New fusidane-type nortriterpenoids from the Arctic marine-derived fungus Simplicillium lamellicola culture medium with their inhibitory effect on benign prostatic hyperplasia.

Three new fusidane-type nortriterpenoids, simplifusinolide A, 24-epi simplifusinolide A, and simplifusidic acid L (1-3), were isolated from the EtOAc extract of the Arctic marine-derived fungus Simplicillium lamellicola culture medium, together with fusidic acid (4) and 16-O-deacetylfusicid acid (5). The structures of the isolated compounds were elucidated by NMR and MS analyses. The absolute configurations of compounds 1-3 were established by the quantum mechanical calculations of electronic circular dichroism and gauge-including atomic orbital NMR chemical shifts, followed by DP4 + analysis. Benign prostatic hyperplasia (BPH) is a major urological disorder in men worldwide. The anti-BPH potentials of the isolated compounds were evaluated using BPH-1 and WPMY-1 cells. Treatment with simplifusidic acid L (3) and fusidic acid (4) significantly downregulated the mRNA levels of the androgen receptor (AR) and its downstream effectors, inhibiting the proliferation of BPH-1 cells. Specifically, treatment with 24-epi simplifusinolide A (2) significantly suppressed the cell proliferation of both BPH-1 and DHT-stimulated WPMY-1 cells by inhibiting AR signaling. These results suggest the potential of 24-epi simplifusinolide A (2), simplifusidic acid L (3) and fusidic acid (4) as alternative agents for BPH treatment by targeting AR signaling.

Functional production, characterization, and immobilization of a cold-adapted cutinase from Antarctic Rhodococcus sp.

A lipolytic enzyme (Rcut) was discovered from the Rhodococcusstrain (RosL12) isolated from the Antarctic Ross Sea. The corresponding gene composed of 651 bases encoding 216 amino acids. It was found to be a cutinase gene through BLAST search. Rcut has a signal sequence consisting of 29 amino acids. An active Rcut was produced after the intact gene containing the signal sequence was transformed into Escherichia coli Rosetta-gami™ 2 (DE3) pLysS. Rcut was purified through a nickel-nitrilotriacetic acid purification system and a carboxymethyl Sepharose column chromatography. Its specific activity was 2190 U/mg. Rcut showed the highest activity at 40 °C and had a low activation energy of 3.16 kcal/mol. This means that it is a typical cold-adapted enzyme. Rcut showed high activity towards medium chain fatty acids (C4-C10). Rcut degraded polycaprolactone and polyethylene terephthalate, suggesting that it could be used for decomposition of synthetic plastics causing environmental pollution. Rcut was immobilized on methacrylate-divinyl benzene bead. This immobilized Rcut (immRcut) showed higher thermal stability than the free enzyme. ImmRcut performed transesterification of various esters and ethanol in a non-polar solvent, suggesting that it could be used for the synthesis of industrially useful ester compounds.

Citromycin Isolated from the Antarctic Marine-Derived Fungi, Sporothrix sp., Inhibits Ovarian Cancer Cell Invasion via Suppression of ERK Signaling.

Recently, microorganisms and their metabolites in the Antarctic marine environment have attracted attention as useful sources for novel therapeutics, including anticancer drugs. Here, we investigated the effects of citromycin, isolated from the Antarctic marine-derived fungus, Sporothrix sp., on human ovarian cancer cells. Citromycin inhibited the migration and invasion of human ovarian cancer SKOV3 and A2780 cells, but had no cytotoxic activity against them. Additionally, it inhibited the expression of epithelial-mesenchymal transition (EMT) markers and the activation of matrix metalloproteinase (MMP)-2 and MMP9. Moreover, extracellular signal-regulated kinase (ERK)-1/2 signaling was inhibited after citromycin treatment, and the ectopic expression of ERK negated the anti-invasive activity of citromycin. Our findings suggest that citromycin inhibits the migration and invasion of human ovarian cancer cells by downregulating the expression levels of EMT markers and MMP-2/9 via inhibition of the ERK1/2 pathway.

