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Sulfated polysaccharides are effective immunostimulating agents by activating several intracellular signaling pathways. A sulfated (1 → 3)/(1 → 4)-linked galactofucan TCP-3 with promising immunomodulatory effects was purified from a marine macroalga Turbinaria conoides. The immune-enhancing potential of TCP-3 (100-400 mg/kg BW) was evaluated on cyclophosphamide-induced immunosuppressed animals by increasing bone marrow cellularity (10-13 cells/femur/mL x 10 6 ), α-esterase activity (1200-1700 number of positive cells/4000 BMC), interferon-γ (1.31-1.49 pg/mL), interleukin-2 (3.49-3.99 pg/mL) secretion, and WBC count (> 3000 cells/cu mm). The proliferation of lymphocytes for in vitro and in vivo conditions was enhanced by administering TCP-3 besides regulating the secretion of pro-inflammatory cytokines (interleukin-6/1β/12, tumor necrosis factor-α, transforming growth factor-β), and an inducible isoform of nitric oxide synthase. A promising reduction of viral copy formation was observed by administering TCP-3 (< 2 × 10 7 number) on SARS CoV-2 (delta variant) induced Vero cells in comparison with the infected group (> 5 × 10 7 number)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Inflammation is one of the most significant causes of several chronic diseases, which includes the expression of cytokines activating immune cells to up-regulate the inflammatory cascade. Polysaccharides from marine macroalgae are promising anti-inflammatory agents because of their potential to attenuate inflammatory cytokines. The triangular sea bell Turbinaria decurrens (Sargassaceae) among marine macroalgae is ubiquitous in oceanic waters, and a sulfated polygalactofucan SPTd-2 [→3-(α-L-fucp-(2-OSO 3 - )-(1 → 4)-α-L-fucp-(3-OAc)-(1 → 4)-β-D-galp-(1→] was purified from the species. The studied polygalactofucan SPTd-2 exhibited anti-inflammatory activities against cyclooxygenase-2 (IC 50 10.56 μM) and 5-lipoxygenase (IC 50 3.36 μM) with a greater selectivity index (2.35) than ibuprofen (0.44), besides attenuating pro-inflammatory cytokine production, including tumor necrosis factor-α, transforming growth factor-β, interleukin-2, 1β, and interferon-γ. Quantitative real-time polymerase chain reaction displayed that SPTd-2 blocked the mRNA of interferon-γ and interleukin-2, in the human monocytic cell line THP-1. The results showed the potential of SPTd-2 to attenuate inflammation-associated disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tumor protein or cellular tumor antigen p53, is considered a critical transcriptional regulation factor, which can suppress the growth of tumor cells by activating other functional genes. The current study appraised the p53 activation pathways, which could be used as an alternative therapeutic strategy for the treatment of hepatocellular and ductal carcinoma. Algal polysaccharides have been used as emerging sources of bioactive natural pharmacophores. A sulfated galactofucan characterized as [→1)-O-4-sulfonato-α-fucopyranose-(3 → 1)-α-fucopyranose-(3→] as the main branch with [→1)-6-O-acetyl-β-galactopyranose-(4→] as side chain isolated from marine macroalga Turbinaria ornata exhibited prospective apoptosis on HepG2 (hepatocellular carcinoma) and MCF7 (ductal carcinoma) cells. Annexin V-fluorescein isothiocyanate-propidium iodide study displayed higher early apoptosis in MCF7 and HepG2 cell lines (56 and 24.2%, respectively) treated with TOP-3 (at IC 50 concentration) than those administered with standard camptothecin. Upregulation of the p53 gene expression was perceived in TOP-3 treated HepG2 and MCF7 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Three Δ 5 steroid analogues, marginoids A-C were purified from the organic extract of marine veined octopus Amphioctopus marginatus (Taki, 1964) (family Octopodidae) distributed on the Asian and Mediterranean coasts. Their structures were elucidated as (5Z)-3β-acetoxy-cholesta-5-en-25-ethylene-22β-hydroxy-23,26-lactone (marginoid A), (5Z, 25Z)-3β-yl-(1'-(E)-3'-hydroxy-4'-methyl-hex-5'-enoate)-22-oxo-26-furanyl-cholesta-5,25-diene (marginoid B), and (5Z)-3β-yl-(7'-methoxypropan-8'-yl)-tetrahydro-2H-pyran-2-one-cholesta-5,24-dien (marginoid C) based on extensive spectroscopic experiments. Marginoid B with hydroxyl-methyl-hexanoate at the C-3 position in conjunction with the heterocyclic furanyl ring displayed superior anti-hyperglycemic properties as acknowledged by its promising serine protease dipeptidyl peptidase-4 attenuation potential (IC 50 3.49 µM) displaying comparable activity with the standard DPP-4 inhibitor (DPP-4i) diprotin A (IC 50 4.53 µM). The anti-hyperglycemic properties were corroborated by the promising antioxidant activities (IC 50  ∼ 0.8-1.0 mM) of these Δ 5 steroids, marginoids A-C. Sizeably greater electronic properties, balanced hydrophobic-lipophilic properties (log P OW 6.4-8.3), and comparatively lower steric factors were directly proportional to their bioactive properties. Molecular simulation studies in the binding sites of DPP-4 and lesser binding energy (-12.17 kcal/mol) and inhibition constant (Ki 1.20 nM) of marginoid B could be correlated with anti-hyperglycemic properties. Promising bioactivities of marginoid B isolated from A. marginatus are anticipated for nutraceutical applications against hyperglycemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Biochemical investigation of crude