Elegans Model System Research Articles

CeMbio - TheCaenorhabditis elegansMicrobiome Resource

The study of microbiomes by sequencing has revealed a plethora of correlations between microbial community composition and various life-history characteristics of the corresponding host species. However, inferring causation from correlation is often hampered by the sheer compositional complexity of microbiomes, even in simple organisms. Synthetic communities offer an effective approach to infer cause-effect relationships in host-microbiome systems. Yet the available communities suffer from several drawbacks, such as artificial (thus non-natural) choice of microbes, microbe-host mismatch (e.g., human microbes in gnotobiotic mice), or hosts lacking genetic tractability. Here we introduce CeMbio, a simplified natural Caenorhabditis elegans microbiota derived from our previous meta-analysis of the natural microbiome of this nematode. The CeMbio resource is amenable to all strengths of the C. elegans model system, strains included are readily culturable, they all colonize the worm gut individually, and comprise a robust community that distinctly affects nematode life-history. Several tools have additionally been developed for the CeMbio strains, including diagnostic PCR primers, completely sequenced genomes, and metabolic network models. With CeMbio, we provide a versatile resource and toolbox for the in-depth dissection of naturally relevant host-microbiome interactions in C. elegans.

Diverse Roles of PUF Proteins in Germline Stem and Progenitor Cell Development in C. elegans.

Stem cell development depends on post-transcriptional regulation mediated by RNA-binding proteins (RBPs) (Zhang et al., 1997; Forbes and Lehmann, 1998; Okano et al., 2005; Ratti et al., 2006; Kwon et al., 2013). Pumilio and FBF (PUF) family RBPs are highly conserved post-transcriptional regulators that are critical for stem cell maintenance (Wickens et al., 2002; Quenault et al., 2011). The RNA-binding domains of PUF proteins recognize a family of related sequence motifs in the target mRNAs, yet individual PUF proteins have clearly distinct biological functions (Lu et al., 2009; Wang et al., 2018). The C. elegans germline is a simple and powerful model system for analyzing regulation of stem cell development. Studies in C. elegans uncovered specific physiological roles for PUFs expressed in the germline stem cells ranging from control of proliferation and differentiation to regulation of the sperm/oocyte decision. Importantly, recent studies started to illuminate the mechanisms behind PUF functional divergence. This review summarizes the many roles of PUF-8, FBF-1, and FBF-2 in germline stem and progenitor cells (SPCs) and discusses the factors accounting for their distinct biological functions. PUF proteins are conserved in evolution, and insights into PUF-mediated regulation provided by the C. elegans model system are likely relevant for other organisms.

BIOPHYSICAL STUDIES OF SUPPRESSOR OF TAU-2 (SUT2)

Studies in a Caenorhabditis elegans model system of human tauopathies, by Brian Kraemer's laboratory, have shown that the Suppressor of Tau-2 (SUT2) protein promotes the accumulation of tau aggregates. Increased SUT2 levels promotes aggregated tau-related disorders, including neuronal swelling and increased degeneration of neurons and axons. When SUT2 is removed, tau aggregation and the associated neurotoxic effects are decreased: neurodegenerative changes are alleviated, and motor dysfunction is improved. The suppression of mammalian SUT2 (MSUT2) in a human cell tauopathy model system also decreases the amount of aggregated tau. These data strongly suggest that MSUT2 is a good therapeutic target of tauopathy diseases, since the inhibition of only one protein would be necessary for an effective neuroprotective strategy. Molecular biology, protein purification and NMR spectroscopy. The region in SUT2 that is involved contains a structured region known as the PWI domain. The roles and functional mechanisms of PWI domains are unknown, but our preliminary studies suggest that it may generally mediate protein-protein interactions. The region within ZYG-12 that is bound by the PWI domain is within the first 196 residues. Gene sequences for the PWI domains from the C. elegans and human SUT2 proteins have already been acquired, and the corresponding protein has been expressed and purified to homogeneity. Preliminary studies using Nuclear Magnetic Resonance spectroscopy have already revealed that the C. elegans SUT2 protein construct is amenable to structure determination. Our research will provide the first molecular structure of a PWI domain-containing biomolecular complex. Structural details of the SUT2/Zyg-12 complex will provide an insight into the mechanism by which the proteins promote formation of neurodegenerative aggregates, and potentially aid in the design of therapeutics. Structure-based in silico screening will identify small molecules that may interact with the interfacing surfaces and prevent the protein-protein interaction. A small molecule inhibitor would be an excellent tool to test the role of the interaction in C. elegans and human tauopathy model systems and could be a novel neuroprotective therapeutic strategy that prevents the formation of disease- associated tau aggregates.

