Unlocking the Potential of Octocoral-Derived Secondary Metabolites against Neutrophilic Inflammatory Response.

Inflammation is a critical defense mechanism that is utilized by the body to protect itself against pathogens and other noxious invaders. However, if the inflammatory response becomes exaggerated or uncontrollable, its original protective role is not only demolished but it also becomes detrimental to the affected tissues or even to the entire body. Thus, regulating the inflammatory process is crucial to ensure that it is resolved promptly to prevent any subsequent damage. The role of neutrophils in inflammation has been highlighted in recent decades by a plethora of studies focusing on neutrophilic inflammatory diseases as well as the mechanisms to regulate the activity of neutrophils during the overwhelmed inflammatory process. As natural products have demonstrated promising effects in a wide range of pharmacological activities, they have been investigated for the discovery of new anti-inflammatory therapeutics to overcome the drawbacks of current synthetic agents. Octocorals have attracted scientists as a plentiful source of novel and intriguing marine scaffolds that exhibit many pharmacological activities, including anti-inflammatory effects. In this review, we aim to provide a summary of the neutrophilic anti-inflammatory properties of these marine organisms that were demonstrated in 46 studies from 1995 to the present (April 2023). We hope the present work offers a comprehensive overview of the anti-inflammatory potential of octocorals and encourages researchers to identify promising leads among numerous compounds isolated from octocorals over the past few decades to be further developed into anti-inflammatory therapeutic agents.

Extract of Ficus septica modulates apoptosis and migration in human oral squamous cell carcinoma cells.

According to the alarming statistical analysis of global cancer, there are over 19 million new diagnoses and more than 10 million deaths each year. One such cancer is the oral squamous cell carcinoma (OSCC), which requires new therapeutic strategies. Ficus septica extract has been used in traditional medicine to treat infectious diseases. In this study, we examined the anti-proliferative effects of an extract of F. septica bark (FSB) in OSCC cells. Our results showed that FSB caused a concentration-dependent reduction in the viability of SCC2095 OSCC cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and was less sensitive to fibroblasts. In addition, FSB induced apoptosis by activating caspases, accompanied by the modulation of Akt/mTOR/NF-κB and mitogen-activated protein kinase signaling. Moreover, FSB increased reactive oxygen species generation in a concentration-dependent manner in SCC2095 cells. Furthermore, FSB inhibited cell migration and modulated the levels of the cell adhesion molecules including E-cadherin, N-cadherin, and Snail in SCC2095 cells. Pinoresinol, a lignan isolated from FSB, showed antitumor effects in SCC2095 cells, implying that this compound might play an important role in FSB-induced OSCC cell death. Taken together, FSB is a potential anti-tumor agent against OSCC cells.

Towards Sustainable Medicinal Resources through Marine Soft Coral Aquaculture: Insights into the Chemical Diversity and the Biological Potential.

In recent decades, aquaculture techniques for soft corals have made remarkable progress in terms of conditions and productivity. Researchers have been able to obtain larger quantities of soft corals, thus larger quantities of biologically active metabolites, allowing them to study their biological activity in many pharmacological assays and even produce sufficient quantities for clinical trials. In this review, we summarize 201 secondary metabolites that have been identified from cultured soft corals in the era from 2002 to September 2022. Various types of diterpenes (eunicellins, cembranes, spatanes, norcembranes, briaranes, and aquarianes), as well as biscembranes, sterols, and quinones were discovered and subjected to bioactivity investigations in 53 different studies. We also introduce a more in-depth discussion of the potential biological effects (anti-cancer, anti-inflammatory, and anti-microbial) and the mechanisms of action of the identified secondary metabolites. We hope this review will shed light on the untapped potential applications of aquaculture to produce valuable secondary metabolites to tackle current and emerging health conditions.

MS/MS Molecular Networking Unveils the Chemical Diversity of Biscembranoid Derivatives, Neutrophilic Inflammatory Mediators from the Cultured Soft Coral Sarcophyton trocheliophorum.

