Hypertonicity contributes to seawater aspiration-induced lung injury: Role of hypoxia-inducible factor 1α.

Drowning is an important public health problem, but the mechanism of acute lung injury induced by near-drowning is rarely reported. The aim of this study is to investigate the role of hypertonicity and HIF-1α in seawater aspiration-induced lung injury. Diverse solutions were used to study the effect of hypertonicity on hypoxia, inflammation, vascular leakage, edema, and HIF-1α expression in lungs of rats. The relationship between hypertonicity and hypoxia, when they induced HIF-1α, was studied and the roles of ATM, PI3K, and p38 in the course of hypertonicity inducing HIF-1α were investigated. At last, our conclusion was verified with HIF-1α inhibitor and inducer in seawater aspiration rats. The results showed that hypertonicity, but not isotonicity and hypotonicity, promoted hypoxia, inflammation, vascular leakage, edema, and HIF-1α expression in lungs. Hypertonicity not only induced HIF-1α in a time- and dose-dependent manner but also could increase HIF-1α synergistically with hypoxia in AEC. Furthermore, hypertonicity increased HIF-1α by promoting its mRNA expression through both ATM and PI3K activation and by suppressing its protein degradation through p38 activation. During hyperosmotic stress, the increased HIF-1α promoted the production of the inflammatory cytokines in NR8383 and elevated monolayer permeability through increasing VEGF in RLMVEC. In conclusion, hypertonicity induced by aspirated seawater aggravated lung injury through increasing HIF-1α which promoted inflammation and edema in lung tissues in rats.

Microbial transformation of resibufogenin by Curvularia lunata AS 3.4381.

In this paper, the microbial transformation of resibufogenin by Curvularia lunata AS 3.4381 was investigated, and four transformed products were isolated and characterized as 3-epi-resibufogenin (2), 12α-hydroxy-3-epi-resibufogenin (3), 12-oxo-16ß-hydroxy-3-epi-resibufogenin (4), and 12ß,15-epoxy-3-epi-bufalin-14,15-ene (5). Among them, 4 and 5 are new compounds, and isomerization, hydroxylation, and oxidation reactions in microbial transformation process were observed. Additionally, the cytotoxicities of transformed products (2-5) were also investigated.

Biotransformation of osthole by Alternaria longipes.

The biotransformation of osthole (1) by Alternaria longipes was carried out, and five transformed products were obtained in the present research work. Based on their extensive spectral data, the structures of these metabolites were characterized as 4'-hydroxyl-osthole (2), 4'-hydroxyl-2',3'-dihydroosthole (3), 2',3'-dihydroxylosthole (4), osthole-4'-oic acid methyl ester (5), and osthole-4'-oic acid glucuron-1-yl ester (6), respectively. Among them, products 5 and 6 were new compounds.

Optimization and characterization of dry powder of fanhuncaoin for inhalation based on selection of excipients.

In this study, dry powder formulations for inhalation of fanhuncaoin, a newly discovered antiinflammatorily active compound isolated from Chinese herb, were designed to optimize the composition and further explore the relationship between the composition, the physical properties and the aerosolization performance. Dry powders were prepared by spray-drying using leucine, chitosan, chitosan oligosaccharide and dipalmitoyl phosphatidylcholine (DPPC) as excipients. Following spray-drying, resultant powders were characterized using scanning electron microscopy, tapped density analysis, laser diffractometry, thermogravimetric analysis and differential scanning calorimetry. The aerosol behaviour of the powders was studied in a Twin Stage Impinger at an airflow rate of 60 l/min using a HandiHaler® inhaler device. Results revealed that the nature and the relative proportion of the excipients greatly influenced the physical characteristics of the powders and their aerodynamic behavior. Among the combinations tested, the composition ratio of fanhuncaoin/leucine/chitosan/chitosan oligosaccharide/DPPC of 10/45/33.75/11.25/0.4 (w/w/w/w/w) prepared in a total solid mass of 1% (w/v) formulation was found to be particularly optimal and exhibited a tapped density of 0.44 g/cm³, an aerodynamic diameter of 2.24 µm and an respirable fraction of 51.29%. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.

[A new trincallane derivative from Salacia hainanensis Chun et How].

Chemical constituents of the roots and stem of Salacia hainanensis Chun et How were isolated and purified with column chromatography on silica gel, Sephadex LH-20 and preparative HPLC. Their structures were elucidated based on physicochemical and spectral spectroscopic analysis. Depending on the activities of anti-alpha-glucosidase and inhibiting AGEs (advanced glycation end products, AGEs) formation in vitro, nine compounds were identified as 26, 27-dihydroxy-7, 24-tirucalladien-3-one (1), abruslactone A (2), lupeol (3), 21alpha, 30-dihydroxy-D: A-friedooleanan-3-one (4), 15alpha-hydroxyfriedelan-3-one (5), friedelin (6), mangiferin (7), epicatechin (8) and beta-sitosterol (9), separately. Among them, compound 1 is a new compound, and compound 2 was isolated from the Salacia genus for the first time, while, compounds 3, 4, 5, 8 were obtained from this plant for the first time.

