlighting their role in orchestrating specific synaptic connections between these neurons. Our work establishes an innovative computational strategy for decoding the genetic programming of neuronal type connectivity. It not only sets a new benchmark for single-cell transcriptomic analysis of synaptic connections but also paves the way for mechanistic studies of neural circuit assembly and genetic manipulation of circuit wiring.


Assuntos
Caenorhabditis elegans , Conectoma , Neurônios , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Camundongos , Neurônios/fisiologia , Análise de Célula Única , Modelos Neurológicos
5.
Proc Natl Acad Sci U S A ; 121(25): e2322588121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38861598

RESUMO

The nematode intestine is the primary site for nutrient uptake and storage as well as the synthesis of biomolecules; lysosome-related organelles known as gut granules are important for many of these functions. Aspects of intestine biology are not well understood, including the export of the nutrients it imports and the molecules it synthesizes, as well as the complete functions and protein content of the gut granules. Here, we report a mass spectrometry (MS)-based proteomic analysis of the intestine of the Caenorhabditis elegans and of its gut granules. Overall, we identified approximately 5,000 proteins each in the intestine and the gonad and showed that most of these proteins can be detected in samples extracted from a single worm, suggesting the feasibility of individual-level genetic analysis using proteomes. Comparing proteomes and published transcriptomes of the intestine and the gonad, we identified proteins that appear to be synthesized in the intestine and then transferred to the gonad. To identify gut granule proteins, we compared the proteome of individual intestines deficient in gut granules to the wild type. The identified gut granule proteome includes proteins known to be exclusively localized to the granules and additional putative gut granule proteins. We selected two of these putative gut granule proteins for validation via immunohistochemistry, and our successful confirmation of both suggests that our strategy was effective in identifying the gut granule proteome. Our results demonstrate the practicability of single-tissue MS-based proteomic analysis in small organisms and in its future utility.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Lisossomos , Proteômica , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteômica/métodos , Lisossomos/metabolismo , Proteoma/metabolismo , Intestinos , Mucosa Intestinal/metabolismo , Gônadas/metabolismo , Espectrometria de Massas/métodos , Organelas/metabolismo
6.
Planta Med ; 90(7-08): 576-587, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38843797

RESUMO

The average age of the population is increasing worldwide, which has a profound impact on our society. This leads to an increasing demand for medicines and requires the development of new strategies to promote health during the additional years. In the search for resources and therapeutics for improved health during an extended life span, attention has to be paid to environmental exposure and ecosystem burdens that inevitably emerge with the extended consumption of medicines and drug development, even in the preclinical stage. The hereby introduced sustainable strategy for drug discovery is built on 3Rs, "R: obustness, R: eliability, and saving R: esources", inspired by both the 3Rs used in animal experiments and environmental protection, and centers on the usefulness and the variety of the small model organism Caenorhabditis elegans for detecting health-promoting natural products. A workflow encompassing a multilevel screening approach is presented to maximize the amount of information on health-promoting samples, while considering the 3Rs. A detailed, methodology- and praxis-oriented compilation and discussion of proposed C. elegans health span assays and more disease-specific assays are presented to offer guidance for scientists intending to work with C. elegans, thus facilitating the initial steps towards the integration of C. elegans assays in their laboratories.


Assuntos
Produtos Biológicos , Caenorhabditis elegans , Caenorhabditis elegans/efeitos dos fármacos , Animais , Produtos Biológicos/farmacologia , Descoberta de Drogas/métodos
7.
Sci Rep ; 14(1): 13177, 2024 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849503

