Mallotumides A-C: Potent Cytotoxic Cycloheptapeptides from the Roots of Mallotus spodocarpus.

The structures of potent cytotoxic cycloheptapeptides, mallotumides A-C (1-3, respectively) isolated from the roots of Mallotus spodocarpus Airy Shaw, were elucidated by extensive spectroscopic analysis. The absolute configuration of 1 was determined by single-crystal X-ray crystallographic data. All three cycloheptapeptides exhibited potent cytotoxicity against various cancer cell lines with IC50 values ranging from 0.60 to 4.02 nM.

Mass spectral analysis of secondary metabolites from Zingiber montanum rhizome extract using UHPLC-HR-ESI-QTOF-MS/MS.

INTRODUCTION: Zingiber montanum (J.Koenig) Link ex A.Dietr. is a popular medicinal plant in Thailand. Its rhizomes have been used as an ingredient in various Thai traditional medicine formulas. While many reports have focused on the chemical constituents and biological activities of this plant, a comprehensive study on secondary metabolite profiling using tandem mass spectrometry has, to this point, never been documented. OBJECTIVE: To analyze the chemical constituents in Z. montanum rhizomes using ultra-high performance liquid chromatography coupled with ultra-high-resolution electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-HR-ESI-QTOF-MS/MS) analyses and to utilize the characteristic fragmentation patterns of these compounds to facilitate their identification. METHODOLOGY: UHPLC-HR-ESI-QTOF-MS/MS in positive ion mode was used for chemical identification of secondary metabolites from the ethanolic extract of the plant material. MS/MS data of some known reference compounds, together with detailed fragmentation pattern information of several compounds obtained from the crude extract, were used to elucidate their chemical structures. RESULTS: In this work, one benzaldehyde, ten phenylbutenoid monomers, six curcuminoids, and nine phenylbutenoid dimers were assigned based on their characteristic fragment ions. Among these compounds, 2-(3,4-dimethoxystyryl)oxirane was tentatively suggested as a potential new compound. Several characteristic fragment ions from these compounds were assigned and the relative ion abundance of these was also used to differentiate the chemical structures of compounds having the same molecular mass. CONCLUSIONS: The results will benefit future high-throughput screening of bioactive compounds and method development for the quality control of raw materials and herbal drugs derived from Z. montanum rhizome extracts.

Acute and subchronic oral toxicity studies of Nelumbo nucifera stamens extract in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Since the use of Nelumbo nucifera stamens in herbal medicines as well as in cosmetic products are highly prevalent in Thailand and increasing worldwide, acute and subchronic toxicity studies to confirm the safe use of Nelumbo nucifera stamens are warranted. AIM OF THE STUDY: Acute and subchronic oral toxicity studies of Nelumbo nucifera stamens extract in rats were performed in the present study in order to evaluate its safety. MATERIALS AND METHODS: In acute toxicity study, Nelumbo nucifera stamens extract was administered by oral gavage to Sprague-Dawley rats (5 males and 5 females) at a dose of 5000 mg/kg. In subchronic toxicity study, the extract at doses of 50, 100, and 200mg/kg/day were given orally to groups of rats (6 rats/dose/sex) for 90 consecutive days. RESULTS: The extract at a dose of 5000 mg/kg produced no treatment-related signs of toxicity or mortality in any of the animals tested during 14 days of the study. In the repeated dose 90-day oral toxicity study, there was no significant difference in body weight between the control and all treatment groups with the exception of the body weight of the female group treated with 200mg/kg/day of the extract which was statistically significantly less than that of its control counterpart on day 90 but the percent weight changes of both groups were almost similar. Some statistically significant differences in hematological and biochemical parameters as well as in some internal organ weights of both male and female rats treated with the extract at the highest dose were observed. However, no abnormality of internal organs was observed in both gross and histopathological examinations. CONCLUSIONS: These results suggest that the oral lethal dose of Nelumbo nucifera stamens extract for male and female rats is in excess of 5000 mg/kg and the no-observed-adverse-effect level (NOAEL) of the extract for both male and female rats is considered to be 200mg/kg/day.

A novel cycloheptapeptide exerts strong anticancer activity via stimulation of multiple apoptotic pathways in caspase-3 deficient cancer cells.

BACKGROUND: VR3848 is a novel cycloheptapeptide, isolated from a Euphorbiaceae plant, which can suppress proliferation of various tumor cells at nanomolar concentration. Due to its novelty and potency, the molecular process of tumor cell growth inhibition was investigated intensively. MATERIALS AND METHODS: MCF-7 cells, a caspase-3 deficient cancer cell line, were treated with VR3848. The genetic response was monitored using cDNA array analysis. RESULTS: Expression alterations of caspase, bcl-2 family members, death receptor, death adaptor, death ligands, stress response, cell cycle machinery, mitogen-activated protein kinases (MAPKs) and proto-oncogene were found which can be linked into three apoptotic pathways. The first was the death receptor-mediated pathway, which was confirmed by functional inhibition of caspase-8 and -10. The second pathway was via ER-stress apoptosis demonstrated by up-regulation of ER-stress genes and the release of caspase-12 into the cytoplasm. The third pathway involved mitochondrial membrane leakage which was elucidated by down-regulation of anti-apoptotic bcl-2 and an increased level of cytosolic apoptosis-inducing factor (AIF). Cell cycle arrest was observed which may have been a direct effect of VR3848 or a consequence of DNA strand breaks which in turn stimulated cell cycle arrest. CONCLUSION: VR3848 inhibited MCF-7 cancer cell growth through an activation of three related apoptotic pathways.