Biscembranoids are the distinctive tetraterpenoids owing a 14/6/14 membered tricyclic scaffold that have been mainly discovered in the soft corals, especially the genera Sarcophyton, Lobophytum and Sinularia. Recent findings have demonstrated the great anti-inflammatory potential of biscembranoid analogues in human neutrophils, motivating more chemical and biological explorations targeting these marine-derived natural products. In the current study, the chemical diversity of biscembranoids derived from the cultured-type Sarcophyton trocheliophorum von Marenzeller was illustrated through MS/MS molecular networking (MN) profiling approach. Based on the MN patterns, the prioritization of unknown biscembranoid derivatives was putatively analyzed. As a result, the biscembrane targeting isolation afforded two new metabolites, sarcotrochelides A (1) and B (2), along with six known analogues (3-8). Their structures and relative configurations were determined by spectroscopic methods. In vitro neutrophil inflammatory inhibition was further investigated for all isolates based on reduced superoxide anion (O2•-) generation detections. Compounds 5-8 showed significant dose-dependently inhibitory effects, suggesting the cruciality of 6,7-dihydrooxepin-2(5H)-one moiety and saturated γ-lactone ring in their reactive oxygen species (ROS)-dependent anti-inflammatory properties.

The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids.

Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1-10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50-7.67 µM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.

Isomalabaricane Triterpenes from the Marine Sponge Rhabdastrella sp.

The marine sponge of the genus Geodia, Jaspis, Rhabdastrella, and Stelletta are characterized chemically by a variety of isomalabaricane triterpenes. This class of compounds drew spotlights in marine lead discovery due to their profound anti-proliferative properties. Further research on exploring its chemical diversity led to the identifications of two new isomalabaricane-type triterpenes rhabdastin H (1) and rhabdastin I (2). Their structures were unraveled using a series of spectroscopic approaches. These isolates were found to exhibit unique structural features with the only reported tetrahydrofuran functionality among all marine-derived isomalabaricanes. Both compounds 1 and 2 showed activities against K562 (IC50 11.7 and 9.8 µM) and Molt4 (IC50 16.5 and 11.0 µM) leukemic cells in MTT cell proliferative assay.

Scalarane-Type Sesterterpenoids from the Marine Sponge Lendenfeldia sp. Alleviate Inflammation in Human Neutrophils.

Sponge-derived scalaranes are remarkable sesterterpenoids previously found to exhibit profound inhibitory effects against neutrophilic inflammation. In our current work, we constructed the metabolomic profile of marine sponge Lendenfeldia sp. for the first time using a tandem mass spectrometry (MS/MS) molecular networking approach. The results highlighted the rich chemical diversity of these scalaranes, motivating us to conduct further research to discover novel scalaranes targeting neutrophilic inflammation. MS- and NMR-assisted isolation and elucidation led to the discovery of seven new homoscalaranes, lendenfeldaranes K-Q (1-7), characterized by methylation at C-24, together with five known derivatives, lendenfeldarane B (8), 25-nor-24-methyl-12,24-dioxoscalar-16-en-22-oic acid (9), 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (10), felixin B (11), and 23-hydroxy-20-methyldeoxoscalarin (12). Scalaranes 1-4 and 6-12 were assayed against superoxide anion generation and elastase release, which represented the neutrophilic inflammatory responses of respiratory burst and degranulation, respectively. The results indicated that 1-3 and 6-12 exhibited potential anti-inflammatory activities (IC50 for superoxide anion scavenging: 0.87~6.57 µM; IC50 for elastase release: 1.12~6.97 µM).

12-Deacetyl-12-epi-Scalaradial, a Scalarane Sesterterpenoid from a Marine Sponge Hippospongia sp., Induces HeLa Cells Apoptosis via MAPK/ERK Pathway and Modulates Nuclear Receptor Nur77.

12-Deacetyl-12-epi-scalaradial, a scalarane sesterterpenoid from a marine sponge Hippospongia sp, has been reported to possess cytotoxic activity on HepG2, MCF-7, and HCT-116 cells. However, there is no research to indicate that 12-deacetyl-12-epi-scalaradial exhibited anticancer effect on cervical cancer HeLa cells. The aim of this study was to investigate the anticancer activity of 12-deacetyl-12-epi-scalaradial against HeLa cells and to explore the mechanism. The results from a methylthiazolyldiphenyl-tetrazolium (MTT) assay suggested that 12-deacetyl-12-epi-scalaradial suppressed the proliferation of HeLa cells and flow cytometry analysis showed 12-deacetyl-12-epi-scalaradial could induce the apoptosis of HeLa cells in dose- and time-dependent manner. Western blotting analysis demonstrated that 12-deacetyl-12-epi-scalaradial triggered apoptosis via mediating the extrinsic pathway and was found to suppress MAPK/ERK pathway which was associate with cancer cell death. Nur77, a critical number of orphan nuclear receptors, plays diverse roles in tumor development as a transcription factor and has been considered as a promising anticancer drug target. The dual-luciferase reporter assays suggested that 12-deacetyl-12-epi-scalaradial could selectively enhance the trans-activation activity of Nur77. Furthermore, Western blotting analysis and fluorescence quenching showed that 12-deacetyl-12-epi-scalaradial could induce the phosphorylation of Nur77 and interact with the ligand-binding domain (LBD) of Nur77. Our research confirmed 12-deacetyl-12-epi-scalaradial as a potential agent for cervical cancer therapy and provided a view that 12-deacetyl-12-epi-scalaradial may be a modulator of Nur77.