solvent extract of pharaoh cuttlefish Sepia pharaonis (family Sepiidae) led to the isolation of two undescribed disecolactonic ergosteroids, pharaonoids A-B. The compounds were characterized as 11β-acteoxy-7α-hydroxy-19-Nor-1,10:9,10-disecoergosta-3-ene-6 1 -oxa-1-one (pharaonoid A) and 11β-hydroxy-19-Nor-1,10:9,10-disecoergosta-3-ene-6 1 -oxa-1-one (pharaonoid B) in conjunction with spectroscopic analysis encompassing one and two-dimensional nuclear magnetic resonance and mass spectrometric analyses. Pharaonoid A, bearing an acetoxy and hydroxyl groups, respectively at C-11 and C-7 positions exhibited considerably greater inhibition potential against carbohydrate hydrolysing enzymes α-amylase (IC 50 1.14 mM) and α-glucosidase (IC 50 1.23 mM) than those displayed by pharaonoid B (IC 50 1.49/1.38 mM), and was proportionate with those exhibited by standard drug acarbose (IC 50 0.60 and 0.40 mM, respectively), thereby recognizing the anti-hyperglycemic potential of pharaonoid A. Promising anti-oxidant property for pharaonoid A (IC 50  ∼ 1 mM) could conceivably corroborate its attenuation potential against carbohydrate digestive enzymes. Greater electronic parameters along with optimum lipophilic-hydrophobic balance of pharaonoid A were directly corroborated to the anti-carbolytic properties occurring via transcellular mechanism. Greater binding energies (-9.50 kcal mol -1 ) and inhibition constant (Ki 48.21 nM) at the active site of α-amylase enzyme were displayed by pharaonoid A than those exhibited by its B analogue. Promising bioactive properties of the disecolactonic steroids isolated from the marine pharaoh cuttlefish are anticipated to be utilized as functional food components and potential nutraceuticals against oxidative stress and hyperglycemic disorders., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Bioactive compounds with angiotensin-I converting enzyme attenuation potential are deemed as therapeutic agents for hypertension owing to their capacity to suppress the conversion of angiotensin-I into the vasoconstrictor angiotensin-II. In an aim to develop natural angiotensin-I converting enzyme (ACE-I) inhibitors from marine algae, three 6, 6-spiroketals, spirornatas A-C were isolated from the organic extract of the spiny brown marine macroalga Turbinaria ornata (Turner) (family Sargassaceae). Spirornata A exhibited comparatively greater ACE-I attenuation potential (IC 50 4.5 μM) than those displayed by other studied spiroketals (IC 50 4.7-4.9 μM), and its activity was comparable to the ACE inhibitory agent captopril (IC 50 4.3 μM). Greater antioxidant properties of spirornata A against oxidants (IC 50 1.1-1.3 mM) also substantiated its potential attenuation property against ACE-I. Structure-activity correlation studies showed that electronic properties (topological polar surface area, 71) and balanced hydrophilic-lipophilic parameters (partition coefficient of logarithmic octanol-water ∼3.2) of spirornata A appeared to play pivotal roles in the inhibition of the targeted enzyme. Predicted drug-likeness and other physicochemical parameters appeared to attribute to the acceptable oral bioavailability of spiroketal derivatives. Additionally, the least binding energy of spirornata A with ACE-I (-10.5 kcal/mol) coupled with the maximum number of hydrogen-bonding interactions with allosteric sites of the zinc-dependent dicarboxypeptidyl peptidase could recognize its potential therapeutic application against hypertensive diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Marine heterotrophs are treasured bio-resources of antimicrobial metabolites, and herein we report the biosynthetic potential of Bacillus amyloliquefaciens (ex. Fukumoto) Priest et al. (Bacillaceae) strain MTCC 12713 isolated from an intertidal macroalga Kappaphycus alvarezii (Doty) L.M.Liao (Rhodophyta: Solieriaceae). The bacterium showed promising biological activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. Genome mining of B. amyloliquefaciens MTCC 12713 predicted the gene clusters coding for biosynthesis of antibacterial metabolites. Bioactivity-guided purification was directed to isolate four homologous members of trans-acyltransferase polyketide synthase-derived antibiotics, which were classified as macrobrevin analogues. The compounds exhibited antibacterial activities against nosocomial pathogens, for example, methicillin-resistant S. aureus, vancomycin-resistant E. faecalis, Klebsiella pneumoniae and Pseudomonas aeruginosa with a range of MIC values from 1.56 to 6.25 μg/mL, although standard antibiotic chloramphenicol was active at 6.25-12.5 μg/mL. Conspicuously, the macrobrevin compound encompassing hexahydro-41-hydroxy-macrobrevin-31-acetate functionality, displayed considerably greater antagonistic activities against methicillin-resistant S. aureus, vancomycin-resistant E. faecalis, Vibrio parahaemolyticus, P. aeruginosa, K. pneumoniae, and Streptococcus pyogenes (MIC 1.56 μg/mL) compared to the positive controls and other macrobrevin analogues. Trans-AT polyketide synthase-stimulated biosynthetic pathway of macrobrevin compounds, through repetitive decarboxylative Claisen condensation between acetyl-S-KS domain and malonate-S-ACP units could corroborate the structural elucidation. In the genome mining study, among the 34 biosynthetic gene clusters, a hybrid trans-acyltransferase (trans-AT) pks/nrps gene cluster, which extends up to ∼81 Kb, was