RESUMO

Overconsumption of dietary sugar can lead to many negative health effects including the development of Type 2 diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Recently, the human intestinal microbiota, strongly associated with our overall health, has also been known to be affected by diet. However, mechanistic insight into the importance of the human intestinal microbiota and the effects of chronic sugar ingestion has not been possible largely due to the complexity of the human microbiome which contains hundreds of types of organisms. Here, we use an interspecies C. elegans/E. coli system, where E. coli are subjected to high sugar, then consumed by the bacterivore host C. elegans to become the microbiota. This glucose-fed microbiota results in a significant lifespan reduction accompanied by reduced healthspan (locomotion), reduced stress resistance, and changes in behavior and feeding. Lifespan reduction is also accompanied by two potential major contributors: increased intestinal bacterial density and increased concentration of reactive oxygen species. The glucose-fed microbiota accelerated the age-related development of intestinal cell permeability, intestinal distention, and dysregulation of immune effectors. Ultimately, the changes in the intestinal epithelium due to aging with the glucose-fed microbiota results in increased susceptibility to multiple bacterial pathogens. Taken together, our data reveal that chronic ingestion of sugar, such as a Western diet, has profound health effects on the host due to changes in the microbiota and may contribute to the current increased incidence of ailments including inflammatory bowel diseases as well as multiple age-related diseases.


Assuntos
Caenorhabditis elegans , Escherichia coli , Microbioma Gastrointestinal , Glucose , Mucosa Intestinal , Caenorhabditis elegans/microbiologia , Animais , Glucose/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Longevidade , Suscetibilidade a Doenças
8.
Nat Commun ; 15(1): 4904, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851828

RESUMO

Age-related depletion of stem cells causes tissue degeneration and failure to tissue regeneration, driving aging at the organismal level. Previously we reported a cell-non-autonomous DAF-16/FOXO activity in antagonizing the age-related loss of germline stem/progenitor cells (GSPCs) in C. elegans, indicating that regulation of stem cell aging occurs at the organ system level. Here we discover the molecular effector that links the cell-non-autonomous DAF-16/FOXO activity to GSPC maintenance over time by performing a tissue-specific DAF-16/FOXO transcriptome analysis. Our data show that dos-3, which encodes a non-canonical Notch ligand, is a direct transcriptional target of DAF-16/FOXO and mediates the effect of the cell-non-autonomous DAF-16/FOXO activity on GSPC maintenance through activating Notch signaling in the germ line. Importantly, expression of a human homologous protein can functionally substitute for DOS-3 in this scenario. As Notch signaling controls the specification of many tissue stem cells, similar mechanisms may exist in other aging stem cell systems.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Fatores de Transcrição Forkhead , Células Germinativas , Receptores Notch , Transdução de Sinais , Células-Tronco , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Células Germinativas/metabolismo , Receptores Notch/metabolismo , Receptores Notch/genética , Células-Tronco/metabolismo , Células-Tronco/citologia , Envelhecimento/metabolismo , Envelhecimento/genética , Humanos
9.
Int J Biol Macromol ; 272(Pt 1): 132833, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38834112

RESUMO

Chicken meat processing generates a substantial number of byproducts, which are either underutilized or improperly disposed. In this study, we employed in silico approaches to identify antioxidant peptides in chicken liver byproducts. Notably, the peptide WYR exhibited remarkable 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging activity with an IC50 of 0.13 ± 0.01 mg/mL and demonstrated stability under various conditions, including thermal, pH, NaCl, and simulated gastrointestinal digestion. Molecular docking analysis revealed significant hydrogen bonding interactions, while molecular dynamics showed differential stability with ABTS and 2,2-Diphenyl-1-picrylhydrazyl (DPPH). WYR exhibited improved stress resistance, decreased levels of reactive oxygen species (ROS), elevated the activities of superoxide dismutase (SOD) and catalase (CAT), and modulated the expression of crucial genes through the insulin/insulin-like growth factor (IIS) signaling pathway, mitogen-activated protein kinase (MAPK), and heat shock transcription factor-1 (HSF-1) pathways. These effects collectively contributed to the extension of Caenorhabditis elegans' lifespan. This study not only provides an effective method for antioxidant peptide analysis but also highlights the potential for enhancing the utilization of poultry byproducts.