Sponge-Derived 24-Homoscalaranes as Potent Anti-Inflammatory Agents.

Scalarane-type sesterterpenoids are known for their therapeutic potential in cancer treatments. However, the anti-inflammatory properties of this class of metabolites remain elusive. Our current work aimed to investigate the anti-inflammatory scalaranes from marine sponge Lendenfeldia sp., resulting in the isolation of six new 24-homoscalaranes, lendenfeldaranes E-J (1-6). The structures of the new metabolites were determined by extensive spectroscopic analyses, and the absolute configuration of 1 was established by electronic circular dichroism (ECD) calculations. Compounds 2 and 3 were discovered to individually reduce the generation of superoxide anions, and compound 1 displayed an inhibitor effect on the release of elastase. These three compounds were proven to be the first anti-neutrophilic scalaranes.

13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity Against Oral Cancer Cells Through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts.

13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.

Probing Anti-Proliferative 24-Homoscalaranes from a Sponge Lendenfeldiasp.

In the current study, an NMR spectroscopic pattern-based procedure for probing scalarane derivatives was performed and four new 24-homoscalaranes, lendenfeldaranes A-D (1- 4), along with three known compounds, 12α-acetoxy-22-hydroxy-24-methyl-24-oxoscalar-16-en- 25-al (5), felixin F (6), and 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (7) were isolated from the sponge Lendenfeldia sp. The structures of scalaranes 1-7 were elucidated on the basis of spectroscopic analysis. Scalaranes 1-7 were further evaluated for their cytotoxicity toward a series of human cancer cell lines and the results suggested that 5 and 7 dominated in the anti- proliferative activity of the extract. The 18-aldehyde functionality was found to play a key role in their activity.

Natural Products from Octocorals of the Genus Dendronephthya (Family Nephtheidae).

In this review, 170 natural substances, including steroid, diterpenoid, sesquiterpenoid, peptide, prostaglandin, base, chlorolipid, bicyclolactone, amide, piperazine, polyketide, glycerol, benzoic acid, glycyrrhetyl amino acid, hexitol, pentanoic acid, aminoethyl ester, octadecanone, alkaloid, and a 53-kD allergenic component from octocorals belonging to genus Dendronephthya, were listed. Some of these compounds displayed potential bioactivities.

Briarenols I-K, New Anti-inflammatory 8,17-Epoxybriaranes from the Octocoral Briareum excavatum (Briareidae).

Five 8,17-epoxybriaranes, including three new compounds-briarenols I-K (1-3), along with two known analogues, briaexcavatolide P (4) and briaexcavatin P (5), were isolated from the octocoral Briareum excavatum. The structures of briaranes 1-3 were elucidated by spectroscopic methods, including 1D and 2D NMR studies and (+)-HRESIMS. Briarane 4 exerted inhibition effects on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) release from RAW 264.7.

New Furanocembranoids from Briareum violaceum.

Three new furanocembranoids-briaviodiol F (1) and briaviotriols A (2) and B (3)-along with a known analogue, briaviodiol A (4), were obtained from a cultured-type octocoral Briareum violaceum. The structures of cembranoids 1⁻3 were elucidated by using spectroscopic methods. In vitro study demonstrated that compounds 2 and 4 exerted inhibition effects on inducible nitric oxide synthase (iNOS) release from RAW 264.7, a macrophage cell line that originated from a mouse monocyte macrophage, stimulated with lipopolysaccharides.

Fragilides U-W: New 11,20-Epoxybriaranes from the Sea Whip Gorgonian Coral Junceella fragilis.

Three new 11,20-epoxybriaranes-fragilides U-W (1-3), as well as two known metabolites, junceellonoid D (4) and junceellin (5), were obtained from the octocoral Junceella fragilis. The structures of briaranes 1-3 were elucidated by spectroscopic methods and briaranes 3 and 5 displayed inhibition effects on inducible nitric oxide synthase (iNOS) release from RAW264.7.