recognized in the genome of B. amyloliquefaciens MTCC 12713. The pks/nrps cluster revealed 46% similarity to trans-AT PKS-derived macrobrevin isolated from a mesophilic bacterium Brevibacillus sp. Leaf182 associated with the phyllosphere of the wild-type genotype of Arabidopsis thaliana. The binding positions for macrobrevins with S. aureus peptide deformylase showed docking score of larger than 14 kcal/mol, which was considerably greater than macrolactin N and actinonin (<10 kcal/mol). These present findings documented that the marine heterotrophic B. amyloliquefaciens MTCC 12713 could be used to develop prospective antibacterial agents belonging to macrobrevin analogues for biotechnological and pharmaceutical applications., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Intertidal marine brown alga Turbinaria conoides (J.Agardh) Kützing (family Sargassaceae) is considered as one of the largely abundant species, available in the coastal zones of the Indian subcontinent. Bioactivity-guided chromatographic fractionation of the organic extract of T. conoides resulted in three previously undescribed macrocyclic lactone homologues, named as conoidecyclics A-C. Conoidecyclic A displayed greater attenuation potential against cyclooxygenase-2 (IC 50 1.75 mM) and 5-lipoxygenase (IC 50 4.24 mM) in comparison with other analogues. Conoidecyclic A exhibited higher attenuation potential against 5-lipoxygenase than that displayed by an anti-inflammatory agent, ibuprofen (IC 50 4.51 mM). The higher selectivity index of conoidecyclic A (1.79) recognized its selective attenuation potential against the inducible cyclooxygenase-2 enzyme. Inhibition potential of conoidecyclic A against angiotensin converting enzyme-I (IC 50 1.23 mM) and protein tyrosine phosphatase-1B (IC 50 1.39 mM) were non-competitive, as deduced by kinetic studies. In-silico molecular modeling study of conoidecyclic A with the allosteric sites of the targeted enzymes exhibited least binding energy of -14.51 to -11.27 kcal mol -1 compared to those exhibited by other studied macrolide homologues. Reaction kinetic studies of conoidecyclic A coupled with lesser apparent V max inferred that it could efficiently bind with the allosteric site of targeted enzymes in a non-competitive manner to diminish the reaction velocity resulting in enzyme inhibition. Drug-likeness and predictive pharmacokinetic parameters of conoidecyclic A exhibited an acceptable oral bioavailability. These reports inferred that conoidecyclic A encompassing pentacosa macrocyclic moiety could be a promising therapeutic lead to inhibit the enzymes related to the development and progression of pathological conditions leading to inflammation, hypertension and type-2 diabetes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Naturally occurring polysaccharide-structured nanoparticles have developed as promising materials for treatment of bone health disorders. Silver nanoparticle (ST-Ag NP ) structured from sulfated polygalacto-fucopyranose comprising of recurring structural entities of 2-SO 3 -α-(1 → 3)-fucopyranose and 6-O-acetyl-β-(1 → 4)-galactopyranose isolated from marine macroalga Sargassum tenerrimum demonstrated potential activities associated with osteogenesis. Subsequent treatment with ST-Ag NP , activity of alkaline phosphatase (63 mU/mg) was raised in osteoblast stem cells (human mesenchymal, hMSC) than that in control (30 mU/mg). Intense growth of mineralized nodule on the surface of hMSC was apparent following treatment with ST-Ag NP . Increased population of bone morphogenic protein-2 (23%) and osteocalcin + cells (50%) on M2 macrophages were apparent following treatment with ST-Ag NP (0.25 mg/mL). Glucocorticoid-induced in vivo animal model studies of ST-Ag NP exhibited significant recovery of serum biochemical parameters along with serum estradiol and parathyroid hormone compared to disease control. Disease-induced groups treated with ST-Ag NP showed the disappearance of osteoporotic cavities in the trabecular bone. Following treatment with ST-Ag NP , serum calcium and phosphorus contents were significantly recovered., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The tumor suppressor proteins p53 and p27 exhibited a significant role in the survival of cells and regulation of cellular division and growth. In majority of the human tumors, particularly in hepatocellular carcinoma, these proteins are inactivated by mutation or deletion, and are considered to predict the pathophysiology related to liver cancer. The present study evaluated the activation of the p53 and p27 pathways as a useful therapeutic tool to attenuate hepatocellular carcinoma. Three undescribed homologous chromanone derivatives, hyrtiosones A-C were isolated from the organic extract of marine demosponge Hyrtios erectus (family Thorectidae). Preliminary bioactivity assessments found that hyrtiosone A exhibited prospective anti-inflammatory (IC 50  1.02-1.86 mM) and antioxidant (IC 50  0.74-0.83 mM) properties. Molecular docking analysis of the hyrtiosones using p53-murine double minute complex revealed lesser docking parameters for hyrtiosone A (binding energy -11.12 kcal mol -1 , docking score -12.18 kcal mol -1 ) thereby attributing its greater bioactivity. Hyrtiosone A was furthermore analyzed for in vitro anticancer activity in hepatocellular carcinoma HepG2 cells. Morphological assessment of hyrtiosone A treated HepG2 cell line by acridine