Harmine suppresses hyper-activated Ras\u2013MAPK pathway by selectively targeting oncogenic mutated Ras/Raf in Caenorhabditis elegans

BackgroundMutationally activated Ras proteins are closely linked to a wide variety of human cancers. Hence, there has been an intensive search for anti-Ras therapies for cancer treatment. The sole Ras gene, which encodes LET-60, in Caenorhabditis elegans regulates vulval development. While the loss of let-60 function leads to failure of vulva formation, the let-60(n1046gf) allele, which contains a missense mutation mimicking a Ras codon 13 mutation found in human cancers, results in extra vulval tissue, a phenotype named Muv (multiple vulvas).MethodsBy taking advantage of the easy-to-score Muv phenotype of let-60(n1046gf), we used a step-by-step screening approach (from crude extract to active fraction to active natural compound) to search for inhibitors of oncogenic Ras. Mutants of other key components in the Ras–mitogen-activated protein kinase (MAPK) pathway were used to identify other candidate targets.ResultsThe natural compound harmine, isolated from the plant Peganum harmala, was found to suppress the Muv phenotype of let-60(n1046gf). In addition, harmine targets the hyper-activation of the Ras/MAPK pathway specifically caused by overexpression or mutated forms of LET-60/Ras and its immediate downstream molecule LIN-45/Raf. Finally, harmine can be absorbed into the worm body and probably functions in its native form, rather than requiring metabolic activation.ConclusionIn sum, we have revealed for the first time the anti-Ras activity of harmine in a C. elegans model system. Our results revealed the potential anti-cancer mechanism of harmine, which may be useful for the treatment of specific human cancers that are associated with oncogenic Ras mutations.

Mosloflavone attenuates the quorum sensing controlled virulence phenotypes and biofilm formation in Pseudomonas aeruginosa PAO1: In vitro, in vivo and in silico approach

Quorum sensing (QS) is the cell density dependent communication network which coordinates the production of pathogenic determinants in majority of pathogenic bacteria. Pseudomonas aeruginosa causes hospital-acquired infections by virtue of its well-defined QS network. As the QS regulatory network in P. aeruginosa regulates the virulence determinants and antibiotic resistance, attenuating the QS system seems to be influential in developing next-generation anti-infective agents. In the current study, the QS attenuation potential of a flavonoid, mosloflavone was investigated against P. aeruginosa virulence and biofilm formation. Mosloflavone inhibited the pyocyanin production, LasB elastase and chitinase by 59.52 ± 2.74, 35.90 ± 4.34 and 61.18 ± 5.52% respectively. The QS regulated biofilm formation and development was also reduced when supplemented with sub-MIC of mosloflavone. The gene expression studies of mosloflavone using RT-PCR depicted its ability to down-regulate the expression levels of QS regulated virulence genes such as lasI (60.64%), lasR (91.70%), rhlI (57.30%), chiC (90.20%), rhlA (47.87%), rhlR (21.55%), lasB (37.80%), phzM (42.40%), toxA (61.00%), aprA (58.4%), exoS (78.01%), algD (46.60%) and pelA (50.45%). The down-regulation of QS virulence phenotypes by mosloflavone could be attributed to its binding affinity with the QS regulatory proteins, LasR and RhlR by competitively inhibiting the binding of natural autoinducers as evidenced from simulation studies. Mosloflavone also exhibited promising potential in controlling bacterial infection in Caenorhabditis elegans model system, in vivo. The anti-biofilm and anti-QS potential of mosloflavone in the current study illustrated the candidature of mosloflavone as a promising biocide.

