Koichi Nakae

Decalpenic acid, a novel small molecule from Penicillium verruculosum CR37010, induces early osteoblastic markers in pluripotent mesenchymal cells

Osteoblasts are the cells responsible for bone formation during embryonic development and adult life. Small compounds that could induce osteoblast differentiation might be promising sources of therapies for bone diseases such as osteoporosis. During screening for inducers of osteoblast differentiation of mouse pluripotent mesenchymal C3H10T1/2 cells, we isolated a small compound from the fermentation broth of Penicillium verruculosum CR37010. This compound, named decalpenic acid, bears a decalin moiety with a tetraenoic acid side chain. Treatment of C3H10T1/2 cells with decalpenic acid alone induced the expression of early osteoblast markers, such as alkaline phosphatase activity and osteopontin mRNA, but did not induce the late osteoblast marker osteocalcin mRNA or adipocyte markers under our experimental conditions.

Migrastatin acts as a muscarinic acetylcholine receptor antagonist

Migrastatin and its analogs have various biological activities such as inhibition of cell migration and anchorage-independent growth of cancer cells. Although its biosynthesis and chemical synthesis have been under investigation, little is known about the biological target of migrastatin. Here, we found that migrastatin inhibited intracellular calcium mobilization induced by carbachol in neuroblastoma SK-N-SH cells without affecting Ca2+ mobilization and cAMP accumulation induced by ligands of other receptors. The binding of [3H] N-methyl- scopolamine, an antagonist for muscarinic receptor was also inhibited by migrastain. Functionally, migrastatin inhibited Ca2+ mobilization induced by carbachol in primary cultures of smooth muscle cells of rat bladder. This study reveals that migrastatin acts as a muscarinic acetylcholine receptor antagonist.

A New Teleocidin Analog from Streptomyces sp. MM216-87F4 Induces Substance P Release from Rat Dorsal Root Ganglion Neurons

A new teleocidin analog was isolated from the fermentation medium of Streptomyces sp. MM216-87F4 and its structure was elucidated as 14-O-(N-acetylglucosaminyl) teleocidin A (GlcNAc-TA). GlcNAc-TA induces the translocation of protein kinases Cα and θ fused with enhanced green fluorescent protein (PKCα-EGFP and PKCθ-EGFP) to the plasma membrane in stable transfectants, and reduces intracellular calcium mobilization induced by agonists of G-protein coupled receptors in various cell lines without causing irritation of the mouse ear. Further, GlcNAc-TA sensitizes the release of excitatory neuropeptides substance P induced by capsaicin from primary-cultured dorsal root ganglion (DRG) neurons of the rat and GlcNAc-TA alone also triggers substance P release in a dose-dependent manner. This study provides the first observation that a teleocidin analog without a free hydroxyl group at C-14 acts as a PKC activator and directly induces the release of excitatory neuropeptide.

Sacchathridine A, a prostaglandin release inhibitor from Saccharothrix sp.

Sacchathridine A (1) was isolated from the fermentation broth of strain Saccharothrix sp. MI559-46F5. The structure was determined as a new naphthoquinone derivative with an acetylhydrazino moiety by a combination of NMR, MS spectral analyses, and chemical degradation. Compound 1 showed inhibitory activity of prostaglandin E2 release in a concentration-dependent manner from human synovial sarcoma cells, SW982, with an IC50 value of 1.0 μM, but had no effect on cell growth up to 30 μM.

Vegfrecine, an inhibitor of VEGF receptor tyrosine kinases isolated from the culture broth of Streptomyces sp.

A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.

Antipain Y, a new antipain analog that inhibits neurotransmitter release from rat dorsal root ganglion neurons

Antipain Y, a new antipain analog that inhibits neurotransmitter release from rat dorsal root ganglion neurons

Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology

Microbial metabolites have attracted increasing interest as a source of therapeutics and as probes for biological mechanisms. New microbial metabolites and derivatives targeted at inflammation and bone disease therapy have been identified by focusing on prostaglandin release, osteoblast differentiation and immune cell functions. These modulators of inflammatory processes and bone disease contribute to our understanding of biological mechanisms and support identification of the therapeutic potential of drug lead candidates. The present review describes recent advances in the chemistry and analysis of inhibitors of prostaglandin release or other functional molecules of immune cells, as well as inducers of osteoblast differentiation, including biological and pharmacological activities.