orange/ethidium bromide fluorescence staining revealed greater number of apoptotic cells, and was found to be comparable with the cells treated with the standard doxorubicin. Further the Annexin V-fluorescein isothiocyanate assay of hyrtiosone A treated HepG2 cell line by flow cytometry displayed greater number of early apoptotic cells (51.24%) than that exhibited by the standard (21.45%). Cell cycle distribution analysis showed that hyrtiosone A arrested the S and G2/M phase of cell cycle and upregulate the gene expression of p53 and p27 in hepatocellular carcinoma HepG2 cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Nuclear factor-kappa B is an inducible transcription element, which was considered as an important regulator of immune functions, and plays a critical role to induce inflammatory reactions. In this study, we have demonstrated the anti-inflammatory potentials of previously undescribed (4 → 13)-abeo-euryfuranyls (1-2) from the spineless cuttlefish Sepiella inermis in lipopolysaccharide-stimulated macrophages. The euryfuranyl bearing (4 → 13)-abeo-euryfuranyl-2-ene-6-hydroxymethyl-propanoate framework (compound 1) displayed prominent inhibitory effects against pro-inflammatory cyclooxygenase-2 (IC 50 0.36 mM) and 5-lipoxygenase (IC 50 0.70 mM). Additionally, it suppressed the generation of inducible nitric oxide synthase along with cyclooxygenase-2 and 5-lipoxygenase in lipopolysaccharide-stimulated macrophages. The euryfuranyl analogue (1) down-regulated the mRNA expression of cyclooxygenase-2 and nuclear factor-κB signaling pathway in lipopolysaccharide-activated macrophage cells by hindering the degradation of inhibitor-κB proteins, and transfer of the subunit NF-κB p 65 to the nucleus from the cytosol. These results demonstrated that the euryfuranyl analogue could be explored as a promising anti-inflammatory therapeutic lead attenuating nuclear factor-κB signaling cascade., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Four biogenic β-sitosterol analogues were identified from methanolic extract of the leaves of loop-root mangrove Rhizophora mucronata. These were characterized as 4, 14, 23-trimethyl-3β-sitosterol (1), 7-ethyl-3β-sitosterol (2), sitosteryl-3β-(3 3 E)-pent-3 3 -enoate (3) and 12α-hydroxy-3β-sitosterol (4) based on comprehensive spectroscopic techniques. Anti-inflammatory activities of β-sitosterol 4 against pro-inflammatory enzymes 5-lipoxygenase and cyclooxygenase-2 were found to be significantly higher (IC 50 1.85 and 1.92 mM, respectively) compared to those demonstrated by compounds of 1-3 (p < 0.05). These β-sitosterol analogues disclosed superior selectivity indices (1.43-2.07) with regard to inducible cyclooxygenase-2 than its constitutive isoform cyclooxygenase-1, when compared to the standard, ibuprofen (0.44). Antioxidant properties of 12α-hydroxy-β-sitosterol (4) were found to be significantly greater (IC 50 1.43-1.67 mM) than those of other sitosterol analogues. Structure-activity correlation analyses put forward that the bioactive potencies of the titled β-sitosterols were positively correlated to their electronic parameters. Molecular docking simulations were carried out in the active sites of 5-lipoxygenase/cyclooxygenase-2, and the docking scores and binding energies of the studied β-sitosterol analogues were positively correlated with their attenuation properties against 5-lipoxygenase and cyclooxygenase-2., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Two pregnane-type of steroid derivatives characterized as 5α-pregna-3β-methyl pent-3-enoate-12β, 16β diol-20-one (clathroid A) and 12β,15β- dihydroxypregna-4,6-diene-3,20-dione (clathroid B) were purified from the crude extract of the marine sponge, Clathria (Thalysias) vulpina (family Microcionidae) by extensive chromatographic fractionation. Spectroscopic methods including nuclear magnetic resonance spectroscopy were employed to characterize the purified clathroids A-B. The studied compounds exhibited duel inhibitory potentials against pro-inflammatory cyclooxygenase-2 and 5-lipoxygenase (median inhibitory concentration, IC 50  < 1 mM), whereas the attenuation property of clathroid A against 5-lipoxygenase (IC 50 0.85 mM) was greater than the standard anti-inflammatory ibuprofen (IC 50 4.51 mM, p < 0.05). Greater selectivity index (anti cyclooxygense-2/anti cyclooxygense-1) of the studied clathroids (>1) than ibuprofen (0.43) attributed the greater selective attenuation properties towards pro-inflammatory inducible cyclooxygenase-2 than its constitutive isoenzyme cyclooxygenase-1. The antioxidant potentials of clathroid A against 2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (IC 50 0.80 mM) and diphenyl-1-picrylhydrazyl (IC 50 0.83 mM) free radicals were greater than those of clathroid B (IC 50 0.86-0.96 mM). Structure-activity analyses showed that the bioactivities of the clathroids were directly related to their electronic parameters coupled with permissible hydrophobic properties. Clathroid A exhibited grater electronic parameter (topological polar surface area tPSA, 83.83) than clathroid B (74.60) and ibuprofen (37.30), which were found to be in agreement with the prospective anti-inflammatory profile of clathroid A. Clathroid A exhibited higher number of hydrogen bonding interactions with 5-lipoxygenase active site and lesser docking values, such as docking score (DS -12.90 kcal mol -1 ) and inhibition constant (Ki 1.11 