Anti-ageing and anti-Parkinsonian effects of natural flavonol, tambulin from Zanthoxyllum aramatum promotes longevity in Caenorhabditis elegans.

Ageing is a progressive deterioration in functional and structural well-being of the body, accompanied with age-associated neurological disorders such as Parkinson's disease (PD), Alzheimer's disease and Huntington's disease. PD is marked with motor function decline, progressive neurodegeneration due to aggregation of insoluble α-synuclein in the dopaminergic neuron. Here we investigated the effect of tambulin (3,5-dihydroxy-7,8-dimethoxy-2-(4-methoxyphenyl) chromen-4-one), a hydroxy substituted flavanol isolated from fruits of Zanthoxyllum armatum DC (Family-Rutaceae) for its longevity promoting and neuromodulatory activities using Caenorhabditis elegans model system. Our results show that tambulin treatment significantly enhance lifespan and stress tolerance in worms, along with mitigation of ageing biomarkers like lipofuscin and protein carbonyl. In line with the alleviated ROS levels, tambulin treatment led to upregulated mRNA expression of ROS scavenging genes viz., sod-1, sod-3, and ctl-2. Upregulation in daf-16 gene indicates the involvement of insulin signaling pathway in tambulin mediated longevity. Tambulin treatment exhibited curtailed PD manifestations in terms of reduced α-synuclein levels, lipid accumulation, improved locomotary behavior and dopamine levels. Altogether, our data suggest that tambulin mediated alleviation of PD manifestations possibly involved PD counter protective machinery as evident through upregulated mRNA expression of lagr-1, ymel-1, pdr-1, ubc-12, and lrk-1. Our studies present tambulin as a potential molecule for its properties against ageing and Parkinson's disease. Further studies are speculated to realize the mechanistic and pharmacological aspects of tambulin.

Pmr-1 gene affects susceptibility of Caenorhabditis elegans to Staphylococcus aureus infection through glycosylation and stress response pathways' alterations

ABSTRACTCalcium signaling can elicit different pathways involved in an extreme variety of biological processes. Calcium levels must be tightly regulated in a spatial and temporal manner in order to be efficiently and properly utilized in the host physiology. The Ca2+-ATPase, encoded by pmr-1 gene, was first identified in yeast and localized to the Golgi and it appears to be involved in calcium homeostasis. PMR-1 function is evolutionary conserved from yeast to human, where mutations in the orthologous gene ATP2C1 cause Hailey-Hailey disease. In this work, we used the Caenorhabditis elegans model system to gain insight into the downstream response elicited by the loss of pmr-1 gene. We found that pmr-1 knocked down animals not only showed defects in the oligosaccharide structure of glycoproteins at the cell surface but also were characterized by reduced susceptibility to bacterial infection. Although increased resistance to the infection might be related to lack of regular recognition of C. elegans surface glycoproteins by microbial agents, we provide genetic evidence that pmr-1 interfered nematodes mounted a stronger innate immune response to Gram-positive bacterial infection. Thus, our observations indicate pmr-1 as a candidate gene implicated in mediating the worm’s innate immune response.