Anti-Inflammatory Effects Exerted by 14-Methoxyalternate C from Antarctic Fungal Strain Pleosporales sp. SF-7343 via the Regulation of NF-κB and JAK2/STAT3 in HaCaT Human Keratinocytes.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a profound negative impact on patients' quality of life. Four known secondary fungal metabolites were found in the chemical study of the Antarctic fungus Pleosporales sp. SF-7343, including 14-methoxyalternate C (1), 5'-methoxy-6-methyl-biphenyl-3,4,3'-triol (2), 3,8,10-trihydroxy-4-methoxy-6-methylbenzocoumarin (3), and alternariol monomethyl ether (4). Additionally, we identified the skin anti-inflammatory composition from the SF-7343 strain. Interleukin-8 and -6 Screening results showed that compound 1 inhibited IL-8 and IL-6 in tumor necrosis factor-α/interferon-γ stimulated HaCaT cells. Compound 1 showed inhibitory effects on MDC and RANTES. It also downregulated the expression of intercellular adhesion molecule-1 (ICAM-1) and upregulated the expression of involucrin. The results of the mechanistic study showed that compound 1 inhibited the nuclear translocation of nuclear factor-kappa B p65 and STAT3. In conclusion, this study demonstrates the potential of the Antarctic fungal strain SF-7343 as a bioactive resource to inhibit skin inflammation, such as AD.

Identification of Potential Anti-Neuroinflammatory Inhibitors from Antarctic Fungal Strain Aspergillus sp. SF-7402 via Regulating the NF-κB Signaling Pathway in Microglia.

Microglia play a significant role in immune defense and tissue repair in the central nervous system (CNS). Microglial activation and the resulting neuroinflammation play a key role in the pathogenesis of neurodegenerative disorders. Recently, inflammation reduction strategies in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the anti-neuroinflammatory potential of compounds from the Antarctic fungi strain Aspergillus sp. SF-7402 in lipopolysaccharide (LPS)-stimulated BV2 cells. Four metabolites were isolated from the fungi through chemical investigations, namely, 5-methoxysterigmatocystin (1), sterigmatocystin (2), aversin (3), and 6,8-O-dimethylversicolorin A (4). Their chemical structures were elucidated by extensive spectroscopic analysis and HR-ESI-MS, as well as by comparison with those reported in literature. Anti-neuroinflammatory effects of the isolated metabolites were evaluated by measuring the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in LPS-activated microglia at non-cytotoxic concentrations. Sterigmatocystins (1 and 2) displayed significant effects on NO production and mild effects on TNF-α and IL-6 expression inhibition. The molecular mechanisms underlying this activity were investigated using Western blot analysis. Sterigmatocystin treatment inhibited NO production via downregulation of inducible nitric oxide synthase (iNOS) expression in LPS-stimulated BV2 cells. Additionally, sterigmatocystins reduced nuclear translocation of NF-κB. These results suggest that sterigmatocystins present in the fungal strain Aspergillus sp. are promising candidates for the treatment of neuroinflammatory diseases.

Anti-inflammatory spiroditerpenoids from Penicillium bialowiezense.

Inflammation is a vital process that maintains tissue homeostasis. However, it is widely known that uncontrolled inflammation can contribute to the development of various diseases. This study aimed to discover anti-inflammatory metabolites from Penicillium bialowiezense. Seven spiroditerpenoids, including two new compounds, breviones P and Q (1 and 2), were isolated and characterized by various spectroscopic and spectrometric methods. All isolated compounds were initially tested for their inhibitory effects against lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 macrophages. Of these, brevione A (3) exhibited this activity with a half-maximal inhibitory concentration value of 9.5 µM. Further mechanistic studies demonstrated that 3 could suppress the expression of pro-inflammatory cytokines and mediators, such as NO, prostaglandin E2, interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-12 by inhibiting the activation of nuclear factor-kappa B and c-Jun N-terminal kinase.

Chemical constituents from basidiomycete Basidioradulum radula culture medium and their cytotoxic effect on human prostate cancer DU-145 cells.

Eight new naphtho[1,2-c]furan derivatives (1-8) along with six known analogues (9-14) were isolated from culture medium of the basidiomycete Basidioradulum radula. The structures of these compounds were identified using spectroscopic analysis, and their absolute configurations were resolved using X-ray diffraction, ECD, and VCD. Compounds 7 and 14 inhibited the cell viability of human prostate cancer DU-145 cells with IC50 values of 7.54 ± 0.03 µM and 5.04 ± 0.03 µM, respectively. At 8 µM, compounds 7 and 14 increased the percentage of apoptotic cells and upregulated the protein expression related to the apoptosis caspase pathways in DU-145 cells. Furthermore, the hallmarks of cells undergoing apoptosis, such as chromatin condensation, were also observed at this concentration. However, compound 7 and 14 showed no effect on the proliferation of splenocytes isolated from cyclophosphamide-induce immunosuppressed mice.

