Oh SW et al. (2006) Nat Genet "Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation."

Dixit BL, Raha T, Tissenbaum HA, Green MR, Oh SW, Mukhopadhyay A

[Nat Genet, 2006]

DAF-16, a forkhead transcription factor, is a key regulator of longevity, metabolism and dauer diapause in Caenorhabditis elegans. The precise mechanism by which DAF-16 regulates multiple functions, however, is poorly understood. Here, we used chromatin immunoprecipitation (ChIP) to identify direct targets of DAF-16. We cloned 103 target sequences containing consensus DAF-16 binding sites and selected 33 targets for further analysis. Expression of most of these genes is regulated in a DAF-16-dependent manner, and inactivation of more than half of these genes significantly altered DAF-16-dependent functions, including life span, fat storage and dauer formation. Our results show that the ChIP-based cloning strategy leads to greater enrichment for DAF-16 target genes than previous screening strategies. We also demonstrate that DAF-16 is recruited to multiple promoters to coordinate regulation of its downstream targets. The large number of target genes discovered provides insight into how DAF-16 controls diverse biological functions.

Oh SW et al. (2005) Proc Natl Acad Sci U S A "JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16."

Oh SW, Davis RJ, Jiang F, Svrzikapa N, Mukhopadhyay A, Tissenbaum HA

[Proc Natl Acad Sci U S A, 2005]

DAF-16/forkhead transcription factor, the downstream target of the insulin-like signaling in Caenorhabditis elegans, is indispensable for both lifespan regulation and stress resistance. Here, we demonstrate that c-Jun N-terminal kinase (JNK) is a positive regulator of DAF-16 in both processes. Our genetic analysis suggests that the JNK pathway acts in parallel with the insulin-like signaling pathway to regulate lifespan and both pathways converge onto DAF-16. We also show that JNK-1 directly interacts with and phosphorylates DAF-16. Moreover, in response to heat stress, JNK-1 promotes the translocation of DAF-16 into the nucleus. Our findings define an interaction between two well conserved proteins, JNK-1 and DAF-16, and provide a mechanism by which JNK regulates longevity and stress resistance.

Pandey T et al. (2020) Exp Gerontol "Swertiamarin, a secoiridoid glycoside modulates nAChR and AChE activity."

Smita SS, Mishra A, Sammi SR, Pandey R, Pandey T

[Exp Gerontol, 2020]

The ailments related to a malfunction in cholinergic functioning currently employ the use of inhibitors for acetylcholinesterase (AChE) and N-methyl-d-aspartate (NMDA) receptors. The present study was designed to elucidate the potential of swertiamarin (SW), a secoiridoidal glycoside isolated from Enicostemma littorale in curtailing the cholinergic dysfunction. Using Caenorhabditis elegans as a model, SW was found to enhance neurotransmission by modulating AChE and nicotinic acetylcholine receptor (nAChR) activity; being orchestrated through up-regulation of unc-17 and unc-50. SW exhibited AChE inhibition both in vivo and cell-free system. The in silico molecular docking of SW and human AChE (hAChE) displayed good binding energy of -6.02. Interestingly, the increase in aldicarb and levamisole sensitivity post SW treatment was curtailed to a significant level in daf-16 and skn-1 mutants. SW raised the level of the endogenous antioxidant enzymes through up-regulation of sod-3 and gst-4 that act downstream to DAF-16 and SKN-1, imparting protection against neurodegeneration. The outcome of our study displays SW as a potential natural molecule for the amelioration of cholinergic dysfunction. Moreover, the study also indicates that SW elicits antioxidant response via up-modulation of daf-16 possibly through unc-17 upregulation. Further research on SW pertaining to the underlying mechanism and potential is expected to significantly advance the current understanding and design of possible ameliorative or near ameliorative regimens for cholinergic dysfunction.

Mukhopadhyay A et al. (2006) Exp Gerontol "Worming pathways to and from DAF-16/FOXO."

