Seco-polyprenylated acylphloroglucinols from Hypericum elodeoides induced cell cycle arrest and apoptosis in MCF-7 cells via oxidative DNA damage.

Four undescribed seco-polyprenylated acylphloroglucinols (seco-PAPs), elodeoidesones A-D (1-4), were characterized from Hypericum elodeoides. Compound 1 represents the 1,6-seco-PAPs with fascinating 5/5 fused ring, while 2-4 possess a 1,2-seco-PAPs skeleton with a five-membered lactone core. Their structures including absolute configurations were established by spectroscopic analyses and quantum chemical computations. A possible biosynthetic pathway of 1-4 from normal PAPs was proposed. All the isolates were investigated for their cytotoxicity against tumor cells. Notably, 1 inhibited the proliferation of MCF-7 cells with the IC50 value of 7.34 µM. Mechanism investigation indicated that 1 induced MCF-7 cells apoptosis by blocking cell cycle at S phase via inducing oxidative DNA damage.

Dysideanones F-G and dysiherbols D-E, unusual sesquiterpene quinones with rearranged skeletons from the marine sponge Dysidea avara.

Four new sesquiterpene quinone meroterpenoids, dysideanones F-G (1-2) and dysiherbols D-E (3-4), were isolated from the marine sponge Dysidea avara collected from the South China Sea. The new structures were elucidated by extensive analysis of spectroscopic data including HR-MS and 1D and 2D NMR spectra, and their absolute configurations were assigned by single-crystal X-ray diffraction and ECD calculations. Anti-inflammatory evaluation showed that dysiherbols D-E (3-4) exhibited moderate inhibitory activity on TNF-α-induced NF-κB activation in human HEK-293T cells with IC50 values of 10.2 and 8.6 µmol·L-1, respectively.

Phenolic glycosides and flavonoids with antioxidant and anticancer activities from Desmodium caudatum.

Descaudatine A (1), an undescribed phenolic glycoside, along with a known analogue (2) and ten flavonoids (3-12), were isolated from the whole plant of Desmodium caudatum. Compounds 1 and 4 exhibited potent antioxidant activities with the IC50 of 58.59 µM and 31.31 µM, respectively, which were approached to that of the positive control Vitamin C (IC50 = 46.32 µM). Meanwhile, 12 showed moderate antioxidant activity with the IC50 of 173.9 µM. Besides, compounds 3 and 6 inhibited the proliferation of HeLa cells with IC50 values of 56.14 µM and 69.04 µM, respectively. Further studies indicated that 3 and 6 could dose-dependently induce PARP cleavage and might trigger caspase-3, 8, 9 activation to induce apoptosis. RXRα is an ideal anticancer target of nuclear receptor. The reporter gene assay of RXRα indicated that 3 and 6 could inhibited the 9-cis-RA induced RXRα transcription in a concentration-dependent manner.

Cytotoxic polyprenylated phloroglucinol derivatives from Hypericum elodeoides Choisy modulating the transactivation of RXRα.

Hyperelodione D (1), an undescribed polyprenylated phloroglucinol derivative possessing 6/6/5/5 fused tetracyclic core, together with hyperelodiones E-F (2-3), two unreported analogues bearing 6/5/5 fused tricyclic structure, were isolated from Hypericum elodeoides Choisy. Their planar structures were elucidated by spectroscopic analysis (HRESIMS, 1D and 2D NMR) and their absolute configurations were determined by comparison of experimental and calculated ECD data. The cytotoxicity and retinoid X receptor-α (RXRα) related activities of the isolates were evaluated and the plausible biogenetic pathways of 1-3 were proposed.

Cytotoxic compound triacremoniate from Marine Fungus Acremonium citrinum. MMF4.

Two new compounds, triacremoniate (1) and dietziamide C (2) along with known compounds ß-Adenosine (3) and acrepyrone A (4) were obtained from the mangrove-derived fungus Acremonium citrinum. MMF4. Their structures were unambiguously determined by extensive spectroscopic methods, including UV, IR, HRESIMS and NMR. Triacremoniate (1) can promote apoptosis of HeLa cells by increasing the PARP cleavage and the phosphorylation of JNK and p38.

Secondary metabolites of petri-dish cultured Antrodia camphorata and their hepatoprotective activities against alcohol-induced liver injury in mice.

Antrodia camphorata, a well-known and highly valued edible medicinal mushroom with intriguing activities like liver protection, has been traditionally used for the treatment of alcoholic liver disease. A. camphorata shows highly medicinal and commercial values with the demand far exceeds the available supply. Thus, the petri-dish cultured A. camphorata (PDCA) is expected to develope as a substitute. In this paper, nineteen triterpenes were isolated from PDCA, and thirteen of them were the unique anthroic acids in A. camphorata, including the main content antcin K, which suggested that PDCA produced a large array of the same anthroic acids as the wild one. Furthermore, no obvious acute toxicity was found suggesting the edible safety of PDCA. In mice alcohol-induced liver injury model, triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) had been reduced by the PDCA powder as well as the main content antcin K, which indicated that the PDCA could protect alcoholic liver injury in mice model and antcin K could be the effective component responsible for the hepatoprotective activities of PDCA against alcoholic liver diseases.