Assuntos
Antioxidantes , Caenorhabditis elegans , Galinhas , Fígado , Simulação de Acoplamento Molecular , Peptídeos , Animais , Caenorhabditis elegans/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/química , Peptídeos/química , Peptídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento/efeitos dos fármacos , Simulação por Computador , Superóxido Dismutase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Catalase/metabolismo
10.
Sci Total Environ ; 940: 173641, 2024 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-38825205

RESUMO

From both environment and health perspectives, sustainable management of ever-growing soil contamination by heavy metal is posing a serious global concern. The potential ecotoxicity of cadmium (Cd) to soil and ecosystem seriously threatens human health. Developing efficient, specific, and long-term remediation technology for Cd-contaminated soil is impending to synchronously minimize the bioavailability and ecotoxicity of Cd. In the present study, zinc oxide/graphene oxide nanocomposite (ZnO/GO) was developed as a novel amendment for remediating Cd-contaminated soil. Our results showed that ZnO/GO effectively decreased the available soil Cd content, and increased pH and cation exchange capacity (CEC) in both Cd-spiked standard soil and Cd-contaminated mine field soil through the interaction between ZnO/GO and soil organic acids. Using Caenorhabditis elegans (C. elegans) as a model organism for soil safety evaluation, ZnO/GO was further proved to decrease the ecotoxicity of Cd-contaminated soil. Specifically, ZnO/GO promoted Cd excretion and declined Cd storage in C. elegans by increasing the expression of gene ttm-1 and decreasing the level of gene cdf-2, which were responsible for Cd transportation and Cd accumulation, respectively. Moreover, the efficacy of ZnO/GO in remediating the properties and ecotoxicity of Cd-contaminated soil increased gradually with the time gradient, and could maintain a long-term effect after reaching the optimal remediation efficiency. Our findings established a specific and long-term strategy to simultaneously improve soil properties and reduce ecotoxicity of Cd-contaminated soil, which might provide new insights into the potential application of ZnO/GO in soil remediation for both ecosystem and human health.


Assuntos
Cádmio , Recuperação e Remediação Ambiental , Grafite , Nanocompostos , Poluentes do Solo , Óxido de Zinco , Óxido de Zinco/toxicidade , Cádmio/toxicidade , Recuperação e Remediação Ambiental/métodos , Animais , Disponibilidade Biológica , Caenorhabditis elegans/efeitos dos fármacos , Solo/química
11.
Sci Adv ; 10(24): eadk9481, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38865452

RESUMO

The molecular mechanisms underlying diversity in animal behavior are not well understood. A major experimental challenge is determining the contribution of genetic variants that affect neuronal gene expression to differences in behavioral traits. In Caenorhabditis elegans, the neuroendocrine transforming growth factor-ß ligand, DAF-7, regulates diverse behavioral responses to bacterial food and pathogens. The dynamic neuron-specific expression of daf-7 is modulated by environmental and endogenous bacteria-derived cues. Here, we investigated natural variation in the expression of daf-7 from the ASJ pair of chemosensory neurons. We identified common genetic variants in gap-2, encoding a Ras guanosine triphosphatase (GTPase)-activating protein homologous to mammalian synaptic Ras GTPase-activating protein, which modify daf-7 expression cell nonautonomously and promote exploratory foraging behavior in a partially DAF-7-dependent manner. Our data connect natural variation in neuron-specific gene expression to differences in behavior and suggest that genetic variation in neuroendocrine signaling pathways mediating host-microbe interactions may give rise to diversity in animal behavior.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Variação Genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica , Sistemas Neurossecretores/metabolismo , Comportamento Alimentar , Comportamento Animal/fisiologia , Neurônios/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta
12.
Cell Mol Life Sci ; 81(1): 252, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38849591

RESUMO

Animals have evolved to seek, select, and exploit food sources in their environment. Collectively termed foraging, these ubiquitous behaviors are necessary for animal survival. As a foundation for understanding foraging, behavioral ecologists established early theoretical and mathematical frameworks which have been subsequently refined and supported by field and laboratory studies of foraging animals. These simple models sought to explain how animals decide which strategies to employ when locating food, what food items to consume, and when to explore the environment for new food sources. These foraging decisions involve integration of prior experience with multimodal sensory information about the animal's current environment and internal state. We suggest that the nematode Caenorhabditis elegans is well-suited for a high-resolution analysis of complex goal-oriented behaviors such as foraging. We focus our discussion on behavioral studies highlighting C. elegans foraging on bacteria and summarize what is known about the underlying neuronal and molecular pathways. Broadly, we suggest that this simple model system can provide a mechanistic understanding of decision-making and present additional avenues for advancing our understanding of complex behavioral processes.