Tissenbaum HA, Oh SW, Mukhopadhyay A

[Exp Gerontol, 2006]

In Caenorhabditis elegans, the insulin/IGF-1 signaling pathway controls many biological processes such as life span, fat storage, dauer diapause, reproduction and stress response . This pathway is comprised of many genes including the insulin/IGF-1 receptor (DAF-2) that signals through a conserved PI 3-kinase/AKT pathway and ultimately down-regulates DAF-16, a forkhead transcription factor (FOXO). DAF-16 also receives input from several other pathways that regulate life span such as the germline and the JNK pathway [Hsin, H., Kenyon, C., 1999. Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362-366; Oh, S.W., Mukhopadhyay, A., Svrzikapa, N., Jiang, F., Davis, R.J., Tissenbaum, H.A., 2005. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl. Acad. Sci. USA 102, 4494-4499]. Therefore, DAF-16 integrates signals from multiple pathways and regulates its downstream target genes to control diverse processes. Here, we discuss the signals to and from DAF-16, with a focus on life span regulation.

Bo S et al. (2023) Front Genet "A novel approach to analyze the association characteristics between post-spliced introns and their corresponding mRNA."

Ning P, Sun Q, Bo S, Wang H, Weng Y, Zhao X, Liang Y, Lu Z, Yuan N, Li Z

[Front Genet, 2023]

Studies have shown that post-spliced introns promote cell survival when nutrients are scarce, and intron loss/gain can influence many stages of mRNA metabolism. However, few approaches are currently available to study the correlation between intron sequences and their corresponding mature mRNA sequences. Here, based on the results of the improved Smith-Waterman local alignment-based algorithm method (SW method) and binding free energy weighted local alignment algorithm method (BFE method), the optimal matched segments between introns and their corresponding mature mRNAs in Caenorhabditis elegans (C.elegans) and their relative matching frequency (RF) distributions were obtained. The results showed that although the distributions of relative matching frequencies on mRNAs obtained by the BFE method were similar to the SW method, the interaction intensity in 5'and 3'untranslated regions (UTRs) regions was weaker than the SW method. The RF distributions in the exon-exon junction regions were comparable, the effects of long and short introns on mRNA and on the five functional sites with BFE method were similar to the SW method. However, the interaction intensity in 5'and 3'UTR regions with BFE method was weaker than with SW method. Although the matching rate and length distribution shape of the optimal matched fragment were consistent with the SW method, an increase in length was observed. The matching rates and the length of the optimal matched fragments were mainly in the range of 60%-80% and 20-30bp, respectively. Although we found that there were still matching preferences in the 5'and 3'UTR regions of the mRNAs with BFE, the matching intensities were significantly lower than the matching intensities between introns and their corresponding mRNAs with SW method. Overall, our findings suggest that the interaction between introns and mRNAs results from synergism among different types of sequences during the evolutionary process.

Eom HJ et al. (2015) Environ Health Toxicol "Effect of aspect ratio on the uptake and toxicity of hydroxylated-multi walled carbon nanotubes in the nematode, Caenorhabditis elegans."

Jeong JS, Choi J, Eom HJ

[Environ Health Toxicol, 2015]

OBJECTIVES: In this study, the effect of tube length and outer diameter (OD) size of hydroxylated-multi walled carbon nanotubes (OH-MWCNTs) on their uptake and toxicity was investigated in the nematode Caenorhabditis elegans using a functional mutant analysis. METHODS: The physicochemical properties of three different OH-MWCNTs were characterized. Uptake and toxicity were subsequently investigated on C. elegans exposed to MWCNTs with different ODs and tube lengths. RESULTS: The results of mutant analysis suggest that ingestion is the main route of MWCNTs uptake. We found that OH-MWCNTs with smaller ODs were more toxic than those with larger ODs, and OH-MWCNTs with shorter tube lengths were more toxic than longer counterparts to C. elegans. CONCLUSIONS: Overall the results suggest the aspect ratio affects the toxicity of MWCNTs in C. elegans. Further thorough study on the relationship between physicochemical properties and toxicity needs to be conducted for more comprehensive understanding of the uptake and toxicity of MWCNTs.

Yu Y et al. (2020) ACS Chem Biol "Untargeted Approach for Revealing Electrophilic Metabolites."