Anti-Inflammatory Effects of Metabolites from Antarctic Fungal Strain Pleosporales sp. SF-7343 in HaCaT Human Keratinocytes.

Chemical investigation of the Antarctic fungi Pleosporales sp. SF-7343 revealed four known secondary fungal metabolites: alternate C (1), altenusin (2), alternariol (3), and altenuene (4). The compound structures were identified primarily by NMR and MS analyses. Atopic dermatitis, an inflammatory disease, is driven by the abnormal activation of T helper (Th) 2 cells and barrier dysfunction. We attempted to identify the anti-inflammatory components of SF-7343. Initial screening showed that compounds 1 and 3 inhibited the secretion of interleukin-8 and -6 in tumor necrosis factor-α/interferon-γ-treated HaCaT cells, and these compounds also showed inhibitory effects on CCL5 and CCL22. Compounds 1 and 3 also downregulated the protein expression levels of intercellular adhesion molecule-1 and upregulated the expression of filaggrin and involcurin. The mechanism study results showed that compounds 1 and 3 inhibited nuclear translocation of nuclear factor-kappa B p65 and the phosphorylation of STAT1 and STAT3. Compound 1, but not compound 3, significantly promoted the expression of heme oxygenase (HO)-1. The effects of compound 1 were partly reversed by co-treatment with a HO-1 inhibitor, tin protoporphyrin IX. Taken together, this study demonstrates the potential value of Antarctic fungal strain SF-7343 isolates as a bioresource for bioactive compounds to prevent skin inflammation.

Potential of Ramalin and Its Derivatives for the Treatment of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is still unclear, and presently there is no cure for the disease that can be used for its treatment or to stop its progression. Here, we investigated the therapeutic potential of ramalin (isolated from the Antarctic lichen, Ramalina terebrata), which exhibits various physiological activities, in AD. Specifically, derivatives were synthesized based on the structure of ramalin, which has a strong antioxidant effect, BACE-1 inhibition activity, and anti-inflammatory effects. Therefore, ramalin and its derivatives exhibit activity against multiple targets associated with AD and can serve as potential therapeutic agents for the disease.

PTP1B Inhibitory Secondary Metabolites from an Antarctic Fungal Strain Acremonium sp. SF-7394.

Chemical investigation of the Antarctic lichen-derived fungal strain Acremonium sp. SF-7394 yielded a new amphilectane-type diterpene, acrepseudoterin (1), and a new acorane-type sesquiterpene glycoside, isocordycepoloside A (2). In addition, three known fungal metabolites, (-)-ternatin (3), [D-Leu]-ternatin (4), and pseurotin A (5), were isolated from the EtOAc extract of the fungal strain. Their structures were mainly elucidated by analyzing their NMR and MS data. The absolute configuration of 1 was proposed by electronic circular dichroism calculations, and the absolute configuration of the sugar unit in 2 was determined by a chemical method. The inhibitory effects of the isolated compounds on protein tyrosine phosphatase 1B (PTP1B) were evaluated by enzymatic assays; results indicated that acrepseudoterin (1) and [D-Leu]-ternatin (4) dose-dependently inhibited the enzyme activity with IC50 values of 22.8 ± 1.1 µM and 14.8 ± 0.3 µM, respectively. Moreover, compound 1 was identified as a competitive inhibitor of PTP1B.

Anti-inflammatory effects of methanol extracts from the Antarctic lichen, Amandinea sp. in LPS-stimulated raw 264.7 macrophages and zebrafish.