nM) than those recorded by clathroid B (DS -10.49 kcal mol -1 ; Ki 13.88 nM). The molecular binding properties of clathroid A with 5-lipoxidase inferred that its docking score/ binding energy were positively correlated with their in vitro bioactivie potentilas. A putative biosynthetic pathway of the studied clathroids was proposed from a pregnenolone precursor. The present study recognized the potential of clathroid A isolated from C. (Thalysias) vulpina as prospective anti-inflammatory lead that could find its use in medicinal applications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Consumption of marine alga-based polysaccharides as additional functional foods can endow with health benefits by diminishing the risk of chronic diseases. A polygalacto-fucopyranose characterized as [→1)-2, 4-SO 3 -α-Fucp-(3 → 1)-{2-SO 3 -α-Fucp-(3→}] with [(4 → 1)-6-OAc-β-Galp-(4→] side chain isolated from marine alga Sargassum wightii exhibited potential antihypertensive activity. Upon treatment with studied polygalactofucan (50 mg/kg BW), serum hypertension biomarkers troponin-T (1.3 pg/mL), troponin-I (1.2 μg/dL) and angiotensin-II converting enzyme (0.18 pg/mL) were significantly recovered in hypertensive rats compared to disease control. Serum cardiovascular risk indices of diseased rats were significantly decreased (< 10%, p < 0.05) after administration of the studied galactofucan (50 mg/kg BW) related to hypertension group (> 17%), and were comparable with standard antihypertensive agent telmisartan (8.3-10.2% at 2 mg/kg BW). The studied compound was safe for consumption as obvious from the high LD 50 value (>5 g/kg), and could be developed as a prospective functional food ingredient attenuating the pathophysiological attributes causing hypertension-related conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cyclooxygenase-2 has been recognized to catalyze the formation of inflammatory prostaglandins from arachidonic acid. Attenuation potential against cyclooxygenase-2 coupled with greater anti-inflammatory selectivity index were contemplated to be vital indicators to assess anti-inflammatory activities of bioactive compounds. In the present study, two undescribed fourteen-membered macrocyclic lactones, procerolide A and B were isolated to homogeneity from the organic extract of the marine sponge Clathria procera (family: Microcionidae). Procerolide B exhibited greater attenuation potential against cyclooxygenase-2 (IC 50 0.89 mM) than that displayed by procerolide A, whereas 5-lipoxygenase inhibitory activity of procerolide B (IC 50 1.08 mM) was significantly greater than that displayed by procerolide A (IC 50 0.95 mM) and anti-inflammatory agent ibuprofen (IC 50 4.50 mM). Additionally, greater anti-inflammatory selectivity index of the procerolides (~1.3) than the synthetic agent (0.43) was accounted for the selective inhibition of the compounds towards cyclooxygenase-2. Higher electronic properties (topological polar surface area of > 100) along with lesser steric properties (molar volume < 300 cm 3 ) of the compounds compared to the standard supported their significant anti-inflammatory potential. Additionally, procerolide B exhibited comparatively lesser binding energy with aminoacyl residues of cyclooxygenase-2 (-9.82 kcal/mol) thereby recognizing its prospective therapeutic use against inflammatory pathogenesis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Heterotrophic Gamma-proteobacterium Shewanella algae MTCC 12715, associated with an intertidal red algae Hypnea valentiae, presented broad-spectra of antibacterial activities against pathogenic bacteria bringing about nosocomial infection. Bioassay-guided fractionation of the bacterial crude extract resulted in two undescribed macrocyclic polyketide analogs, with anti-infective activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis (MIC 3.1-5.0 µg/mL). In order to identify the polyketide biosynthetic machinery termed type-I polyketide synthase (pks-I) encoding biologically active secondary metabolites in this strain, the ketosynthase-coding regions of DNA with ≈700 bp size, were amplified, and the partial sequence was submitted in the GenBank (accession number MH157093). The titled compounds were classified under macrocyclic polyketides bearing dodecahydropyrano-trioxacyclooctadecine-dione and trioxo-octadecahydro-1H-benzo[o]tetraoxacyclopentacosine-carboxylate functionalities. Structure-activity correlation analysis displayed that hydrophobic descriptor of the studied compounds could play a prominent role in its anti-infective property against the opportunistic pathogens. Further, in silico molecular docking studies were performed in the allosteric sites of penicillin-binding protein (PBP2a) coded by mecA genes of MRSA, and the best binding pose for each compound (docking score -8.47 kcal/mol and -9.58 kcal/mol, respectively) could be correlated with their in vitro antibacterial activities. The pks-I assisted biosynthetic pathway of macrocyclic polyketides through step-wise decarboxylative condensation initiated by malonate-acyl carrier protein corroborated their structural attributes. Chemical mining of the studied macroalgae-associated heterotrophic bacterium thus revealed the promising antagonistic properties of macrocyclic polyketides isolated from Shewanella algae MTCC 12715 against multidrug-resistant pathogens., (Copyright © 2020. Published by Elsevier Inc.)

