Ge YL et al. (2002) Anticancer Res "Effects of adenoviral gene transfer of C. elegans n-3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells."

Kang ZB, Chen Z, Leaf A, Kang JX, Cluette-Brown J, Laposata M, Ge YL

[Anticancer Res, 2002]

Background: Current evidence from both experimental and human studies indicates that omega-6 polyunsaturated fatty acids (n-6 PUFAs) promote breast tumor development, whereas long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) exert suppressive effects. The ratio of n-6 to n-3 fatty acids appears to be an important factor in controlling tumor development. Human cells usually have a very high n-6/n-3 fatty acid ratio because they cannot convert n-6 PUFAs to n-3 PUFAs due to lack of an n-3 desaturase found in C. elegans. Materials and Methods: Adenoviral strategies were used to introduce the C. elegans fat-1 gene encoding an n-3 fatty acid desaturase into human breast cancer cells followed by examination of the n-6/n-3 fatty acid ratio and growth of the cells. Results: Infection of MCF-7 cells with an adenovirus carrying the fat-1 gene resulted in a high expression of the n-3 fatty acid desaturase. Lipid analysis indicated a remarkable increase in the levels of n-3 PUFAs accompanied with a large decrease in the contents of n-6 PUFAs, leading to a change of the n-6/n-3 ratio from 12.0 to 0.8. Accordingly, production of the eicosanoids derived from n-6 PUFA was reduced significantly in cells expressing the fat-1 gene. Importantly, the gene transfer induced mass cell death and inhibited cell proliferation. Conclusion: The gene transfer of the n-3 fatty acid desaturase, as a novel approach, can effectively modify the n-6/n-3 fatty acid ratio of human tumor cells and provide an anticancer effect, without the need of exogenous n-3 PUFA supplementation. These data also increase the understanding of the effects of n-3 fatty acids and the n-6/n-3 ratio on cancer prevention and treatment.

Xu T et al. (2022) Food Funct "Longevity-promoting properties of ginger extract in Caenorhabditis elegans via the insulin/IGF-1 signaling pathway."

Tao M, Pan S, Xu T, Wu T, Li R, Xu X

[Food Funct, 2022]

Ginger is a traditional medicinal and edible plant with multiple health-promoting properties. Nevertheless, the effects and potential mechanism of ginger on antiaging remain unknown. The aim of this study was to comprehend the antiaging effects and potential mechanism of ginger in Caenorhabditis elegans (C. elegans). The current findings showed that the lifespan of C. elegans was prolonged by 23.16% with the supplementation of 60 μg mL-1 ginger extract (GE), and the extension of lifespan was mainly attributed to the major bioactive compounds in GE, 6-, 8-, 10-gingerol and 6-, 8-, 10-shogaol. Subsequently, GE promoted healthy aging by improving nematode movement and attenuating lipofuscin accumulation, and enhanced stress tolerance by up-regulating the expression of stress-related genes and activating DAF-16 and SKN-1. Moreover, lifespan assays of relative mutants revealed that GE mediated extension of lifespan via the insulin/IGF-1 signaling (IIS) pathway. In summary, GE endowed nematodes (C. elegans) with longevity and stress resistance in an IIS pathway dependent manner.

Aranaz P et al. (2021) Nutrients "Grifola frondosa (Maitake) Extract Reduces Fat Accumulation and Improves Health Span in C. elegans through the DAF-16/FOXO and SKN-1/NRF2 Signalling Pathways."

Vettorazzi A, Fabra MJ, Aranaz P, Pena A, Castellari M, Parlade J, Gonzalez-Navarro CJ, Pera J, Martinez-Abad A, Milagro FI, Lopez-Rubio A

[Nutrients, 2021]

In recent years, food ingredients rich in bioactive compounds have emerged as candidates to prevent excess adiposity and other metabolic complications characteristic of obesity, such as low-grade inflammation and oxidative status. Among them, fungi have gained popularity for their high polysaccharide content and other bioactive components with beneficial activities. Here, we use the <i>C. elegans</i> model to investigate the potential activities of a <i>Grifola frondosa</i> extract (GE), together with the underlying mechanisms of action. Our study revealed that GE represents an important source of polysaccharides and phenolic compounds with in vitro antioxidant activity. Treatment with our GE extract, which was found to be nongenotoxic through a <i>SOS/umu</i> test, significantly reduced the fat content of <i>C. elegans</i>, decreased the production of intracellular ROS and aging-lipofuscin pigment, and increased the lifespan of nematodes. Gene expression and mutant analyses demonstrated that the in vivo anti-obesity and antioxidant activities of GE were mediated through the <i>daf-2/daf-16</i> and <i>skn-1/nrf-2</i> signalling pathways, respectively. Taken together, our results suggest that our GE extract could be considered a potential functional ingredient for the prevention of obesity-related disturbances.

