54 Papers found (0.01 seconds)

Umansky C et al. (2022) Nat Commun "Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity."

Martinefski MR, Bollini M, Sommer N, Pak O, Monge ME, Crossan GP, Umansky C, Pontel LB, Morellato AE, Rieckher M, Kolesnikova K, Fernandez GA, Reingruber H, Scheidegger MA, Schumacher B

[

Nat Commun,

2022]

Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking, likely contributing to the onset of the human DNA repair condition Fanconi Anaemia. Mutations in the genes coding for FA detoxifying enzymes underlie a human inherited bone marrow failure syndrome (IBMFS), even in thepresence of functional DNA repair, raising the question of whether FA causes relevant cellular damage beyond genotoxicity. Here, we report that FA triggers cellular redox imbalance in human cells and in Caenorhabditis elegans. Mechanistically, FA reacts with the redox-active thiol group of glutathione (GSH), altering the GSH:GSSG ratio and causing oxidative stress. FA cytotoxicity is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which metabolizes FA-GSH products, lastly yielding reduced GSH. Furthermore, we show that GSH synthesis protects human cells from FA, indicating an active role of GSH in preventing FA toxicity. These findings might be relevant for patients carrying mutations in FA-detoxification systems and could suggest therapeutic benefits from thiol-rich antioxidants like N-acetyl-L-cysteine.

Li H et al. (2021) Int J Mol Sci "Ferulic Acid Supplementation Increases Lifespan and Stress Resistance via Insulin/IGF-1 Signaling Pathway in C. elegans."

Zhao Z, Li H, Yu X, Guan S, Wang L, Meng F

[

Int J Mol Sci,

2021]

Ferulic acid (FA) is a naturally-occurring well-known potent antioxidant and free radical scavenger. FA supplementation is an effective strategy to delay aging, but the underlying mechanism remains unknown. In the present study, we examined the effects of FA on lifespan extension and its mechanism of FA in Caenorhabditis elegans (C. elegans). Results suggested that FA increased the lifespan of C. elegans, rather than altering the growth of E. coli OP50. Meanwhile, FA promoted the healthspan of C. elegans by improving locomotion and reducing fat accumulation and polyQ aggregation. FA increased the resistance to heat and oxidative stress through reducing ROS. The upregulating of the expression of the hlh-30, skn-1, and hsf-1 were involved in the FA-mediated lifespan extension. Furthermore, FA treatment had no impact on the lifespan of daf-2, hlh-30, skn-1, and hsf-1 mutants, confirming that insulin/IGF-1 signaling pathway and multiple longevity mechanisms were associated with the longevity mechanism of FA. We further found that mitochondrial signaling pathway was modulation involved in FA-mediated lifespan extension. With the results from RNA-seq results and mutants lifespan assay. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of FA in C. elegans.

Rieckher M et al. (2024) Nucleic Acids Res "Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging."

Alquezar-Artieda N, Vaddavalli PL, Bourached-Silva N, Schumacher B, Wiesner E, Blindauer T, Pontel LB, Greger K, Gallrein C, Backhaus M, Rieckher M, Mares D

[

Nucleic Acids Res,

2024]

Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences.

Chen MT et al. (2024) Free Radic Biol Med "Melatonin derivative 6a protects Caenorhabditis elegans from formaldehyde neurotoxicity via ADH5."

Zhou JJ, Wu ZJ, Han RT, Ma AJ, Fu P, Ma QW, Feng N, Chen MT

[

Free Radic Biol Med,

2024]

Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aβ) transgenic nematodes by lowering endogenous FA levels and reducing Aβ aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aβ toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.

Wang N et al. (2020) Food Chem Toxicol "Ferulic acid delayed amyloid -induced pathological symptoms by autophagy pathway via a fasting-like effect in Caenorhabditis elegans."

Alwayli D, Li H, Wang Y, Zhao L, Muhammad F, Ge G, Ullah I, Zhou Y, Ma W, Wang C, Wang N, Zhi D

[

Food Chem Toxicol,

2020]

The amyloid (A) generation or aggregation plays a crucial role in Alzheimer's disease (AD). Autophagy agonists, which function as the clearance of A, could be the potential drug candidates against AD. In staple food crops, ferulic acid (FA) is an enormously copious and almost ubiquitous phenolic antioxidant. In the present study, FA significantly inhibited A-induced pathological symptoms of paralysis and hypersensitivity to exogenous serotonin, meanwhile restrained A monomers, oligomers, and deposits in AD C. elegans. FA increased the expression of autophagy reporter LGG-1 and enhanced autophagy flux. However, the autophagy inhibitors abolished the restrictive action of FA on the worm paralysis phenotype. According to these results, FA triggered autophagy and ameliorated A-induced pathological symptoms by the autophagy pathway. Moreover, FA activated the HLH-30 transcription factor to nuclear localization, which acts upstream of autophagy in fasted animals, reduced the level of lipids, but affected nor the growth of E.coli OP50, neither animal food intake behavior. These suggest that FA induced a fasting-like effect to activate the autophagy pathway. Additionally, FA ameliorated poly Q aggregations in Huntington's disease worm. Thus, FA could not only affect AD, broadly but also neurodegenerative diseases characterized by misfolded or aggregated proteins.

Deng X et al. (2021) Cancer Res "Disabling the Fanconi Anemia Pathway in Stem Cells Leads to Radioresistance and Genomic Instability."