Assuntos
Caenorhabditis elegans , Tomada de Decisões , Comportamento Alimentar , Neurônios , Animais , Caenorhabditis elegans/fisiologia , Tomada de Decisões/fisiologia , Comportamento Alimentar/fisiologia , Neurônios/fisiologia , Modelos Biológicos
13.
Commun Biol ; 7(1): 694, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844830

RESUMO

Wounding initiates intricate responses crucial for tissue repair and regeneration. Yet, the gene regulatory networks governing wound healing remain poorly understood. Here, employing single-worm RNA sequencing (swRNA-seq) across 12 time-points, we delineated a three-stage wound repair process in C. elegans: response, repair, and remodeling. Integrating diverse datasets, we constructed a dynamic regulatory network comprising 241 transcription regulators and their inferred targets. We identified potentially seven autoregulatory TFs and five cross-autoregulatory loops involving pqm-1 and jun-1. We revealed that TFs might interact with chromatin factors and form TF-TF combinatory modules via intrinsically disordered regions to enhance response robustness. We experimentally validated six regulators functioning in transcriptional and translocation-dependent manners. Notably, nhr-76, daf-16, nhr-84, and oef-1 are potentially required for efficient repair, while elt-2 may act as an inhibitor. These findings elucidate transcriptional responses and hierarchical regulatory networks during C. elegans wound repair, shedding light on mechanisms underlying tissue repair and regeneration.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Redes Reguladoras de Genes , Cicatrização , Animais , Caenorhabditis elegans/genética , Cicatrização/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Análise de Sequência de RNA , Regulação da Expressão Gênica
14.
Chem Biol Drug Des ; 103(6): e14558, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38828741

RESUMO

This study aimed to explore the active components and the effect of Hedyotis diffusa (HD) against Alzheimer's disease (AD) via network pharmacology, molecular docking, and experimental evaluations. We conducted a comprehensive screening process using the TCMSP, Swiss Target Prediction, and PharmMapper databases to identify the active components and their related targets in HD. In addition, we collected potential therapeutic targets of AD from the Gene Cards, Drugbank, and OMIM databases. Afterward, we utilized Cytoscape to establish both protein-protein interaction (PPI) networks and compound-target (C-T) networks. To gain further insights into the functional aspect, we performed GO and KEGG pathway analyses using the David database. Next, we employed Autodock vina to estimate the binding force between the components and the hub genes. To validate our network pharmacology findings, we conducted relevant experiments on Caenorhabditis elegans, further confirming the reliability of our results. Then a total of six active compounds and 149 therapeutic targets were detected. Through the analysis of the association between active compounds, therapeutic targets, and signaling pathways, it was observed that the therapeutic effect of HD primarily encompassed the inhibition of Aß, suppression of AChE activity, and mitigating oxidative stress. Additionally, our investigation revealed that the key active compounds in HD primarily consisted of iridoids, which exhibited resistance against AD by acting on the Alzheimer's disease pathway and the AGE-RAGE signaling pathway in diabetic complications.


