Xyloketal B exerts antihypertensive effect in renovascular hypertensive rats via the NO-sGC-cGMP pathway and calcium signaling.

Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. (No 2508). We previously showed that Xyl-B promoted endothelial NO release and protected against atherosclerosis through the Akt/eNOS pathway. Vascular NO production regulates vasoconstriction in central and peripheral arteries and plays an important role in blood pressure control. In this study, we examined whether Xyl-B exerted an antihypertensive effect in a hypertensive rat model, and further explored the possible mechanisms underlying its antihypertensive action. Administration of Xyl-B (20 mg·kg-1·d-1, ip, for 12 weeks) significantly decreased the systolic and diastolic blood pressure in a two-kidney, two-clip (2K2C) renovascular hypertensive rats. In endothelium-intact and endothelium-denuded thoracic aortic rings, pretreatment with Xyl-B (20 µmol/L) significantly suppressed phenylephrine (Phe)-induced contractions, suggesting that its vasorelaxant effect was attributed to both endothelial-dependent and endothelial-independent mechanisms. We used SNP, methylene blue (MB, guanylate cyclase inhibitor) and indomethacin (IMC, cyclooxygenase inhibitor) to examine which endothelial pathway was involved, and found that MB, but not IMC, reversed the inhibitory effects of Xyl-B on Phe-induced vasocontraction. Moreover, Xyl-B increased the endothelial NO bioactivity and smooth muscle cGMP level, revealing that the NO-sGC-cGMP pathway, rather than PGI2, mediated the anti-hypertensive effect of Xyl-B. We further showed that Xyl-B significantly attenuated KCl-induced Ca2+ entry in smooth muscle cells in vitro, which was supposed to be mediated by voltage-dependent Ca2+ channels (VDCCs), and reduced ryanodine-induced aortic contractions, which may be associated with store-operated Ca2+ entry (SOCE). Taken together, these findings demonstrate that Xyl-B exerts significant antihypertensive effects not only through the endothelial NO-sGC-cGMP pathway but also through smooth muscle calcium signaling, including VDCCs and SOCE.

Xyloketal B attenuates atherosclerotic plaque formation and endothelial dysfunction in apolipoprotein e deficient mice.

Our previous studies demonstrated that xyloketal B, a novel marine compound with a unique chemical structure, has strong antioxidant actions and can protect against endothelial injury in different cell types cultured in vitro and model organisms in vivo. The oxidative endothelial dysfunction and decrease in nitric oxide (NO) bioavailability are critical for the development of atherosclerotic lesion. We thus examined whether xyloketal B had an influence on the atherosclerotic plaque area in apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet and investigated the underlying mechanisms. We found in our present study that the administration of xyloketal B dose-dependently decreased the atherosclerotic plaque area both in the aortic sinus and throughout the aorta in apoE-/- mice fed a high-fat diet. In addition, xyloketal B markedly reduced the levels of vascular oxidative stress, as well as improving the impaired endothelium integrity and NO-dependent aortic vasorelaxation in atherosclerotic mice. Moreover, xyloketal B significantly changed the phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt without altering the expression of total eNOS and Akt in cultured human umbilical vein endothelial cells (HUVECs). Here, it increased eNOS phosphorylation at the positive regulatory site of Ser-1177, while inhibiting phosphorylation at the negative regulatory site of Thr-495. Taken together, these findings indicate that xyloketal B has dramatic anti-atherosclerotic effects in vivo, which is partly due to its antioxidant features and/or improvement of endothelial function.

Loddigesiinols G-J: α-glucosidase inhibitors from Dendrobium loddigesii.

Four new polyphenols, loddigesiinols G-J (compounds 1-4) and a known compound, crepidatuol B (5), were isolated from the stems of Dendrobium loddigesii that have long been used in Traditional Chinese Medicine and have recently been used to treat type 2 diabetes. Compounds 1-5 structures were elucidated based on spectroscopic analysis. The absolute configurations of compounds 1-4 were determined using theoretical calculations of electronic circular dichroism (ECD), and the absolute configuration of compound 5 was determined by a comparison of the experimental ECD spectra and the literature data. Compounds 1-5 are strong inhibitors of α-glucosidase, with IC50 values of 16.7, 10.9, 2.7, 3.2, and 18.9 µM, respectively. Their activities were significantly stronger than trans-resveratrol as a positive control (IC50 values of 27.9 µM).

