Xie K et al. (2024) J Leukoc Biol "Hederagenin reduces Aβ-induced oxidative damage, decreases Aβ deposition and promotes cell survival by the P13 K/Akt signaling pathway."

Hu J, Yao X, Xie K, Shan Y, Wang Q, Lv J, Shi Y, Zhao Y, Yang S, Xu L, Wang H

[J Leukoc Biol, 2024]

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. β-amyloid (Aβ) is one of the typical pathological features of AD, and its accumulation leads to neuronal death from oxidative stress. Here, we found that hederagenin (HG), a natural product, exhibits anti-tumor, anti-inflammatory, anti-depressant, anti-neurodegenerative biological activities. However, whether HG has anti-Aβ activity remains unclear. Based on the characteristics of HG, it is hypothesized that HG has biological activity against Aβ injury. Therefore, Aβ-injured SH-SY5Y cells were constructed, and the protective effect of HG against Aβ injury was further evaluated using C. elegans. The results showed that HG increased superoxide dismutase activity, effectively reduced Aβ-induced oxidative damage, and reduced apoptosis via the PI3 K/Akt signaling pathway. HG inhibited Aβ deposition and delayed senescence and paralysis in the C. elegans strain, CL4176. HG showed inhibitory effects on Aβ; therefore, more natural active products are expected to be applied in AD therapy.

Kim HN et al. (2011) Analyst "Rhodamine hydrazone derivatives as Hg2+ selective fluorescent and colorimetric chemosensors and their applications to bioimaging and microfluidic system."

Nam SW, Jin Y, Swamy KM, Kim Y, Yoon J, Park S, Kim HN, Kim SJ, Chen X

[Analyst, 2011]

In this paper, we report new rhodamine hydrazone derivatives bearing thiol and carboxylic acid groups as selective fluorescent and colorimetric chemosensors for Hg(2+). The ring-opening process of spirolactam enables the large fluorescent enhancement and colorimetric change upon the addition of Hg(2+). The sample containing Hg(2+) was mixed with one of the chemosensors in a microchannel where the sensor was examined using confocal laser scanning microscopy. A plot of the fluorescent intensities of both chemosensors versus the log concentration of Hg(2+) exhibited a linear response (r(2)=0.95) in the range of 1 nM-1 M, and the detection limits were 1 nM and 4.2 nM, respectively. Both chemosensors also enable the visualization of Hg(2+) accumulated in the nematode Caenorhabditis elegans previously exposed to nanomolar concentrations of Hg(2+).

Wyatt LH et al. (2016) Environ Sci Technol "Antagonistic Growth Effects of Mercury and Selenium in Caenorhabditis elegans Are Chemical-Species-Dependent and Do Not Depend on Internal Hg/Se Ratios."

Hsu-Kim H, Diringer SE, Rogers LA, Pan WK, Meyer JN, Wyatt LH

[Environ Sci Technol, 2016]

The relationship between mercury (Hg) and selenium (Se) toxicity is complex, with coexposure reported to reduce, increase, and have no effect on toxicity. Different interactions may be related to chemical compound, but this has not been systematically examined. Our goal was to assess the interactive effects between the two elements on growth in the nematode Caenorhabditis elegans, focusing on inorganic and organic Hg (HgCl2 and MeHgCl) and Se (selenomethionine, sodium selenite, and sodium selenate) compounds. We utilized aqueous Hg/Se dosing molar ratios that were either above, below, or equal to 1 and measured the internal nematode total Hg and Se concentrations for the highest concentrations of each Se compound. Observed interactions were complicated, differed between Se and Hg compounds, and included greater-than-additive, additive, and less-than-additive growth impacts. Biologically significant interactions were only observed when the dosing Se solution concentration was 100-25000 times greater than the dosing Hg concentration. Mitigation of growth impacts was not predictable on the basis of internal Hg/Se molar ratio; improved growth was observed at some internal Hg/Se molar ratios both above and below 1. These findings suggest that future assessments of the Hg and Se relationship should incorporate chemical compound into the evaluation.

Wu Q et al. (2011) Environ Toxicol Pharmacol "Association of oxidative stress with the formation of reproductive toxicity from mercury exposure on hermaphrodite nematode Caenorhabditis elegans."

Wang D, Liu P, Li Y, Wu Q, He K

[Environ Toxicol Pharmacol, 2011]

Here we selected HgCl(2) to investigate the mechanism of Hg toxicity on reproduction in hermaphrodite nematodes. Accompanied with decrease of brood size, Hg exposure caused severe deficits in egg number in uterus, egg laying and reproductive structures, including gonad arms and vulva, and formation of protruding phenotype for vulva. Meanwhile, Hg exposure induced severe stress response and oxidative damage in gonad and vulva. Pre-treatment with vitamin E, a potent antioxidant, at the L2-larval stage prevented the oxidative damage and formation of reproductive deficits in Hg exposed nematodes; however, pre-treatment with paraquat, a regent generating superoxide anions, induced more severe reproductive deficits in Hg exposed nematodes. Moreover, Hg exposure increased expression of clk-2 and isp-1 genes, whose mutations decrease ROS production, and decreased expression of mev-1 and gas-1 genes, whose mutations increase ROS production. Thus, oxidative stress may be essential for the induction of reproductive deficits in Hg exposed hermaphrodite nematodes.

Ramki K et al. (2023) Methods "An aggregation-induced emission-based ratiometric fluorescent chemosensor for Hg(II) and its application in Caenorhabditis elegans imaging."