Angiotensin converting enzyme (ACE) is a multifunctional enzyme involved in translation of angiotensin-I (Ang I ) to vasoconstrictor angiotensin-II (Ang II ). A sulfated N-acetylglucosamino-glucuronopyranosyl-arabinopyranan characterized as poly-[(2-methoxy-β-arabinopyranosyl)-(1 → 3)-(β-glucurono)-(1 → 4)-(2-acetamido-2-deoxy-3,6-di-O-sulfonato-β-glucopyranose)] was purified and reported first time from the edible portion of Amphioctopus neglectus and evaluated for various pharmacological properties. The polysaccharide exhibited potential ACE attenuation property (IC 50 0.11 mg mL -1 ), whereas molecular docking simulations displayed its efficient binding at the ACE active site with lesser inhibitory constant (K i ) of 17.36 nM and binding energy (-10.59 kcal mol -1 ). The in-vitro analysis showed that the studied polysacharide attenuated Ang II prompted cardiac hypertrophy at 50 μg mL -1 in the cardiomyoblast cells, whereas 48% reduction in cellular surface area with extended viability could be correlated with anti-hypertrophic properties of the studied polysaccharide. The sulfated N-acetylglucosamino-glucuronopyranosyl-arabinopyranan purified from A. neglectus could function as a prospective functional lead against the pathophysiological conditions leading to hypertension., Competing Interests: Declaration of competing interest No conflict of interest was reported by the authors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cyclooxygenase-2 is one of the prominent enzymes to cause an increased production of prostaglandins during inflammation and immune responses. Cyclooxygenase-2 expression is up-regulated in inflammatory conditions owing to the induction by different inflammatory stimuli including cytokines, and therefore, the expression studies of cyclooxygenase-2 in lipopolysaccharide-induced macrophage cells (RAW 264.7 cell line) could be used for screening of the compounds with anti-inflammatory potential. The present study evaluated the anti-inflammatory properties of four homologous stomopneulactones A-D, classified under the class of macrocyclic lactones isolated from the solvent extract of the long-spined sea urchin Stomopneustes variolaris (familyStomopneustidae) in the lipopolysaccharide-induced macrophages. The structures of these isolated compounds were assigned using detailed spectroscopic techniques. Stomopneulactone D bearing 5-butyl-4-hydroxy-12-oxo-1-oxa-5,9-cyclododecadienyl moiety exhibited relatively greater anti-inflammatory potentials against cyclooxygenase-2 (IC 50  ~ 2 mM) and 5-lipoxygenase (IC 50 2.6 mM) than those displayed by other macrocyclic lactones. The studied compounds displayed higher selectivity index values (anti-cyclooxygenase-1 IC50 /anti-cyclooxygenase-2 IC50  > 1), which designated the selective anti-inflammatory potentials of the macrocyclic lactones against inducible inflammatory mediators than those exhibited by the anti-inflammatory agent ibuprofen (0.43). The in silico molecular modelling analyses of the stomopneulactones with cyclooxygenase-2/5-lipoxygenase enzymes recorded lowest binding energy (-7.71 and -9.60 kcal mol -1 , respectively) and docking score (-8.82 and -11.12 kcal mol -1 , respectively) for stomopneulactone D along with its higher electronic parameter (topological polar surface area of 72.83), which further confirmed its greater anti-inflammatory potential than other compounds in the series. Stomopneulactone D also inhibited the generation of inducible nitric oxide synthase, intracellular reactive oxygen species, along with 5-lipoxygenase and cyclooxygenase-2 in the lipopolysaccharide-stimulated macrophage cells. Additionally, the studied macrocyclic lactone decreased the mRNA expression of cyclooxygenase-2 in the inflammatory cells in dose-dependent manner, which demonstrated the therapeutic potential of stomopneulactone D in down-regulating the inflammatory pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Three macrolides bearing the carbon framework of oxabicyclo[21.3.1]heptacosa-ene-diones (A and B) and oxabicyclo[19.3.1]pentacosa-ene-dione (C) were isolated and characterised from the organic extract of the intertidal red seaweed Gracilaria salicornia (family Gracilariaceae), which were named as salicornolides A-C. These natural macrolides were conformationally pre-organised ring structure providing diverse functionalities, and their potential bioactive properties led to the development of pharmacophores with anti-inflammatory properties. The 21-membered pyran-enclosed salicornolide B displayed greater cyclooxygenase-2 (IC 50 COX-2 1.13 mM) inhibitory activity than those exhibited by the 21-membered aryl salicornolide A and 19-membered salicornolide C (IC 50 COX-2-1.2 mM). The attenuating potential of the studied compounds against pro-inflammatory enzyme, 5-lipoxygenase (IC 50 LOX < 1.5 mM) was significantly greater than that displayed by the non-steroidal anti-inflammatory ibuprofen (IC 50 4.5 mM), whereas the selectivity indices exhibited by salicornolides against cyclooxygenase-2 was significantly higher (1.18-1.41, P < 0.05) when compared to that of ibuprofen (SI 0.43) attributing the greater selectivity profile of the former towards inducible pro-inflammatory mediators than the latter. The minimal binding energy of salicornolide B (-9.64 kcal mol -1 ), a greater number of hydrogen-bonds and lesser inhibitory constant (Ki 85.15 nM) might be responsible for effective