A strategy to find novel candidate anti-Alzheimer's disease drugs by constructing interaction networks between drug targets and natural compounds in medical plants.

BACKGROUND: Alzheimer' disease (AD) is an ultimately fatal degenerative brain disorder that has an increasingly large burden on health and social care systems. There are only five drugs for AD on the market, and no new effective medicines have been discovered for many years. Chinese medicinal plants have been used to treat diseases for thousands of years, and screening herbal remedies is a way to develop new drugs. METHODS: We used molecular docking to screen 30,438 compounds from Traditional Chinese Medicine (TCM) against a comprehensive list of AD target proteins. TCM compounds in the top 0.5% of binding affinity scores for each target protein were selected as our research objects. Structural similarities between existing drugs from DrugBank database and selected TCM compounds as well as the druggability of our candidate compounds were studied. Finally, we searched the CNKI database to obtain studies on anti-AD Chinese plants from 2007 to 2017, and only clinical studies were included. RESULTS: A total of 1,476 compounds (top 0.5%) were selected as drug candidates. Most of these compounds are abundantly found in plants used for treating AD in China, especially the plants from two genera Panax and Morus. We classified the compounds by single target and multiple targets and analyzed the interactions between target proteins and compounds. Analysis of structural similarity revealed that 17 candidate anti-AD compounds were structurally identical to 14 existing approved drugs. Most of them have been reported to have a positive effect in AD. After filtering for compound druggability, we identified 11 anti-AD compounds with favorable properties, seven of which are found in anti-AD Chinese plants. Of 11 anti-AD compounds, four compounds 5,862, 5,863, 5,868, 5,869 have anti-inflammatory activity. The compound 28,814 mainly has immunoregulatory activity. The other six compounds have not yet been reported for any biology activity at present. DISCUSSION: Natural compounds from TCM provide a broad prospect for the screening of anti-AD drugs. In this work, we established networks to systematically study the connections among natural compounds, approved drugs, TCM plants and AD target proteins with the goal of identifying promising drug candidates. We hope that our study will facilitate in-depth research for the treatment of AD in Chinese medicine.

Bioactive prenylated xanthones from the stems of Cratoxylum cochinchinense.

Cochinchinones M-U (1-9), together with 12 known compounds (10-21), were isolated from the stems of Cratoxylum cochinchinense (Lour.) Blume. Their structures were determined on the basis of extensive spectroscopic data analyses. In addition, their retinoid X receptor-α transcriptional activities were evaluated using an in vitro assay.

[Chemical constituents in higher polar substances from Desmodium caudatum].

In this study the chemical constituents of the higher polar sustances from Desmodium caudatum were investigated.The compounds were isolated by using column chromatographies over silicagel, polyamide, ODS, Sephadex LH-20, and preparative HPLC. The structures of these compounds were identified on the basis of NMR and MS spectra. Thirteen compounds were obtained and their structures were identified as vanillin(1), loliolide(2), indole-3-carboxaldehyde(3), salicylic acid(4), swertisin(5), saccharumoside C(6), isosinensin (7), kaempferol 3-O-ß-D-glucopyranoside-7-O-α-L-rhamnopyranoside (8), isovitexin (9), vitexin (10), nothofagin(11), resveratroloside (12), and 2"-α-rhamnopyranosyl-7-O-methylvitexin (13). Except for compound 5, the remaining compounds were isolated from D. caudatum for the first time. Compounds 2, 3, 6-8, 11-13 were separated from the genus Desmodium for the first time.

[Chemical constituents from Elephantopus tomentosus].

OBJECTIVE: To study the chemical constituents of Elephantopus tomentosus. METHOD: The compounds were isolated by repeated HP20 macro porous adsorption resin column combined with Sephadex LH-20, ODS and silica gel chromatographies. The structures were identified on the basis of extensive spectroscopic data analysis and by comparison of their spectral data reported. RESULT: Eighteen compounds were identified as 2-deethoxy-2beta-hydroxyphantomolin (1), 2beta-hydroxy-2-deethoxy-8-O-deacylphantomolin-8-O-tiglinate (2), 2beta-methoxy-2-deethoxyphantomolin (3), 2beta-methoxy-2-deethoxy-8-O-deacylphantomolin-8-O-tiglinate (4), molephantin (5), molephantinin (6), tricin (7), luteolin (8), quercetin (9), 3beta-friedelinol (10), 3beta-hydroxyolean-12-en-28-oic acid (11), 3, 5-di-O-caffeoyl quinic acid (12), 3,4-di-O-caffeoyl quinic acid (13), syringaresinol-4-beta-D-glucopyranoside (14), xylogranatinin (15), byzantionoside B (16), 2'-hydroxycinnamaldehyde (17), and caffeic acid ethyl ester (18). CONCLUSION: Compounds 9, 11, 14-18 were separated from Elephantopus for the first time.

