One new spirocyclic lactone and one new benzopyran derivative from Aspergillus terreus.

One new spirocyclic lactone, terreinlactone C (1), and one new benzopyran derivative, 2,2-dimethyl-3-hydroxychroman-6-aldehyde (2), were discovered from the fungus Aspergillus terreus. The chemical structures of compounds 1 and 2 were elucidated by detailedly analyzing NMR and HRESIMS data. Compound 1 is the first natural product with a 1-oxaspiro[4.5]decan-2-one ring system and a possible biogenetic pathway is proposed. Two compounds were tested for their cytotoxic activities against five human cancer cell lines.[Formula: see text].

Indole diketopiperazines from endophytic Chaetomium sp 88194 induce breast cancer cell apoptotic death.

Diketopiperazines are important secondary metabolites of the fungi with variety bioactivities. Several species belonging to genus Chaetomium produce compounds of this class, such as chetomin. To identify new antitumor agents, secondary metabolites of fungus Chaetomium sp 88194 were investigated and three new indole diketopiperazines, Chaetocochins G (1), Oidioperazines E (2) and Chetoseminudin E (3), along with two known compounds Chetoseminudins C (4) and N-acetyl-ß-oxotryptamine (5), were obtained. Chaetocochins G and Chetoseminudin E were recrystallized in CHCl3 containing a small amount of MeOH, and their structures with absolute configuration were established by spectroscopic data interpretation and single-crystal X-ray diffraction analysis. The absolute configuration of Oidioperazines E was defined by comparing of experimental and calculated electronic circular dichroism spectra. These isolates were also evaluated the anticancer activity, and Chaetocochins G displayed more potent cytotoxicity in MCF-7 cells than the common chemotherapeutic agent (5-fluorouracil) associated with G2/M cell cycle arrest. More importantly, Chaetocochins G induced cell apoptotic death via caspase-3 induction and proteolytic cleavage of poly (ADP-ribose) polymerase, concomitantly with increased Bax and decreased Bcl-2 expression. Our findings suggested that indole diketopiperazines from endophytic Chaetomium sp 88194 may be potential resource for developing anti-cancer reagents.

Cytotoxicity and apoptosis-inducing effect of steroidal saponins from Dioscorea zingiberensis Wright against cancer cells.

Steroidal saponins from Dioscorea zingiberensis Wright (DZW) have shown cytotoxic activity in cancer cells. In this study, we isolated and identified seven steroidal saponins from the rhizomes of DZW: diosgenin, trillin, diosgenin diglucoside, deltonin, zingiberensis saponin (ZS), protodeltonin and parvifloside. Our results showed that these seven compounds inhibited the proliferation of a panel of established human and murine cancer cell lines in vitro. ZS had more cytotoxic effect than the other saponins, even close to doxorubicin on the murine colon carcinoma cell line C26. The proliferation inhibitory effect of ZS was associated with its apoptosis-inducing effect by activation of caspase-3 and caspase-9 and specific proteolytic cleavage of poly (ADP-ribose) polymerase. Exposure of C26 to ZS also resulted in Bax upregulation and Bcl-2 downregulation. In conclusion, the findings of this study demonstrated that ZS is an effective natural agent for cancer therapy, which may be mediated, in part, by induction of apoptosis, and DZW's potential as an anticancer agent is worth being further investigated.

TP-58, a novel thienopyridine derivative, protects mice from concanavalinA-induced hepatitis by suppressing inflammation.

Hepatitis represents a ubiquitous human health problem but effective therapies with limited side effects are still lacking. In this study, we investigated the effect and mechanism of TP-58, a novel thienopyridine derivative, on a murine fulminant hepatitis model induced by concanavalin A (ConA). We found TP-58 markedly alleviated ConA-caused liver injury and increased survival ratio of mice injected with a lethal dose of ConA. Oral administration of TP-58 significantly alleviated ConA-caused liver injury in mice by the reduction of serum aminotransferases and liver necrosis.The analysis of proinflammatory cytokines showed that TP-58 decreased both hepatic mRNA expressions and serum protein levels of TNF-α and IL-6. And the result from LPS-stimulated RAW 264.7 cells showed TP-58 suppressed the production of TNF-α, IL-6, and Nitro Oxide (NO) in the supernatant of LPS-stimulated RAW 264.7 cells. The study of activation of nuclear factor-κB (NF-κB) by electrophoretic mobility shift assay (EMSA) showed that TP-58 inhibited the activation of NF-κB both in vivo and in vitro. The inhibitory effect was also accompanied by a parallel reduction of IκB phosphorylation. These results indicate that TP-58 protects against liver injury by inhibition of the NF-κB-mediated inflammation and suggest a potential role of TP-58 against acute liver injury and other inflammatory diseases.

[The antagonistic effect of PI3K-gamma inhibitor AS605240 on cardiac hypertrophy and cardiac fibrosis induced by isoproterenol in rats].

OBJECTIVE: To investigate the therapeutic effect of PI3Kgamma inhibitor AS605240 on cardiac hypertrophy and cardiac fibrosis induced by Isoproterenol in rats. METHODS: Wistar rats were randomly divided into three groups (n = 10), control group, ISO group (vehicle group) and AS605240 group. The rats in control group without any treatment. The rats in ISO and AS605240 group were given ISO 10 mg/kg for 3 days and 5 mg/kg for another 11 days by subcutaneous injection to prepare the animal model of cardiac fibrosis. Rats in AS605240 group were given AS605240 50 mg/(kg x d) by intraperitoneal injection continuously for 14 days. The vehicle group received the intraperitoneal injection of an equal volume of 0.5% carboxymethylcellulose. Twenty-four hours after the last treatment, rats were sacrificed. Heart, body weight, cardiac function and the CVF were measured. RESULTS: Compared with the control group, the HW/BW of ISO group was increased significantly (P < 0.05) with a increased collagen inter cardiac muscle cells (P < 0. 05). Compared with ISO group, histological examination of the heart showed that AS605240 significantly relieved the rat cardiac fibrosis and reduced heart/body weight ratios in experimental cardiac fibrosis (P < 0.05). CONCLUSION: AS605240 may be an effective antagonist for cardiac hypertrophy and cardiac fibrosis.

Deltonin, a steroidal saponin, inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis and antiangiogenesis.

Deltonin, a steroidal saponin, isolated from Dioscorea zingiberensis Wright (DZW), has shown high-cytotoxic activity in cancer cells. However, its mechanisms and in vivo anti-cancer effects remain unknown. In the present study, we evaluated the effects and explored the anti-tumor mechanisms of deltonin on a panel of colon cancer cell lines and in a mouse model of murine colon cancer C26. Deltonin had more cytotoxic effect on C26 cells than 5-fluorouracil had, promoting dramatic G2-M phase arrest and apoptosis in C26 cells in a concentration-dependent manner; oral administration of deltonin significantly inhibited the tumor growth and prolonged survival of the tumor bearing mice. The deltonin treatment caused a noticeable apoptosis in tumor tissue, which associated with increased levels of Bax, activated caspase-3, caspase-9, and cleaved poly (ADPribose) polymerase, decreased pro-caspase-8, pro-caspase-9, Bcl-2 expression levels and extracellular signal-regulated kinase-1/2 activity; and dose-dependently inhibit angiogenesis. In conclusion, the findings in this study demonstrated that deltonin is an effective natural agent for cancer therapy, which may be mediated, in part, by induction of apoptosis, as well as involve mitogen-activated protein kinase pathways, and inhibition of angiogenesis.