Marine pharmacology in 2018: Marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action.

The 2018 marine pharmacology literature review represents a continuation of the previous 11 reviews of a series initiated in 1998. Preclinical marine pharmacology research during 2018 was performed by investigators in 44 countries and contributed novel pharmacology for 195 marine compounds. The peer-reviewed marine natural products pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 53 compounds, 73 compounds which presented antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 69 compounds were reported to show miscellaneous mechanisms of action which may contribute upon further investigation to several pharmacological classes. Thus, in 2018, the preclinical marine natural product pharmacology pipeline continued to report novel pharmacology as well as new lead compounds for the clinical marine pharmaceutical pipeline, which currently contributes to therapeutic strategies for several disease categories.

Lipopolysaccharide from the Cyanobacterium Geitlerinema sp. Induces Neutrophil Infiltration and Lung Inflammation.

Glucocorticoid-resistant asthma, which predominates with neutrophils instead of eosinophils, is an increasing health concern. One potential source for the induction of neutrophil-predominant asthma is aerosolized lipopolysaccharide (LPS). Cyanobacteria have recently caused significant tidal blooms, and aerosolized cyanobacterial LPS has been detected near the cyanobacterial overgrowth. We hypothesized that cyanobacterial LPS contributes to lung inflammation by increasing factors that promote lung inflammation and neutrophil recruitment. To test this hypothesis, c57Bl/6 mice were exposed intranasally to LPS from the cyanobacterium member, Geitlerinema sp., in vivo to assess neutrophil infiltration and the production of pro-inflammatory cytokines and chemokines from the bronchoalveolar fluid by ELISA. Additionally, we exposed the airway epithelial cell line, A549, to Geitlerinema sp. LPS in vitro to confirm that airway epithelial cells were stimulated by this LPS to increase cytokine production and the expression of the adhesion molecule, ICAM-1. Our data demonstrate that Geitlerinema sp. LPS induces lung neutrophil infiltration, the production of pro-inflammatory cytokines such as Interleukin (IL)-6, Tumor necrosis factor-alpha, and Interferongamma as well as the chemokines IL-8 and RANTES. Additionally, we demonstrate that Geitlerinema sp. LPS directly activates airway epithelial cells to produce pro-inflammatory cytokines and the adhesion molecule, Intercellular Adhesion Molecule-1 (ICAM-1), in vitro using the airway epithelial cell line, A549. Based on our findings that use Geitlerinema sp. LPS as a model system, the data indicate that cyanobacteria LPS may contribute to the development of glucocorticoid-resistant asthma seen near water sources that contain high levels of cyanobacteria.

RSK1 vs. RSK2 Inhibitory Activity of the Marine ß-Carboline Alkaloid Manzamine A: A Biochemical, Cervical Cancer Protein Expression, and Computational Study.

Manzamines are complex polycyclic marine-derived ß-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA's differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.

Marine Pharmacology in 2016-2017: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The review of the 2016-2017 marine pharmacology literature was prepared in a manner similar as the 10 prior reviews of this series. Preclinical marine pharmacology research during 2016-2017 assessed 313 marine compounds with novel pharmacology reported by a growing number of investigators from 54 countries. The peer-reviewed literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 123 marine natural products, 111 marine compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 79 marine compounds displayed miscellaneous mechanisms of action which upon further investigation may contribute to several pharmacological classes. Therefore, in 2016-2017, the preclinical marine natural product pharmacology pipeline generated both novel pharmacology as well as potentially new lead compounds for the growing clinical marine pharmaceutical pipeline, and thus sustained with its contributions the global research for novel and effective therapeutic strategies for multiple disease categories.

Classical and Alternative Activation of Rat Microglia Treated with Ultrapure Porphyromonas gingivalis Lipopolysaccharide In Vitro.