Effects of Aging Treatment on the Microstructures and Mechanical Properties of a TC18 Alloy.

In the present work, the effects of aging treatment on the microstructures of a TC18 alloy are studied. The influence of aging treatment on the tensile properties and failure mechanisms is systematically analyzed. It is found that the size and morphology of the primary α (αp) phases are insensitive to aging temperature and time. Furthermore, the aging temperature and time dramatically influence the precipitation of the secondary α (αs) phases. Massive αs phases precipitate and gradually coarsen, and finally weave together by increasing the aging temperature or extending the aging time. The variations in αp and αs phases induced by aging parameters also affect the mechanical properties. Both yield strength (YS) and ultimate tensile strength (UTS) first increase and then decrease by increasing the aging temperature and time, while ductility first decreases and then increases. There is an excellent balance between the strengths and ductility. When the aging temperature is changed from 450 to 550 °C, YS varies from 1238.6 to 1381.6 MPa, UTS varies from 1363.2 to 1516.8 MPa, and the moderate elongation ranges from 9.0% to 10.3%. These results reveal that the thickness of αs phases is responsible for material strengths, while the content of α phases can enhance material ductility. The ductile characteristics of the alloy with coarser αs phases are more obvious than those with thinner αs phases. Therefore, the aging treatment is helpful for the precipitation and homogeneous distribution of αs phases, which are essential for balancing the strengths and ductility of the studied Ti alloy.

Investigation on Mechanism of Microstructure Evolution during Multi-Process Hot Forming of GH4169 Superalloy Forging.

Typically, in the manufacturing of GH4169 superalloy forgings, the multi-process hot forming that consists of pre-deformation, heat treatment and final deformation is required. This study focuses on the microstructural evolution throughout hot working processes. Considering that δ phase can promote nucleation and limit the growth of grains, a process route was designed, including pre-deformation, aging treatment (AT) to precipitate sufficient δ phases, high temperature holding (HTH) to uniformly heat the forging, and final deformation. The results show that the uneven strain distribution after pre-deformation has a significant impact on the subsequent refinement of the grain microstructure due to the complex coupling relationship between the evolution of the δ phase and recrystallization behavior. After the final deformation, the fine-grain microstructure with short rod-like δ phases as boundaries is easy to form in the region with a large strain of the pre-forging. However, necklace-like mixed grain microstructure is formed in the region with a small strain of the pre-forging. In addition, when the microstructure before final deformation consists of mixed grains, dynamic recrystallization (DRX) nucleation behavior preferentially depends on kernel average misorientation (KAM) values. A large KAM can promote the formation of DRX nuclei. When the KAM values are close, a smaller average grain size of mixed-grain microstructure is more conductive to promote the DRX nucleation. Finally, the interaction mechanisms between δ phase and DRX nucleation are revealed.

Secondary metabolites of a mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) from the South China Sea.

The mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) was cultivated in potato dextrose liquid medium, and one rare thiophene compound (1), together with anhydrojavanicin (2), 8-O-methylbostrycoidin (3), 8-O-methyljavanicin (4), botryosphaerone D (5), 6-ethyl-5-hydroxy-3,7-dimethoxynaphthoquinone (6), 3ß,5α-dihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (7), 3ß,5α,14α-trihydroxy-(22E,24R)-ergosta-7, 22-dien-6-one (8), NGA0187 (9) and beauvericin (10), were isolated. Their structures were elucidated by analysis of spectroscopic data. This is the first report of a natural origin for compound 6. Moreover, compounds 3, 4, 5, 7, 8 and 10 were obtained from marine microorganism for the first time. In the bioactive assays in vitro, compounds 2, 3, 9 and 10 displayed remarkable inhibiting actions against α-acetylcholinesterase (AChE) with IC50 values 2.01, 6.71, 1.89, and 3.09 µM, respectively. Furthermore, in the cytotoxicity assays, compounds 7 and 10 exhibited strong or moderate cytotoxic activities against MCF-7, A549, Hela and KB cell lines with IC50 values 4.98 and 2.02 (MCF-7), 1.95 and 0.82 (A549), 0.68 and 1.14 (Hela), and 1.50 and 1.10 µM (KB), respectively; compound 8 had weak inhibitory activities against these tumor cell lines; compounds 1, 2, 3, 4, 5, 6 and 9 exhibited no inhibitory activities against them.

