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[
Mar Drugs,
2019]
Several known sesquiterpenoid quinones and quinols (<b>1</b>-<b>9</b>), and kauamide (<b>10</b>), a new polyketide-peptide containing an 11-membered heterocycle, were isolated from the extracts of the Hawaiian marine sponge <i>Dactylospongia</i><i>elegans</i>. The planar structure of <b>10</b> 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 <i>N</i>-MeLeu residue, respectively. Compounds <b>1</b> and <b>3</b> showed moderate inhibition of -secretase 1 (BACE1), whereas <b>1</b>-<b>9</b> exhibited moderate to potent inhibition of growth of human glioma (U251) cells. Compounds <b>1</b>-<b>2</b> and <b>4</b>-<b>7</b> were also active against human pancreatic carcinoma (Panc-1) cells.
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[
J Nat Prod,
2019]
To explore the chemical diversity of metabolites from new species of Dothideomycetes, the ex-type strain of <i>Sparticola junci</i> was investigated. Seven highly oxygenated and functionalized spirodioxynaphthalene natural products incorporating carboxyalkylidene-cyclopentanoid (<b>1</b>-<b>4</b>), carboxyl-functionalized oxabicyclo[3.3.0]octane (<b>5</b>-<b>6</b>), and annelated 2-cyclopentenone/-lactone (<b>7</b>) 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 (<b>2</b>) exhibited inhibitory activity against the Gram-positive bacteria <i>Bacillus subtilis</i>, <i>Micrococcus luteus</i>, and <i>Staphylococcus aureus</i>, while sparticolin G (<b>7</b>) showed antifungal activities against <i>Schizosaccharomyces pombe</i> and <i>Mucor hiemalis</i>. All other sparticolins were only weakly active against <i>S. aureus</i> and also showed weak activities against the nematode <i>Caenorhabditis elegans</i>. Compounds <b>2</b> and <b>7</b> also showed moderate cytotoxic activities against seven mammalian cell lines.
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[
Biosci Biotechnol Biochem,
2019]
The nematocidal activities of the fatty acid esters of d-allose were examined using the larvae of <i>C. elegans</i>. Among the fatty acid esters, 6-<i>O</i>-octanoyl-d-allose (<b>3</b>) showed significant activity. 6-<i>O</i>-octanoyl-d-glucose (<b>5</b>) showed no activity, indicating that the D-allose moiety is essential for the nematocidal activity of <b>3</b>. A nonhydrolyzable alkoxy analog 6-<i>O</i>-octyl-d-allose (<b>6</b>) also showed activity equivalent to that of <b>3</b>.
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[
Biomolecules,
2021]
<i>Ozoroa insignis</i> 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 <i>Ozoroa insignis</i>, the anthelmintic principles could be isolated through bioassay-guided isolation using <i>Caenorhabditis elegans</i> and identified by NMR spectroscopic analysis and mass spectrometric studies. Isolated 6-[8(<i>Z</i>)-pentadecenyl] anacardic (<b>1</b>), 6-[10(<i>Z</i>)-heptadecenyl] anacardic acid (<b>2</b>), and 3-[7(<i>Z</i>)-pentadecenyl] phenol (<b>3</b>) were evaluated against the 5 parasitic organisms <i>Schistosoma mansoni</i> (adult and newly transformed schistosomula), <i>Strongyloides ratti</i>, <i>Heligmosomoides polygyrus</i>, <i>Necator americanus</i>, and <i>Ancylostoma ceylanicum</i>, which mainly infect humans and other mammals. Compounds <b>1</b>-<b>3</b> showed good activity against <i>Schistosoma mansoni</i>, with compound <b>1</b> 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 <b>2</b> and <b>3</b> showed antiproliferative activity in both cancer cell lines, while compound <b>1</b> exhibited antiproliferative activity only on PC-3 cells. With an IC<sub>50</sub> value of 43.2 M, compound <b>3</b> was found to be the most active of the 3 investigated compounds.
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Eifler-Lima VL, Garcia SC, Sauer E, Figueiro F, das Neves GM, Rockenbach L, Kagami LP, Munhoz T, Oliveira Batasttini AM, Goethel G, Goncalves IL
[
Future Med Chem,
2020]
<b>Background:</b> 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. <b>Materials & methods:</b> 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 <i>Caenorhabditis elegans</i> as the model. <b>Results & conclusion:</b> DHPMs <b>9</b>, <b>13</b> and <b>17</b> 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 G<sub>2</sub>/M and cell death by apoptosis. In addition, compound <b>13</b>was able to modulate the reactive oxygen species production <i>in vivo</i> in <i>C. elegans</i>. The biphenyl dihydropyrimidinthiones provided a safety profile in <i>C. elegans</i>.
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[
Nat Prod Res,
2020]
A new highly oxygenated germacranolide, carcerlane A (<b>1</b>), together with four known highly oxygenated germacranolides (<b>2</b>-<b>5</b>), was isolated from an ethanol extract of the whole plant of <i>Carpesium nepalense</i> var. <i>lanatum</i> (C.B.Clarke) Kitam. The structures were determined by HRESIMS and extensive analysis of their spectroscopic data including IR, 1D and 2D NMR spectra. To our best knowledge, it was the first time to report the phytochemical investigation on this plant. The anti-Alzheimer's disease (AD) activities of <b>1</b>-<b>5</b> were evaluated using <i>Caenorhabditis elegans</i> AD pathological model. All the tested compounds showed that they have the anti-AD bioactivities of delaying worms paralysis.