The possible relationship between periodontal disease resulting from the infection of gingival tissue by the Gram-negative bacterium Porphyromonas gingivalis (P. gingivalis) and the development of neuroinflammation remains under investigation. Recently, P. gingivalis lipopolysaccharide (LPS) was reported in the human brain, thus suggesting it might activate brain microglia, a cell type participating in neuroinflammation. We tested the hypothesis of whether in vitro exposure to ultrapure P. gingivalis LPS may result in classical and alternative activation phenotypes of rat microglia, with the concomitant release of cytokines and chemokines, as well as superoxide anion (O2-), thromboxane B2 (TXB2), and matrix metalloprotease-9 (MMP-9). After an 18-h exposure of microglia to P. gingivalis LPS, the concentration-dependent responses were the following: 0.1-100 ng/mL P. gingivalis LPS increased O2- generation, with reduced inflammatory mediator generation; 1000-10,000 ng/mL P. gingivalis LPS generated MMP-9, macrophage inflammatory protein 1α (MIP-1α/CCL3), macrophage inflammatory protein-2 (MIP-2/CXCL2) release and significant O2- generation; 100,000 ng/mL P. gingivalis LPS sustained O2- production, maintained MMP-9, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) release, and triggered elevated levels of MIP-1α/CCL3, MIP-2/CXCL2, and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL-1), with a very low release of lactic dehydrogenase (LDH). Although P. gingivalis LPS was less potent than Escherichia coli (E. coli) LPS in stimulating TXB2, MMP-9, IL-6 and interleukin 10 (IL-10) generation, we observed that it appeared more efficacious in enhancing the release of O2-, TNF-α, MIP-1α/CCL3, MIP-2/CXCL2 and CINC-1/CXCL-1. Our results provide support to our research hypothesis because an 18-h in vitro stimulation with ultrapure P. gingivalis LPS resulted in the classical and alternative activation of rat brain microglia and the concomitant release of cytokines and chemokines.

6-Deoxy- and 11-Hydroxytolypodiols: Meroterpenoids from the Cyanobacterium HT-58-2.

Chemical investigation of cyanobacterial strain HT-58-2, which most closely aligns with the genus Brasilomena, has led to the isolation of two compounds related to tolypodiol. The structures and absolute configuration of 6-deoxytolypodiol (1) and 11-hydroxytolypodiol (2) were elucidated by spectroscopic and spectrometric analysis. While tolypodiol previously showed anti-inflammatory activity in a mouse ear edema assay, only 2 reduced in vitro thromboxane B2 and superoxide anion (O2-) generation from Escherichia coli lipopolysaccharide-activated rat neonatal microglia to any appreciable degree.

Marine Pharmacology in 2014-2015: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, Antiviral, and Anthelmintic Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The systematic review of the marine pharmacology literature from 2014 to 2015 was completed in a manner consistent with the 1998-2013 reviews of this series. Research in marine pharmacology during 2014-2015, which was reported by investigators in 43 countries, described novel findings on the preclinical pharmacology of 301 marine compounds. These observations included antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral, and anthelmintic pharmacological activities for 133 marine natural products, 85 marine compounds with antidiabetic, and anti-inflammatory activities, as well as those that affected the immune and nervous system, and 83 marine compounds that displayed miscellaneous mechanisms of action, and may probably contribute to novel pharmacological classes upon further research. Thus, in 2014-2015, the preclinical marine natural product pharmacology pipeline provided novel pharmacology as well as new lead compounds for the clinical marine pharmaceutical pipeline, and thus continued to contribute to ongoing global research for alternative therapeutic approaches to many disease categories.

Biochemical and Functional Analysis of Cyanobacterium Geitlerinema sp. LPS on Human Monocytes.