Xyloketal B exhibits its antioxidant activity through induction of HO-1 in vascular endothelial cells and zebrafish.

We previously reported that a novel marine compound, xyloketal B, has strong antioxidative actions in different models of cardiovascular diseases. Induction of heme oxygenase-1 (HO-1), an important endogenous antioxidant enzyme, has been considered as a potential therapeutic strategy for cardiovascular diseases. We here investigated whether xyloketal B exhibits its antioxidant activity through induction of HO-1. In human umbilical vein endothelial cells (HUVECs), xyloketal B significantly induced HO-1 gene expression and translocation of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) in a concentration- and time-dependent manner. The protection of xyloketal B against angiotensin II-induced apoptosis and reactive oxygen species (ROS) production could be abrogated by the HO-1 specific inhibitor, tin protoporphyrin-IX (SnPP). Consistently, the suppressive effects of xyloketal B on NADPH oxidase activity could be reversed by SnPP in zebrafish embryos. In addition, xyloketal B induced Akt and Erk1/2 phosphorylation in a concentration- and time-dependent manner. Furthermore, PI3K inhibitor LY294002 and Erk1/2 inhibitor U0126 suppressed the induction of HO-1 and translocation of Nrf-2 by xyloketal B, whereas P38 inhibitor SB203580 did not. In conclusion, xyloketal B can induce HO-1 expression via PI3K/Akt/Nrf-2 pathways, and the induction of HO-1 is mainly responsible for the antioxidant and antiapoptotic actions of xyloketal B.

New bisabolane sesquiterpenoids from a marine-derived fungus Aspergillus sp. isolated from the sponge Xestospongia testudinaria.

Three new phenolic bisabolane sesquiterpenoid dimers, disydonols A-C (1-3), and one known compound (S)-(+)-sydonol (4) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Their structures were elucidated on the basis of comprehensive spectral analysis including 1D and 2D NMR spectra and HR-ESI-MS. These compounds were evaluated for cytotoxic activity against HepG-2 and Caski human tumour cell lines. Among them, compounds 1 and 3 exhibited cytotoxicity against the two cell lines.

Bioactive hydroanthraquinones and anthraquinone dimers from a soft coral-derived Alternaria sp. fungus.

Five new hydroanthraquinone derivatives, tetrahydroaltersolanols C-F (1-4) and dihydroaltersolanol A (5), and five new alterporriol-type anthranoid dimers, alterporriols N-R (12-16), along with seven known analogues (6-11 and 17), were isolated from the culture broth and the mycelia of Alternaria sp. ZJ-2008003, a fungus obtained from a Sarcophyton sp. soft coral collected from the South China Sea. Their structures and the relative configurations were elucidated using comprehensive spectroscopic methods including 1D and 2D NOE spectra as well as single-crystal X-ray crystallography. Compound 13 represents the first isolated alterporriol dimer with a C-4-C-4' linkage, and the absolute configuration of 4 was determined using the modified Mosher's method. Compounds 1 and 15 exhibited antiviral activity against the porcine reproductive and respiratory syndrome virus (PRRSV), with IC50 values of 65 and 39 µM, respectively. Compound 14 showed cytotoxic activity against PC-3 and HCT-116 cell lines, with IC50 values of 6.4 and 8.6 µM, respectively.

Antibacterial anthraquinone derivatives from a sea anemone-derived fungus Nigrospora sp.

Chemical investigation of a marine-derived fungus Nigrospora sp., isolated from an unidentified sea anemone, yielded two new hydroanthraquinone analogues, 4a-epi-9α-methoxydihydrodeoxybostrycin (1) and 10-deoxybostrycin (2), together with seven known anthraquinone derivatives (3-9). The structures of the two new compounds were established through extensive NMR spectroscopy as well as a single-crystal X-ray diffraction analysis using Cu Kα radiation. The antibacterial activities of compounds 1-9 and 10 acetyl derivatives (6a, 7a, 8a-8g, 9a) were evaluated in vitro. Compound 6a, the acetylated derivative of 6, exhibited promising activity against Bacillus cereus with an MIC value of 48.8 nM, which was stronger than that of the positive control ciprofloxacin (MIC = 1250 nM). Analysis of the antibacterial screening data for the metabolites and their acetyl derivatives revealed the key structural features required for this activity.

