Search Results (11)

This study investigates the anti-inflammatory effects of the marine diterpene glycosides pseudopterosin A-D (PsA-D) in mitigating nickel sulfate (NiSO₄)-induced skin sensitization. In dermal dendritic cell (DDC) surrogates, PsA-D pre-treatment significantly reduced NiSO₄-induced upregulation of key activation surface markers, cluster of differentiation (CD)54 (~1.2-fold), and CD86 (~1.6-fold). Additionally, PsA-D inhibited the NiSO₄-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by suppressing inhibitor of kappa B alpha (IκBα) degradation. Furthermore, PsA-D suppressed inflammatory responses by inhibiting the NiSO₄-induced secretion of pro-inflammatory cytokines, including interleukin (IL)-8 (~6.8-fold), IL-6 (~2.2-fold), and IL-1β (~5.3-fold). In a full-thickness human skin model incorporating DDC surrogates, topical application of PsA-D effectively attenuated NiSO₄-induced mRNA expression of IL-8 (~2.1-fold), IL-6 (~2.6-fold), and IL-1β (~2.2-fold), along with the key inflammatory mediators cyclooxygenase-2 (COX-2) (~3.5-fold) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) (~2.1-fold). Overall, PsA-D demonstrated comparable efficacy to dexamethasone, a benchmark corticosteroid, providing a promising therapeutic alternative to corticosteroids for the treatment of skin sensitization and allergic contact dermatitis. However, to maximize PsA-D’s therapeutic potential, future studies on optimizing the bioavailability and formulation of PsA-D are required. Full article

A treasure trove of naturally occurring biomolecules can be obtained from sea living organisms to be used as potential antioxidant and anti-inflammatory agents. These bioactive molecules can target signaling molecules involved in the severity of chronic autoimmune diseases such as rheumatoid arthritis (RA). The intracellular tyrosine kinases family, Janus kinases (JAKs, includes JAK1, JAK2, and JAK3), is implicated in the pathogenesis of RA through regulating several cytokines and inflammatory processes. In the present study, we conducted molecular docking and structural analysis investigations to explore the role of a set of bioactive molecules from marine sources that can be used as JAKs’ specific inhibitors. Around 200 antioxidants and anti-inflammatory molecules out of thousands of marine molecules found at the Comprehensive Marine Natural Products Database (CMNPD) website, were used in that analysis. The details of the interacting residues were compared to the recent FDA approved inhibitors tofacitinib and baricitinib for data validation. The shortlisted critical amino acids residues of our pharmacophore-based virtual screening were LYS905, GLU957, LEU959, and ASP1003 at JAK1, GLU930 and LEU932 at JAK2, and GLU905 and CYS909 of JAK3. Interestingly, marine biomolecules such as Sargachromanol G, Isopseudopterosin E, Seco-Pseudopterosin, and CID 10071610 showed specific binding and significantly higher binding energy to JAK1 active/potential sites when being compared with the approved inhibitors. In addition, Zoanthoxanthin and Fuscoside E bind to JAK2′s critical residues, GLU930 and LEU932. Moreover, Phorbaketal and Fuscoside E appear to be potential candidates that can inhibit JAK3 activity. These results were validated using molecular dynamics simulation for the docked complexes, JAK1(6sm8)/SG, JAK2 (3jy9)/ZAX, and JAK3 (6pjc)/Fuscoside E, where stable and lower binding energy were found based on analyzing set of parameters, discussed below (videos are attached). A promising role of these marine bioactive molecules can be confirmed in prospective preclinical/clinical investigations using rheumatoid arthritis models. Full article

Biomolecules of marine origin have many applications in the field of biotechnology and medicine, but still hold great potential as bioactive substances against different diseases. The purification or total synthesis of marine metabolites is expensive, and requires a reliable selection method to reveal their pharmaceutical potential prior to clinical validation. This study aimed to explore the hidden potential of natural products from the gorgonian genus Antillogorgia as anti-SARS-CoV-2 agents, via binding affinity assessments and molecular dynamics (MDs) simulations. The three-dimensional protein structures of the nsp16–nsp10 complex, nsp13, and nsp14 were acquired from the RCSB PDB database. All 165 natural products (NPs) were discovered using the PubChem, ChemSpider, and CMNPD databases. The freeware Autodock Vina was used to conduct the molecular docking procedure, once the proteins and ligands were prepared using BIOVIA discovery studio and Avogadro software v1.95. Before running MDs simulations using the CABS-flex 2.0 website, the binding affinity assessments and amino acid interactions were carefully examined. Just twelve NPs were selected, and five of those NPs interacted optimally with the catalytic amino acids of proteins. To conclude, pseudopterosin A (−8.0 kcal/mol), seco-pseudopterosin A (−7.2 kcal/mol), sandresolide B (−6.2 kcal/mol), elisabatin A (−7.0 kcal/mol), and elisapterosin A (−10.7 kcal/mol) appeared to be the most promising candidates against the nsp16–nsp10, nsp13, and nsp14 proteins. Full article

