Combination Treatment of Deep Sea Water and Fucoidan Attenuates High Glucose-Induced Insulin-Resistance in HepG2 Hepatocytes.

Insulin resistance (IR) plays a central role in the development of several metabolic diseases, which leads to increased morbidity and mortality rates, in addition to soaring health-care costs. Deep sea water (DSW) and fucoidans (FPS) have drawn much attention in recent years because of their potential medical and pharmaceutical applications. This study investigated the effects and mechanisms of combination treatment of DSW and FPS in improving IR in HepG2 hepatocytes induced by a high glucose concentration. The results elucidated that co-treatment with DSW and FPS could synergistically repress hepatic glucose production and increase the glycogen level in IR-HepG2 cells. In addition, they stimulated the phosphorylation levels of the components of the insulin signaling pathway, including tyrosine phosphorylation of IRS-1, and serine phosphorylation of Akt and GSK-3ß. Furthermore, they increased the phosphorylation of AMPK and ACC, which in turn decreased the intracellular triglyceride level. Taken together, these results suggested that co-treatment with DSW and FPS had a greater improving effect than DSW or FPS alone on IR. They might attenuate IR by targeting Akt/GSK-3ß and AMPK pathways. These results may have some implications in the treatment of metabolic diseases.

Chemical constituents from Euphorbia wallichii and their biological activities.

One rare diterpenoid which was an unusual phorbol derivative possessing a 5-ene-7-oxo functional group, wallichiioid A (1), and 17 known compounds (2-18) were isolated from the aerial parts of Euphorbia wallichii. The structures and relative configuration of these compounds were elucidated on the basis of extensive spectroscopic interpretation. All the known compounds were isolated from E. wallichii for the first time. Diterpenoids 1-5 were tested for their cytotoxicity against five cancer cell lines (A-549, MCF-7, Hep G2, HeLa, and P388) and showed IC(50) values in the range of 8.19-29.72 µg/mL. The antiangiogenic activities of diterpenoids 1-5 were also evaluated using a zebrafish model.

Jatropholane-type diterpenes from Euphorbia sikkimensis.

Four new jatropholane-type diterpenes (1-4), named sikkimenoids A-D, were isolated from the aerial parts of Euphorbia sikkimensis. The structural elucidations of 1-4 were accomplished by extensive NMR analyses, and their absolute configurations were established by ECD calculations. Compound 2 exhibited weak antiangiogenic activity with an IC(50) value of 43.0 µM when evaluated using a zebrafish model.

A Combination of Deep-Sea Water and Fucoidan Alleviates T2DM through Modulation of Gut Microbiota and Metabolic Pathways.

Fucoidan and deep-sea water (DSW) are attractive marine resources for treating type 2 diabetes (T2DM). In this study, the regulation and mechanism associated with the co-administration of the two were first studied using T2DM rats, induced by a high fat diet (HFD) and streptozocin (STZ) injection. Results demonstrate that, compared to those with DSW or FPS alone, the orally administered combination of DSW and FPS (CDF), especially the high dose (H-CDF), could preferably inhibit weight loss, decrease levels of fasting blood glucose (FBG) and lipids, and improve hepatopancreatic pathology and the abnormal Akt/GSK-3ß signaling pathway. The fecal metabolomics data show that H-CDF could regulate the abnormal levels of metabolites mainly through the regulation of linoleic acid (LA) metabolism, bile acid (BA) metabolism, and other related pathways. Moreover, H-CDF could adjust the diversity and richness of bacterial flora and enrich bacterial groups, such as Lactobacillaceae and Ruminococcaceae UCG-014. In addition, Spearman correlation analysis illustrated that the interaction between the gut microbiota and BAs plays an essential role in the action of H-CDF. In the ileum, H-CDF was verified to inhibit activation of the farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) pathway, which is regulated by the microbiota-BA-axis. In conclusion, H-CDF enriched Lactobacillaceae and Ruminococcaceae UCG-014, thereby changing BA metabolism, linoleic acid metabolism, and other related pathways, as well as enhancing insulin sensitivity and improving glucose and lipid metabolism.

A novel influenza A (H1N1) vaccine in various age groups.