Assuntos
Doença de Alzheimer , Caenorhabditis elegans , Hedyotis , Simulação de Acoplamento Molecular , Farmacologia em Rede , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Hedyotis/química , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Acetilcolinesterase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia
15.
Proc Natl Acad Sci U S A ; 121(25): e2321228121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38857399

RESUMO

Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of Caenorhabditis elegans neurons extend lifespan, a phenomenon with previously unclear mechanisms. Our study reveals that neuronal cilia defects trigger the unfolded protein response of the endoplasmic reticulum (UPRER) within intestinal cells, a process dependent on the insulin/insulin-like growth factor 1 (IGF-1) signaling transcription factor and the release of neuronal signaling molecules. While inhibiting UPRER doesn't alter the lifespan of wild-type worms, it normalizes the extended lifespan of ciliary mutants. Notably, deactivating the cyclic nucleotide-gated (CNG) channel TAX-4 on the ciliary membrane promotes lifespan extension through a UPRER-dependent mechanism. Conversely, constitutive activation of TAX-4 attenuates intestinal UPRER in ciliary mutants. Administering a CNG channel blocker to worm larvae activates intestinal UPRER and increases adult longevity. These findings suggest that ciliary dysfunction in sensory neurons triggers intestinal UPRER, contributing to lifespan extension and implying that transiently inhibiting ciliary channel activity may effectively prolong lifespan.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Cílios , Longevidade , Resposta a Proteínas não Dobradas , Animais , Caenorhabditis elegans/metabolismo , Cílios/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Intestinos/citologia , Transdução de Sinais , Neurônios/metabolismo , Retículo Endoplasmático/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Mucosa Intestinal/metabolismo
16.
Sci Rep ; 14(1): 13713, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877105

RESUMO

Jujubae Fructus, the fruit of Ziziphus jujuba Mill has been used as one of the medicine food homology species for thousands of years in China. Studies have shown that the active ingredients of Jujubae Fructus have a variety of biological effects, but its role in the aging process still lacks knowledge. Here, we investigated the effect of Jujubae Fructus extract (JE) on Caenorhabditis elegans lifespan and its potential mechanism. The lifespan of C. elegans treated with JE was signifificantly increased in a dose-dependent manner. In addition, JE treatment prolonged the reproductive period and increased normal activity during aging in C. elegans. Similarly, JE supplementation also enhanced the resistance to heat and oxidative stress in C. elegans. Furthermore, the mutant worms' lifespan assays demonstrated that JE requires daf-16 to prolong lifespan. DAF-16::GFP analysis of TJ356 showed that JE treatment translocates DAF-16::GFP to nucleus in transgenic worms. By analyzing the downstream of daf-16, we identify that JE may regulate sod3 downstream of daf-16. Mutant worms' lifespan and transgenic reporter gene expression assays revealed that increasing SOD-3 expression was critical for extending longevity in C. elegans with JE therapy. Collectively, these data indicate that JE may have an important role in C. elegans longevity that is dependent on DAF-16 and SOD-3.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Fatores de Transcrição Forkhead , Longevidade , Estresse Oxidativo , Extratos Vegetais , Superóxido Dismutase , Ziziphus , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Longevidade/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Extratos Vegetais/farmacologia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Ziziphus/química , Estresse Oxidativo/efeitos dos fármacos , Frutas/química
17.
Proc Natl Acad Sci U S A ; 121(25): e2318838121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38870057

RESUMO

Hertwig's rule states that cells divide along their longest axis, usually driven by forces acting on the mitotic spindle. Here, we show that in contrast to this rule, microtubule-based pulling forces in early Caenorhabditis elegans embryos align the spindle with the short axis of the cell. We combine theory with experiments to reveal that in order to correct this misalignment, inward forces generated by the constricting cytokinetic ring rotate the entire cell until the spindle is aligned with the cell's long axis. Experiments with slightly compressed mouse zygotes indicate that this cytokinetic ring-driven mechanism of ensuring Hertwig's rule is general for cells capable of rotating inside a confining shell, a scenario that applies to early cell divisions of many systems.


