Tsuyoshi Ikeda

Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B in tumor cells and tumor-associated macrophages.

Tumor‐associated macrophages (TAM) of M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with glioblastoma. We screened the natural compounds possessing an inhibitory effect on M2 polarization in human monocyte‐derived macrophages. Among 130 purified natural compounds examined, corosolic acid significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, and also suppressed the secretion of IL‐10, one of the anti‐inflammatory cytokines preferentially produced by M2 macrophages, thus suggesting that corosolic acid suppresses M2 polarization of macrophages. Furthermore, corosolic acid inhibited the proliferation of glioblastoma cells, U373 and T98G, and the activation of signal transducer and activator of transcription‐3 (STAT3) and nuclear factor‐kappa B (NF‐κB) in both human macrophages and glioblastoma cells. These results indicate that corosolic acid suppresses the M2 polarization of macrophages and tumor cell proliferation by inhibiting both STAT3 and NF‐κB activation. Therefore, corosolic acid might be a potential new tool for tumor prevention and therapy. (Cancer Sci 2011; 102: 206–211)

α-Tomatine, the major saponin in tomato, induces programmed cell death mediated by reactive oxygen species in the fungal pathogen Fusarium oxysporum

The tomato saponin α‐tomatine has been proposed to kill sensitive cells by binding to cell membranes followed by leakage of cell components. However, details of the modes of action of the compound on fungal cells are poorly understood. In the present study, mechanisms involved in α‐tomatine‐induced cell death of fungi were examined using a filamentous pathogenic fungus Fusarium oxysporum. α‐Tomatine‐induced cell death of F. oxysporum (TICDF) occurred only under aerobic conditions and was blocked by the mitochondrial F0F1‐ATPase inhibitor oligomycin, the caspase inhibitor D‐VAD‐fmk, and protein synthesis inhibitor cycloheximide. Fungal cells exposed to α‐tomatine showed TUNEL‐positive nuclei, depolarization of transmembrane potential of mitochondria, and reactive oxygen species (ROS) accumulation. These results suggest that TICDF occurs through a programmed cell death process in which mitochondria play a pivotal role. Pharmacological studies using inhibitors suggest that α‐tomatine activates phosphotyrosine kinase and monomeric G‐protein signaling pathways leading to Ca2+ elevation and ROS burst in F. oxysporum cells.

Notoamide O, a structurally unprecedented prenylated indole alkaloid, and notoamides P-R from a marine-derived fungus, Aspergillus sp.

Notoamides O-R were isolated from a marine-derived Aspergillus sp. Notoamide O possesses a novel hemiacetal/hemiaminal ether functionality hitherto unknown among this family of prenylated indole alkaloids. The structure represents an unusual branch point for the oxidative modification of other members in the family of prenylated indole alkaloids in the biogenetic pathway.

Tomatidine and lycotetraose, hydrolysis products of α‐tomatine by Fusarium oxysporum tomatinase, suppress induced defense responses in tomato cells

Many fungal pathogens of tomato produce extracellular enzymes, collectively known as tomatinases, that detoxify the preformed antifungal steroidal glycoalkaloid α‐tomatine. Tomatinase from the vascular wilt pathogen of tomato Fusarium oxysporum f. sp. lycopersici cleaves α‐tomatine into the aglycon tomatidine (Td) and the tetrasaccharide lycotetraose (Lt). Although modes of action of α‐tomatine have been extensively studied, those of Td and Lt are poorly understood. Here, we show that both Td and Lt inhibit the oxidative burst and hypersensitive cell death in suspension‐cultured tomato cells. A tomatinase‐negative F. oxysporum strain inherently non‐pathogenic on tomato was able to infect tomato cuttings when either Td or Lt was present. These results suggest that tomatinase from F. oxysporum is required not only for detoxification of α‐tomatine but also for suppression of induced defense responses of host.

Astragalosides isolated from the root of Astragalus Radix inhibit the formation of advanced glycation end products.