Development of transgenic Caenorhabditis elegans expressing human transthyretin as a model for drug screening

Familial amyloid polyneuropathy is a hereditary systemic amyloidosis caused by a mutation in the transthyretin (TTR) gene. Amyloid deposits in tissues of patients contain not only full-length TTR but also C-terminal TTR fragments. However, in vivo models to evaluate the pathogenicity of TTR fragments have not yet been developed. Here, we generated transgenic Caenorhabditis elegans strains expressing several types of TTR fragments or full-length TTR fused to enhanced green fluorescent protein in the body wall muscle cells and analyzed the phenotypes of the worms. The transgenic strain expressing residues 81–127 of TTR, which included the β-strands F and H, formed aggregates and caused defective worm motility and a significantly shortened lifespan compared with other strains. These findings suggest that the C-terminal fragments of TTR may contribute to cytotoxicity of TTR amyloidosis in vivo. By using this C. elegans model system, we found that (−)-epigallocatechin-3-gallate, a major polyphenol in green tea, significantly inhibited the formation of aggregates, the defective motility, and the shortened lifespan caused by residues 81–127 of TTR. These results suggest that our newly developed C. elegans model system will be useful for in vivo pathological analyses of TTR amyloidosis as well as drug screening.

Antioxidant and anti-aging potential of Juniper berry (Juniperus communis L.) essential oil in Caenorhabditis elegans model system

Plant and plant products including essential oils are globally acclaimed for their medicinal and therapeutic values. It’s an age-old practice, owing to their safety and protective effects against reactive oxygen species (ROS)/oxidative stresses. Aging is a global challenge and needs proper attention to check on its causative factors. The increased ROS production/oxidative stress is one of the major contributing factors endorses aging and age-related disorders. To this end, the present study was designed to explore the in vivo-antioxidant and anti-aging potentials of Juniper berry essential oil (JBEO) by using Caenorhabditis elegans as a model organism. Present work investigated the impact of different doses (0, 10, 50, 100 ppm) on lifespan and healthspan of C. elegans. The present study revealed that lower dose (10 ppm) was highly effective and enhanced the lifespan of C. elegans by 18.54% as compared to the control. Similarly, same concentration, i.e. 10 ppm was also showing potential against various oxidative and thermal stresses. The JBEO treated worms showed 30.40% more survival under thermal stress as compared to control. Besides the increased survival percent of worms, the elevated expression of SOD-3 (39.49%) and GST-4 (25.13%) was also observed, indicating oxidative stress resistance in worms. The screening studies on mutants of C. elegans for prediction of mechanism demonstrated the involvement of major conserved transcription factors (DAF-16, SKN-1, and HSF-1) which coordinates in the stress-induced transcription and extends longevity. Overall, here we unrevealed potentials of JBEO in anti-stressor activities and lifespan extension in C. elegans. Thus, in future, more studies on JBEO will pave paths for commercialization of essential oils in the formulations of antiaging products.

Efficacy of 7-benzyloxyindole and other halogenated indoles to inhibit Candida albicans biofilm and hyphal formation.

SummaryCertain pathogenic bacteria and yeast form biofilms on biotic and abiotic surfaces including medical devices and implants. Hence, the development of antibiofilm coating materials becomes relevant. The virulence of those colonizing pathogens can be reduced by inhibiting biofilm formation rather than killing pathogens using excessive amounts of antimicrobials, which is touted as one of the main reasons for the development of drug resistance. Candida albicans is an opportunistic fungal pathogen, and the transition of yeast cells to hyphal cells is believed to be a crucial virulence factor. Previous studies have shown that indole and its derivatives possess antivirulence properties against various bacterial pathogens. In this study, we used various indole derivatives to investigate biofilm‐inhibiting activity against C. albicans. Our study revealed that 7‐benzyloxyindole, 4‐fluoroindole and 5‐iodoindole effectively inhibited biofilm formation compared to the antifungal agent fluconazole. Particularly, 7‐benzyloxyindole at 0.02 mM (4.5 μg ml−1) significantly reduced C. albicans biofilm formation, but had no effect on planktonic cells, and this finding was confirmed by a 2,3‐bis‐(2‐methoxy‐4‐nitro‐5‐sulfophenyl)‐2H‐tetrazolium‐5‐carboxanilide (XTT) assay and three‐dimensional confocal laser scanning microscopy. Scanning electron microscopy analyses revealed that 7‐benzyloxyindole effectively inhibited hyphal formation, which explains biofilm inhibition. Transcriptomic analysis showed that 7‐benzyloxyindole downregulated the expressions of several hypha/biofilm‐related genes (ALS3,ECE1,HWP1 and RBT1). A C. albicans‐infected Caenorhabditis elegans model system was used to confirm the antivirulence efficacy of 7‐benzyloxyindole.

