scholarly journals NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gabriel A Guerrero ◽  
Maxime J Derisbourg ◽  
Felix AMC Mayr ◽  
Laura E Wester ◽  
Marco Giorda ◽  
...  
Keyword(s):  
Stress Resistance ◽  
Protein Gene ◽  
Intraflagellar Transport ◽  
Pathogen Resistance ◽  
Nuclear Hormone Receptor ◽  
P38 Map Kinase ◽  
C Elegans ◽  
Xenobiotic Detoxification ◽  
P Glycoprotein ◽  
A Cell

Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent, while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 was necessary to regulate a subset of PGPs. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants.

scholarly journals NHR-8 regulated P-glycoproteins uncouple xenobiotic stress resistance from longevity in chemosensory C. elegans mutants

2019 ◽  
Author(s):  
Gabriel A. Guerrero ◽  
Matías D. Hartman ◽  
Klara Schilling ◽  
Felix A.M.C. Mayr ◽  
Ryan Lu ◽  
...  
Keyword(s):  
Stress Resistance ◽  
Intraflagellar Transport ◽  
Pathogen Resistance ◽  
Nuclear Hormone Receptor ◽  
P38 Map Kinase ◽  
Xenobiotic Stress ◽  
C Elegans ◽  
Xenobiotic Detoxification ◽  
A Cell ◽  
Necessary And Sufficient

AbstractLongevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent while TM resistance was pmk-1 independent. Inhibition of P-glycoproteins with verapamil suppressed tunicamycin resistance and expression of P-glycoprotein xenobiotic detoxification genes was elevated in osm-3 mutants. The nuclear hormone receptor nhr-8 was necessary and sufficient to regulate P-glycoproteins and tunicamycin resistance in a cholesterol-dependent fashion. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants.

scholarly journals NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Collin Yvès Ewald ◽  
John M Hourihan ◽  
Monet S Bland ◽  
Carolin Obieglo ◽  
Iskra Katic ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Stress Resistance ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Transcriptional Response ◽  
Redox Signaling ◽  
P38 Map Kinase ◽  
C Elegans ◽  
Cellular Processes ◽  
Rhoa Gtpase ◽  
Adaptive Stress Response

Transient increases in mitochondrially-derived reactive oxygen species (ROS) activate an adaptive stress response to promote longevity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases produce ROS locally in response to various stimuli, and thereby regulate many cellular processes, but their role in aging remains unexplored. Here, we identified the C. elegans orthologue of mammalian mediator of ErbB2-driven cell motility, MEMO-1, as a protein that inhibits BLI-3/NADPH oxidase. MEMO-1 is complexed with RHO-1/RhoA/GTPase and loss of memo-1 results in an enhanced interaction of RHO-1 with BLI-3/NADPH oxidase, thereby stimulating ROS production that signal via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3 to promote stress resistance and longevity. Either loss of memo-1 or increasing BLI-3/NADPH oxidase activity by overexpression is sufficient to increase lifespan. Together, these findings demonstrate that NADPH oxidase-induced redox signaling initiates a transcriptional response that protects the cell and organism, and can promote both stress resistance and longevity.

Streblus asper Lour. exerts MAPK and SKN-1 mediated anti-aging, anti-photoaging activities and imparts neuroprotection by ameliorating Aβ in Caenorhabditis elegans

2021 ◽  
pp. 1-17
Author(s):  
Mani Iyer Prasanth ◽  
James Michael Brimson ◽  
Dicson Sheeja Malar ◽  
Anchalee Prasansuklab ◽  
Tewin Tencomnao
Keyword(s):  
Oxidative Stress ◽  
Caenorhabditis Elegans ◽  
Stress Resistance ◽  
Vital Role ◽  
Transgenic Strain ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
C Elegans ◽  
Streblus Asper

BACKGROUND: Streblus asper Lour., has been reported to have anti-aging and neuroprotective efficacies in vitro. OBJECTIVE: To analyze the anti-aging, anti-photoaging and neuroprotective efficacies of S. asper in Caenorhabditis elegans. METHODS: C. elegans (wild type and gene specific mutants) were treated with S. asper extract and analyzed for lifespan and other health benefits through physiological assays, fluorescence microscopy, qPCR and Western blot. RESULTS: The plant extract was found to increase the lifespan, reduce the accumulation of lipofuscin and modulate the expression of candidate genes. It could extend the lifespan of both daf-16 and daf-2 mutants whereas the pmk-1 mutant showed no effect. The activation of skn-1 was observed in skn-1::GFP transgenic strain and in qPCR expression. Further, the extract can extend the lifespan of UV-A exposed nematodes along with reducing ROS levels. Additionally, the extract also extends lifespan and reduces paralysis in Aβ transgenic strain, apart from reducing Aβ expression. CONCLUSIONS: S. asper was able to extend the lifespan and healthspan of C. elegans which was independent of DAF-16 pathway but dependent on SKN-1 and MAPK which could play a vital role in eliciting the anti-aging, anti-photoaging and neuroprotective effects, as the extract could impart oxidative stress resistance and neuroprotection.