The aim of the present study was to determine the anti-inflammatory effect of an extracts isolated from the lichen. Amandinea sp. was collected from the Antarctic and extracted with methanol. The basic screening of the anti-inflammatory property of the extracts was done using the NO assay. The extracts showed very little cytotoxicity, and reduced NO production in LPS-stimulated RAW 264.7 cells in a dose-dependent manner. Furthermore, the extracts inhibited LPS-induced release of pro-inflammatory cytokines such as interleukin-6 (IL-6), and tumor necrosis factor-α(TNF-α), and inflammatory mediators inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). The extracts also reduced the cytosolic p-IκB-α level and the level of the nuclear factor p65. We examined the anti-inflammatory effects of the extracts using zebrafish in vivo. The extracts reduced the amount of reactive oxygen species (ROS) in LPS-induced zebrafish larvae and inhibited the mRNA expression of inflammatory cytokines and mediators in a tail-cutting induced model. These results are similar to those obtained in vitro with RAW 264.7 cells. Collectively, the data suggest that the extracts may contain one of more compounds with anti-inflammatory effects. Further studies are required to identify the candidate compound/s and to understand the mechanism of action of the extract.

Terrein suppressed lipopolysaccharide-induced neuroinflammation through inhibition of NF-κB pathway by activating Nrf2/HO-1 signaling in BV2 and primary microglial cells.

In the course of our continuous investigation on the bioactive marine-derived fungal metabolites, terrein was isolated from marine-derived fungal strain Penicillium sp. SF-7181. Terrein inhibited the overproduction of pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated BV2 and primary microglial cells. This compound also repressed the LPS-induced production of pro-inflammatory cytokines, interleukin (IL)-1ß and IL-6. These inhibitory effects of terrein were associated with the inactivation of the nuclear factor kappa B (NF-κB) pathway through suppression of the translocation of p65/p50 heterodimer into the nucleus, the phosphorylation and degradation of inhibitor kappa B (IκB)-α and the DNA binding activity of the p65 subunit. In addition, terrein induced the protein expression of heme oxygenase (HO)-1 through the activation of nuclear transcription factor erythroid-2 related factor 2 (Nrf2) in BV2 and primary microglial cells. The anti-inflammatory effect of terrein was blocked by pre-treatment with a selective HO-1 inhibitor, suggesting that its anti-neuroinflammatory effect is mediated by HO-1 induction.

Anti-Inflammatory and Protein Tyrosine Phosphatase 1B Inhibitory Metabolites from the Antarctic Marine-Derived Fungal Strain Penicillium glabrum SF-7123.

A chemical investigation of the marine-derived fungal strain Penicillium glabrum (SF-7123) revealed a new citromycetin (polyketide) derivative (1) and four known secondary fungal metabolites, i.e, neuchromenin (2), asterric acid (3), myxotrichin C (4), and deoxyfunicone (5). The structures of these metabolites were identified primarily by extensive analysis of their spectroscopic data, including NMR and MS data. Results from the initial screening of anti-inflammatory effects showed that 2, 4, and 5 possessed inhibitory activity against the excessive production of nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated BV2 microglial cells, with IC50 values of 2.7 µM, 28.1 µM, and 10.6 µM, respectively. Compounds 2, 4, and 5 also inhibited the excessive production of NO, with IC50 values of 4.7 µM, 41.5 µM, and 40.1 µM, respectively, in LPS-stimulated RAW264.7 macrophage cells. In addition, these compounds inhibited LPS-induced overproduction of prostaglandin E2 in both cellular models. Further investigation of the most active compound (2) revealed that these anti-inflammatory effects were associated with a suppressive effect on the over-expression of inducible nitric oxide synthase and cyclooxygenase-2. Finally, we showed that the anti-inflammatory effects of compound 2 were mediated via the downregulation of inflammation-related pathways such as those dependent on nuclear factor kappa B and p38 mitogen-activated protein kinase in LPS-stimulated BV2 and RAW264.7 cells. In the evaluation of the inhibitory effects of the isolated compounds on protein tyrosine phosphate 1B (PTP1B) activity, compound 4 was identified as a noncompetitive inhibitor of PTP1B, with an IC50 value of 19.2 µM, and compound 5 was shown to inhibit the activity of PTP1B, with an IC50 value of 24.3 µM, by binding to the active site of the enzyme. Taken together, this study demonstrates the potential value of marine-derived fungal isolates as a bioresource for bioactive compounds.

Anti-Inflammatory Activity of Lobaric Acid via Suppressing NF-κB/MAPK Pathways or NLRP3 Inflammasome Activation.

