Alcantar-Fernandez J et al. (2019) PLoS One "High-glucose diets induce mitochondrial dysfunction in Caenorhabditis elegans."

Miranda-Rios J, Reynoso-Robles R, Hernandez-Vazquez AJ, Perez Andrade ME, Alcantar-Fernandez J, Velazquez-Arellano A, Gonzalez-Maciel A

[PLoS One, 2019]

Glucose is an important nutrient that dictates the development, fertility and lifespan of all organisms. In humans, a deficit in its homeostatic control might lead to hyperglucemia and the development of obesity and type 2 diabetes, which show a decreased ability to respond to and metabolize glucose. Previously, we have reported that high-glucose diets (HGD) induce alterations in triglyceride content, body size, progeny, and the mRNA accumulation of key regulators of carbohydrate and lipid metabolism, and longevity in Caenorhabditis elegans (PLoS ONE 13(7): e0199888). Herein, we show that increasing amounts of glucose in the diet induce the swelling of both mitochondria in germ and muscle cells. Additionally, HGD alter the enzymatic activities of the different respiratory complexes in an intricate pattern. Finally, we observed a downregulation of ceramide synthases (hyl-1 and hyl-2) and antioxidant genes (gcs-1 and gst-4), while mitophagy genes (pink-1 and dct-1) were upregulated, probably as part of a mitohormetic mechanism in response to glucose toxicity.

Alcantar-Fernandez J et al. (2018) PLoS One "Caenorhabditis elegans respond to high-glucose diets through a network of stress-responsive transcription factors."

Perez-Andrade ME, Salazar-Martinez AM, Miranda-Rios J, Navarro RE, Alcantar-Fernandez J

[PLoS One, 2018]

High-glycemic-index diets, as well as a sedentary lifestyle are considered as determinant factors for the development of obesity, type 2 diabetes, and cardiovascular diseases in humans. These diets have been shown to shorten the life span of C. elegans in a manner that is dependent on insulin signaling, but the participation of other signaling pathways have not been addressed. In this study, we have determined that worms fed with high-glucose diets show alterations in glucose content and uptake, triglyceride content, body size, number of eggs laid, egg-laying defects, and signs of oxidative stress and accelerated aging. Additionally, we analyzed the participation of different key regulators of carbohydrate and lipid metabolism, oxidative stress and longevity such as SKN-1/NRF2, HIF-1/HIF1, SBP-1/SREBP, CRH-1/CREB, CEP-1/p53, and DAF-16/FOXO, in the reduction of lifespan in glucose-fed worms.

Earley, B. et al. (2019) International Worm Meeting "Cadmium is an activating ligand of HIZR-1."

Lyon, M., Cubillas, C., Earley, B., Ahmad, R., Alcantar, A., Warnhoff, K., Kornfeld, K., Phillips, C.

[International Worm Meeting, 2019]

Exposure to the toxic metal cadmium is a global health problem that causes substantial morbidity and mortality in humans. The long-term goal of this research is to understand how organisms detect and respond to cadmium, and how these processes relate to the biology of the structurally similar but physiological metal zinc. The mechanism of cadmium toxicity is not well established, but a prominent theory is that cadmium binds proteins and other bio-molecules, displacing physiologic metals such as zinc, leading to dysfunction. When C. elegans are cultured in excess zinc conditions, zinc binds and activates the nuclear receptor transcription factor HIZR-1. HIZR-1 translocates to the nucleus and directly binds the High Zinc Activation (HZA) DNA enhancer upstream of multiple zinc homeostasis genes. Using transgene GFP promoter fusions, we showed that the HZA element is necessary and sufficient for cadmium-regulated transcription, and that hizr-1 is also necessary for cadmium-regulated transcription. We hypothesized that cadmium directly binds the ligand-binding domain of HIZR-1, leading to transcriptional activation. Consistent with this model, competitive binding assays revealed that HIZR-1 binds cadmium directly. Furthermore, HIZR-1::GFP accumulated in the nucleus upon cadmium exposure. We used multiple approaches to identify ~150 cadmium activated genes; about 30% were dependent on hizr-1 for activation, whereas others were hizr-1 independent. To determine the function of this hizr-1-medited transcriptional response, we analyzed hizr-1(lf) mutants. hizr-1(lf) by itself did not strongly affect cadmium tolerance, but in a sensitized background hizr-1(lf) caused hypersensitivity to cadmium toxicity. These results show that cadmium is an activating ligand of HIZR-1 rather than a destabilizing toxin. The HIZR-1-mediated transcriptional response is only weakly protective against cadmium, suggesting it evolved primarily to perform high zinc homeostasis rather than cadmium detoxification.

Earley BJ et al. (2021) Proc Natl Acad Sci U S A "Cadmium hijacks the high zinc response by binding and activating the HIZR-1 nuclear receptor."

Ahmad R, Alcantar A, Earley BJ, Warnhoff K, Cubillas C, Kornfeld K, Schneider DL, Lyon MD

[Proc Natl Acad Sci U S A, 2021]

Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In <i>Caenorhabditis elegans</i>, high zinc homeostasis is regulated by the high zinc activated nuclear receptor (HIZR-1) transcription factor. To define relationships between the responses to high zinc and cadmium, we analyzed transcription. Many genes were activated by both high zinc and cadmium, and <i>hizr-1</i> was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require <i>hizr-1</i>, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1-mediated transcription via the high zinc activation (HZA) enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed genes that function in three pathways: the <i>pcs-1</i>/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the <i>hizr-1</i>/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the <i>mek-1/sek-1/</i>kinase signaling pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium, as well as a shared pathway.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Tuck S (2011) Curr Biol "Extracellular vesicles: budding regulated by a phosphatidylethanolamine translocase."

Tuck S

[Curr Biol, 2011]

Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.

Viney ME et al. (2004) Naturwissenschaften "Is dauer pheromone of Caenorhabditis elegans really a pheromone?"

Viney ME, Franks NR

[Naturwissenschaften, 2004]

Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.