International Journal of Molecular Sciences

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18 pages, 5920 KiB

Open AccessArticle

WormCNN-Assisted Establishment and Analysis of Glycation Stress Models in C. elegans: Insights into Disease and Healthy Aging

by Yan Pan, Zhihang Huang, Hongxia Cai, Zhiru Li, Jingyuan Zhu, Dan Wu, Wentao Xu, Hexiang Qiu, Nan Zhang, Guojun Li, Shan Gao and Bo Xian

Int. J. Mol. Sci. 2024, 25(17), 9675; https://doi.org/10.3390/ijms25179675 - 6 Sep 2024

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Abstract

Glycation Stress (GS), induced by advanced glycation end-products (AGEs), significantly impacts aging processes. This study introduces a new model of GS of Caenorhabditis elegans by feeding them Escherichia coli OP50 cultured in a glucose-enriched medium, which better simulates human dietary glycation compared to [...] Read more.

Glycation Stress (GS), induced by advanced glycation end-products (AGEs), significantly impacts aging processes. This study introduces a new model of GS of Caenorhabditis elegans by feeding them Escherichia coli OP50 cultured in a glucose-enriched medium, which better simulates human dietary glycation compared to previous single protein–glucose cross-linking methods. Utilizing WormCNN, a deep learning model, we assessed the health status and calculated the Healthy Aging Index (HAI) of worms with or without GS. Our results demonstrated accelerated aging in the GS group, evidenced by increased autofluorescence and altered gene expression of key aging regulators, daf-2 and daf-16. Additionally, we observed elevated pharyngeal pumping rates in AGEs-fed worms, suggesting an addictive response similar to human dietary patterns. This study highlights the profound effects of GS on worm aging and underscores the critical role of computer vision in accurately assessing health status and aiding in the establishment of disease models. The findings provide insights into glycation-induced aging and offer a comprehensive approach to studying the effects of dietary glycation on aging processes. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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15 pages, 6024 KiB

Open AccessArticle

Antibiotics Trigger Host Innate Immune Response via Microbiota–Brain Communication in C. elegans

by Yangyang Wu, Guanqun Li and Hongyun Tang

Int. J. Mol. Sci. 2024, 25(16), 8866; https://doi.org/10.3390/ijms25168866 - 14 Aug 2024

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Abstract

Besides their direct bactericidal effect, antibiotics have also been suggested to stimulate the host immune response to defend against pathogens. However, it remains unclear whether any antibiotics may stimulate the host immune response by affecting bacterial activity. In this study, reasoning that genetic [...] Read more.

Besides their direct bactericidal effect, antibiotics have also been suggested to stimulate the host immune response to defend against pathogens. However, it remains unclear whether any antibiotics may stimulate the host immune response by affecting bacterial activity. In this study, reasoning that genetic mutations inhibit bacterial activities and, thereby, may mimic the effects of antibiotics, we performed genome-wide screening and identified 77 E. coli genes whose inactivation induces C. elegans cyp-14A4, representing an innate immune and detoxification response. Further analyses reveal that this host immune response can clearly be induced through either inactivating the E. coli respiratory chain via the bacterial cyoB mutation or using the antibiotic Q203, which is able to enhance host survival when encountering the pathogen Pseudomonas aeruginosa. Mechanistically, the innate immune response triggered by both the cyoB mutation and Q203 is found to depend on the host brain response, as evidenced by their reliance on the host neural gene unc-13, which is required for neurotransmitter release in head neurons. Therefore, our findings elucidate the critical involvement of the microbiota–brain axis in modulating the host immune response, providing mechanistic insights into the role of antibiotics in triggering the host immune response and, thus, facilitating host defense against pathogens. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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16 pages, 3555 KiB

Open AccessArticle

JNK Signaling Positively Regulates Acute Ethanol Tolerance in C. elegans

by Changhoon Jee and Enkhzul Batsaikhan

Int. J. Mol. Sci. 2024, 25(12), 6398; https://doi.org/10.3390/ijms25126398 - 10 Jun 2024

Cited by 1 | Viewed by 1046

Abstract

Alcohol use disorder (AUD) is a chronic neurobehavioral condition characterized by a cycle of tolerance development, increased consumption, and reinstated craving and seeking behaviors during withdrawal. Understanding the intricate mechanisms of AUD necessitates reliable animal models reflecting its key features. Caenorhabditis elegans ( [...] Read more.