Huang CH et al. (2015) J Nutr Biochem "Analysis of lifespan-promoting effect of garlic extract by an integrated metabolo-proteomics approach."

Hsu FY, Wu YH, Liang SS, Kuo CJ, Hsu AL, Chiou SH, Huang CH, Zhong L, Tseng MY

[J Nutr Biochem, 2015]

The beneficial effects of garlic (Allium sativum) consumption in treating human diseases have been reported worldwide over a long period of human history. The strong antioxidant effect of garlic extract (GE) has also recently been claimed to prevent cancer, thrombus formation, cardiovascular disease and some age-related maladies. Using Caenorhabditis elegans as a model organism, aqueous GE was herein shown to increase the expression of longevity-related FOXO transcription factor daf-16 and extend lifespan by 20%. By employing microarray and proteomics analysis on C. elegans treated with aqueous GE, we have systematically mapped 229 genes and 46 proteins with differential expression profiles, which included many metabolic enzymes and yolky egg vitellogenins. To investigate the garlic components functionally involved in longevity, an integrated metabolo-proteomics approach was employed to identify metabolites and protein components associated with treatment of aqueous GE. Among potential lifespan-promoting substances, mannose-binding lectin and N-acetylcysteine were found to increase daf-16 expression. Our study points to the fact that the lifespan-promoting effect of aqueous GE may entail the DAF-16-mediated signaling pathway. The result also highlights the utility of metabolo-proteomics for unraveling the complexity and intricacy involved in the metabolism of natural products in vivo.

Sanjeeva Reddy C et al. (2010) Chem Pharm Bull (Tokyo) "Synthesis, nematicidal and antimicrobial activity of 3-(5-3-methyl-5-[(3-methyl-7-5-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo[b]furan-5-yl)methyl]benzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(aryl)-1,3-thiazolan-4-one."

Chandrashekar Rao D, Yakub V, Sanjeeva Reddy C, Nagaraj A

[Chem Pharm Bull (Tokyo), 2010]

A new series of 3-(5-3-methyl-5-[(3-methyl-7-5-[2-(aryl)-4-oxo-1,3-thiazolan-3-yl]-1,3,4-thiadiazol-2-ylbenzo[b]furan-5-yl)methyl]benzo[b]furan-7-yl-1,3,4-thiadiazol-2-yl)-2-(aryl)-1,3-thiazolan-4-one 5a-j has been synthesized by the reaction of N2-[(E)-1-(4-methylphenyl)methylidene]-5-(3-methyl-5-[3-methyl-7-(5-[(E)-1-(4-methylphenyl)methylidene]amino-1,3,4-thiadiazol-2-yl)benzo[b]furan-5-yl]methylbenzo[b]furan-7-yl)-1,3,4-thiadiazol-2-amine 4a-j with thioglycolic acid. Chemical structures of all the new compounds were established by their IR, 1H-NMR, 13C-NMR, MS and elemental data. The 5a-j have been assayed for their nematicidal activity against Ditylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique. The screened data reveal that, the 5e is most effective against D. myceliophagus and C. elegans with 50% lethal dose (LD(50)) of 170 and 190 ppm, respectively and is almost equal to the activity of standard levamisole. The 5h and 5j are also most active against C. elegans with LD(50) of 200 ppm and D. myceliophagus with LD(50) of 190 ppm, respectively. Further, the 5a-j were screened for their antibacterial activity against three representative, Gram-positive bacteria viz. Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538p and Micrococcus luteus IFC 12708, and three Gram-negative bacteria viz. Proteus vulgaris ATCC 3851, Salmonella typhimurium ATCC 14028 and Escherichia coli ATCC 25922, and also screened for their antifungal activity against four fungal organisms viz. Candida albicans ATCC 10231, Aspergillus fumigatus HIC 6094, Trichophyton rubrum IFO 9185 and Trichophyton mentagrophytes IFO 40996. Most of these new compounds showed appreciable activity against the test bacteria and fungi, and emerged as potential molecules for further development.