New 8-Hydroxybriaranes from the Gorgonian Coral Junceella fragilis (Ellisellidae).

Three new 8-hydroxybriaranes-fragilides R-T (1-3) were obtained from a sea whip gorgonian coral Junceella fragilis. The structures of briaranes 1-3 were elucidated by using spectroscopic methods, including 1D (1H and 13C NMR), 2D (COSY, HSQC, HMBC, and NOESY experiments) NMR studies, and (+)-HRESIMS. Fragilides S and T (2 and 3) are the only briaranes known to possess 8α-hydroxy and 17ß-methyl groups, respectively. Briarane 2 exerted an inhibition effect on iNOS release from RAW264.7; a macrophage cell line that originated from a mouse monocyte macrophage, stimulated with lipopolysaccharides.

New 1,4-Dienonesteroids from the Octocoral Dendronephthya sp.

Two new steroids, dendronesterones D (1) and E (2), featuring with 1,4-dienone moiety, along with three known steroids, methyl 3-oxochola-4,22-diene-24-oate (3), 5α,8α-epidioxy-24(S)- methylcholesta-6,22-dien-3ß-ol (4), and 5α,8α-epidioxy-24(S)-methylcholesta-6,9(11),22-trien-3ß-ol (5), were isolated from an octocoral Dendronephthya sp. The structures of steroids 1 and 2 were elucidated by using spectroscopic methods and steroid 1 was found to exhibit significant in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-induced RAW264.7 macrophage cells by inhibiting the expression of the iNOS protein.

New 11,20-Epoxybriaranes from the Gorgonian Coral Junceella fragilis (Ellisellidae).

Two new 11,20-epoxybriaranes, fragilides P (1) and Q (2), as well as two known analogues, robustolide F (3) and juncin Z (4), were obtained from the gorgonian coral Junceella fragilis. The structures, including the absolute configurations of briaranes 1 and 2, were elucidated by using spectroscopic methods and comparing the spectroscopic and rotation data with those of known related analogues. Briarane 4 decreased the generation of superoxide anions by human neutrophils. The propionate group in 1 is rarely found.

Aquaculture Soft Coral Lobophytum crassum as a Producer of Anti-Proliferative Cembranoids.

Our continuous search for marine bioactive secondary metabolites led to the screening of crude extracts from a variety of aquaculture soft corals. The ethyl acetate (EtOAc) extract of Lobophytum crassum showed a distinctive chemical profile that was different from the wild type. It demonstrated significant anti-proliferative activity against Molt 4 leukemia cell with an IC50 value of 1 µg/mL after 24 h. Chemical investigation focusing on the unique peaks in L. crassum profile led to the discovery of a new α-tocopherol crassumtocopherol C (1), and two new cembrane-based diterpenoids culobophylins D (2) and E (3), along with ten known cembranoids (4-13). The structures of these isolates were elucidated using extensive spectroscopic techniques and a comparison with previously published data of related metabolites. Compound 2 was found to possess the first identified saturated internal C4-O-C14 linkage six-membered ring among all cembrane-type diterpenoids. The anti-proliferative activity of all the isolates (except 3) was evaluated against a limited panel of leukemia cell lines (Molt 4, K562, U937, and Sup-T1). The major compounds 8 and 10 exhibited the most anti-proliferative potent effect, with IC50 values ranging from 1.2 to 7.1 µM. The Structure Activity Relationship (SAR) of the isolates suggested that the presence of lactone moieties is crucial for the anti-proliferative activity against leukemia cells. Our work indicated that the development of an efficient aquaculture protocols for soft corals led to the discovery of new secondary metabolites with unique structural features. Such protocols can lead to a sustainable supply of biologically active compounds in enough quantities for the pharmaceutical industry.

Briaviolides K-N, New Briarane-Type Diterpenoids from Cultured Octocoral Briareum violaceum.

Four new briarane diterpenoids, briaviolides K-N (1-4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1-4 were identified. This study employed an in vitro model of lipopolysaccharide (LPS)-induced inflammation in the murine macrophage RAW 264.7 cell line, and found that among the four briaranes, briarane 2 possessed anti-inflammatory activity against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in cells. In addition, principal component analysis using the chemical global positioning system (ChemGPS) for natural products (ChemGPS-NP) was employed in order to analyze the structure-activity relationship (SAR), and the results indicated that the ring conformation of the compound has a leading role in suppressing the expressions of pro-inflammatory iNOS and COX-2 proteins in macrophages.