Metabolites of the mangrove fungus Xylaria sp. BL321 from the South China Sea.

Two new lactones, 1 and 2, together with five known compounds, 3-7, were isolated from the marine mangrove fungus Xylaria sp. BL321. Their structures were determined by comprehensive analysis of their MS and NMR spectroscopic data. The absolute configurations of 1 and 2 were established on the basis of electronic circular dichroism calculations. It was found that the exocyclic double bond of 1 rearranged into a cyclic double bond to form a new crystal compound (1a) in diluted NaOH solution. Compound 3 was isolated for the first time as a natural product; its absolute configuration was determined by single-crystal X-ray crystallography. Compounds 4-7 displayed cytotoxicity against human breast cancer cell lines MCF-7 and MDA-MB-435, while compounds 1- 3 were inactive (IC(50) > 50 µM).

Synthesis and antitumor activities of derivatives of the marine mangrove fungal metabolite deoxybostrycin.

Deoxybostrycin (1) is an anthraquinone compound derived from the marine mangrove fungus Nigrospora sp. No. 1403 and has potential to be a lead for new drugs because of its various biological properties. A series of new derivatives (2-22) of deoxybostrycin were synthesized. The in vitro cytotoxicity of all the new compounds was tested against MDA-MB-435, HepG2 and HCT-116 cancer cell lines. Most of the compounds exhibit strong cytotoxicity with IC50 values ranging from 0.62 to 10 µM. Compounds 19, 21 display comparable cytotoxicity against MDA-MB-435 to epirubicin, the positive control. The primary screening results indicate that the deoxybostrycin derivatives might be a valuable source of new potent anticancer drug candidates.

Marine cyclotripeptide X-13 promotes angiogenesis in zebrafish and human endothelial cells via PI3K/Akt/eNOS signaling pathways.

Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.

Modeling Dynamic Recrystallization Behavior in a Novel HIPed P/M Superalloy during High-Temperature Deformation.

The dynamic recrystallization (DRX) features and the evolution of the microstructure of a new hot isostatic pressed (HIPed) powder metallurgy (P/M) superalloy are investigated by hot-compression tests. The sensitivity of grain dimension and DRX behavior to deformation parameters is analyzed. The results reveal that the DRX features and grain-growth behavior are significantly affected by deformation conditions. The DRX process is promoted with a raised temperature/true strain or a reduced strain rate. However, the grains grow up rapidly at relatively high temperatures. At strain rates of o.1 s-1 and 1 s-1, a uniform microstructure and small grains are obtained. Due to the obvious differences in the DRX rate at various temperatures, the piecewise DRX kinetics equations are proposed to predict the DRX behavior. At the same time, a mathematical model for predicting the grain dimension and the grain growth behavior is established. To further analyze the DRX behavior and the changes in grain dimension, the hot deformation process is simulated. The developed grain-growth equation as well as the piecewise DRX kinetics equations are integrated into DEFORM software. The simulated DRX features are consistent with the test results, indicating that the proposed DRX kinetics equations and the established grain-growth model can be well used for describing the microstructure evolution. So, they are very useful for the practical hot forming of P/M superalloy parts.

Aspergilones A and B, two benzylazaphilones with an unprecedented carbon skeleton from the gorgonian-derived fungus Aspergillus sp.

Two novel benzylazaphilone derivatives with an unprecedented carbon skeleton, aspergilone A (1), and its symmetrical dimer with a unique methylene bridge, aspergilone B (2), have been isolated from the culture broth of a marine-derived fungus Aspergillus sp. from a gorgonian Dichotella gemmacea. Their structures and relative stereochemistries of 1 and 2 were elucidated using a combination of NMR spectroscopy and X-ray crystallography. Compound 1 not only exhibited in vitro selective cytotoxicity but also showed potent antifouling activity.

Potent antifouling resorcylic acid lactones from the gorgonian-derived fungus Cochliobolus lunatus.