Cyanobacterial blooms are an increasing source of environmental toxins that affect both human and animals. After ingestion of cyanobacteria, such as Geitlerinema sp., toxins and lipopolysaccharide (LPS) from this organism induce fever, gastrointestinal illness, and even death. However, little is known regarding the effects of cyanobacterial LPS on human monocytes after exposure to LPS upon ingestion. Based on our previous data using Geitlerinema sp. LPS (which was previously named Oscillatoria sp., a genus belonging to the same order as Geitlerinema), we hypothesized that Geitlerinema sp. LPS would activate human monocytes to proliferate, phagocytose particles, and produce cytokines that are critical for promoting proinflammatory responses in the gut. Our data demonstrate that Geitlerinema sp. LPS induced monocyte proliferation and TNF-α, IL-1, and IL-6 production at high concentrations. In contrast, Geitlerinema sp. LPS is equally capable of inducing monocyte-mediated phagocytosis of FITC-latex beads when compared with Escherichia coli LPS, which was used as a positive control for our experiments. In order to understand the mechanism responsible for the difference in efficacy between Geitlerinema sp. LPS and E. coli LPS, we performed biochemical analysis and identified that Geitlerinema sp. LPS was composed of significantly different sugars and fatty acid side chains in comparison to E. coli LPS. The lipid A portion of Geitlerinema sp. LPS contained longer fatty acid side chains, such as C15:0, C16:0, and C18:0, instead of C12:0 found in E. coli LPS which may explain the decreased efficacy and toxicity of Geitlerinema sp. LPS in comparison to E. coli LPS.

Cyanobacteria Scytonema javanicum and Scytonema ocellatum Lipopolysaccharides Elicit Release of Superoxide Anion, Matrix-Metalloproteinase-9, Cytokines and Chemokines by Rat Microglia In Vitro.

Cosmopolitan Gram-negative cyanobacteria may affect human and animal health by contaminating terrestrial, marine and freshwater environments with toxins, such as lipopolysaccharide (LPS). The cyanobacterial genus Scytonema (S) produces several toxins, but to our knowledge the bioactivity of genus Scytonema LPS has not been investigated. We recently reported that cyanobacterium Oscillatoria sp. LPS elicited classical and alternative activation of rat microglia in vitro. Thus, we hypothesized that treatment of brain microglia in vitro with either cyanobacteria S. javanicum or S. ocellatum LPS might stimulate classical and alternative activation with concomitant release of superoxide anion (O2-), matrix metalloproteinase-9 (MMP-9), cytokines and chemokines. Microglia were isolated from neonatal rats and treated in vitro with either S. javanicum LPS, S. ocellatum LPS, or E. coli LPS (positive control), in a concentration-dependent manner, for 18 h at 35.9 °C. We observed that treatment of microglia with either E. coli LPS, S. javanicum or S. ocellatum LPS generated statistically significant and concentration-dependent O2-, MMP-9 and pro-inflammatory cytokines IL-6 and TNF-α, pro-inflammatory chemokines MIP-2/CXCL-2, CINC-1/CXCL-1 and MIP-1α/CCL3, and the anti-inflammatory cytokine IL-10. Thus, our results provide experimental support for our working hypothesis because both S. javanicum and S. ocellatum LPS elicited classical and alternative activation of microglia and concomitant release of O2-, MMP-9, cytokines and chemokines in a concentration-dependent manner in vitro. To our knowledge this is the first report on the toxicity of cyanobacteria S. javanicum and S. ocellatum LPS to microglia, an immune cell type involved in neuroinflammation and neurotoxicity in the central nervous system.

Marine Pharmacology in 2012-2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The peer-reviewed marine pharmacology literature from 2012 to 2013 was systematically reviewed, consistent with the 1998-2011 reviews of this series. Marine pharmacology research from 2012 to 2013, conducted by scientists from 42 countries in addition to the United States, reported findings on the preclinical pharmacology of 257 marine compounds. The preclinical pharmacology of compounds isolated from marine organisms revealed antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral and anthelmitic pharmacological activities for 113 marine natural products. In addition, 75 marine compounds were reported to have antidiabetic and anti-inflammatory activities and affect the immune and nervous system. Finally, 69 marine compounds were shown to display miscellaneous mechanisms of action which could contribute to novel pharmacological classes. Thus, in 2012-2013, the preclinical marine natural product pharmacology pipeline provided novel pharmacology and lead compounds to the clinical marine pharmaceutical pipeline, and contributed significantly to potentially novel therapeutic approaches to several global disease categories.

Effects of cyanobacteria Oscillatoria sp. lipopolysaccharide on B cell activation and Toll-like receptor 4 signaling.