Longevity and Stress Resistant Property of 6-Gingerol from Zingiber officinale Roscoe in Caenorhabditis elegans.

In order to discover lifespan-extending compounds made from natural resources, activity-guided fractionation of Zingiber officinale Roscoe (Zingiberaceae) ethanol extract was performed using the Caenorhabditis elegans (C. elegans) model system. The compound 6-gingerol was isolated from the most active ethyl acetate soluble fraction, and showed potent longevity-promoting activity. It also elevated the survival rate of worms against stressful environment including thermal, osmotic, and oxidative conditions. Additionally, 6-gingerol elevated the antioxidant enzyme activities of C. elegans, and showed a dose-depend reduction of intracellular reactive oxygen species (ROS) accumulation in worms. Further studies demonstrated that the increased stress tolerance of 6-gingerol-mediated worms could result from the promotion of stress resistance proteins such as heat shock protein (HSP-16.2) and superoxide dismutase (SOD-3). The lipofuscin levels in 6-gingerol treated intestinal worms were decreased in comparison to the control group. No significant 6-gingerol-related changes, including growth, food intake, reproduction, and movement were noted. These results suggest that 6-gingerol exerted longevity-promoting activities independently of these factors and could extend the human lifespan.

Shatavarin IV elicits lifespan extension and alleviates Parkinsonism in Caenorhabditis elegans

Shatavarin IV (SIV), a steroidal saponin, is a major bioactive phytomolecule present in roots of Asparagus racemosus (Liliaceae) known for its anticancer activity. Age-associated neurodegenerative Parkinson’s disease (PD) is characterised by alpha-synuclein aggregation in dopaminergic neuron resulting in neurodegeneration. The invention of bioactive molecules that delay aging and age-associated disorders endorses development of natural phytomolecule as a therapeutic agent for curing age-related diseases. Therefore, the present study for the first time explores the potential of SIV against aging and Parkinsonism utilising Caenorhabditis elegans model system. SIV significantly attenuated oxidative stress in terms of intracellular reactive oxygen species (ROS) as well as oxidative damage including protein carbonylation and also promotes longevity. SIV also significantly increased the mRNA expression of stress responsive genes namely sod-1, sod-2, sod-3, gst-4, gst-7 and ctl-2 suggesting its anti-oxidant property that might be contributed in the modulation of oxidative stress and promoting lifespan. Additionally, SIV improved PD symptoms by reducing the alpha-synuclein aggregation, lipid accumulation and enhancing dopamine level. Altogether, present findings indicate that SIV possibly utilising ubiquitin-mediated proteasomal system and attenuating oxidative stress by up-regulating PD-associated genes pdr-1, ubc-12 and pink-1. Therefore, this study is a forward step in exploring the anti-aging and anti-Parkinsonism potential of bioactive compound SIV in C. elegans.

Lifespan-extending and stress resistance properties of brazilin from Caesalpinia sappan in Caenorhabditis elegans.