Sashidhara KV et al. (2014) ChemMedChem "Benzofuran-chalcone hybrids as potential multifunctional agents against Alzheimer's disease: synthesis and in vivo studies with transgenic Caenorhabditis elegans."

Dodda RP, Kumar V, Kumar M, Sridhar B, Siddiqi MI, Haque R, Modukuri RK, Nazir A, Jadiya P, Sashidhara KV

[ChemMedChem, 2014]

In the search for effective multifunctional agents for the treatment of Alzheimer's disease (AD), a series of novel hybrids incorporating benzofuran and chalcone fragments were designed and synthesized. These hybrids were screened by using a transgenic Caenorhabditis elegans model that expresses the human -amyloid (A) peptide. Among the hybrids investigated, (E)-3-(7-methyl-2-(4-methylbenzoyl)benzofuran-5-yl)-1-phenylprop-2-en-1-one (4 f), (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-phenylprop-2-en-1-one (4 i), and (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one (4 m) significantly decreased A aggregation and increased acetylcholine (ACh) levels along with the overall availability of ACh at the synaptic junction. These compounds were also found to decrease acetylcholinesterase (AChE) levels, reduce oxidative stress in the worms, lower lipid content, and to provide protection against chemically induced cholinergic neurodegeneration. Overall, the multifunctional effects of these hybrids qualify them as potential drug leads for further development in AD therapy.

Srinivas A et al. (2017) Acta Chim Slov "Synthesis, Nematicidal and Antifungal Properties of Hybrid Heterocyclics."

Srinivas A, Karthik P, Sunitha M, Reddy KV

[Acta Chim Slov, 2017]

A new series of 5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-2,6-diphenyl-3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazoles 10a-r was synthesized by the reaction of chalcone derivatives of 2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-phenylthiazolidin-4-one 9 with aryl/alkyl hydrazines. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS and elemental analysis. The compounds 10a-r were evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique. Among them, compounds containing N-benzylpyrazole moiety (10d, 10j, 10p), and N- methylpyrazole moiety (10f, 10i, 10r) showed significant nematicidal activity against both tested nematodes with LD50 160-210 ppm, almost equal to oxamyl standard. Further, these compounds 10a-r were screened for their antifungal (MZI, MIC, and MFC) activity against four fungal organisms viz, Candida albicans (ATCC 102331), Aspergillus fumigates (HIC 6094), Trichophyton rubrum (IFO 9185) and Trichophyton mentagrophytes (IFO 40996). Most of the new compounds showed appreciable activity against the tested fungi, and emerged as potential molecules for further development.

Hsu DR et al. (1991) International C. elegans Meeting "Genetic and Molecular Analysis of dpy(y130), a Gene Essential for the Hermapbrodite Mode of Dosage Compensation"

Hsu DR, Meyer BJ

[International C. elegans Meeting, 1991]