Alcohol use disorder (AUD) is a chronic neurobehavioral condition characterized by a cycle of tolerance development, increased consumption, and reinstated craving and seeking behaviors during withdrawal. Understanding the intricate mechanisms of AUD necessitates reliable animal models reflecting its key features. Caenorhabditis elegans (C. elegans), with its conserved nervous system and genetic tractability, has emerged as a valuable model organism to study AUD. Here, we employ an ethanol vapor exposure model in Caenorhabditis elegans, recapitulating AUD features while maintaining high-throughput scalability. We demonstrate that ethanol vapor exposure induces intoxication-like behaviors, acute tolerance, and ethanol preference, akin to mammalian AUD traits. Leveraging this model, we elucidate the conserved role of c-jun N-terminal kinase (JNK) signaling in mediating acute ethanol tolerance. Mutants lacking JNK signaling components exhibit impaired tolerance development, highlighting JNK’s positive regulation. Furthermore, we detect ethanol-induced JNK activation in C. elegans. Our findings underscore the utility of C. elegans with ethanol vapor exposure for studying AUD and offer novel insights into the molecular mechanisms underlying acute ethanol tolerance through JNK signaling. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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18 pages, 2673 KiB

Open AccessArticle

Nicotine Motivated Behavior in C. elegans

by Chinnu Salim, Enkhzul Batsaikhan, Ann Ke Kan, Hao Chen and Changhoon Jee

Int. J. Mol. Sci. 2024, 25(3), 1634; https://doi.org/10.3390/ijms25031634 - 29 Jan 2024

Cited by 1 | Viewed by 1765

Abstract

To maximize the advantages offered by Caenorhabditis elegans as a high-throughput (HTP) model for nicotine dependence studies, utilizing its well-defined neuroconnectome as a robust platform, and to unravel the genetic basis of nicotine-motivated behaviors, we established the nicotine conditioned cue preference (CCP) paradigm. [...] Read more.

To maximize the advantages offered by Caenorhabditis elegans as a high-throughput (HTP) model for nicotine dependence studies, utilizing its well-defined neuroconnectome as a robust platform, and to unravel the genetic basis of nicotine-motivated behaviors, we established the nicotine conditioned cue preference (CCP) paradigm. Nicotine CCP enables the assessment of nicotine preference and seeking, revealing a parallel to fundamental aspects of nicotine-dependent behaviors observed in mammals. We demonstrated that nicotine-elicited cue preference in worms is mediated by nicotinic acetylcholine receptors and requires dopamine for CCP development. Subsequently, we pinpointed nAChR subunits associated with nicotine preference and validated human GWAS candidates linked to nicotine dependence involved in nAChRs. Functional validation involves assessing the loss-of-function strain of the CACNA2D3 ortholog and the knock-out (KO) strain of the CACNA2D2 ortholog, closely related to CACNA2D3 and sharing human smoking phenotypes. Our orthogonal approach substantiates the functional conservation of the α2δ subunit of the calcium channel in nicotine-motivated behavior. Nicotine CCP in C. elegans serves as a potent affirmation of the cross-species functional relevance of GWAS candidate genes involved in nicotine seeking associated with tobacco abuse, providing a streamlined yet comprehensive system for investigating intricate behavioral paradigms within a simplified and reliable framework. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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Review

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21 pages, 3885 KiB

Open AccessReview

Modeling Host–Pathogen Interactions in C. elegans: Lessons Learned from Pseudomonas aeruginosa Infection

by Gábor Hajdú, Csenge Szathmári and Csaba Sőti

Int. J. Mol. Sci. 2024, 25(13), 7034; https://doi.org/10.3390/ijms25137034 - 27 Jun 2024

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Abstract

Infections, such as that by the multiresistant opportunistic bacterial pathogen Pseudomonas aeruginosa, may pose a serious health risk, especially on vulnerable patient populations. The nematode Caenorhabditis elegans provides a simple organismal model to investigate both pathogenic mechanisms and the emerging role of [...] Read more.

Infections, such as that by the multiresistant opportunistic bacterial pathogen Pseudomonas aeruginosa, may pose a serious health risk, especially on vulnerable patient populations. The nematode Caenorhabditis elegans provides a simple organismal model to investigate both pathogenic mechanisms and the emerging role of innate immunity in host protection. Here, we review the virulence and infection strategies of P. aeruginosa and host defenses of C. elegans. We summarize the recognition mechanisms of patterns of pathogenesis, including novel pathogen-associated molecular patterns and surveillance immunity of translation, mitochondria, and lysosome-related organelles. We also review the regulation of antimicrobial and behavioral defenses by the worm’s neuroendocrine system. We focus on how discoveries in this rich field align with well-characterized evolutionary conserved protective pathways, as well as on potential crossovers to human pathogenesis and innate immune responses. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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13 pages, 1004 KiB