Ramasamy SK, Ramki K, Sakthivel P, Sundararaj P, Thiruppathi G

[Methods, 2023]

A chromone-based ratiometric fluorescent probe L2 was developed for the selective detection of Hg(II) in a semi-aqueous solution based on aggregation-induced emission (AIE) and chelation-enhanced fluorescence (CHEF) effect. The probe L2 fluoresced significantly at 498 nm in its aggregated state, and when chelated with Hg(II), the soluble state fluoresced 1-fold higher. In addition, Job's plot reveals that the probe forms a 1:1 stoichiometry complex with Hg(II) with an association constant of 9.1 × 10³M^-1 estimated by the BH plot. The probe L2 detects Hg(II) down to 22.47 nM without interference from other interfering ions. The FTIR, ESI mass, and DFT-based computational studies investigated the binding mechanism of probe L2 with Hg(II). Taking advantage of its AIE characteristics, the probe L2 was successfully applied for bio-capability analysis in Caenorhabditis elegans (a nematode worm) imaging of Hg(II) in a living model.

Xu W et al. (2011) Cancer Cell "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases."

Wang P, Liu J, Xu YH, Yang H, Xu W, Liu LX, Zhao SM, Wang B, Kim SH, Xiao MT, Xiong Y, Zhang Y, Ito S, Frye S, Jiang WQ, Lei QY, Zhang JY, Guan KL, Liu Y, Yang C, Yang Y

[Cancer Cell, 2011]

IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of alpha-ketoglutarate (alpha-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple alpha-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as alpha-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce alpha-KG and accumulate an alpha-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

Riedinger C et al. (2018) J Biol Chem "High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans."

Riedinger C, Nawroth PP, Herzig S, Mendler M, Fleming T, Okun J, Schlotterer A, Hammes HP

[J Biol Chem, 2018]

The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de-novo synthesis. It metabolizes AICAR, which is an AMP analogue, leading to activation of AMPK. It was investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG) mediated DNA damage response and AICAR mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damages and shortening of lifespan. HG up-regulated the expression and activity of Caenorhabditis elegans homologue of ATIC, C55F2.1 (atic-1), as well as increased the levels of reactive oxygen species (ROS) and methylglyoxalderived advanced glycation endproducts (MG-AGEs). Overexpression of atic-1 decreased lifespan and head motility and increased neuronal damage under both standard (S) and high glucose (HG) conditions. Inhibition of atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, ROS and MG-AGE accumulation. This effect was independent of an effect on DNA damage or antioxidant defense pathways, such as superoxide dismutase (sod-3) or glyoxalase-1 (glod-4), but was dependent upon AMPK and an accumulation of AICAR. Through AMPK, AICAR treatment also reduced the negative effects of HG. The mitochondrial inhibitor rotenone abolished the AICAR/AMPK-induced amelioration of HG effects, pointing to mitochondria as a prime target of the glucotoxic effects in C. elegans. We conclude that atic-1 is involved in glucotoxic effects under HG conditions, either by blocked atic-1 expression or via AICAR and AMPK induction.

Xing X et al. (2009) Bull Environ Contam Toxicol "Lethality toxicities induced by metal exposure during development in nematode Caenorhabditis elegans."

Rui Q, Wang D, Xing X

[Bull Environ Contam Toxicol, 2009]

Lethality changes were investigated during development in 4 h metal exposed Caenorhabditis elegans. Exposure to examined metals caused severe lethality toxicities in L1- and L2-larvae, in L3-larvae exposed to examined metals at concentrations of 50 and 100 microM and to Pb, Hg, and Cr at the concentration of 2.5 microM, in L4-larvae exposed to examined metals at concentrations of 50 and 100 microM, and in adults exposed to Pb, Hg, and Cr at the concentration of 100 microM. Moreover, the lethality toxicities induced by Pb and Hg in L1 larvae for 4 h could be largely comparable to those in young adults for 24 h.

Zhao Y et al. (2023) Sci Total Environ "Parental treatment with selenium protects Caenorhabditis elegans and their offspring against the reproductive toxicity of mercury."

Pei C, Wu L, Ni S, Zhao Y, Xu A, Nie Y, Sun L, Liu Y

[Sci Total Environ, 2023]

Mercury (Hg) is one of the major pollutants in the environment, which requires effective countermeasures to manage its risk to both human health and the ecosystem. The antagonistic effect of selenium (Se) against methyl mercury (MeHg) and HgCl₂ was evaluated using parent and offspring Caenorhabditis elegans (C. elegans) in this study. Through designated acute exposure of 24 h, our results showed that both MeHg and HgCl₂ induced dose-dependent reproductive toxicity, including increased germ cell apoptosis, decrease in the number of oocytes, brood size, and sperm activation. The increased germ cell apoptosis was even higher in F1 and F2 generations, but returned to control level in F3. Pretreatment of Se significantly suppressed the reproductive toxicity caused by Hg in both parental worms and their offspring, but had little influence on Hg accumulation. The protective role of Se was found closely related to the chemical forms of Hg: mtl-1 and mtl-2 genes participated in reducing the toxicity of HgCl₂, while the gst-4 gene was involved in the reduced toxicity of MeHg. The formation of Se-Hg complex and the antioxidant function of Se were considered as possible antagonistic mechanisms. Our data indicated that pretreatment with Se could effectively protect C. elegans and their offspring against the reproductive toxicity of Hg in different chemical forms, which provided a reference for the prevention of Hg poisoning and essential information for better understanding the detoxification potential of Se on heavy metals.

Senthil Kumar KJ et al. (2016) Oncotarget "A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1."

Lin CC, Wang SY, Chu FH, Senthil Kumar KJ, Wei CC, Liao VH, Gokila Vani M, Mau JL

[Oncotarget, 2016]

The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 M) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, CDK4, CDK6, CDK2 and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated -galactosidase (SA--gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly extended the life span of C. elegans. Taken together, our results suggest the potential application of ANM in age-related diseases or as a preventive reagent against aging process.