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Hwang, Ara B. et al. (2013) International Worm Meeting "Mitochondrial ROS promote longevity and innate immunity via a feedback loop involving HIF-1 and AMPK."

Mair, William, Artan, Murat, Lee, Seung-Jae, Hwang, Ara B., Ryu, Eun-A

[

International Worm Meeting,

2013]

Mild inhibition of mitochondrial respiration promotes longevity across phyla. Recently we reported that reduced respiration lengthens lifespan by increasing reactive oxygen species (ROS) that activate the hypoxia-inducible factor 1 (HIF-1) in C. elegans. Here we elucidated a feedback-regulatory mechanism and functional significance of the ROS-induced longevity. We initially found that mutations in aak-2 (catalytic a subunit of AMP-activated protein kinase [AMPK]) suppressed the longevity induced by an ROS-generating chemical, paraquat (0.25 mM). In addition, we showed that mitochondrial ROS activated AMPK, and that paraquat did not further increase the longevity of gain-of-function AAK-2 transgenic animals. These data suggest that AMPK mediates the longevity induced by mitochondrial ROS. We then investigated the mechanisms by which AMPK contributes to the ROS-induced longevity. We demonstrated that AMPK acts as a negative feedback regulator of internal ROS levels, because aak-2 mutants were hyper-sensitive to ROS and contained increased ROS levels upon paraquat treatment. In contrast, HIF-1 was required for increasing internal ROS levels, suggesting that HIF-1 acts as a positive regulator of ROS. These data imply that feedback regulation by AMPK and HIF-1 ensures balance between the benefit and toxicity of ROS. Next, we determined the relationship between the ROS-induced longevity and innate immunity, because infection by E. coli is the major cause of death of aged C. elegans in laboratory. We found that feeding non-pathogenic bacteria increased the lifespan of wild type but not that of the long-lived mitochondrial isp-1 mutants, which display high levels of ROS. Moreover, isp-1 mutants were resistant to several pathogens, and both aak-2 and hif-1 were required for the enhanced pathogen resistance. Taken together, we propose that the feedback circuit involving AMPK and HIF-1 regulates ROS levels to maintain an optimal immunity and longevity.

Hwang, Ara B. et al. (2011) International Worm Meeting "Inhibition of mitochondrial respiration extends lifespan via reactive oxygen species that increase HIF-1 activity."

Ryu, Eun-A, Hwang, Ara B., Lee, Seung-Jae, Kenyon, Cynthia

[

International Worm Meeting,

2011]

A mild reduction of mitochondrial respiration extends the lifespan of many species including yeast, C. elegans, Drosophila and mice. However, until recently the molecular mechanisms by which impaired respiration promotes longevity are poorly understood. Hypoxia (low oxygen) is an environmental condition that reduces rates of respiration. Thus, it is possible that mechanisms that sense oxygen levels play a role in the longevity response by reduced respiration. By performing a genome-wide RNAi screen to identify genes that affect the activity of the hypoxia inducible factor HIF-1, we found that knockdown of several respiratory-chain genes can activate HIF-1. This increased HIF-1 activity seems to play a crucial role in the longevity induced by reduced respiration, since we found that the long lifespan of respiration-defective clk-1 and isp-1 mutants was suppressed by hif-1 mutations. We also showed that the longevity conferred by down-regulation of vhl-1 (ubiquitin ligase) or egl-9 (prolyl hydroxylase), which normally stabilizes HIF-1 protein, was not additive to the extended lifespan caused by impaired mitochondrial respiration. These data suggest that the reduced respiration and the mutations in the vhl-1 and egl-9 genes act in the same pathway. As a potential mechanism by which conditions that reduce respiration increase HIF-1 activity, we hypothesized that reactive oxygen species (ROS) levels rise in the long-lived mutants with defective respiration, and that this ROS, in turn, may activate HIF-1. We showed that the respiratory clk-1 and isp-1 mutants displayed slightly but significantly elevated levels of ROS. We found that elevating mitochondrial ROS levels chemically, using paraquat, can up-regulate HIF-1 activity. Furthermore, we demonstrated that low levels (e.g. 250 mM and 125 mM) of paraquat can extend the lifespan of C. elegans in a partially hif-1-dependent manner. Together our data imply that the longevity caused by clk-1 and isp-1 respiration mutations is due to HIF-1 activation and that this process is mediated by ROS. Since the lifespan-extending effect of paraquat was partially independent of hif-1, we are currently identifying other genes that contribute to paraquat-induced longevtiy.