Current therapies for treating pancreatic ductal adenocarcinoma (PDAC) are largely ineffective, with the desmoplastic environment established within these tumors being considered a central issue. We established a 3D spheroid co-culture in vitro model using a PDAC cell line (either PANC-1 or Capan-2), combined with stellate cells freshly isolated from pancreatic tumors (PSC) or hepatic lesions (HSC), and human type I collagen to analyze the efficiency of the chemotherapeutic gemcitabine (GEM) as well as two novel drug candidates derived from natural products: pseudopterosin (PsA-D) and O-methyltylophorinidine (TYLO). Traditional 2D in vitro testing of these agents for cytotoxicity on PANC-1 demonstrated IC₅₀ values of 4.6 (±0.47) nM, 34.02 (±1.35) µM, and 1.99 (±0.13) µM for Tylo, PsA-D, and GEM, respectively; these values were comparable for Capan-2: 5.58 (±1.74) nM, 33.94 (±1.02) µM, and 0.41 (±0.06) µM for Tylo, PsA-D, and GEM, respectively. Importantly, by assessing the extent of viable cells within 3D co-culture spheroids of PANC-1 with PSC or HSC, we could demonstrate a significant lack of efficacy for GEM, while TYLO remained active and PsA-D showed slightly reduced efficacy: GEM in PANC-1/PSC (IC₅₀ = >100 µM) or PANC-1/HSC (IC₅₀ = >100 µM) spheroids, TYLO in PANC-1/PSC (IC₅₀ = 3.57 ± 1.30 nM) or PANC-1/HSC (IC₅₀ = 6.39 ± 2.28 nM) spheroids, and to PsA-D in PANC-1/PSC (IC₅₀ = 54.42 ± 12.79 µM) or PANC-1/HSC (IC₅₀ = 51.75 ± 0.60 µM). Microscopic 3D rendering supported these cytotoxicity outcomes, showing little or no morphological spheroid structure change during this period of rapid cell death. Our results support the use of this 3D spheroid co-culture in vitro model having a desmoplastic microenvironment for the identification of possible novel chemotherapeutic drug candidates for PDAC, such as TYLO and PsA-D. Full article

Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities, including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple-negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as-yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that the antiproliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited the invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a coculture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, and the production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to a monoculture. Notably, pseudopterosin indicated to block cytokine elevation, representing key players in tumor progression in the coculture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy. Full article

Pseudopterosins are a group of marine diterpene glycosides which possess an array of biological activities including anti-inflammatory effects. However, despite the striking in vivo anti-inflammatory potential, the underlying in vitro molecular mode of action remains elusive. To date, few studies have examined pseudopterosin effects on cancer cells. However, to our knowledge, no studies have explored their ability to block cytokine release in breast cancer cells and the respective bidirectional communication with associated immune cells. The present work demonstrates that pseudopterosins have the ability to block the key inflammatory signaling pathway nuclear factor κB (NF-κB) by inhibiting the phosphorylation of p65 and IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor) in leukemia and in breast cancer cells, respectively. Blockade of NF-κB leads to subsequent reduction of the production of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and monocyte chemotactic protein 1 (MCP-1). Furthermore, pseudopterosin treatment reduces cytokine expression induced by conditioned media in both cell lines investigated. Interestingly, the presence of pseudopterosins induces a nuclear translocation of the glucocorticoid receptor. When knocking down the glucocorticoid receptor, the natural product loses the ability to block cytokine expression. Thus, we hypothesize that pseudopterosins inhibit NF-κB through activation of the glucocorticoid receptor in triple negative breast cancer. Full article