Because advanced glycation end product (AGE) inhibitors such as pyridoxamine significantly inhibit the development of retinopathy and neuropathy in the streptozotocin-induced diabetic rat, treatment with AGE inhibitors is believed to be a potential strategy for the prevention of lifestyle-related diseases such as diabetic complications. A crude extract of Astragali Radix (AR; roots of Astragalus membranaceus ) inhibits the formation of N(epsilon)-(carboxymethyl)lysine (CML) and pentosidine during the incubation of bovine serum albumin with ribose. In the present study, compounds were isolated from AR that prevented CML and pentosidine formation. Astragalosides significantly inhibited the formation of both CML and pentosidine, and astragaloside V had the strongest inhibitory effect among all if the isolated compounds. These data suggest that AR and astragalosides may be a potentially useful strategy for the prevention of clinical diabetic complications by inhibiting AGEs.

Esculeogenin A, a New Tomato Sapogenol, Ameliorates Hyperlipidemia and Atherosclerosis in ApoE-Deficient Mice by Inhibiting ACAT

Objective—We recently identified esculeoside A, a new spirosolane-type glycoside, with a content in tomatoes that is 4-fold higher than that of lycopene. In the present study, we examined the effects of esculeoside A and esculeogenin A, a new aglycon of esculeoside A, on foam cell formation in vitro and atherogenesis in apoE-deficient mice. Methods and Results—Esculeogenin A significantly inhibited the accumulation of cholesterol ester (CE) induced by acetylated low density lipoprotein (acetyl-LDL) in human monocyte-derived macrophages (HMDM) in a dose-dependent manner without inhibiting triglyceride accumulation, however, it did not inhibit the association of acetyl-LDL to the cells. Esculeogenin A also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-coenzymeA (CoA): cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that esculeogenin A suppresses the activity of both ACAT-1 and ACAT-2. Furthermore, esculeogenin A prevented the expression of ACAT-1 protein, whereas that of SR-A and SR-BI was not suppressed. Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol, triglycerides, LDL-cholesterol, and the areas of atherosclerotic lesions without any detectable side effects. Conclusions—Our study provides the first evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis.

Aaptamine, an alkaloid from the sponge Aaptos suberitoides, functions as a proteasome inhibitor

Aaptamine (1), isoaaptamine (2), and demethylaaptamine (3) were isolated from the marine sponge Aaptossuberitoides collected in Indonesia as inhibitors of the proteasome. They inhibited the chymotrypsin-like and caspase-like activities of the proteasome with IC(50) values of 1.6-4.6 microg/mL, while they showed less inhibition of the trypsin-like activity of the proteasome. The three compounds showed cytotoxic activities against HeLa cells, but their cytotoxicity did not correlate with their potency as proteasome inhibitors, strongly suggesting that their proteasomal inhibitory activity is dispensable to their cytotoxicity.

Onionin A from Allium cepa inhibits macrophage activation.

Onionin A (1), a new, stable, sulfur-containing compound, was isolated from acetone extracts of bulbs of onion (Allium cepa), and its structure was characterized as 3,4-dimethyl-5-(1E-propenyl)-tetrahydrothiophen-2-sulfoxide-S-oxide, on the basis of the results of spectroscopic analysis. This compound showed the potential to suppress tumor-cell proliferation by inhibiting the polarization of M2 alternatively activated macrophages.

Triterpenoids isolated from Zizyphus jujuba inhibit foam cell formation in macrophages.

Because foam cell formation in macrophages is believed to play an essential role in the progression of early atherosclerotic lesions in vivo, prevention of foam cell formation is considered to be one of the major targets for the treatment of atherosclerosis. The present study examined the inhibitory effect of 50 crude plant extracts on foam cell formation. Among those crude extracts, Zizyphi Fructus (ZF) and Zizyphi Semen (ZS) extracts significantly inhibited the foam cell formation induced by acetylated LDL. Furthermore, triterpenoids such as oleanonic acid, pomolic acid, and pomonic acid were the major active compounds, and triterpenoids containing a carboxylic acid at C-28 play an important role in the inhibitory effect on foam cell formation in human macrophages. These data suggest that triterpenoids in Zizyphus jujuba , the plant source of ZF and ZS, may therefore be useful for the prevention of atherosclerosis.

Studies on the chemical constituents of green leaves of Eucommia ulmoides Oliv.

From the green leaves of Eucommia ulmoides Oliv., 12 compounds were isolated: asperuloside, asperulosidic acid, scandoside 10-O-acetate, deacetyl asperulosidic acid, geniposidic acid, aucubin, isoquercetin, quercetin 3-O-sambubioside, rutin, astragalin, kaempherol 3-O-rutinoside and chlorogenic acid. The structures were determined on the basis of spectral data.