Roles of PI3-K/Akt pathways in nanoparticle realgar powders-induced apoptosis in U937 cells.

AIM: To study the mechanism by which nanoparticle realgar powders (NRP) induce human histocytic lymphoma U937 cell apoptosis. METHODS: After the U937 cells were treated with various doses of NRP, the viability of the NRP-induced U937 cells was detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Granular apoptotic bodies with membrane blebbing and condensed nuclei were observed by fluorescence microscopy. The apoptotic ratio induced by NRP was measured by lactate dehydrogenase (LDH) activity-based assay. Caspase-3 and the expressions of Akt, p-Akt, a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (SIRT1), p53, and p-p53 were detected by Western blot analysis. RESULTS: The growth-inhibitory activity of NRP for U937 cells was in a time- and dose-dependent manner. After treatment with various concentrations of NRP for 24 h, the majority of U937 cells underwent apoptosis as measured by LDH assay. In the presence of NRP, wortmannin, the inhibitor of phosphoinositide 3-kinase (PI3-K), and Akt inhibitor KP372-1 augmented the NRP-induced cell apoptosis. When the U937 cells were treated with NRP for the indicated time periods, procaspase-3 was gradually degraded and the activated caspase-3 was significantly increased. The expressions of anti-apoptotic proteins Akt and p-Akt were downregulated. Importantly, the inhibition of SIRT1 contributed to the activation of p53 and the inactivation of the PI3-K/Akt signaling pathway increased the expression of the p53 protein and downregulated the SIRT1 protein expression. CONCLUSION: The PI3-K/Akt signaling pathway plays an important role in NRP-induced U937 cell apoptosis. The reduced SIRT1 expression and activated p53 might be partially due to the inhibition of the PI3-K/Akt pathway triggered by the NRP-induced initiation of U937 cell apoptosis.

A new triterpenoid from Panax ginseng exhibits cytotoxicity through p53 and the caspase signaling pathway in the HepG2 cell line.

A new triterpenoid, 20(R),22(xi),24(S)-dammar-25(26)-ene-3beta,6 alpha,12 beta,20,22,24-hexanol (1), and three known triterpenoids, beta-D-glucopyranoside,(3beta,12 beta)-12,20-dihydroxydammar-24-en-3-yl,6-acetate (2), 20(R)-ginsenoside Rg3 (3), and 20(R)-ginsenoside Rh2 (4), were isolated from the leaves of Panax ginseng. Their structures were determined by chemical analysis and spectral methods (IR, 1D and 2D NMR, HR-ESI-MS). Compounds 1-4 were exhibited various degrees of cytotoxicity in the human hepatoma cell line, HepG2. Compound 1 had the highest cytotoxic potency, with an IC50 value of 20.1 microM, by stimulating p53-mediated cell cycle arrest at the G1 to S phase transition, leading to apoptosis via activation of the caspase signaling pathway.

Nanoparticle realgar powders induce apoptosis in U937 cells through caspase MAPK and mitochondrial pathways.

Nanoparticle realgar powders (NRP) inhibited U937 cell growth in a time and dose-dependent manner. U937 cells treated with NRP showed typical characteristics of apoptosis including the morphological changes and DNA fragmentation. Caspase family inhibitor (z-VAD-fmk), caspase-8, -9 inhibitor (z-IETD-fmk, Ac-LEHD-CHO, respectively) and caspase-3 inhibitor (z-DEVD-fmk) partially prevented NRP -induced apoptosis. Moreover, the classical substrates of caspase-3, poly-ADP ribose polymerase (PARP) was degraded after U937 cells treatment with NRP. In addition, NRP increased the ratio of Bax/Bcl-2 protein expression. Although p38 inhibitor (SB203580) and ERK inhibitor (PD98059) failed to block cell death, JNK inhibitor (SP600125) had marked inhibitory effects on NRP -induced apoptosis. Furthermore, the phosphorylation of JNK was up-regulated, suggesting that JNK was responsible for NRP -induced apoptosis in U937 cells. These results suggested that the caspase, mitochondria and MAPK signal pathways were involved in NRP-induced U937 apoptosis.

Structure and absolute configuration of a diterpenoid from Castanea mollissima.

From the nuts of Castanea mollissima Blume, a new kauranoid diterpene glycoside, named mollioside (1), was isolated. Its structure was established as (4R, 5S, 6R, 8R, 9S, 10S, 13R, 16R) 17-O-beta-D-glucopyranoside, ent-6,7-epoxy-6alpha-hydroxyl-6,7-secokaur-19-oic acid, 6, 19-lactone-16beta, 17-diol on the basis of HR-FAB-MS, 1D, 2D-NMR and CD spectral analysis. The aglycone (1a, named mollissin), also as a new compound, was obtained after enzymatic hydrolysis of 1. Both compounds exhibited significant growth inhibitory activity on HeLa tumor cells, but no activity on A375-S2.