Journal Articles - UP - MSI
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- Anti-inflammatory activity of monosubstituted xestoquinone analogues from the marine sponge Neopetrosia compactaSusana, Shalice R.; Salvador-Reyes, Lilibeth A. (MDPI, 2022-03-22)Chronic inflammation is recognized as a contributor to multiple chronic diseases, such as cancer, cardiovascular, and autoimmune disorders. Here, a natural products-initiated discovery of anti-inflammatory agents from marine sponges was undertaken. From the screening of 231 crude extracts, a total of 30 extracts showed anti-inflammatory activity with no direct cytotoxic effects at 50 μg/mL on RAW 264.7 (ATCC®TIB-71™) murine macrophage cells stimulated with 1 μg/mL lipopolysaccharide (LPS). Bioactivity-guided purification of the anti-inflammatory extract from the sponge Neopetrosia compacta led to the isolation of xestoquinone (1), adociaquinone B (2), adociaquinone A (3), 14-hydroxymethylxestoquinone (4), 15-hydroxymethylxestoquinone (5), and an inseparable 2:1 mixture of 14-methoxyxestoquinone and 15-methoxyxestoquinone (6). Compounds 1–6 caused a concentration-dependent reduction of nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells, with 4–6 having low micromolar IC50 and acceptable selectivity index. Gene expression analysis using qRT-PCR showed that 1, 5, and 6 downregulated Il1b and Nos2 expression by 2.1- to 14.8-fold relative to the solvent control at 10 μM. Xestoquinone (1) and monosubstituted analogues (4–6), but not the disubstituted adociaquinones (2 and 3), caused Nrf2 activation in a luciferase reporter MCF7 stable cells. Compounds 5 and 6 caused a modest increase in Nqo1 gene expression at 10 μM. The anti-inflammatory activity of xestoquinone (1) and monosubstituted analogues (4–6) may, in part, be mediated by Nrf2 activation, leading to attenuation of inflammatory mediators such as IL-1β and NOS2.Samples were collected under gratuitous permit numbers GP-0084-15 and GP-0123-17, issued by the Department of Agriculture of the Philippines. We thank the municipalities of Bolinao, Pangasinan, and Puerto Galera, Oriental Mindoro for permission for sample collection. We acknowledge assistance from Z. L. Malto and DDHP chemical ecology group in obtaining the mass spectrometric data and sample collection, respectively.
- Using constellation pharmacology to characterize a novel α-conotoxin from Conus ateralbusNeves, Jorge L. B.; Urcino, Cristoval; Chase, Kevin; Dowell, Cheryl; Hone, Arik J.; Morgenstern, David; Chua, Victor M.; Ramiro, Iris Bea L.; Imperial, Julita S.; Leavitt, Lee S.; Phan, Jasmine; Fisher, Fernando A.; Watkins, Maren; Raghuraman, Shrinivasan; Tun, Jortan O.; Ueberheide, Beatrix M.; McIntosh, J. Michael; Vasconcelos, Vitor; Olivera, Baldomero M.; Gajewiak, Joanna (MDPI, 2024-02-29)The venom of cone snails has been proven to be a rich source of bioactive peptides that target a variety of ion channels and receptors. α-Conotoxins (αCtx) interact with nicotinic acetylcholine receptors (nAChRs) and are powerful tools for investigating the structure and function of the various nAChR subtypes. By studying how conotoxins interact with nAChRs, we can improve our understanding of these receptors, leading to new insights into neurological diseases associated with nAChRs. Here, we describe the discovery and characterization of a novel conotoxin from Conus ateralbus, αCtx-AtIA, which has an amino acid sequence homologous to the well-described αCtx-PeIA, but with a different selectivity profile towards nAChRs. We tested the synthetic αCtx-AtIA using the calcium imaging-based Constellation Pharmacology assay on mouse DRG neurons and found that αCtx-AtIA significantly inhibited ACh-induced calcium influx in the presence of an α7 positive allosteric modulator, PNU-120596 (PNU). However, αCtx-AtIA did not display any activity in the absence of PNU. These findings were further validated using two-electrode voltage clamp electrophysiology performed on oocytes overexpressing mouse α3β4, α6/α3β4 and α7 nAChRs subtypes. We observed that αCtx-AtIA displayed no or low potency in blocking α3β4 and α6/α3β4 receptors, respectively, but improved potency and selectivity to block α7 nAChRs when compared with αCtx-PeIA. Through the synthesis of two additional analogs of αCtx-AtIA and subsequent characterization using Constellation Pharmacology, we were able to identify residue Trp18 as a major contributor to the activity of the peptide.We thank the Universidade Técnica do Atlântico (UTA; Cabo Verde) and Cabo Verde National Directorate of the Environment for sample collection support. We thank David Ginty (Harvard Univ.) for sharing the transgenic mice. We thank Joseph W. Aman for conducting the initial screening of the venom fractions, Samuel Espino for providing us with the picture of the shells, and Grzegorz Gajewiak for assistance with handling the photos and preparing some of the graphics used in this article.