Cyanobacteria ("blue-green algae"), such as Oscillatoria sp., are a ubiquitous group of bacteria found in freshwater systems worldwide that are linked to illness and in some cases, death among humans and animals. Exposure to cyanobacteria occurs via ingestion of contaminated water or food-products. Exposure of the gut to these bacteria also exposes their toxins, such as lipopolysaccharide (LPS), to B cells in the gut associated lymphoid tissue. However, the effect of Oscillatoria sp. LPS on B cell activation is unknown. To test the hypothesis that Oscillatoria sp. LPS exposure to murine B cells would result in B cell activation, murine B cells were incubated in the absence or presence of Oscillatoria sp. LPS or E. coli LPS as a positive control. The data indicate that Oscillatoria sp. LPS induces B cells to proliferate, upregulate MHC II and CD86, enhance antigen uptake and induce IgM production at low levels. Additional studies demonstrate that this low level of stimulation may be due to incomplete TLR4 signaling induced by Oscillatoria sp. LPS, since IRF-3 is not induced in B cells after stimulation with Oscillatoria sp. LPS. These findings have important implications for the mechanisms of toxicity of cyanobacteria in both humans and animals.

Classical and Alternative Activation of Cyanobacterium Oscillatoria sp. Lipopolysaccharide-Treated Rat Microglia in vitro.

The purpose of this investigation was to test the hypothesis that an in vitro exposure to cyanobacterium Oscillatoria sp. Lipopolysaccharide (LPS) might result in classical and alternative activation of rat neonatal microglia. Using Escherichia coli LPS-primed microglia as a positive control, this study revealed that treatment of rat microglia with Oscillatoria sp. LPS for 17 h in vitro resulted in both classical and alternative activation as well as concomitant pro-inflammatory and anti-inflammatory mediator release, in a concentration-dependent manner: (1) treatment with 0.1-10 000 ng/ml Oscillatoria sp. LPS resulted in minimal lactic dehydrogenase (LDH) release, induced concentration-dependent and statistically significant O2 (-) generation, matrix metalloproteinase-9 (MMP-9) release, generation of the cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and the chemokines macrophage inflammatory protein-2 (MIP-2/CXCL2), interferon γ-induced protein 10 kDa (IP-10/CXCL-10), (MIP-1α/CCL3), monocyte chemotactic protein-1 (MCP-1/CCL2), regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), and the alternative activation cytokine IL-10; (3) in contrast, treatment with 100 000 ng/ml Oscillatoria sp. LPS appeared to damage the microglia cell membrane, because it resulted in minimal O2 (-) generation, statistically significant LDH release, and a decrease in the generation of all the cytokines and chemokines investigated, with the exception of IL-1α and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL1) generation, which was increased. Thus, our results provide experimental support for our working hypothesis, namely that Oscillatoria sp. LPS induces classical and alternative activation of rat brain microglia in vitro in a concentration-dependent manner, namely 0.1-10 000 ng/ml Oscillatoria sp. LPS, when microglia cells were shown to be viable. Furthermore, should cyanobacterium Oscillatoria sp. LPS gain entry into the CNS, our findings suggest that classical and alternative activation of rat brain microglia in vivo, might lead to concomitant mediator release that could result in an interplay between neuroinflammation and neural repair in a concentration-dependent manner.

Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold.

A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel α-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H37Rv and chloroquine-susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4-8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B2 (TXB2) and superoxide anion (O2(-)) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.

Vibrio vulnificus MO6-24/O lipopolysaccharide stimulates superoxide anion, thromboxane B2, matrix metalloproteinase-9, cytokine and chemokine release by rat brain microglia in vitro.

Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system's innate immunity remains undetermined. The purpose of this study was to determine whether V. vulnificus MO6-24/O LPS might activate rat microglia in vitro and stimulate the release of superoxide anion (O2⁻), a reactive oxygen species known to cause oxidative stress and neuronal injury in vivo. Brain microglia were isolated from neonatal rats, and then treated with either V. vulnificus MO6-24/O LPS or Escherichia coli O26:B6 LPS for 17 hours in vitro. O2⁻ was determined by cytochrome C reduction, and matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatinase zymography. Generation of cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), IL-6, and transforming growth factor-beta 1 (TGF-ß1), chemokines macrophage inflammatory protein (MIP-1α)/chemokine (C-C motif) ligand 3 (CCL3), MIP-2/chemokine (C-X-C motif) ligand 2 (CXCL2), monocyte chemotactic protein-1 (MCP-1)/CCL2, and cytokine-induced neutrophil chemoattractant-2alpha/beta (CINC-2α/ß)/CXCL3, and brain-derived neurotrophic factor (BDNF), were determined by specific immunoassays. Priming of rat microglia by V. vulnificus MO6-24/O LPS in vitro yielded a bell-shaped dose-response curve for PMA (phorbol 12-myristate 13-acetate)-stimulated O2⁻ generation: (1) 0.1-1 ng/mL V. vulnificus LPS enhanced O2⁻ generation significantly but with limited inflammatory mediator generation; (2) 10-100 ng/mL V. vulnificus LPS maximized O2⁻ generation with concomitant release of thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and several cytokines and chemokines; (3) 1000-100,000 ng/mL V. vulnificus LPS, with the exception of TXB2, yielded both attenuated O2⁻ production, and a progressive decrease in MMP-9, cytokines and chemokines investigated. Thus concentration-dependent treatment of neonatal brain microglia with V. vulnificus MO6-24/O LPS resulted in a significant rise in O2⁻ production, followed by a progressive decrease in O2⁻ release, with concomitant release of lactic dehydrogenase (LDH), and generation of TXB2, MMP-9, cytokines and chemokines. We hypothesize that the inflammatory mediators investigated may be cytotoxic to microglia in vitro, by an as yet undetermined autocrine mechanism. Although V. vulnificus LPS was less potent than E. coli LPS in vitro, inflammatory mediator release by the former was clearly more efficacious. Finally, we hypothesize that should V. vulnificus LPS gain entry into the CNS, it would be possible that microglia might become activated, resulting in high levels of O2⁻ as well as neuroinflammatory TXB2, MMP-9, cytokines and chemokines.

Dactyloditerpenol acetate, a new prenylbisabolane-type diterpene from Aplysia dactylomela with significant in vitro anti-neuroinflammatory activity.

A new regular diterpene possessing an unusual 1,6-anti-3-methylcyclohex-2-en-1-ol ring system, dactyloditerpenol acetate (1), has been extracted from the tropical sea hare Aplysia dactylomela and its stereostructure elucidated by spectroscopic methods. The absolute configuration of 1 was determined as 1S, 6S, 7R, 10S, and 11R by application of Kishi's method for the assignment of absolute configuration of alcohols. The new diterpene potently inhibited in vitro thromboxane B2 (TXB2) (IC50 0.4µM) and superoxide anion (O2(-)) (IC50 1µM) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.

Marine pharmacology in 2009-2011: marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action.

The peer-reviewed marine pharmacology literature from 2009 to 2011 is presented in this review, following the format used in the 1998-2008 reviews of this series. The pharmacology of structurally-characterized compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities were reported for 102 marine natural products. Additionally, 60 marine compounds were observed to affect the immune and nervous system as well as possess antidiabetic and anti-inflammatory effects. Finally, 68 marine metabolites were shown to interact with a variety of receptors and molecular targets, and thus will probably contribute to multiple pharmacological classes upon further mechanism of action studies. Marine pharmacology during 2009-2011 remained a global enterprise, with researchers from 35 countries, and the United States, contributing to the preclinical pharmacology of 262 marine compounds which are part of the preclinical pharmaceutical pipeline. Continued pharmacological research with marine natural products will contribute to enhance the marine pharmaceutical clinical pipeline, which in 2013 consisted of 17 marine natural products, analogs or derivatives targeting a limited number of disease categories.

Marine sponge Hymeniacidon sp. amphilectane metabolites potently inhibit rat brain microglia thromboxane B2 generation.