scholarly journals Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation

2021 ◽  
Author(s):  
Yuedan Fan ◽  
Wenjuan Zou ◽  
Jia Liu ◽  
Umar Al-Sheikh ◽  
Hankui Cheng ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Temperature Sensitive ◽  
Cold Sensation ◽  
Cold Response ◽  
C Elegans ◽  
Sensory Modalities ◽  
A Cell ◽  
Bona Fide

AbstractSensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

scholarly journals DAX-1 Expression in Human Adrenocortical Neoplasms: Implications for Steroidogenesis

1998 ◽  
Vol 83 (7) ◽  
pp. 2597-2600 ◽  
Author(s):  
M. Reincke ◽  
F. Beuschlein ◽  
E. Lalli ◽  
W. Arlt ◽  
S. Vay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Protein Gene ◽  
Regulatory Protein ◽  
Nuclear Hormone Receptor ◽  
Adrenocortical Tumors ◽  
Steroidogenic Acute Regulatory ◽  
Adrenocortical Carcinomas ◽  
Star Gene ◽  
Functional Phenotype

The DAX-1 gene encodes an orphan nuclear hormone receptor essential for normal fetal development of the adrenal cortex. Recently, DAX-1 has been shown to act as a transcriptional repressor of steroidogenic acute regulatory protein gene expression (StAR), suppressing steroidogenesis. We, therefore, investigated the expression of DAX-1 in a variety of adrenocortical tumors and compared the results with StAR mRNA expression. We found low or absent DAX-1 expression in aldosterone-producing adenomas (n=11: 35±11%; normal adrenals: 100±17%) and in aldosterone-producing adrenocortical carcinomas (n=2: 24 and 36%). Cortisol-producing adenomas showed intermediate DAX-1 expression (n=8; 92±16), as did 3 non-aldosterone-producing carcinomas (72, 132 and 132%). High DAX-1 expression was present in nonfunctional adenomas (n=3; 160±17%). In contrast to DAX-1, StAR mRNA expression did not show significant variations between groups. We did not detect the expected negative correlation between DAX-1 and StAR mRNA in adrenocortical tumors. These data suggest that high DAX-1 expression in adrenocortical tumors is associated with a non-functional phenotype whereas low DAX-1 expression favors mineralo-corticoid secretion. These effects on steroidogenesis are mediated by mechanisms other than repression of StAR gene expression. Our results indicate that DAX-1 may be one of the factors influencing the steroid biosynthesis of adrenocortical neoplasms.

Transcriptional targets of DAF-16 insulin signaling pathway protect C. elegans from extreme hypertonic stress

2005 ◽  
Vol 288 (2) ◽  
pp. C467-C474 ◽  
Author(s):  
S. Todd Lamitina ◽  
Kevin Strange
Keyword(s):  
Insulin Signaling ◽  
Stress Resistance ◽  
Molecular Mechanisms ◽  
Organic Osmolytes ◽  
Dependent Manner ◽  
Animal Cells ◽  
Hypertonic Stress ◽  
C Elegans ◽  
Downstream Target ◽  
Molecular Damage

All cells adapt to hypertonic stress by regulating their volume after shrinkage, by accumulating organic osmolytes, and by activating mechanisms that protect against and repair hypertonicity-induced damage. In mammals and nematodes, inhibition of signaling from the DAF-2/IGF-1 insulin receptor activates the DAF-16/FOXO transcription factor, resulting in increased life span and resistance to some types of stress. We tested the hypothesis that inhibition of insulin signaling in Caenorhabditis elegans also increases hypertonic stress resistance. Genetic inhibition of DAF-2 or its downstream target, the AGE-1 phosphatidylinositol 3-kinase, confers striking resistance to a normally lethal hypertonic shock in a DAF-16-dependent manner. However, insulin signaling is not inhibited by or required for adaptation to hypertonic conditions. Microarray studies have identified 263 genes that are transcriptionally upregulated by DAF-16 activation. We identified 14 DAF-16-upregulated genes by RNA interference screening that are required for age- 1 hypertonic stress resistance. These genes encode heat shock proteins, proteins of unknown function, and trehalose synthesis enzymes. Trehalose levels were elevated approximately twofold in age- 1 mutants, but this increase was insufficient to prevent rapid hypertonic shrinkage. However, age- 1 animals unable to synthesize trehalose survive poorly under hypertonic conditions. We conclude that increased expression of proteins that protect eukaryotic cells against environmental stress and/or repair stress-induced molecular damage confers hypertonic stress resistance in C. elegans daf- 2/ age- 1 mutants. Elevated levels of solutes such as trehalose may also function in a cytoprotective manner. Our studies provide novel insights into stress resistance in animal cells and a foundation for new studies aimed at defining molecular mechanisms underlying these essential processes.

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