Fuks Z, Shaham S, Kolesnick R, Studer L, Deng X, Hsu KS, Higginson DS, Feldman R, Tchieu J, Powell SN

[

Cancer Res,

2021]

Fanconi Anemia (FA) is an inherited genome instability syndrome characterized by interstrand crosslink hypersensitivity, congenital defects, bone marrow failure, and cancer predisposition. Although DNA repair mediated by FA genes has been extensively studied, how inactivation of these genes leads to specific cellular phenotypic consequences associated with FA is not well understood. Here we report that FA stem cells in the C. elegans germline and in murine embryos display marked nonhomologous end joining (NHEJ)-dependent radiation resistance, leading to survival of progeny cells carrying genetic lesions. By contrast, DNA crosslinking does not induce generational genomic instability in FA stem cells, as widely accepted, but rather drives NHEJ-dependent apoptosis in both species. These findings suggest that FA is a stem cell disease reflecting inappropriate NHEJ, which is mutagenic and carcinogenic as a result of DNA misrepair, while marrow failure represents hematopoietic stem cell apoptosis.

Wright DJ et al. (1976) Nematologica "Acetylcholinesterase activity in the region of the nematode nerve ring: Improved histochemical specificity using ultrasonic pretreatment."

Awan FA, Wright DJ

[

Nematologica,

1976]

Panagrellus redivivus, Caenorhabditis elegans, Prionchulus punctatus, Aphelenchus avenae and Ditylenchus dipsaci were stained for cholinesterase activity using the 'direct-colouring' thiocholine method. Enzyme activity was concentrated in the region of the nerve ring in each species. Ultrasonic pretreatment of intact or cut nematodes was found to greatly improve the staining consistency at the nerve ring, and using two substrates (acetylthiocholine and butyrylthiocholine) and three inhibitors (eserine, BW 284C51, and iso-OMPA) this staining was found to be due to acetlycholinesterase (E.C. 3.1.1.7)

Tang H et al. (2017) Cell "Fatty Acids Regulate Germline Sex Determination through ACS-4-Dependent Myristoylation."

Tang H, Han M

[

Cell,

2017]

Fat metabolism has been linked to fertility and reproductive adaptation in animals and humans, and environmental sex determination potentially plays a role in the process. To investigate the impact of fatty acids (FA) on sex determination and reproductive development, we examined and observed an impact of FA synthesis and mobilization by lipolysis in somatic tissues on oocyte fate in Caenorhabditis elegans. The subsequent genetic analysis identified ACS-4, an acyl-CoA synthetase and its FA-CoA product, as key germline factors that mediate the role of FA in promoting oocyte fate through protein myristoylation. Further tests indicated that ACS-4-dependent protein myristoylation perceives and translates the FA level into regulatory cues that modulate theactivities of MPK-1/MAPK and key factors inthe germline sex-determination pathway. These findings, including a similar role of ACS-4 in a male/femalespecies, uncover a likely conserved mechanism by which FA, an environmental factor, regulates sex determination and reproductive development.

Long T et al. (2022) Oxid Med Cell Longev "Ferulic Acid Exerts Neuroprotective Effects via Autophagy Induction in C. elegans and Cellular Models of Parkinson's Disease."

Wu Q, Zhou XG, Wu JM, He CL, Yu L, Tang Y, Chen X, Long T, Wu AG, Qin DL, Wei J, He YN, Law BY, Yu CL

[

Oxid Med Cell Longev,

2022]

Parkinson's disease (PD) is a complex neurological disorder characterized by motor and nonmotor features. Although some drugs have been developed for the therapy of PD in a clinical setting, they only alleviate the clinical symptoms and have yet to show a cure. In this study, by employing the C. elegans model of PD, we found that ferulic acid (FA) significantly inhibited -synuclein accumulation and improved dyskinesia in NL5901 worms. Meanwhile, FA remarkably decreased the degeneration of dopaminergic (DA) neurons, improved the food-sensing behavior, and reduced the level of reactive oxygen species (ROS) in 6-OHDA-induced BZ555 worms. The mechanistic study discovered that FA could activate autophagy in C. elegans, while the knockdown of 3 key autophagy-related genes significantly revoked the neuroprotective effects of FA in -synuclein- and 6-OHDA-induced C. elegans models of PD, demonstrating that FA exerts an anti-PD effect via autophagy induction in C. elegans. Furthermore, we found that FA could reduce 6-OHDA- or H2O2-induced cell death and apoptosis in PC-12 cells. Moreover, FA was able to induce autophagy in stable GFP-RFP-LC3 U87 cells and PC-12 cells, while bafilomycin A1 (Baf, an autophagy inhibitor) partly eliminated the protective effects of FA against 6-OHDA- and H2O2-induced cell death and ROS production in PC-12 cells, further confirming that FA exerts an anti-PD effect via autophagy induction in vitro. Collectively, our study provides novel insights for FA as a potent autophagy enhancer to effectively prevent neurodegenerative diseases such as PD in the future.

Tang H et al. (2021) Cell Rep "Fatty acids impact sarcomere integrity through myristoylation and ER homeostasis."

Han M, Tang H, Cui M

[

Cell Rep,

2021]

Decreased ability to maintain tissue integrity is critically involved in aging and degenerative diseases. Fatty acid (FA) metabolism has a profound impact on animal development and tissue maintenance, but our understanding of the underlying mechanisms is limited. We investigated whether and how FA abundance affects muscle integrity using Caenorhabditis elegans. We show that reducing the overall FA level by blocking FA biosynthesis or inhibiting protein myristoylation leads to disorganization of sarcomere structure and adult-onset paralysis. Further analysis indicates that myristoylation of two ARF guanosine triphosphatases (GTPases) critically mediates the effect of FA deficiency on sarcomere integrity through inducing endoplasmic reticulum (ER) stress and ER unfolded protein response (UPRER), which in turn leads to reduction of the level of sarcomere component PINCH and myosin disorganization. We thus present a mechanism that links FA signal, protein myristoylation, and ER homeostasis with muscle integrity, which provides valuable insights into the regulatory role of nutrients and ER homeostasis in muscle maintenance.

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