The effects of five Hymeniacidon sp. amphilectane metabolites (1-5) and two semi-synthetic analogs (6 and 7) on thromboxane B(2) (TXB(2)) and superoxide anion (O(2)(-)) generation from Escherichia coli LPS-activated rat brain microglia were investigated. All Hymeniacidon sp. metabolites and analogs potently inhibited TXB(2) (IC(50)=0.20-4.69µM) with low lactate dehydrogenase release and minimal mitochondrial dehydrogenase inhibition. While a lack of O(2)(-) inhibition would suggest that Hymeniacidon sp. metabolites and derivatives inhibit TXB(2) synthesis by a cyclooxygenase-dependent mechanism, their pharmacologic potency and limited in vitro cytotoxicity warrants further investigation to develop them as lead compounds to modulate enhanced TBX(2) release by activated microglia in neuroinflammatory disorders.

Cyanobacterial Microcystis aeruginosa lipopolysaccharide elicits release of superoxide anion, thromboxane B2, cytokines, chemokines, and matrix metalloproteinase-9 by rat microglia.

Microcystis aeruginosa (M. aeruginosa) is a cosmopolitan Gram-negative cyanobacterium that may contaminate freshwater by releasing toxins, such as lipopolysaccharide (LPS) during aquatic blooms, affecting environmental and human health. The putative toxic effects of cyanobacterial LPS on brain microglia, a glial cell type that constitutes the main leukocyte-dependent source of reactive oxygen species in the central nervous system, are presently unknown. We tested the hypothesis that in vitro concentration- and time-dependent exposure to M. aeruginosa LPS strain UTCC 299 would activate rat microglia and the concomitant generation of superoxide anion (O2⁻). After a 17-h exposure of microglia to M.aeruginosa LPS, the following concentration-dependent responses were observed: 0.1-100 ng/ml M. aeruginosa LPS enhanced O2⁻ generation, with limited inflammatory mediator generation; 1000-10,000 ng/ml M. aeruginosa LPS caused thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and macrophage inflammatory protein-2 (MIP-2/CXCL2) release, concurrent with maximal O2⁻ generation; 100,000 ng/mL M. aeruginosa LPS deactivated O2⁻ production but maintained elevated levels of TXB2, MMP-9, tumor necrosis factor-α (TNF-α), interleukin 1-α (IL-1α), and interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP-1α/CCL3), and MIP-2/CXCL2, with concomitant lactic dehydrogenase release. Although M. aeruginosa LPS was consistently less potent than Escherichia coli LPS, with the exception of O2⁻, TXB2, and MCP-1/CCL2 generation, it was more efficacious because higher levels of MMP-9, TNF-α, IL-1α, IL-6, MIP-1α/CCL3, and MIP-2/CXCL2 were produced. Our in vitro studies suggest that one or more of the inflammatory mediators released during M. aeruginosa LPS stimulation of microglia may play a critical role in the subsequent ability of microglia to generate O2⁻. To our knowledge, this is the first experimental evidence that LPS isolated from a M. aeruginosa strain, can activate brain microglia in vitro, as well as the release of O2⁻, and other inflammatory mediators hypothesized to be involved in neuroinflammation and neurodegeneration.

Marine pharmacology in 2007-8: Marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous system, and other miscellaneous mechanisms of action.

The peer-reviewed marine pharmacology literature in 2007-8 is covered in this review, which follows a similar format to the previous 1998-2006 reviews of this series. The preclinical pharmacology of structurally characterized marine compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 74 marine natural products. Additionally, 59 marine compounds were reported to affect the cardiovascular, immune and nervous systems as well as to possess anti-inflammatory effects. Finally, 65 marine metabolites were shown to bind to a variety of receptors and miscellaneous molecular targets, and thus upon further completion of mechanism of action studies, will contribute to several pharmacological classes. Marine pharmacology research during 2007-8 remained a global enterprise, with researchers from 26 countries, and the United States, contributing to the preclinical pharmacology of 197 marine compounds which are part of the preclinical marine pharmaceuticals pipeline. Sustained preclinical research with marine natural products demonstrating novel pharmacological activities, will probably result in the expansion of the current marine pharmaceutical clinical pipeline, which currently consists of 13 marine natural products, analogs or derivatives targeting a limited number of disease categories.