Three new 14-membered resorcylic acid lactones, two with a rare natural acetonide group and one with a 5-chloro-substituted lactone, named cochliomycins A-C (1-3), together with four known analogues, zeaenol (4), LL-Z1640-1 (5), LL-Z1640-2 (6), and paecilomycin F (7), were isolated from the culture broth of Cochliobolus lunatus, a fungus obtained from the gorgonian Dichotella gemmacea collected in the South China Sea. Their structures and the relative configurations of 1-3 were elucidated using comprehensive spectroscopic methods including NOESY spectra and chemical conversions. A transetherification reaction was also observed in which cochliomycin B (2) in a solution of CDCl(3) slowly rearranged to give cochliomycin A (1) at room temperature. These resorcylic acid lactones were evaluated against the larval settlement of barnacle Balanus amphitrite, and antifouling activity was detected for the first time for this class of metabolites. The antibacterial and cytotoxic activities of these compounds were also examined.

Lobophorin C and D, new kijanimicin derivatives from a marine sponge-associated actinomycetal strain AZS17.

Marine sponge Hymeniacidon sp. was collected from coastal waters of the East China Sea to isolate symbiotic microorganisms. The resulting sponge-associated actinomycete, Streptomyces carnosus strain AZS17, was cultivated in a 20 L volume of medium for production of bioactive secondary metabolites. Bioassay-guided isolation and purification by varied chromatographic methods yielded two new compounds of kijanimicin derivatives, AS7-2 and AS9-12. Their structures were elucidated by spectroscopy and comparison with literatures. Results showed these two compounds were structurally similar to the previously reported compounds lobophorin A and B, yet differed in specific bond forms, stereochemistry and optical activities. The two novel compounds were named lobophorin C and D. In vitro cytotoxicity investigation by MTT assay indicated their selective activities. Lobophorin C displayed potent cytotoxic activity against the human liver cancer cell line 7402, while lobophorin D showed significant inhibitory effect on human breast cancer cells MDA-MB 435.

Statistical research on marine natural products based on data obtained between 1985 and 2008.

Since the 1960s, more than 20,000 compounds were discovered from marine organisms. In this paper we performed a quantitative analysis for the novel marine natural products reported between 1985 and 2008. The data was extracted mainly from the reviews of Faulkner and Blunt [1-26]. The organisms producing these marine natural products are divided into three major biological classes: marine microorganisms (including phytoplankton), marine algae and marine invertebrate. The marine natural products are divided into seven classes based on their chemical structure: terpenoids, steroids (including steroidal saponins), alkaloids, ethers (including ketals), phenols (including quinones), strigolactones, and peptides. The distribution and the temporal trend of these classes (biological classes and chemical structure classes) were investigated. We hope this article provides a comprehensive perspective on the research of marine natural products.

Three bianthraquinone derivatives from the mangrove endophytic fungus Alternaria sp. ZJ9-6B from the South China Sea.

Three new bianthraquinone derivatives, alterporriol K (1), L (2) and M (3), along with six known compounds were obtained from extracts of the endophytic fungus Alternaria sp. ZJ9-6B, isolated from the mangrove Aegiceras corniculatum collected in the South China Sea. Their structures were elucidated by one- and two-dimensional NMR spectroscopy, MS data analysis and circular dichroism measurements. Compounds 1, 2 and 3 were first isolated alterporriols with a C-2-C-2' linkage. The crystallographic data of tetrahydroaltersolanol B (7) was reported for the first time. In the primary bioassays, alterporriol K and L exhibited moderate cytotoxic activity towards MDA-MB-435 and MCF-7 cells with IC50 values ranging from 13.1 to 29.1 µM.

Synthesis and cytotoxic evaluation of eremophilane sesquiterpene 07H239-A derivatives.

Nine new derivatives (6-14) of the eremophilane sesquiterpene 07H239-A (5) were designed and semisynthesized with two types of R-groups by amidation. Most of them were active against five human tumor cell lines, and compounds 6-10 were more potent than the natural product 5. In particular, compounds 6 and 9 exhibited the strongest cytotoxic activity against MDA-MB-435 with IC50 values of 0.91 and 0.96 µM, respectively. Preliminary structure-activity relationships (SARs) analysis indicated that the 14-carboxyl in 5 was an ideal target for chemical modification, and the side chain of 5 might play a necessary role in facilitating their cytotoxic potencies.