This study contributes to the continual discovery of lifespan-extending compounds from plants, using the Caenorhabditis elegans model system. An ethyl acetate soluble fraction of methanol extract from the heartwood of Caesalpinia sappan showed a significant lifespan-extending activity. Subsequent activity-guided chromatography of the ethyl acetate-soluble fraction led to the isolation of brazilin. Brazilin showed potent 2,2-diphenyl-1-picrylhydrazyl radical scavenging and superoxide anion quenching activities and also revealed a lifespan-extending activity in C. elegans under normal culture conditions. Brazilin also exhibited the protective effects against thermal, oxidative and osmotic stress conditions to improve the survival rate of the nematode. Furthermore, brazilin elevated superoxide dismutase (SOD) activity and decreased intracellular reactive oxygen species accumulation in C. elegans. Further studies showed that brazilin-mediated increased stress tolerance of worms could be due to increased expressions of stress resistance proteins such as heat shock protein (HSP-16.2) and superoxide dismutase (SOD-3). Besides, there were no significant, brazilin-induced changes in aging-related factors, including progeny production, food intake, and growth, indicating brazilin influences longevity activity independent of affecting these factors. Brazilin increased the body movement of aged worms, indicating brazilin affects the healthspan and lifespan of nematode. These results suggest that brazilin contributes to the lifespan of C. elegans under both normal and stress conditions by increasing the expressions of stress resistance proteins.

Comparative phytochemical analysis of Phlogacanthus thyrsiflorus Nees: Implications on attenuation of pro-oxidants and pathogen virulence in Caenorhabditis elegans model system

Background: Phlogacanthus thyrsiflorus Nees (P. thyrsiflorus) of Acanthaceae family is endogenous to sub-tropical Himalayas. It has been reported to be used traditionally in Jaintia tribe of Meghalaya, India for treatment of many ailments.Objectives: The aim was to detect the active compounds present in the leaves for evaluation of in vitro free radicals scavenging potentials. Leaves protective actions in vivo will be investigated using Caenorhabditis elegans (C. elegans) model system utilizing wild type and mutant strains and the phenomena of host-pathogens interactions.Materials and methods: Gas chromatography/ Mass spectrometry (GC/MS) was used for detection of different compounds present. The versatility of leaf extracts to scavenge different free radicals generated in vitro was assessed with different in vitro methods. Survival analysis of wild type and mutant strains C. elegans under enhanced pro-oxidants exposure was investigated in vivo. Fast killing assay was also performed to study the extracts modulatory activity on host C. elegans survival under pathogen Pseudomonas aeruginosa infection.Results: Forty compounds were detected in methanolic fraction of the extract with variable percentages. Both aqueous and methanol extract possessed remarkable, versatile free radical scavenging activity irrespective of the types of free radical generated. The in vivo experiments are in compliance, with observable increased survival ability percentage of C. elegans under intense exogenous oxidative stress and pathogen infection.Conclusion: Our findings enlightened the different compounds present with versatility of P. thyrsiflorus in tackling different free radicals generated both in vitro and in vivo that highly support for its candidature as a good antioxidant source. Our findings may justify the historical relevance of this plant in herbal remedies that could form the basis for inquiry of new active principles.Keywords: Free radicals, Oxidative stress, Caenorhabditis elegans, Phlogacanthus thyrsiflorus, Phytochemicals

An antidiabetic polyherbal phytomedicine confers stress resistance and extends lifespan in Caenorhabditis elegans.

An Ayurvedic polyherbal extract (PHE) comprising six herbs viz. Berberis aristata, Cyperus rotundus, Cedrus deodara, Emblica officinalis, Terminalia chebula and Terminalia bellirica is mentioned as an effective anti-hyperglycemic agent in 'Charaka Samhita', the classical text of Ayurveda. Previously, antidiabetic drug metformin was found to elicit antiaging effects and PHE was also found to exhibit antidiabetic effects in humans. Therefore, we screened it for its in vivo antioxidant antiaging effect on stress and lifespan using human homologous Caenorhabditis elegans model system. The effect on aging is evaluated by studying effect of PHE on mean survival in worms. The stress modulatory potential was assessed by quantification of intracellular ROS level, autofluorescent age pigment lipofuscin, oxidative and thermal stress assays. Additionally, stress response was quantified using gene reporter assays. The 0.01µg/ml dose of PHE was able to enhance mean lifespan by 16.09% (P<0.0001) in C. elegans. Furthermore, PHE treated worms demonstrated oxidative stress resistance in both wild type and stress hypersensitive mev-1 mutant along with upregulation of stress response genes sod-3 and gst-4. The delayed aging under stress can be attributed to its direct reactive oxygen species-scavenging activity and regulation of some age associated genes like daf-2, daf-16, skn-1, sod-3 and gst-4 in wild-type worms. Additonally, PHE delayed age related paralysis phenotype in CL4176 transgenic worms. Altogether, our results suggest PHE significantly improves the oxidative stress and life span in C. elegans. Overall the present study suggests this polyherbal formulation might play important role in regultaing aging and related complications like diabetes.

