Histone deacetylase (HDAC) has been highlighted as one of key players in tumorigenesis and angiogenesis. Recently, several derivatives of psammaplin (Psams) from a marine sponge have been known to inhibit the HDAC activity, but the molecular mechanism for the inhibition has not fully understood. Here, we explored the mode of action of Psams for the inhibition of HDAC activity in the molecular and cellular level. Among the derivatives, psammaplin A (Psam A) showed the potent inhibitory activity in enzyme assay and anti-proliferation assay with IC50 value of 0.003 and 1 microM, respectively. Psam A selectively induced hyperacetylation of histones in the cells, resulting in the upregulation of gelsolin, a well-known HDAC target gene, in a transcriptional level. In addition, reduced Psam A showed a stronger inhibitory activity than that of non-reduced one. Notably, glutathione-depleted cells were not sensitive to Psam A, implying that cellular reduction of the compound is responsible for the HDAC inhibition of Psam A after uptake into the cells. Together, these data demonstrate that Psam A could exhibit its activity under the reduced condition in the cells and be a new natural prodrug targeting HDAC.
Tyrosine/*analogs & derivatives/chemistry/pharmacology ; Prodrugs/chemistry/*pharmacology ; Oxidation-Reduction ; Molecular Structure ; Humans ; Histones/metabolism ; Histone Deacetylases/*antagonists & inhibitors/*classification/genetics/metabolism ; Hela Cells ; Enzyme Inhibitors/chemistry/*pharmacology ; Disulfides/chemistry/*pharmacology ; Cell Proliferation ; Biological Products/chemistry/*pharmacology ; Acetylation

Comprehensive chemical analysis of extracts and fractions of marine actinomycete strains led to the discovery of a new minor secondary metabolite, salternamide E (1), from a saltern-derived halophilic Streptomyces strain. The planar structure of salternamide E (1) was elucidated by a combinational analysis of spectroscopic data including NMR, MS, UV, and IR. The absolute configuration of salternamide E (1) was determined by circular dichroism spectroscopic analysis. Salternamide E displayed weak cytotoxicity against various human carcinoma cell lines.
Cell Line ; Circular Dichroism ; Humans ; Streptomyces*

Many active compounds present in Rhododendron brachycarpum have been used in traditional Oriental medicine for the treatment of various skin diseases. However, the precise mechanism of action of the compounds isolated from R. brachycarpum and their relevance as therapeutics for the treatment of psoriasis remain elusive. In this study, we report that rhododendrin isolated from R. brachycarpum strongly inhibits imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. We showed that topical treatment with rhododendrin reduces IMQ-induced skin hyperplasia, inflammatory mononuclear cell infiltration and the expression of pro-inflammatory mediators in mouse skin. In addition, we found that rhododendrin inhibits the activation of the TLR-7/NF-κB and mitogen-activated protein kinase pathways in both IMQ-induced psoriasis-like skin inflammation in mice and in normal human epidermal keratinocytes treated with IMQ. These results suggest that rhododendrin has an anti-inflammatory effect and can be used as a therapeutic to fight against psoriasis and other inflammatory skin diseases.
Animals ; Humans ; Hyperplasia ; Inflammation* ; Keratinocytes ; Medicine, East Asian Traditional ; Mice* ; Protein Kinases ; Psoriasis ; Rhododendron ; Skin Diseases ; Skin*

Sarcotragin C (1), a new sesterterpene metabolite was isolated from a Sarcotragus sp. sponge collected from Chuja Island, Korea. On the basis of the combined spectroscopic analyses, the structure of this compound was determined to be a linear norsesterterpene containing a leucine-derived gamma-lactam moiety. This compound exhibited moderate cytotoxicity against K562 and A549 cell-lines.
Korea ; Porifera*

Inflammation is a part of the complex biological responses of a tissue to injury that protect the organ by removing injurious stimuli and initiating the healing process, and is considered as a mechanism of innate immunity. To identify biologically active compounds against pathogenic inflammatory and immune responses, we fractionated water, aqueous methanol and n-hexane layers from nine kinds of leguminosae and examined anti-inflammatory activity of the fractions in human keratinocytes and mouse skin. Among the fractions, rf3 and rf4, isolated from the aqueous methanol layer of Astragalus sinicus L., exhibited the strongest reactive oxygen species (ROS)-scavenging and anti-inflammatory activities as measured by inhibition of the intracellular ROS production, nuclear factor-kappaB (NF-kappaB), janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphatidylinositol 3-kinase/Akt signaling in cytokine-stimulated human keratinocytes, as well as by effects on T-cell differentiation in mouse CD4+ T cells. In addition, topical application of rf3 and rf4 suppressed the progression of psoriasis-like dermatitis and expression of pro-inflammatory mediators in interleukin (IL)-23-injected mouse ears. Our results suggest that Astragalus sinicus L. may ameliorate chronic inflammatory skin diseases due to its antioxidant and anti-inflammatory activities via regulation of the intracellular ROS production, NF-kappaB, JAK/STAT and PI3/Akt signaling cascades as well as immune responses, and these results are the first report that Astragalus sinicus L. exhibits pharmacological activity.
Animals ; Anti-Inflammatory Agents/isolation & purification/*pharmacology/therapeutic use ; Astragalus Plant/*chemistry ; Cell Line ; Dermatitis/drug therapy ; Humans ; Interleukin-23/pharmacology ; Janus Kinases/metabolism ; Keratinocytes/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Plant Extracts/isolation & purification/*pharmacology/therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; STAT Transcription Factors/metabolism ; Skin/*drug effects/metabolism

Two meroterpenoids (1 and 2) along with twelve known compounds (3 – 14) were isolated from the culture broth of a Penicillium sp. fungus collected from Chuja-do, Korea. Based on the results of a combination of spectroscopic analyses, the new compounds, preaustinoids E (1) and F (2), were determined to be epimeric austin-type penta-cyclic lactones.
Fungi ; Korea ; Lactones ; Penicillium

Purpose: A three-drug combination of cyclophosphamide, bortezomib, and dexamethasone (CVD) shows significant efficacy and manageable toxicity as induction therapy in patients with multiple myeloma. Materials and Methods: In this phase II study, we enrolled 45 patients who achieved a very good partial response (VGPR) or partial response (PR) after autologous stem cell transplantation (ASCT) and evaluated the efficacy and toxicity of CVD consolidation. CVD consolidation comprised three cycles of cyclophosphamide 300 mg/m2 orally on days 1, 8, and 15, and bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15, and 22, along with dexamethasone 20 mg orally or intravenously on days 1 and 2, 8 and 9, 15 and 16, and 22 and 23. Results: At enrollment, 39 patients (86.7%) showed VGPR, and nine (13.3%) presented with PR. Nineteen patients (45.2%) achieved a complete response or better as their best response after the end of consolidation. Overall, 22 of 42 patients (52.4%) experienced an improved response status with CVD consolidation. Three-year overall survival and progression-free survival rates were 89.0% and 42.7%, respectively. The most common non-hematologic toxicities were peripheral neuropathy and infection (20.5%), with no grade ≥ 3 neuropathy observed. Conclusion These results showed that CVD consolidation therapy improved the response with reasonable toxicity in patients with residual disease after ASCT. This trial was registered with the Clinical Research Information Service, Republic of Korea (KCT0001327).