Sakoguchi H et al. (2016) Bioorg Med Chem Lett "Growth inhibitory effect of d-arabinose against the nematode Caenorhabditis elegans: Discovery of a novel bioactive monosaccharide."

Shintani T, Izumori K, Sato M, Sakoguchi H, Okuma K, Yoshihara A

[

Bioorg Med Chem Lett,

2016]

Biological activities of unusual monosaccharides (rare sugars) have largely remained unstudied until recently. We compared the growth inhibitory effects of aldohexose stereoisomers against the animal model Caenorhabditis elegans cultured in monoxenic conditions with Escherichia coli as food. Among these stereoisomers, the rare sugar d-arabinose (d-Ara) showed particularly strong growth inhibition. The IC50 value for d-Ara was estimated to be 7.5mM, which surpassed that of the potent glycolytic inhibitor 2-deoxy-d-glucose (19.5mM) used as a positive control. The inhibitory effect of d-Ara was also observed in animals cultured in axenic conditions using a chemically defined medium; this excluded the possible influence of E. coli. To our knowledge, this is the first report of biological activity of d-Ara. The d-Ara-induced inhibition was recovered by adding either d-ribose or d-fructose, but not d-glucose. These findings suggest that the inhibition could be induced by multiple mechanisms, for example, disturbance of d-ribose and d-fructose metabolism.

Kwon, Namseop et al. (2013) International Worm Meeting "3-D Worm Tracker for C. elegans."

Lee, Seung-Jae, Je, Jung Ho, Kwon, Namseop, Hwang, Ara B.

[

International Worm Meeting,

2013]

Various tracking systems have been developed to quantify the behavior of C. elegans, a genetic model organism for studying animal behaviors. The tracking systems, however, provide two dimensional (2-D) imaging and thus have limitations in understanding the behaviors of worms freely moving in 3-D environments. Here, we introduce a 3-D worm tracker (3DWT) that is capable of analyzing trajectories and postures of worms crawling in 3-D environments. The prototype 3DWT was based on a stereoscopic imaging system that consisted of two cameras aligned at right angles, recording stereoscopic images of a single worm moving in a 3-D sample chamber. From these two 2-D images, 3-D information such as the trajectories or the postures of the worm in 3-D environments was reconstructed by stereomatching. We found that the trajectories and the postures in 3-D environments are not restricted in a single 2-D plane. This result confirms the idea that the movements of C. elegans in 3-D environments are more complex than those of worms moving on agar plates. For analyzing the kinematics of C. elegans, we introduced "bending vector" that is defined by the magnitude and direction of the bending at each body part of a worm. The bending vectors with various directions propagated from head to tail during the worms' forward runs, suggesting that the bending vector can be a useful analytic parameter for understanding complex undulatory patterns of worms in 3-D environments. Currently, we are improving our 3DWT to automatically track a worm by recording the stereoscopic images on a single camera, instead of two cameras, using four mirrors. We are furthermore enhancing the throughput and accuracy of the reconstruction process by incorporating additional camera perpendicularly to the stereoscopic configuration. We believe that our 3DWT would provide new opportunities to analyze the behaviors of C. elegans in 3-D environments and would help understand its behaviors in nature.

Neupane RP et al. (2019) Mar Drugs "Cytotoxic Sesquiterpenoid Quinones and Quinols, and an 11-Membered Heterocycle, Kauamide, from the Hawaiian Marine Sponge Dactylospongia elegans."