The genes dpy-26, dpy-27, and dpy-28, have previously been shown to be required for proper dosage compensation in XX animals. Mutations in any of these genes result in a matemal-effect, XX-specific lethality due to disruption of the hermaphrodite mode of dosage compensation and subsequent overexpression of X-linked genes. Genetic analysis has suggested that these genes act together to regulate X-linked gene expression in XX animals. dpy(yl30) may be a new member of this family of dosage compensation genes. Originally isolated as a suppressor of the xol-l XO-specific lethality, yl30 displays temperature-sensitive zygotic and maternal phenotypes. At 25 , homozygous dpy XX progeny of heterozygous mothers are viable, but slightly Dpy, Egl, and Pvul. dpylDf progeny of Dfl + mothers display the same 25 phenotypes and are also completely viable. At 15 these animals are essentially wild type. In contrast, at 20 or 25 , homozygous dpy XX progeny of dpy mothers are inviable (>99%). At 15 , these animals are generally inviable with a small number of Dpy escapers. Three additional alleles, yl85, yl86, and yl87 have been isolated in a non-complementation screen. All three possess a similar temperature-sensitive, maternal- effect lethal phenotype. dpy(yl 30etc) differs from the other dosage compensation dpy genes in several respects. l) At the restrictive temperature, dpy(yl30etc) progeny of dpyldpy mothers are completely inviable whereas animals mutant for dpy2C, dpy-27, and dpy-28 invariably give rise to a small number of Dpy escapers. 2) dpy(yl 30 etc) appears to be required in XO as well as XX animals. dpy(yl 30etc) males from dpyldpy mothers are fully viable, but are clearly not wild type, appearing small, scrawny and Unc. The more severly affected of these animals are often constipated and possess necrotic, disorganized tail structures. dpy males from heterozygous mothers are similary affected but to a lesser degree. 3) dpy(yl 30etc), possesses a strict matemal-effect component such that dpyl+ progeny of dpyldpy mothers are viable, but not fully wild type. 4) dpy(yl 30) rescues xol-l XO animals in a manner similar to the sdc genes. This result suggests a possible cryptic sex-determination function of dpy(yl 30etc). In addition, dpyl + xol-l XO progeny of dpyldpy mothers are viable, again demonstrating a strict maternal-effect component of the dpy mutant phenotype. We have cloned dpy(yl 30) in order to learn how dosage compensation is implemented at a molecular level. Pools of cosmids near the myo-3 locus (0.lmu away from dpy(yl 30etc)) were injected into dpy(yl 87) hermaphrodites looking for rescue of the XX-specific lethality. Rescue was obtained with the cosmid C09F3. Subclones and deletions of this cosmid have narrowed down the rescuing region down to 4kb. Northem blot analysis of poly A+ RNAs prepared from N2 eggs using the smallest rescuing fragment as a probe has revealed 2 transcripts of 1.3kb and 0.7kb. The 0.7kb transcript is highly abundant. The same pattem and abundance of transcripts is detected in him-8(el489) eggs, which are 40% XO. Sequencing of this gene is in progress.

Morita S et al. (2001) Physica A "Geometrical structure of the neuronal network of Caenorhabditis elegans."

Funabashi Y, Morita S, Oka K, Oshio K, Osana Y, Kawamura K

[Physica A, 2001]

The neuronal network of the soil nematode Caenorhabditis elegans (C. elegans), which is a good prototype for biological studies, is investigated. Here, the neuronal network is simplified as a graph. We use three indicators to characterize the graph; vertex degree, generalized eccentricity (GE), and complete subgraphs. The graph has the central part and the strong clustering structure. We present a simple model, which shows that the neuronal network has a high-dimensional geometrical structure.

Honig M et al. (2018) Eur J Med Chem "New cytokinin derivatives possess UVA and UVB photoprotective effect on human skin cells and prevent oxidative stress."

Vostalova J, Voller J, Gruz J, Ulrichova J, Svobodova AR, Plihalova L, Spichal L, Dolezal K, Strnad M, Kadlecova A, Honig M

[Eur J Med Chem, 2018]

Eleven 6-furfurylaminopurine (kinetin, Kin) derivatives were synthesized to obtain biologically active compounds. The prepared compounds were characterized using¹H NMR, mass spectrometry combined with HPLC purity determination and elemental C, H, N analyses. The biological activity of new derivatives was tested on plant cells and tissues in cytokinin bioassays, such as tobacco callus, detached wheat leaf chlorophyll retention bioassay and Amaranthus bioassay. The selected compounds were subsequently tested on normal human dermal fibroblasts (NHDF) and keratinocyte cell lines (HaCaT) to exclude possible phototoxic effects and, on the other hand, to reveal possible UVA and UVB photoprotective activity. The protective antioxidant activity of the prepared cytokinin derivatives was further studied and compared to previously prepared antisenescent compound 6-furfurylamino-9-(tetrahydrofuran-2-yl)purine (Kin-THF) using induced oxidative stress (OS) on nematode Caenorhabditis elegans damaged by 5-hydroxy-1,4-naphthoquinone (juglone), a generator of reactive oxygen species. The observed biological activity was interpreted in relation to the structure of the prepared derivatives. The most potent oxidative stress protection of all the prepared compounds was shown by 6-(thiophen-2-ylmethylamino)-9-(tetrahydrofuran-2-yl)purine (6) and 2-chloro-6-furfurylamino-9-(tetrahydrofuran-2-yl)purine (9) derivatives and the results were comparable to Kin-THF. Compounds 6 and 9 were able to significantly protect human skin cells against UV radiation invitro. Both the derivatives 6 and 9 showed higher protective activity in comparison to previously known structurally similar compounds Kin and Kin-THF. The obtained results are surprising due to the fact that the prepared compounds showed to be inactive in the ORAC assay which proved that the compounds did not act as direct antioxidants as they were unable to directly scavenge oxygen radicals.