Lobaric acid (LA) is a constituent of the lichen Stereocaulon alpinum. LA has multiple biological activities, including antibacterial and antioxidant ones. The purpose of this study was to investigate the effect of LA and its mechanism on lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Macrophages were pretreated with different concentrations of LA (0.2 - 20 µM), followed by LPS stimulation. LA treatment of LPS stimulated macrophages decreased their nitric oxide production and the expression of cyclooxygenase-2 and prostaglandin E2. LA also significantly reduced the production of tumor necrosis factor-α and interleukin (IL)-6 by inhibiting the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). Additionally, LA inhibited the production of IL-1ß and IL-18, as well as caspase-1 maturation, by inhibition of NLRP3 inflammasome activation in LPS/ATP-stimulated cells. These results strongly suggest that LA could inhibit inflammation by downregulating NF-κB/MAPK pathways and NLRP3 inflammasome activation in activated macrophages. These results reveal a new therapeutic approach to modulate inflammatory diseases linked to deregulated inflammasome activities.

Anti-inflammatory effect of 3,7-dimethyl-1,8-hydroxy-6-methoxyisochroman via nuclear factor erythroid 2-like 2-mediated heme oxygenase-1 expression in lipopolysaccharide-stimulated RAW264.7 and BV2 cells.

Objective: The isochroman-type fungal metabolite 3,7-dimethyl-1,8-hydroxy-6-methoxyisochroman (DMHM) was isolated from the extracts of a marine-derived fungal strain of Penicillium sp. SF-6013. In this study, we investigated the effect of DMHM on inflammatory response. Materials and methods: Anti-inflammatory effects of DMHM were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, qRT-PCR, and western blot analysis. Results: DMHM revealed that it suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) in LPS-stimulated RAW264.7 and BV2 cells. Furthermore, DMHM decreased the mRNA expression of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-6. Therefore, DMHM was further investigated to elucidate the mechanisms of its anti-inflammatory properties; the results indicated that its effect was mediated by the suppression of the nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK) MAPK pathways. Furthermore, the anti-inflammatory activity of DMHM correlated with its induction of heme oxygenase-1 (HO)-1 expression via activation of the nuclear factor erythroid 2-like 2 (Nrf2) pathway. Discussion and conclusions: Collectively, the results of this study suggest that DMHM inhibited several inflammatory pathways including the NF-κB and MAPK pathways, and induced Nrf2-mediated HO-1 expression, demonstrating its potential usefulness for treating inflammatory and neuroinflammatory diseases.

Ramalin, an antioxidant compound derived from Antarctic lichen, prevents progression of liver fibrosis induced by dimethylnitrosamine (DNM) in rats.

Hepatic fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), primarily collagen, within the liver. Because reactive oxygen species (ROS) has been implicated in its pathogenesis, the use of antioxidants as a potential treatment has been broadly explored. Here, we investigated the hepatoprotective properties of ramalin (RM), a compound extracted from the Antarctic lichen Ramalina terebrata, against hepatic fibrosis in vitro and in vivo. RM suppressed hepatic stellate cell (HSC) activation in vitro without any significant signs of adverse effects on the cells tested, and the accumulation of ECM was dramatically reduced in the liver tissue. Oral administration of RM in rats noticeably improved the gross appearance of the liver with increased body and liver weight relative to the DMN injected rats, and all of the serum biochemical markers returned to the normal range. RM treatment have ameliorated hepatic fibrosis in rats induced by DMN by repressing α-smooth muscle actin (α-SMA) and upregulating heme oxygenase-1 (HO-1). In addition, RM significantly reduced collagen accumulation, and levels of malondialdehyde (MDA) and hydroxyproline (HP) in the liver tissue of DMN injected rats. The efficacy exerted by RM was through erythroid 2-related factor 2 (Nrf2) mediated antioxidant response proteins such as HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO-1). Our results show the beneficial effect of RM against the progression of hepatic fibrosis.

Islandinium minutum subsp. barbatum subsp. nov. (Dinoflagellata), a New Organic-Walled Dinoflagellate Cyst from the Western Arctic: Morphology, Phylogenetic Position Based on SSU rDNA and LSU rDNA, and Distribution.