Williams PG, Neupane JB, Yip MLR, Turkson J, Parrish SM, Yoshida WY, Head JD, Harper MK, Neupane RP

[

Mar Drugs,

2019]

Several known sesquiterpenoid quinones and quinols (1-9), and kauamide (10), a new polyketide-peptide containing an 11-membered heterocycle, were isolated from the extracts of the Hawaiian marine sponge Dactylospongiaelegans. The planar structure of 10 was determined from spectroscopic analyses, and its relative and absolute configurations were established from density functional theory (DFT) calculations of the GIAO NMR shielding tensors, and advanced Marfey's analysis of the N-MeLeu residue, respectively. Compounds 1 and 3 showed moderate inhibition of -secretase 1 (BACE1), whereas 1-9 exhibited moderate to potent inhibition of growth of human glioma (U251) cells. Compounds 1-2 and 4-7 were also active against human pancreatic carcinoma (Panc-1) cells.

Chen CH et al. (2024) J Agric Food Chem "Novel Flavonol Alkaloids in Green Tea: Synthesis, Detection, and Anti-Alzheimer's Disease Effect in a Transgenic Caenorhabditis elegans CL4176 Model."

Ke JP, Liu Z, Yang Z, Liu G, Yang Y, Chen CH, Bao GH, Li JY, Yao G, Zhang YX

[

J Agric Food Chem,

2024]

Novel N-ethy-2-pyrrolidinone-substituted flavonols, myricetin alkaloids A-C (1-3), quercetin alkaloids A-C (4a, 4b, and 5), and kaempferol alkaloids A and B (6 and 7), were prepared from thermal reaction products of myricetin, quercetin, kaempferol─l-theanine, respectively. We used HPLC-ESI-HRMS/MS to detect 1-7 in 14 cultivars of green tea and found that they were all present in "Shuchazao," "Longjing 43", "Fudingdabai", and "Zhongcha 108" green teas. The structures of 1-4 and 6 were determined by extensive 1D and 2D NMR spectroscopies. These flavonol alkaloids along with their skeletal flavonols were assessed for anti-Alzheimer's disease effect based on molecular docking, acetylcholinesterase inhibition, and the transgenic Caenorhabditis elegans CL4176 model. Compound 7 strongly binds to the protein amyloid β (Aβ1-42) through hydrogen bonds (BE: -9.5 kcal/mol, Ki: 114.3 nM). Compound 3 (100 μM) is the strongest one in significantly extending the mean lifespan (13.4 ± 0.5 d, 43.0% promotion), delaying the Aβ1-42-induced paralysis (PT50: 40.7 ± 1.9 h, 17.1% promotion), enhancing the locomotion (140.0% promotion at 48 h), and alleviating glutamic acid (Glu)-induced neurotoxicity (153.5% promotion at 48 h) of CL4176 worms (p < 0.0001).

Phukhamsakda C et al. (2019) J Nat Prod "Sparticolins A-G, Biologically Active Oxidized Spirodioxynaphthalene Derivatives from the Ascomycete Sparticola junci."

Hyde KD, Phukhamsakda C, Cheng T, Macabeo APG, Stadler M, Huch V

[

J Nat Prod,

2019]

To explore the chemical diversity of metabolites from new species of Dothideomycetes, the ex-type strain of Sparticola junci was investigated. Seven highly oxygenated and functionalized spirodioxynaphthalene natural products incorporating carboxyalkylidene-cyclopentanoid (1-4), carboxyl-functionalized oxabicyclo[3.3.0]octane (5-6), and annelated 2-cyclopentenone/-lactone (7) units, sparticolins A-G, were isolated from submerged cultures of the fungus. Their chemical structures including their relative (and absolute) configurations were established through spectroscopic and X-ray crystallographic analyses. Sparticolin B (2) exhibited inhibitory activity against the Gram-positive bacteria Bacillus subtilis, Micrococcus luteus, and Staphylococcus aureus, while sparticolin G (7) showed antifungal activities against Schizosaccharomyces pombe and Mucor hiemalis. All other sparticolins were only weakly active against S. aureus and also showed weak activities against the nematode Caenorhabditis elegans. Compounds 2 and 7 also showed moderate cytotoxic activities against seven mammalian cell lines.