binding towards 5-lipoxygenase, and that could attribute its greater anti-inflammation potential than those displayed by other compounds. The putative biosynthetic cascade initiated by malonate-acyl carrier protein unambiguously confirmed the structural attributions of the titled macrocyclic lactones. The undescribed salicornolides A-C from seaweed Gracilaria salicornia attenuating pro-inflammatory 5-lipoxygense might be considered as prospective natural anti-inflammatory leads for pharmaceutical applications., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A lactonic steroid with an unprecedented 1, 10: 8, 9-disecoergostane framework was identified from the ethyl acetate-methanol extract of buccinid gastropod mollusk, Babylonia spirata collected from the southwestern coast of Indian peninsular region. The compound was characterized as 1, 10: 8, 9-disecoergosta-8-en-A-homo-6a-oxa-1-one by exhaustive spectroscopic methods including two-dimensional nuclear magnetic resonance and mass spectroscopic investigations. The disecosteroid displayed moderate carbolytic enzyme inhibition activity as distinguished by its inhibitive effects against α-amylase and α-glucosidase (IC 50 0.40 and 0.54 mg/mL, respectively). The anti-inflammatory (5-lipoxidase inhibitory) activity of the titled secondary metabolite was found to be superior (IC 50  < 0.85 mg/mL) than the commercial anti-inflammatory drug (ibuprofen IC 50  > 0.85 mg/mL). However, significantly greater antioxidant property was recorded for the studied disecosteroid as evaluated by in vitro 2, 2-diphenyl-1-picrylhydrazyl radical inhibition potential (IC 50 0.30 mg/mL) than that of standard, α-tocopherol (IC 50  > 0.50 mg/mL). The in silico molecular docking studies were conducted to explain the anti-5-lipoxidase and anti-α-amylase properties of the isolated compound. The molecular binding interactions of the ligands with the pro-inflammatory 5-lipoxidase and the carbolytic enzyme α-amylase, demonstrated that their binding energies/docking scores were positively associated with their in vitro bioactivities. A plausible pathway for the biosynthetic origin of lactonic disecosteroid in B. spirata was proposed from an ergosterol precursor. Structure-activity correlation study demonstrated that the biological activities of the disecosteroid were directly proportional to their electronic properties allied with lesser steric restrictions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Two unusual △ 5 sterols with unprecedented skeletons were isolated from the organic extract of muricid gastropod Chicoreus ramosus collected off the Gulf of Mannar Coast. This is the first report of isolation of bioactive sterols endowed with anti-inflammatory potentials from this species. The compounds were characterized as (5Z)-24a-homo-cholesta-5,24a 1 (24a 2 ) dien-3β-ol (1) and 27(25 → 23)-abeo-(5Z)-3β-hydroxy-24-isopropyl cholesteno-26,23-lactone (2) by the interpretation of a series of spectroscopic techniques involving two-dimensional nuclear magnetic resonance and mass spectral data. The compound 1 is unusual in that it has an ethylene attachment stemming from the additional methylene group at the 24a position of the steroid side chain, whereas compound 2 has a unique side chain bearing a γ-valerolactone ring. The △ 5 sterol bearing ethylene group (1) displayed comparatively better antidiabetic activity as characterized by inhibitory effects towards α-amylase and α-glucosidase enzymes (IC 50 1.97 mM and 1.78 mM, respectively), whereas the cholestenolactone analogue (2) manifested higher anti-inflammatory activity (IC 50 1.42 mM) as determined by in vitro 5-lipoxygenase inhibitory potential. Structure-activity correlation study showed that the biological activities of the studied sterols were directly related to their electronic properties. The homosterol (1) exhibiting improved antidiabetic properties showed higher lipophilic character coupled with lesser steric restrictions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The estuarine Corbiculid bivalve black clam, Villorita cyprinoides collected from the Southwestern coastline regions of Arabian Sea are significant resources of nutritional and bioactive pluralities. The purification of ethyl acetate:methanol (EtOAc:MeOH) extract of V. cyprinoides characterized a previously undisclosed specialized abeo-pregnane-type sterol derivative 19 (10 → 5) abeo-20-methyl-pregn-10-en-3β-yl-hex-(3'E)-enoate (1) along with two cholestenols (22E),(24 1 E)-24 1 ,24 2 -dihomocholesta-5,22,24 1 -trien-3β-ol (2) and (22E)-24 1 -homocholesta-5,22-dien-(3β,24 1 β)-diol (3). These compounds were characterized by comprehensive spectroscopic investigations. The anti-inflammatory (anti-cyclooxygenase-1, 2/5-lipoxidase) activities of 1 were considerably higher (IC 50  < 1.10 mg/mL) than 2-3 (IC 50  > 1.10 mg/mL). These studied compounds registered greater selectivity indices (∼1.03) against cyclooxygenase-2 than cyclooxygenase-1. The antioxidant property of abeo-pregnane-type sterol as determined by in vitro 2,2'-azino-bis-(3-ethyl-benzthiazoline-6-sulfonic acid) quenching potential was significantly greater (IC 50 0.94 mg/mL) than those of substituted dihomocholesta-trien-ol (2) and homocholesta-dien-diol (3) (IC 50  > 1.00 mg/mL). Structure-activity relationship studies demonstrated that bioactive potentials of the titled compounds were linearly related to their electronic factors along