- Total polyphenol content of tropical marine and coastal flora: Potentials for food and nutraceutical applicationsNarvarte, Bienson Ceasar V.; Genovia, Tom Gerald T.; Hinaloc, Lourie Ann R.; Gonzaga, Shienna Mae C.; Tabonda-Nabor, April Mae; Palecpec, Flora Maye R.; Dayao, Helen M.; Roleda, Michael Y. (Springer, 2023-07-08)The marine environment is abundant in natural products that are beneficial to humans. Among these compounds are the polyphenols produced by marine flora as secondary metabolites and used as a defense against stressful environmental conditions. Accordingly, recent pharmacological and biomedical studies showed that polyphenols from marine and coastal floras have several important bioactivities including antioxidant property. In this study, we measured the total polyphenol content (TPC) of 75 species of marine-associated flora. The TPC of their methanolic extracts was measured spectrophotometrically using the Folin-Ciocalteu assay and was expressed both as mg phloroglucinol equivalent per g of dry weight (mg PGE g−1 DW) and as mg gallic acid equivalent per g dry weight (mg GAE g−1 DW). The TPC values are higher when expressed in terms of GAE compared to PGE. Also, the mean TPC of tracheopytes (229 ± 43.0 mg PGE g−1 DW) was higher compared to the mean TPC of macroalgae (69.4 ± 9.59 mg PGE g−1 DW). For macroalgae, ochrophytes (97.9 ± 22.7 mg PGE g−1 DW) had the highest mean TPC followed by chlorophytes (80.0 ± 20.5 mg PGE g−1 DW) and rhodophytes (49.5 ± 8.60 mg PGE g−1 DW). Moreover, our study also showed that TPC varied between young and mature tissues, among different color morphotypes and different parts of the plants. Although the concentrations of total polyphenols varied among species, ages, strains and parts of the plant, our study showed that marine and coastal floras are rich sources of polyphenols that could be further examined for their biological activities and other applications in food industry.
- Total synthesis and bioactivity evaluation of hydrophobic microcionamide‐inspired peptidesInocentes, Carl Rogel V.; Salvador‐Reyes, Lilibeth A.; Villaraza, Aaron Joseph L. (Wiley, 2023-01)In this report, we describe the facile synthesis of four microcionamide-inspired peptides where the atypical 2-phenylethylenamine (2-PEA) functional group in the marine natural product, microcionamide A, was replaced with a similarly-aromatic but more easily incorporated tryptophan (Trp) residue. Compounds 1–4 were synthesized using a standard Fmoc-based solid-phase synthesis strategy followed by iodine-mediated on-resin cyclization for disulfide-bridged compounds 1–3. Compound 1 showed antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa, with minimum inhibitory concentrations (MICs) of 9.1 μM and 15 μM, respectively. The inactivity of alanine analogs 2–4 against these pathogens suggests that the N-terminal Val, the cyclic scaffold, the contiguous Ile residues, and consequently, the hydrophobicity of compound 1 are essential for antibacterial activity. Compound 1 also favorably exhibited minimal cytotoxicity against normal mammalian cell lines. In summary, we have synthesized an analog of microcionamide A where replacement of the 2-PEA moiety with a Trp residue retained the antibacterial activity and with favorably low cytotoxicity.