Assuntos
Caenorhabditis elegans , Fuso Acromático , Animais , Caenorhabditis elegans/embriologia , Camundongos , Fuso Acromático/metabolismo , Microtúbulos/metabolismo , Citocinese/fisiologia , Rotação , Zigoto/metabolismo , Zigoto/citologia , Zigoto/crescimento & desenvolvimento , Embrião não Mamífero/citologia , Desenvolvimento Embrionário/fisiologia , Modelos Biológicos
18.
Methods Cell Biol ; 188: 1-34, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38880519

RESUMO

Caenorhabditis elegans is a nematode that has been used as an animal model for almost 50years. It has primitive and simple tissues and organs, making it an ideal model for studying neurological pathways involved in neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). C. elegans has conserved neurological pathways and is able to mimic human diseases, providing valuable insights into the human disease phenotype. This methodological review presents current approaches to generate neurodegenerative-like models of AD and PD in C. elegans, and evaluates the experiments commonly used to validate the diseases. These experimental approaches include assessing survival, fertility, mobility, electropharyngeogram assays, confocal mitochondrial imaging, RNA extraction for qRT-PCR or RT-PCR, and rate of defecation. This review also summarizes the current knowledge acquired on AD and PD using the aforementioned experimental approaches. Additionally, gaps in knowledge and future directions for research are also discussed in the review.


Assuntos
Doença de Alzheimer , Caenorhabditis elegans , Modelos Animais de Doenças , Doenças Neurodegenerativas , Caenorhabditis elegans/genética , Animais , Humanos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo
19.
Methods Cell Biol ; 188: 89-108, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38880530

RESUMO

Autosomal Dominant Optic Atrophy (ADOA) is a rare neurodegenerative condition, characterized by the bilateral loss of vision due to the degeneration of retinal ganglion cells. Its primary cause is linked to mutations in OPA1 gene, which ultimately affect mitochondrial structure and function. The current lack of successful treatments for ADOA emphasizes the need to investigate the mechanisms driving disease pathogenesis and exploit the potential of animal models for preclinical trials. Among such models, Caenorhabditis elegans stands out as a powerful tool, due its simplicity, its genetic tractability, and its relevance to human biology. Despite the lack of a visual system, the presence of mutated OPA1 in the nematode recapitulates ADOA pathology, by stimulating key pathogenic features of the human condition that can be studied in a fast and relatively non-laborious manner. Here, we provide a detailed guide on how to assess the therapeutic efficacy of chemical compounds, in either small or large scale, by evaluating three crucial phenotypes of humanized ADOA model nematodes, that express pathogenic human OPA1 in their GABAergic motor neurons: axonal mitochondria number, neuronal cell death and defecation cycle time. The described methods can deepen our understanding of ADOA pathogenesis and offer a practical framework for developing novel treatment schemes, providing hope for improved therapeutic outcomes and a better quality of life for individuals affected by this currently incurable condition.


Assuntos
Caenorhabditis elegans , Modelos Animais de Doenças , Atrofia Óptica Autossômica Dominante , Animais , Caenorhabditis elegans/genética , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Autossômica Dominante/tratamento farmacológico , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Mutação , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos
20.
Mol Biol Evol ; 41(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38880992

RESUMO

Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The TRA-2 domain that mediates contact with TRA-1 is conserved in Caenorhabditis. By comparing the interaction of these proteins in two species, we identified a striking change in how sexual development is controlled. Identical mutations in this domain promote oogenesis in Caenorhabditis elegans but promote spermatogenesis in Caenorhabditis briggsae. Furthermore, the effects of these mutations involve the male-promoting gene fem-3 in C. elegans but are independent of fem-3 in C. briggsae. Finally, reciprocal mutations in these genes show that C. briggsae TRA-2 binds TRA-1 to prevent expression of spermatogenesis regulators. By contrast, in C. elegans TRA-1 sequesters TRA-2 in the germ line, allowing FEM-3 to initiate spermatogenesis. Thus, we propose that the flow of information within the sex determination pathway has switched directions during evolution. This result has important implications for how evolutionary change can occur.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Processos de Determinação Sexual , Espermatogênese , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Masculino , Espermatogênese/genética , Feminino , Caenorhabditis/genética , Evolução Biológica , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Mutação , Oogênese/genética , Evolução Molecular , Autofertilização , Proteínas de Ligação a DNA , Fatores de Transcrição
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