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[
Parasitology,
1991]
Pine wilt is the most serious disease of native pines in Japan and potentially the most important nematode disease of conifers in the world. The pinewood nematode Bursaphelenchus xylophilus was found to be the casual agent. Difficulties arose with respect to the precise identity of some isolates of B. xylophilus and of similar species B. mucronatus and B. fraudulentus. Restriction enzyme analyses of repetitive DNA revealed bands specific for the species B. xylophilus, B. mucronatuus and B. fraudulentus. Hybridization patterns obtained with
unc-22 gene of C. elegans, clearly identified B. xylophilus, B. mucronatus and B. fraudulentus as well as the different geographic isolates of these species. Furthermore, it is possible to define the phylogenetic relationships between the different populations constituting the 'pine wood
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[
Mar Drugs,
2019]
Bioassay-guided fractionation of marine-derived fungi revealed that the EtOAc fraction from the fermentation broth of a mutated fungal strain <i>Streptomyces nitrosporeus</i> YBH10-5 had lipid-lowering effects in HepG2 cells. Chromatographic separation of the EtOAc fraction resulted in the isolation of 11 PKS-based derivatives, including a structurally unique meroterpenoid namely nitrosporeunol H (<b>1</b>). The structure of compound <b>1</b> was determined by the analysis of spectroscopic data. Further bioassay resulted in farnesylquinone (<b>2</b>) and its analogues to exert in vivo fat-reducing effects in <i>C.</i><i>elegans</i> worm model. The underlying mode of action of compound <b>2</b> in the context of live worms was investigated, uncovering that compound <b>2</b> enhanced the mitochondrial -oxidation rate and changed the transcriptional level of energy metabolism genes. Additional experiments revealed that compound <b>2</b> exerted its effects in <i>C. elegans</i> partially through repressing FAT-5, an isoform of stearoyl-CoA desaturase (SCD) which catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids, thereafter leading to the modification of the fatty acid profile. Thus, compound <b>2</b> was suggested to be a promising lead for further optimization to treat obesity.
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[
Infect Immun,
2003]
Lymphatic filariasis is a tropical disease caused by the nematode parasites Wuchereria bancrofti and Brugia malayi. Whereas the protective potential of T lymphocytes in filarial infection is well documented, investigation of the role of B lymphocytes in antifilarial immunity has been neglected. In this communication, we examine the role of B lymphocytes in antifilarial immunity, using Brugia pahangi infections in the murine peritoneal cavity as a model. We find that B lymphocytes are required for clearance of primary and challenge infections with B. pahangi third-stage larvae (L3). We assessed the protective potential of peritoneal B lymphocytes by adoptive transfer experiments. Primed but not naive peritoneal B cells from wild-type mice that had been immunized with B. pahangi L3 protected athymic recipients from challenge infection. We evaluated possible mechanisms by which B cells mediate protection. Comparisons of cytokine mRNA expression between B-lymphocyte-deficient and immunocompetent mice following B. pahangi infection suggest that B cells are required for the early production of Th2-type cytokines by peritoneal cells. In addition, B-cell-deficient mice demonstrate a defect in inflammatory cell recruitment to the peritoneal cavity following B. pahangi infection. The data demonstrate a critical role of B lymphocytes in antifilarial immunity in naive mice and in the memory response in primed mice.
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Di Martino RMC, Gobbi S, Belluti F, Martinez A, Rampa A, Paglione M, Martinez-Gonzalez L, Tarozzi A, Seghetti F, Di Schiavi E, Perez C, Pruccoli L, Bisi A
[
ACS Chem Neurosci,
2020]
Common co-pathogenic factors, including oxidative stress and neuroinflammation, are found to play a vital role in the development of neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Nowadays, owing to the multifactorial character of the diseases, no effective therapies are available, thus underlying the need for new strategies. Overexpression of the enzyme GSK-3 and downregulation of Nrf2/ARE pathway are responsible for a decrease in antioxidant defence effects. These pieces of evidence underline the usefulness of dual GSK-3 inhibitor/Nrf2 inducers. In this regard, to design a dual modulator, the structures of a curcumin-based analogue, as GSK-3 inhibitor, and a diethyl fumarate fragment, as Nrf2 inducer, were combined. Among the hybrids, <b>5</b> and <b>6</b> proved to effectively inhibit GSK-3, while <b>4</b> and <b>5</b> showed a marked ability to activate Nrf2 together to increase the neuronal resistance to oxidative stress. These last pieces of evidence translated into specific neuroprotective effects of <b>4</b> and <b>5</b> against PD pathological events including neurotoxicity elicited by -synuclein aggregates and 6-hydroxydopamine. Hybrid <b>5</b> also showed neuroprotective effects in a <i>C. elegans</i> model of PD where the activation of GSK-3 is intimately involved in Nrf2 regulation. In summary, <b>5</b> emerged as an interesting multitarget derivative, valuable to be exploited in a multitarget PD perspective.