Syzygium aromaticum(L.) elicits lifespan extension and attenuates age-related Aβ-induced proteotoxicity inCaenorhabditis elegans

AbstractClove (Syzygium aromaticum) is a popular medicinal plant which has been traditionally used in India as spice and medicine to counter various ailments. However, the stress modulatory and antiaging potential of this plant is yet to be characterized. Therefore, the present study evaluates the effect of clove oil (CO) on oxidative stress, lifespan, mobility, and the expression of aging-related proteins using Caenorhabditis elegans model system. The CO (10 ppm) was found to extend mean lifespan in worms by 21.4% (p < 0.001) under normal and by 63% (p < 0.0001) under juglone-induced oxidative stress conditions. The extension of mean lifespan in mev-1 mutant and elevated expression of gst-4 and sod-3 confirmed stress modulatory effects of CO. Additionally, the CO reduced intracellular ROS and Aβ1–42 proteotoxicity. Altogether, the present study unravels the anti-aging and stress modulatory potential of CO and suggests CO as a potential pharmaceutical entity in modulating aging process.

Peptides from sesame cake extend healthspan of Caenorhabditis elegans via upregulation of skn-1 and inhibition of intracellular ROS levels

The peptides from sesame cake (PSC) which are the main by-product of agricultural processing of sesame were prepared. To evaluate benefits of PSC for health and longevity, antioxidant activity and anti-aging effects were studied in vitro and in a Caenorhabditis elegans (C. elegans) model system. PSC exhibited antioxidant activity in vitro, and induced beneficial effects on lifespan and several health parameters of C.elegans, including pharyngeal pumping rate, locomotion and lipofuscin accumulation. In a mev-1 mutant, PSC increased lifespan, and it enhanced oxidative stress tolerance in wild-type nematodes. After treatment with PSC, SOD activity, GSH content, and GSH/GSSG ratio were increased, leading to low intracellular ROS levels in C. elegans. PSC up-regulated skn-1 mRNA, and its target gene gcs-1, and abolished the extension of lifespan in skn-1 mutant, indicating that PSC-mediated longevity is dependent on activation of the skn-1/Nrf-2 transcription factor. Current results warrant research into the use of PSC as nutraceuticals for overall health improvement.

Acacetin promotes healthy aging by altering stress response in Caenorhabditis elegans

The progression in lifespan has been associated with elevated intracellular reactive oxygen species (ROS) and oxidative stress level which contributes to development of age related disorders. The discovery of lifespan modulating phytomolecules may promote development of natural therapies against age related afflictions. Acacetin (5,7-dihydroxy-4-methoxyflavone), is a naturally occurring flavonoid known to possess therapeutic properties. To this end, the present study evaluates effect of acacetin (AC) on lifespan, stress and neurotoxicity for the first time by using well-established free living, multicellular Caenorhabditis elegans model system. The 25 μM dose of AC significantly prolonged the mean lifespan of worms by 27.31% in comparison to untreated control and other tested doses of AC. Additionally, AC enhanced stress resistance against oxidative and thermal stress in worms. Furthermore, AC attenuated age related intracellular ROS level, aggregation of age pigment lipofuscin and increased the mean survival in stress hypersensitive mev-1 mutant by 40.5%. AC supplementation also reduced the alpha synuclein aggregation in transgenic worm model of Parkinson’s disease. The enhanced stress resistance, lifespan and alleviation of age related pathology can be attributed to increment in stress modulatory enzymes like superoxide dismutase (SOD) and catalase (CAT) level. Altogether the results suggest AC exposure maintains stress level, health span and extends mean lifespan of C. elegans. The longevity promoting and neuromodulatory effects of AC are mediated by up regulation of the stress response genes sod-3 and gst-4. The present finding gives new insights of natural remedies and their future prospects in developing therapeutic interventions for managing age related diseases.