A study of modern sediment from the Western Arctic has revealed the presence of a distinctive brown-colored cyst with a spherical central body bearing unbranched processes that are usually solid with a small basal pericoel. Distinctive barbs project from some processes, and process tips are usually minutely expanded into conjoined barbs. The archeopyle is apical and saphopylic. This cyst corresponds to Islandinium? cezare morphotype 2 of Head et al. (2001, J. Quat. Sci., 16:621). Phylogenetic analyses based on the small and large subunit rRNA genes infer close relationship with Islandinium minutum, the type of which is that of the genus. Re-examination of specimens of I. minutum reveals the presence of minute barbs on its processes, but differences with Islandinium? cezare morphotype 2 remain based on size, process distribution, and barb development. Furthermore, the internal transcribed spacer shows I. minutum to be distinct from this morphotype. On the basis of these small but discrete differences, we propose the new subspecies Islandinium minutum subsp. barbatum subsp. nov. Molecular sequencing of other cysts encountered, namely Echinidinium karaense, an unidentified flattened cyst, and "Polykrikos quadratus", places them in the Monovela clade, the latter showing greater morphological variability than previously thought.

Total Syntheses of Lobaric Acid and Its Derivatives from the Antarctic Lichen Stereocaulon alpinum.

The first total syntheses of the natural products lobaric acid (1) and its derivatives isolated from the Antarctic lichen Stereocaulon alpinum are reported in this study. Lobarin (3), with a pseudodepsidone structure, was synthesized first in 11 steps by utilizing an Ullmann aryl ether coupling reaction, and lobaric acid was synthesized in an additional three steps by a seven-membered lactonization reaction. Various derivatives were also obtained from the prepared lobaric acid, and the synthetic compounds exhibited significant PTP1B inhibitory activities.

Anti-Cancer Activity of Lobaric Acid and Lobarstin Extracted from the Antarctic Lichen Stereocaulon alpnum.

Lobaric acid and lobarstin, secondary metabolites derived from the antarctic lichen Stereocaulon alpnum, exert various biological activities, including antitumor, anti-proliferation, anti-inflammation, and antioxidant activities. However, the underlying mechanisms of these effects have not yet been elucidated in human cervix adenocarcinoma and human colon carcinoma. In the present study, we evaluated the anticancer effects of lobaric acid and lobarstin on human cervix adenocarcinoma HeLa cells and colon carcinoma HCT116 cells. We show that the proliferation of Hela and HCT116 cells treated with lobaric acid and lobarstin significantly decreased in a dose- and time-dependent manner. Using flow cytometry analysis, we observed that the treatment with these compounds resulted in significant apoptosis in both cell lines, following cell cycle perturbation and arrest in G2/M phase. Furthermore, using immunoblot analysis, we investigated the expression of cell cycle and apoptosis-related marker genes and found a significant downregulation of the apoptosis regulator B-cell lymphoma 2 (Bcl-2) and upregulation of the cleaved form of the poly (ADP-ribose) polymerase (PARP), a DNA repair and apoptosis regulator. These results suggest that lobaric acid and lobarstin could significantly inhibit cell proliferation through cell cycle arrest and induction of apoptosis via the mitochondrial apoptotic pathway in cervix adenocarcinoma and colon carcinoma cells. Taken together, our data suggests that lobaric acid and lobarstin might be novel agents for clinical treatment of cervix adenocarcinoma and colon carcinoma.

Anti-Inflammatory Effects of Curvularin-Type Metabolites from a Marine-Derived Fungal Strain Penicillium sp. SF-5859 in Lipopolysaccharide-Induced RAW264.7 Macrophages.

Chemical study on the extract of a marine-derived fungal strain Penicillium sp. SF-5859 yielded a new curvularin derivative (1), along with eight known curvularin-type polyketides (2-9). The structures of these metabolites (1-9) were established by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). In vitro anti-inflammatory effects of these metabolites were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Among these metabolites, 3-9 were shown to strongly inhibit LPS-induced overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) with IC50 values ranging from 1.9 µM to 18.1 µM, and from 2.8 µM to 18.7 µM, respectively. In the further evaluation of signal pathways involved in these effects, the most active compound, (10E,15S)-10,11-dehydrocurvularin (8) attenuated the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 macrophages. Furthermore, compound 8 was shown to suppress the upregulation of pro-inflammatory mediators and cytokines via the inhibition of the nuclear factor-κB (NF-κB) signaling pathway, but not through the mitogen-activated protein kinase (MAPK) pathway. Based on the comparisons of the different magnitude of the anti-inflammatory effects of these structurally-related metabolites, it was suggested that the opening of the 12-membered lactone ring in curvularin-type metabolites and blocking the phenol functionality led to the significant decrease in their anti-inflammatory activity.