with optimum hydrophobic factors. In addition, molecular docking studies were performed in the active sites of COX-2 and their binding energies and docking scores were well correlated with in vitro anti-COX-2 potentials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previously undescribed fridooleanene triterpenoids 2α-hydroxy-(28,29)-frido-olean-12(13), 21(22)-dien-20-propyl-21-hex-4'(Z)-enoate, 2α-hydroxy-(28,29)-frido-olean-12(13), 21(22)-dien-20-prop-2(E)-en-21-butanoate and oxygenated labdane diterpenoids 2α-hydroxy-8(17), (12E), 14-labdatriene, 3β, 6β, 13α-tri hydroxy 8(17), 12E, 14-labdatriene were purified from the ethyl acetate-methanol and dichloromethane fractions of the air-dried thalli of Sargassum wightii (Sargassaceae), a brown seaweed collected from the Gulf-of-Mannar of Penninsular India. Inhibitory potential of Δ 12 oleanenes towards protein tyrosine phosphatase-1B, the critical regulator of insulin-receptor activity were found to be significantly greater (IC 50 0.1 × 10 -2 and 0.09 × 10 -2  mg/mL, respectively) than the standard sodium metavanadate (IC 50 0.31 × 10 -2  mg/mL). Fridooleanene triterpenoids displayed greater antioxidant activities (IC 50DPPH 0.16-0.18 mg/mL) than the commercially available antioxidants, butylated hydroxytoluene and α-tocopherol (IC 50DPPH 0.25 and 0.63 mg/mL, respectively). In general, the oxygenated labdane diterpenoids displayed significantly lesser antioxidant and tyrosine phosphatase-1B inhibitory properties than those exhibited by the fridooleanenes. Bioactivities of the titled compounds were primarily determined by the electronic and lipophilic parameters and not by the steric descriptors. Molecular docking simulations and kinetic studies were employed to describe the tyrosine phosphatase-1B inhibitory mechanism. The previously undescribed fridooleanene triterpenoids might be used as potential anti-hyperglycaemic pharmacophore leads to reduce the risk of elevated postprandial glucose levels., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Brown seaweed Anthophycus longifolius (Turner) Kützing (family Sargassaceae) associated heterotrophic bacterium Bacillus subtilis MTCC 10403 was found to be a potent isolate with broad range of antibacterial activity against important perceptive food pathogens Vibrio parahaemolyticus, V. vulnificus, and Aeromonas hydrophila. This bacterium was positive for polyketide synthetase gene (KC589397), and therefore, was selected to bioprospect specialized metabolites bearing polyketide backbone. Bioactivity-guided chromatographic fractionation of the ethyl acetate extract of the seaweed-associated bacterium segregated four homologous polyketide furanoterpenoids with potential antibacterial activities against clinically important pathogens. The minimum inhibitory concentration (MIC) assay showed that the referral antibiotics tetracycline and ampicillin were active at 25 μg/mL against the test pathogens, whereas the previously undescribed (4E)-methyl 13-((16-(furan-2-yl) ethyl)-octahydro-7-hydroxy-4-((E)-23-methylbut-21-enyl)-2H-chromen-6-yl)-4-methylpent-4-enoate (compound 1) and methyl 3-(hexahydro-9-((E)-3-methylpent-1-enyl)-4H-furo[3,2-g]isochromen-6-yl) propanoate (compound 3) displayed antibacterial activities against the test pathogens at a lesser concentration (MIC < 7 μg/mL). The title compounds were characterized by comprehensive nuclear magnetic resonance and mass spectroscopic experiments. Polyketide synthase catalyzed putative biosynthetic mechanism additionally corroborated the structural ascriptions of the hitherto undescribed furanoterpenoids from seaweed-associated bacterial symbiont. The electronic and hydrophobic parameters appeared to hold a conspicuous part in directing the antibacterial properties of the compounds. Seaweed-associated B. subtilis MTCC 10403 demonstrated to represent a potential source of antimicrobial polyketides for pharmaceutical applications., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Two oleanenes, olean-18(19)-en-3β-yl-(3,6-dimethyl-3E,6Z-dienoate) and (13α)-27-frido-olean-14(15)-en-(17α)-furanyl-3β-ol representing a class of rare natural pentacyclic triterpenoids were isolated from the chloroform extract of Asiatic mangrove, Rhizophora mucronata Lam. (Family: Rhizophoraceae). The furanyl oleanene exhibited significantly greater antioxidative activities (IC 50 0.73-0.76 mg/mL), than prenylated oleanene (IC 50 0.84-0.96 mg/mL) (P < 0.05). No significant differences in anti-5-lipoxygenase activities of these compounds with the synthetic drug ibuprofen was discernable (IC 50 0.8-0.9 mg/mL), whilst furanyl oleanene demonstrated significantly greater anti-cyclooxygenase-2 (IC 50 0.84 mg/mL) and anti-5-lipoxygenase activities (IC 50 0.78 mg/mL) over prenylated oleanene (IC 50  > 0.90 mg/mL). These compounds exhibited lesser activity against cyclooxygenase-1 than cyclooxygenase-2 isoform, and therefore, their selectivity indices remained significantly greater (anti-cyclooxygenase-1 IC50 /anti-cyclooxygenase-2 IC50  > 1) than the aspirin (0.02) and ibuprofen (0.44). The lipophilic and steric molecular descriptors were found to occupy a prominent role in determining the bioactivities of the compounds. These previously undescribed oleanenes might serve as potential antioxidative and anti-inflammatory lead molecules in medicinal formulations and food industries., (Copyright © 2016 Elsevier Ltd. All rights reserved.)