Sakoguchi H et al. (2019) Biosci Biotechnol Biochem "Nematocidal activity of 6-O-octanoyl- and 6-O-octyl-d-allose against larvae of Caenorhabditis elegans."

Kawanami Y, Sakoguchi H, Ishiyama H, Yanagita RC, Sato M, Shintani T

[

Biosci Biotechnol Biochem,

2019]

The nematocidal activities of the fatty acid esters of d-allose were examined using the larvae of C. elegans. Among the fatty acid esters, 6-O-octanoyl-d-allose (3) showed significant activity. 6-O-octanoyl-d-glucose (5) showed no activity, indicating that the D-allose moiety is essential for the nematocidal activity of 3. A nonhydrolyzable alkoxy analog 6-O-octyl-d-allose (6) also showed activity equivalent to that of 3.

Dube M et al. (2021) Biomolecules "Anthelmintic Activity and Cytotoxic Effects of Compounds Isolated from the Fruits of Ozoroa insignis Del. (Anacardiaceae)."

Haberli C, Fotso GW, Arnold N, Andrae-Marobela K, Saoud M, Rennert R, Dube M, Imming P, Keiser J

[

Biomolecules,

2021]

Ozoroa insignis Del. is an ethnobotanical plant widely used in traditional medicine for various ailments, including schistosomiasis, tapeworm, and hookworm infections. From the so far not investigated fruits of Ozoroa insignis, the anthelmintic principles could be isolated through bioassay-guided isolation using Caenorhabditis elegans and identified by NMR spectroscopic analysis and mass spectrometric studies. Isolated 6-[8(Z)-pentadecenyl] anacardic (1), 6-[10(Z)-heptadecenyl] anacardic acid (2), and 3-[7(Z)-pentadecenyl] phenol (3) were evaluated against the 5 parasitic organisms Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum, which mainly infect humans and other mammals. Compounds 1-3 showed good activity against Schistosoma mansoni, with compound 1 showing the best activity against newly transformed schistosomula with 50% activity at 1M. The isolated compounds were also evaluated for their cytotoxic properties against PC-3 (human prostate adenocarcinoma) and HT-29 (human colorectal adenocarcinoma) cell lines, whereby compounds 2 and 3 showed antiproliferative activity in both cancer cell lines, while compound 1 exhibited antiproliferative activity only on PC-3 cells. With an IC50 value of 43.2 M, compound 3 was found to be the most active of the 3 investigated compounds.

Goncalves IL et al. (2020) Future Med Chem "New pharmacological findings linked to biphenyl DHPMs, kinesin Eg5 ligands: anticancer and antioxidant effects."

Figueiro F, Kagami LP, das Neves GM, Goethel G, Garcia SC, Munhoz T, Eifler-Lima VL, Sauer E, Rockenbach L, Goncalves IL, Oliveira Batasttini AM

[

Future Med Chem,

2020]

Background: Dihydropyrimidin-2-thiones (DHPMs) are a class of heterocyclic compound which have been intensively investigated mainly due to their anticancer activity as kinesin Eg5 inhibitors. Materials & methods: A library of N1 aryl substituted DHPMs were tested against glioma and bladder cancer cell lines. Quantitative structure-activity relationship (QSAR) investigation was performed in order to identify key elements of DHPMs linked with their antiproliferative effect. The toxicity of most active compounds was investigated using Caenorhabditis elegans as the model. Results & conclusion: DHPMs 9, 13 and 17 have been identified as having improved activity against glioma and bladder cell lines as compared with monastrol. Flow cytometry investigations showed that the new compounds induce cell cycle arrest in phase G2/M and cell death by apoptosis. In addition, compound 13was able to modulate the reactive oxygen species production in vivo in C. elegans. The biphenyl dihydropyrimidinthiones provided a safety profile in C. elegans.

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