Isoquinolinequinone Derivatives from a Marine Sponge (Haliclona sp.) Regulate Inflammation in In Vitro System of Intestine

Abstract

Using bio-guided fractionation and based on the inhibitory activities of nitric oxide (NO) and prostaglandin E2 (PGE2), eight isoquinolinequinone derivatives (1–8) were isolated from the marine sponge Haliclona sp. Among these, methyl O-demethylrenierate (1) is a noble ester, whereas compounds 2 and 3 are new O-demethyl derivatives of known isoquinolinequinones. Compound 8 was assigned as a new 21-dehydroxyrenieramycin F. Anti-inflammatory activities of the isolated compounds were tested in a co-culture system of human epithelial Caco-2 and THP-1 macrophages. The isolated derivatives showed variable activities. O-demethyl renierone (5) showed the highest activity, while 3 and 7 showed moderate activities. These bioactive isoquinolinequinones inhibited lipopolysaccharide and interferon gamma-induced production of NO and PGE2. Expression of inducible nitric oxide synthase, cyclooxygenase-2, and the phosphorylation of MAPKs were down-regulated in response to the inhibition of NF-κB nuclear translocation. In addition, nuclear translocation was markedly promoted with a subsequent increase in the expression of HO-1. Structure-activity relationship studies showed that the hydroxyl group in 3 and 5, and the N-formyl group in 7 may be key functional groups responsible for their anti-inflammatory activities. These findings suggest the potential use of Haliclona sp. and its metabolites as pharmaceuticals treating inflammation-related diseases including inflammatory bowel disease.

Development of an Inflammation-Triggered In Vitro “Leaky Gut” Model Using Caco-2/HT29-MTX-E12 Combined with Macrophage-like THP-1 Cells or Primary Human-Derived Macrophages

“…IFN-γ priming of Caco-2 cells together with the stimulation of differentiated THP-1 cells by LPS and IFN-γ, induced an inflammation-like response in their diseased intestine model, evident by intestinal barrier disruption and pro-inflammatory cytokine release. Based on this model of Kämpfer, co-culture models with differentiated Caco-2 cells and PMA-differentiated THP-1 cells in the presence of inflammatory stimulators (e.g., LPS with/without IFN-γ) have been used to evaluate the potential immunomodulatory and anti-inflammatory effects of phytochemicals [ 43 , 72 , 73 ], marine natural products [ 74 , 75 , 76 ], bacterial β-glucans [ 77 ], siRNA-based nanomedicine [ 42 ], bovine milk-derived extracellular vesicles [ 78 ], and probiotic bacteria [ 41 ].…”

Marine natural products

“…425,426 Neopetrosiasins A 995 and B 996 are bis-quinolizidine alkaloids from a Neopetrosia, 427 while a series of renierate 997-999 and renieramycin 1000 alkaloids were sourced from a Vietnamese Haliclona. 428 Four new 3-alkylpyridinium dimer alkaloids, neopetrosidines A-D 1001, 1002-1004 were reported from an Indonesian N. chaliniformis. Although only weakly active against HeLa/Fucci2 uorescently labelled cells, time lapse imaging of the bioassays to assess the antiproliferative effects of 1001 shows it causes an increase in the cell cycle duration, and that it inhibits the cellular mitochondrial membrane potential and hence perturbs cellular bioenergetics.…”

“…425,426 Neopetrosiasins A 995 and B 996 are bis-quinolizidine alkaloids from a Neopetrosia , 427 while a series of renierate 997–999 and renieramycin 1000 alkaloids were sourced from a Vietnamese Haliclona . 428…”

Maramycin, a Cytotoxic Isoquinolinequinone Terpenoid Produced through Heterologous Expression of a Bifunctional Indole Prenyltransferase/Tryptophan Indole-Lyase in S. albidoflavus

“…They are predominantly isolated from marine invertebrates, such as cytotoxic caulibugulones and perfragilins from the bryozoan Caulibugula inermis and Membranipora perfragilis , antineoplastic cribrostatins from the sponge Cribrochalina sp., and antimicrobial and anti-inflammatory renierones from the sponge Renier sp . and Haliclona sp . Hence, it was believed that isoquinolinequinones are natural products of marine invertebrates.…”