Open AccessReview

Caenorhabditis elegans as a Convenient Animal Model for Microbiome Studies

by Cheng-Yeu Wu, Scott Davis, Neekita Saudagar, Shrey Shah, William Zhao, Arnold Stern, Jan Martel, David Ojcius and Hung-Chi Yang

Int. J. Mol. Sci. 2024, 25(12), 6670; https://doi.org/10.3390/ijms25126670 - 18 Jun 2024

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Abstract

Microbes constitute the most prevalent life form on Earth, yet their remarkable diversity remains mostly unrecognized. Microbial diversity in vertebrate models presents a significant challenge for investigating host–microbiome interactions. The model organism Caenorhabditis elegans has many advantages for delineating the effects of host [...] Read more.

Microbes constitute the most prevalent life form on Earth, yet their remarkable diversity remains mostly unrecognized. Microbial diversity in vertebrate models presents a significant challenge for investigating host–microbiome interactions. The model organism Caenorhabditis elegans has many advantages for delineating the effects of host genetics on microbial composition. In the wild, the C. elegans gut contains various microbial species, while in the laboratory it is usually a host for a single bacterial species. There is a potential host–microbe interaction between microbial metabolites, drugs, and C. elegans phenotypes. This mini-review aims to summarize the current understanding regarding the microbiome in C. elegans. Examples using C. elegans to study host–microbe–metabolite interactions are discussed. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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14 pages, 1177 KiB

Open AccessReview

Caenorhabditis elegans as a Screening Model for Probiotics with Properties against Metabolic Syndrome

by Ignacio Goyache, Deyan Yavorov-Dayliev, Fermín I. Milagro and Paula Aranaz

Int. J. Mol. Sci. 2024, 25(2), 1321; https://doi.org/10.3390/ijms25021321 - 22 Jan 2024

Cited by 1 | Viewed by 3024

Abstract

There is a growing need to develop new approaches to prevent and treat diseases related to metabolic syndromes, including obesity or type 2 diabetes, that focus on the different factors involved in the pathogenesis of these diseases. Due to the role of gut [...] Read more.

There is a growing need to develop new approaches to prevent and treat diseases related to metabolic syndromes, including obesity or type 2 diabetes, that focus on the different factors involved in the pathogenesis of these diseases. Due to the role of gut microbiota in the regulation of glucose and insulin homeostasis, probiotics with beneficial properties have emerged as an alternative therapeutic tool to ameliorate metabolic diseases-related disturbances, including fat excess or inflammation. In the last few years, different strains of bacteria, mainly lactic acid bacteria (LAB) and species from the genus Bifidobacterium, have emerged as potential probiotics due to their anti-obesogenic and/or anti-diabetic properties. However, in vivo studies are needed to demonstrate the mechanisms involved in these probiotic features. In this context, Caenorhabditis elegans has emerged as a very powerful simple in vivo model to study the physiological and molecular effects of probiotics with potential applications regarding the different pathologies of metabolic syndrome. This review aims to summarize the main studies describing anti-obesogenic, anti-diabetic, or anti-inflammatory properties of probiotics using C. elegans as an in vivo research model, as well as providing a description of the molecular mechanisms involved in these activities. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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16 pages, 856 KiB

Open AccessReview

Towards Understanding Neurodegenerative Diseases: Insights from Caenorhabditis elegans

by Yingjie Wu, Yining Chen, Xiaochun Yu, Minxing Zhang and Zhaoyu Li

Int. J. Mol. Sci. 2024, 25(1), 443; https://doi.org/10.3390/ijms25010443 - 28 Dec 2023

Cited by 5 | Viewed by 2307

Abstract

The elevated occurrence of debilitating neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and Machado–Joseph disease (MJD), demands urgent disease-modifying therapeutics. Owing to the evolutionarily conserved molecular signalling pathways with mammalian species and facile [...] Read more.

The elevated occurrence of debilitating neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and Machado–Joseph disease (MJD), demands urgent disease-modifying therapeutics. Owing to the evolutionarily conserved molecular signalling pathways with mammalian species and facile genetic manipulation, the nematode Caenorhabditis elegans (C. elegans) emerges as a powerful and manipulative model system for mechanistic insights into neurodegenerative diseases. Herein, we review several representative C. elegans models established for five common neurodegenerative diseases, which closely simulate disease phenotypes specifically in the gain-of-function aspect. We exemplify applications of high-throughput genetic and drug screenings to illustrate the potential of C. elegans to probe novel therapeutic targets. This review highlights the utility of C. elegans as a comprehensive and versatile platform for the dissection of neurodegenerative diseases at the molecular level. Full article

(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives)

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