Antiproliferative cardiac glycosides from the latex of Antiaris toxicaria.

Phytochemical investigation of the latex of Antiaris toxicaria resulted in the isolation of 15 new [antiarosides J-X (1-15)] and 17 known cardiac glycosides. The effects of the cardiac glycosides on apoptosis and the expression of orphan nuclear receptor Nur77 were examined in human NIH-H460 lung cancer cells. Several of the cardiac glycosides induced apoptosis in lung cancer cells, which was accompanied by induction of Nur77 protein expression. Treatment of cancer cells with the cardiac glycosides resulted in translocation of the Nur77 protein from the nucleus to the cytoplasm and subsequent targeting to mitochondria. The results show that the cardiac glycosides exert their apoptotic effect through the Nur77-dependent apoptotic pathway.

Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis.

A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α-mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α-induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α-dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells.

Furocoumarin derivatives from radix Angelicae dahuricae and their effects on RXRα transcriptional regulation.

A novel furocoumarin derivative named oxyalloimperatorin (1), together with seventeen furocoumarins 2-18 were isolated from the radix of Angelica dahurica. The chemical structure of new metabolite was characterized by analysis of IR, NMR, and HR-ESI-MS spectroscopic data. Among the isolated compounds, 13, 16, and 18 (each at 20 µM) could significantly promote the gene transcriptional function of nuclear receptor RXRα. While 7-9, 13, 14, and the new structure 1 (each at 20 µM) showed significant reduction in RXRα gene transcriptional activities induced by 9-cis-retinoid acid. The findings indicated that these furocoumarin skeleton derivatives might hold beneficial effects on many intractable diseases, such as cancer and metabolic diseases, due to their potential activities on regulating the transcriptional activation function of RXRα.

Xanthone and benzophenone glycosides from the stems of Cratoxylum formosum ssp. pruniflorum.

Two new xanthone glycosides, namely pruniflorosides A and B (1, 2), a new benzophenone glycoside, prunifloroside C (3), and a new xanthone, pruniflorone S (4) were isolated from the stems of Cratoxylum formosum ssp. pruniflorum, along with six known xanthones (5-10). Their structures were determined on the basis of extensive spectroscopic analysis. In addition, their retinoid X receptor α (RXRα) transcriptional activities were evaluated in vitro.

Bioactive xanthones from the stems of Cratoxylum formosum ssp. pruniflorum.

Six new compounds, pruniflorones M-R (1-6), together with 19 known compounds (7-25) were isolated from the stems of Cratoxylum formosum ssp. pruniflorum. The structures of the new compounds were established on the basis of extensive spectroscopic data interpretation. In addition, their RXRalpha transcriptional activities were evaluated using an in vitro assay.

The involvement of retinoic acid receptor-alpha in corticotropin-releasing hormone gene expression and affective disorders.

BACKGROUND: Corticotropin-releasing hormone (CRH) is considered the central driving force in the stress response and plays a key role in the pathogenesis of depression. Retinoic acid (RA) has been suggested by clinical studies to be associated with affective disorders. METHODS: First, hypothalamic tissues of 12 patients with affective disorders and 12 matched control subjects were studied by double-label immunofluorescence to analyze the expression of CRH and retinoic acid receptor-alpha (RAR-alpha). Second, critical genes involved in the RA signaling pathways were analyzed in a rat model of depression. Finally, the regulatory effect of RAR-alpha on CRH gene expression was studied in vitro. RESULTS: We found that the expression of RAR-alpha was colocalized with CRH neurons in human hypothalamic paraventricular nucleus (PVN). The density of RAR-alpha-immunoreactive neurons and CRH-RAR-alpha double-staining neurons was significantly increased in the PVN of patients with affective disorders. The ratio of the CRH-RAR-alpha double-staining neurons to the CRH-immunoreactive neurons in affective disorder patients was also increased. Recruitment of RAR-alpha by the CRH promoter was observed in the rat hypothalamus. A dysregulated RA metabolism and signaling was also found in the hypothalamus of a rat model for depression. Finally, in vitro studies demonstrated that RAR-alpha mediated an upregulation of CRH gene expression. CONCLUSIONS: These results suggest that RAR-alpha might contribute to regulating the activity of CRH neurons in vivo, and the vulnerable character of the critical proteins in RA signaling pathways might provide novel targets for therapeutic strategies for depression.