Marriage shrines and worms impacting our understanding of mammalian fertilization.

ABSTRACTGenetic approaches in C. elegans are complementing the biochemical and antibody based strategies traditionally used to study the molecular underpinnings of fertilization in other organisms. A pair of worm studies, one based on forward genetics and one based on reverse genetics, converge on the sperm immunoglobulin superfamily molecule SPE-45. Loss of spe-45 function leads to the production of sperm that cannot fertilize wild-type eggs. This is a strikingly similar phenotype as those seen in mice lacking the immunoglobulin superfamily protein Izumo1. This work sets the stage for leveraging the power of the C. elegans model system to learn more about Izumo-like molecular function but also for the discovery of additional deeply conserved components of fertility pathways.

Study on Lifespan Extension Effect of Leonurine and its Synthetic Fragmental Analogs on Caenorhabditis elegans

노화(aging)는 생명체가 시간의 흐름에 따라 생체의 구조 및 기능이 쇠퇴, 감소되어 질환이 발생하거나 사망률이 증가되는 현상이다. 노화의 정확한 원인은 아직까지 밝혀지지 않았지만, 그 원인을 설명하려는 여러 가지 가설이 제시되고 있다. 이중에서, 노화의 원인을 활성산소(reactive oxygen species; ROS)에 의한 세포손상의 축적으로 설명하는 산화스트레스 이론(oxidative stress theory)이 여러 가지 실험적 증거를 살펴볼 때 신빙성이 있는 이론 중 하나로 여겨지고 있다.1) 이와 같은 산화스트레스 이론에 근거하여 ROS의 제거 및 생성억제 효능을 갖는 천연 및 합성 항산화제(antioxidant)를 이용하여 노화를 늦추고 수명을 연장시키고자 하는 연구가 활발히 진행되고 있다.2,3) 레오누린(leonurine, 1)은 자궁 수축효과를 나타내어 오랫동안 약초로 사용되어 온 익모초(Chinese motherwort; Leonurus Artemisia)의 잎에서 분리된 알칼로이드의 일종이다.4) 최근 연구에 따르면 레오누린은 심근보호 효과 및 허혈성 심근경색 치료 효과를 나타내는데, 이러한 심근 보호 효과는 레오누린의 항산화 활성과 상관관계가 있는 것으로 여겨지고 있다.5) 이에 본 연구에서는 항산화 활성과 수명연장의 상관관계 및 레오누린의 항산화 활성에 착안하여, 레오누린의 수명연장 효과를 예쁜꼬마선충(Caenorhabditis elegans)을 이용하여 평가해보았다. 예쁜꼬마선충은 수명과 세대가 짧고 다루기 쉬우며 포유류와도 많은 구조적, 유전자적 유사성을 지니고 있기 때문에 노화 관련 연구를 위한 좋은 동물모델로 널리 활용되고 있다. 이와 더불어 레오누린의 분절 유도체들(fragmental analogs)을 합성하고 그 유도체 각각의 수명연장 효과를 평가해봄으로써 레오누린의 구조와 수명연장 활성 간의 상관관계를 연구해보고자 하였다(Fig. 1).The current study was conducted to evaluate the lifespan extension effects of leonurine and its synthetic fragmental analogs using Caenohabditis elegans model system. Leonurine significantly prolonged the lifespan of C. elegans in a dose-dependent manner. To dissect the structure-activity relationship between leonurine and lifespan extension activity, seven novel fragmental analogs were synthesized and evaluated. Our study revealed that benzoate part of leonurine is responsible for its lifespan extension property rather than quanidine moiety.