Natural products have provided an invaluable source of inspiration in the drug discovery pipeline. The oceans are a vast source of biological and chemical diversity. Recently, this untapped resource has been gaining attention in the search for novel structures and development of new classes of therapeutic agents. Pseudopterosins are group of marine diterpene glycosides that possess an array of potent biological activities in several therapeutic areas. Few studies have examined pseudopterosin effects during cellular stress and, to our knowledge, no studies have explored their ability to protect synaptic function. The present study probes pseudopterosin A (PsA) for its neuromodulatory properties during oxidative stress using the fruit fly, Drosophila melanogaster. We demonstrate that oxidative stress rapidly reduces neuronal activity, resulting in the loss of neurotransmission at a well-characterized invertebrate synapse. PsA mitigates this effect and promotes functional tolerance during oxidative stress by prolonging synaptic transmission in a mechanism that differs from scavenging activity. Furthermore, the distribution of PsA within mammalian biological tissues following single intravenous injection was investigated using a validated bioanalytical method. Comparable exposure of PsA in the mouse brain and plasma indicated good distribution of PsA in the brain, suggesting its potential as a novel neuromodulatory agent. Full article

Pseudopterosin A (PsA) treatment of growth factor depleted human umbilical vein endothelial cell (HUVEC) cultures formulated in hydroxypropyl-β-cyclodextrin (HPβCD) for 42 h unexpectedly produced a 25% increase in cell proliferation (EC₅₀ = 1.34 × 10⁻⁸ M). Analysis of dose response curves revealed pseudo-first order saturation kinetics, and the uncoupling of cytotoxicity from cell proliferation, thereby resulting in a widening of the therapeutic index. The formulation of PsA into HPβCD produced a 200-fold increase in potency over a DMSO formulation; we propose this could result from a constrained presentation of PsA to the receptor, which would limit non-specific binding. These results support the hypothesis that the non-specific receptor binding of PsA when formulated in DMSO has ostensibly masked prior estimates of specific activity, potency, and mechanism. Collectively, these results suggest that the formulation of PsA and compounds of similar chemical properties in HPβCD could result in significant pharmacological findings that may otherwise be obscured when using solvents such as DMSO. Full article

Pseudopterosins and pseudopteroxazole are intriguing marine natural products that possess notable antimicrobial activity with a commensurate lack of cytotoxicity. New semi-synthetic pseudopteroxazoles, pseudopteroquinoxalines and pseudopterosin congeners along with simple synthetic mimics of the terpene skeleton were synthesized. In order to build structure-activity relationships, a set of 29 new and previously reported compounds was assessed for in vitro antimicrobial and cytotoxic activities. A number of congeners exhibited antimicrobial activity against a range of Gram-positive bacteria including Mycobacterium tuberculosis H₃₇Rv, with four displaying notable antitubercular activity against both replicating and non-replicating persistent forms of M. tuberculosis. One new semi-synthetic compound, 21-((1H-imidazol-5-yl)methyl)-pseudopteroxazole (7a), was more potent than the natural products pseudopterosin and pseudopteroxazole and exhibited equipotent activity against both replicating and non-replicating persistent forms of M. tuberculosis with a near absence of in vitro cytotoxicity. Pseudopteroxazole also exhibited activity against strains of M. tuberculosis H₃₇Rv resistant to six clinically used antibiotics. Full article

To expand the potential of pseudopterosins and seco-pseudopterosins isolated from the octocoral Pseudopterogorgia elisabethae of San Andrés and Providencia islands (southwest Caribbean Sea), we report the anti-microbial profile against four pathogenic microorganisms (Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans) and report a more complete cytotoxic profile against five human cells lines (HeLa, PC-3, HCT116, MCF-7 and BJ) for the compounds PsG, PsP, PsQ, PsS, PsT, PsU, 3-O-acetyl-PsU, seco-PsJ, seco-PsK and IMNGD. For the cytotoxic profiles, all compounds evaluated showed moderate and non-selective activity against both tumor and normal cell lines, where PsQ and PsG were the most active compounds (GI₅₀ values between 5.8 µM to 12.0 µM). With respect to their anti-microbial activity the compounds showed good and selective activity against the Gram-positive bacteria, while they did not show activity against the Gram-negative bacterium or yeast. PsU, PsQ, PsS, seco-PsK and PsG were the most active compounds (IC₅₀ 2.9–4.5 µM) against S. aureus and PsG, PsU and seco-PsK showed good activity (IC₅₀ 3.1–3.8 µM) against E. faecalis, comparable to the reference drug vancomycin (4.2 µM). Full article

Putative precursors in pseudopterosin biosynthesis, the hydrocarbons isoelisabethatriene (10) and erogorgiaene (11), have been identified from an extract of Pseudopterogorgia elisabethae collected in the Florida Keys. Biosynthetic experiments designed to test the utilization of these compounds in pseudopterosin production revealed that erogorgiaene is transformed to pseudopterosins A-D. Together with our previous data, it is now apparent that early steps in pseudopterosin biosynthesis involve the cyclization of geranylgeranyl diphosphate to elisabethatriene followed by the dehydrogenation and aromatization to erogorgiaene. Full article