Maxwell DN, Zhang B, Le HH, Schroeder FC, Wrobel CJJ, Yu Y, Curtis BJ, Pan JY

[ACS Chem Biol, 2020]

Reactive electrophilic intermediates such as coenzyme A esters play central roles in metabolism but are difficult to detect with conventional strategies. Here, we introduce hydroxylamine-based stable isotope labeling to convert reactive electrophilic intermediates into stable derivatives that are easily detectable <i>via</i> LC-MS. In the model system <i>Caenorhabditis elegans</i>, parallel treatment with ¹⁴NH₂OH and ¹⁵NH₂OH revealed &gt;1000 labeled metabolites, e.g., derived from peptide, fatty acid, and ascaroside pheromone biosyntheses. Results from NH₂OH treatment of a pheromone biosynthesis mutant, <i>acox-1.1</i>, suggested upregulation of thioesterase activity, which was confirmed by gene expression analysis. The upregulated thioesterase contributes to the biosynthesis of a specific subset of ascarosides, determining the balance of dispersal and attractive signals. These results demonstrate the utility of NH₂OH labeling for investigating complex biosynthetic networks. Initial results with <i>Aspergillus</i> and human cell lines indicate applicability toward uncovering reactive metabolomes in diverse living systems.

Zhang W et al. (2011) Nanoscale "Biosafety assessment of Gd@C82(OH)22 nanoparticles on Caenorhabditis elegans."

Zhao B, Zhang W, Zhang L, Sun B, Zhao Y, Nie G

[Nanoscale, 2011]

Gd@C(82)(OH)(22), a water-soluble endohedral metallofullerene derivative, has been proven to possess significant antineoplastic activity in mice. Toxicity studies of the nanoparticle have shown some evidence of low or non toxicity in mice and cell models. Here we employed Caenorhabditis elegans (C. elegans) as a model organism to further evaluate the short- and long-term toxicity of Gd@C(82)(OH)(22) and possible behavior changes under normal and stress culture conditions. With treatment of Gd@C(82)(OH)(22) at 0.01, 0.1, 1.0 and 10 g ml(-1) within one generation (short-term), C. elegans showed no significant decrease in longevity or thermotolerance compared to the controls. Furthermore, when Gd@C(82)(OH)(22) treatment was extended up to six generations (long-term), non-toxic effects to the nematodes were found. In addition, data from body length measurement, feeding rate and egg-laying assays with short-term treatment demonstrated that the nanoparticles have no significant impact on the individual growth, feeding behavior and reproductive ability, respectively. In summary, this work has shown that Gd@C(82)(OH)(22) is tolerated well by worms and it has no apparent toxic effects on longevity, stress resistance, growth and behaviors that were observed in both adult and young worms. Our work lays the foundations for further developments of this anti-neoplastic agent for clinical applications.

Liu X et al. (2020) RSC Adv "A naphthalimide-based turn-on fluorescence probe for peroxynitrite detection and imaging in living cells."

Zhou X, Liu X, Cui L, Guo T, Zhang S, Gu F, Zhou W

[RSC Adv, 2020]

Peroxynitrite (ONOO^-) is a potent biological oxidant that plays a significant role in diverse physiological and pathological processes. A novel fluorescent probe HCA-OH was developed for specific and sensitive detection of peroxynitrite, and displayed a significant fluorescence turn-on signal. With low cytotoxicity and good photostability, the probe HCA-OH could be applied in imaging ONOO^- distribution in HepG2 cells and live C. elegans in real time. Therefore, the probe can be a promising tool for imaging in vivo.

Choi, Shin S. et al. (2011) International Worm Meeting "Apoptosis-mediated toxicity of water stable carbon nanoparticles in Caenorhabditis elegans ."

Choi, Shin S., Cha, Yoon J.

[International Worm Meeting, 2011]

The application of nanoparticles in various fields has been evolved rapidly due to its authentic physicochemical properties. The potential biological or environmental toxicity of nanoparticles, however, has been frequently reported using in vitro systems. In this study, the toxicity of fullerene (nC60) and fullerol (C60-OH) in Caenorhabditis elegans was assessed through the measurement of lifespan, body size, and brood size. The water-stable colloids form of nC60 are prepared through the long-term exposure of fullerene, C60 in THF. We confirmed that the oral-administrated carbon nanoparticles were accumulated in the animals for several days after feeding the mixture of bacterial food and nC60 or C60-OH to the L4 larvas of C. elegans. The C60-OH reduced the viability of animals while no decrease in survival was found in the animals fed with nC60. We have also found that both nC60 and C60-OH reduced the reproduction of C. elegans. In order to illuminate the genetic mechanism of toxicity induced by those nanoparticles, the assessment of viability and fertility was carried out using the strains mutated in oxidative stress or programmed cell death regulators.