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BACKGROUND: In previous investigation, we have identified antioxidative effects of water-soluble ethanolic extracts (named as AKE) from Arenaria kansuensis and inferred that these extracts or their constituents may also have antihypoxic activity. A. kansuensis has been widely used in traditional Tibetan medicine for altitude sickness (AS) and has been known as the herb of anti-inflammatory and hypoxia resistance for a long time.PURPOSE: The purpose of this study is to evaluate protective effects of AKE and its major constituents against hypoxia-induced lethality in mice and RSC96 cells.
STUDY DESIGN AND METHODS: Hypoxia-induced lethality in mice was investigated by 3 experimental animal models of hypoxia. Meanwhile, we established a RSC96 cell model of hypoxia which applied to screen and assess the anti-hypoxic activity of compounds isolated from A. kansuensis.
RESULTS: Results indicated that AKE dose-dependently prolonged survival time of hypoxia induced lethality in mice compared to vehicle group and exhibited significantly anti-hypoxic effect. AKE also enhanced the number of red blood cells (RBC) and the concentration of hemoglobin (HB). 8 compounds were bio-guided separated and purified from AKE based on the animal model and cell model of hypoxia. Among which pyrocatechol (C16) and tricin 7-O-β-d-glucopyranoside (C13) were confirmed to express better protective effects on cell damage induced by hypoxia, suggesting that these two compounds are major active constituents of AKE for anti-hypoxia.
CONCLUSION: This study demonstrated that pyrocatechol and tricin 7-O-β-d-glucopyranoside could be therapeutic candidates for treatment of AS. It is the first time to find the major active constituents of AKE for anti-hypoxia. Meanwhile, a RSC96 cell model of hypoxia was established to screen anti-hypoxic activity of compounds for the first time.
A new diarylheptanoid, (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptan-3-one-5-O-β-D-6-Oacetylglucoside (<i>1</i>), together with two known diarylheptanoids, (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptan-3-one-5-O-β-D-glucopyranoside (<i>2</i>) and hirsutanonol (<i>3</i>), were isolated from Saxifraga tangutica. The structures of <i>1-3</i> were elucidated using 1D and 2D NMR spectral data, including high-resolution mass spectra (HR-ESI-MS). It was found that the new compound was acetyl-substituted (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptan-3-one-5-O-β-D-glucopyranoside.
A new isocoumarin, along with 10 known compounds, was isolated from the aerial parts of Aconitum gymnandrum. Their structures were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Among the known compounds, compound 11 was obtained as a natural product for the first time, which was previously reported as a synthetic product. In addition, compounds 1-5, 7 and 9 were tested for their cytotoxicity against four human cancer cell lines. The results showed that compounds 3, 4 and 7 displayed cytotoxicity against lung cancer A549 and gastric cancer MGC80, respectively, whereas 5 and 9 showed selective cytotoxicity against hepatocellular carcinoma HepG2.
<br>Display Omitted<br>• Two new monoterpenes named sibiscolactons A and B (<b>1</b> and <b>2</b>) were isolated from <b>Sibiraea laevigata</b>. • New compounds’ absolute configurations were established by electronic circular dichroism (ECD) calculations. • Eight known phenylpropanoids (<b>3</b>-<b>10</b>) were also obtained from the title plant. • <b>1</b>-<b>10</b> were evaluated for their cytotoxic activity. • Compound <b>3</b> displayed moderate cytotoxicity with IC50 values ranging from 10.8 to 49.2 μg mL−1.<br>Chemical investigation of the ethanol extract of the stalks and infructescence of <b>Sibiraea leavigata</b> led to the isolation of two new monoterpenes named (4<b>R</b>)-2-(2-hydroxy-4-methyl-3-pentenyl)furan-2(5<b>H</b>)-one (<b>1</b>) and (2<b>R</b>,4<b>R</b>)-2-(2-hydroxyethyl)-4-(2-methyl-1-propenyl)furan-5<b>H</b>-2-one (<b>2</b>) along with eight known phenylpropanoids (<b>3-10</b>). Their structures were established on the basis of the interpretation of spectroscopic data and electronic circular dichroism (ECD) calculations. In addition, all of these isolates were evaluated for their cytotoxic activity. The results showed that compound <b>3</b> displayed moderate cytotoxicity with IC50 values ranging from 10.8 to 49.2 μg mL−1 against five cell lines. While <b>1</b> showed selective promotion effects on proliferation of gastric cancer MGC803 and RSC96 cell lines.
Traditional Tibetan medicine provides an abundant source of knowledge on human ailments and their treatment. As such, it is necessary to explore their active single compounds used to treat these ailments to discover lead compounds with good pharmacologic properties. In this present work, animal medicine, Osteon Myospalacem Baileyi extracts have been separated using a two-dimensional preparative chromatographic method to obtain single compounds with high purity as part of the following pharmacological research. Five high-purity cyclic dipeptides from chromatography work were studied for their dihydroorotate dehydrogenase inhibitory activity on recombinant human dihydroorotate dehydrogenase enzyme and compound Fr. 1-4 was found to contain satisfying inhibition activity. The molecular modeling study suggests that the active compound Fr. 1-4 may have a teriflunomide-like binding mode. Then, the energy decomposition study suggests that the hydrogen bond between Fr. 1-4 and Arg136 can improve the binding mode to indirectly increase the van der Waals binding energy. All the results above together come to the conclusion that the 2, 5-diketopiperazine structure group can interact with the polar residues well in the active pocket using electrostatic power. If some proper hydrophobic groups can be added to the sides of the 2, 5-diketopiperazine group, it is believed that better 2, 5-diketopiperazine dihydroorotate dehydrogenase inhibitors will be found in the future.
ETHNOPHARMACOLOGICAL RELEVANCE: Osteon Myospalacem Baileyi, known as Sai long gu (Tibetan language, means "blind rat bone"), is the whole skeleton of Tibet plateau rodentia animal Myospalacem Baileyi. Osteon Myospalacem Baileyi had been widely used in the Tibet region as an anti-osteoporosis drug and since 1991 Osteon Myospalacem Baileyi has been listed in the Pharmacopoeia of People's Republic of China as the first-class animal new medical material. However, the mechanism of its anti-osteoporosis activities is still unclear. It is very desirable to solve this problem for further study.MATERIALS AND METHODS: in this study, preparative chromatography was employed to produce the active fraction ET4 from Osteon Myospalacem Baileyi crude. Flow cytometry and MTT assay were used to evaluate the toxicities of ET4. BMM cells were separated from mouse bone marrow to test the inhibition effects of ET4 on osteoclastogenesis. Western blot was used to find out the pathways, through which ET4 could act on osteoclastogenesis. Q-PCR was used to test the osteoclastogenesis marker genes. At last, immunofluorescence confocal microscopy was used to test the osteoclastogenesis master protein NFATc1 nuclei translocation.
RESULTS: In this study we report that ET4, at the dose of 60μg/mL, significantly inhibited the formation of osteoclasts. Notably, ET4 did not affect the BMM viability at that dose. In addition, Osteon Myospalacem Baileyi could inhibit the expression of osteoclast marker genes, including cathepsin K (CTSK), nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAP, Acp5) dendrite cell-specific transmembrane protein (DC-STAMP), calcitonin receptor (CTR), osteoclast associated and immunoglobulin-like receptor (OSCAR). Mechanistically, ET4 dose- and time-dependently blocked the RANKL-induced activation of ERK and c-Fos as well as the induction of NFATc1 which is essential for OC formation.
CONCLUSIONS: These data suggest that ET4 might be a useful alternative therapy in preventing or treating osteolytic diseases.