BACKGROUND: There is an urgent need for a vaccine that is effective against the 2009 pandemic influenza A (H1N1) virus. METHODS: A split-virus, inactivated candidate vaccine against the 2009 H1N1 virus was manufactured, and we evaluated its safety and immunogenicity in a randomized clinical trial. Subjects were between 3 and 77 years of age, stratified into four age groups. The immunization schedule consisted of two vaccinations, 21 days apart. Subjects were injected with placebo or with vaccine, with or without alum adjuvant, at doses of 7.5 microg, 15 microg, or 30 microg. Serologic analysis was performed at baseline and on days 21 and 35. RESULTS: A total of 2200 subjects received one dose, and 2103 (95.6%) received the second dose, of vaccine or placebo. No severe adverse side effects associated with the vaccine were noted. In the nonadjuvanted-vaccine groups, injection-site or systemic reactions, most mild in nature, were noted in 5.5 to 15.9% of subjects. Among the subjects receiving 15 microg of nonadjuvanted vaccine, a hemagglutination-inhibition titer of 1:40 or more was achieved by day 21 in 74.5% of subjects between 3 and 11 years of age, 97.1% of subjects between 12 and 17 years, 97.1% of subjects between 18 and 60 years, and 79.1% of subjects 61 years of age or older; by day 35, the titer had been achieved in 98.1%, 100%, 97.1%, and 93.3% of subjects, respectively. The proportion with a titer of 1:40 or more was generally highest among the subjects receiving 30 microg of vaccine, with or without adjuvant. Vaccine without adjuvant was associated with fewer local reactions and greater immune responses than was vaccine with adjuvant. CONCLUSIONS: These data suggest that a single dose of 15 microg of hemagglutinin antigen without alum adjuvant induces a typically protective immune response in the majority of subjects between 12 and 60 years of age. Lesser immune responses were seen after a single dose of vaccine in younger and older subjects. (ClinicalTrials.gov number, NCT00975572).

Deep Sea Water Alleviates Tau Phosphorylation and Cognitive Impairment via PI3K/Akt/GSK-3ß Pathway.

Deep sea water (DSW), as a noticeable natural resource, has been demonstrated to contain high levels of beneficial minerals and exert marked anti-diabetes effects. Epidemiological studies show that type 2 diabetes mellitus (T2DM) is closely related to high danger of Alzheimer's disease (AD); moreover, Akt/GSK-3ß signaling is the main underlying pathway that connects these two diseases. Besides, it has been demonstrated that minerals in DSW, such as Mg, Se, and Zn, could effectively treat cognitive deficits associated with AD. Herein, we first observed the protection of DSW against cognitive dysfunction in T2DM rats, then furtherly explored the neuroprotective mechanism in SH-SY5Y cell model. In T2DM rats, DSW obviously elevated the concentrations of elements Mg, V, Cr, Zn, and Se in brain and improved learning and memory dysfunction in behavior assays, including Morris water maze (MWM) and new object recognition (NOR). Western blot (WB) results demonstrated that DSW could stimulate PI3K/Akt/GSK-3ß signaling, arrest Tau hyperphosphorylation at serine (Ser) 396 and threonine (Thr)231, which was confirmed by immunohistochemistry (IHC). In order to further confirm the mechanism, we employed wortmannin to inhibit PI3K in SH-SY5Y cells; results showed that pretreatment with wortmannin almost abolished DSW-induced decreases in phosphorylated Tau. Taken together, these data elucidated that DSW could improve Tau hyperphosphorylation and cognitive impairment, which were closely related with the stimulation of Akt/GSK-3ß signaling, and the neuroprotective effects of DSW should be contributed to the synergistic effects of major and trace elements in it, such as Mg, V, Cr, Zn, and Se. These experimental evidence indicated that DSW may be explored as natural neuroprotective food for the prevention and treatment of AD.

In vitro and in vivo pharmacokinetics of two novel 1,3-cyclic propanyl phosphate ester prodrugs of 18ß-glycyrrhetic acid in rats.

The in vitro metabolism of two novel phosphate prodrugs of glycyrrhetic acid (GA) was studied by the method of incubation in the rat liver microsome and the in vivo plasma pharmacokinetics after injecting intravenously (i.v.) into six rats was investigated, respectively. The prodrugs diminished gradually with time and most of the parent drugs were released in 30 min in vitro. In this paper, the in vivo plasma concentration data were analyzed by compartmental modeling. Both the prodrugs and the corresponding released parent drugs could be described by a two-compartment model, which existed for 48 h in rats. The t(1/2) increases remarkably after i.v. administration to rats when compared with injecting the parent drugs directly.

Octa-kis(2-chloro-benz-yl)di-µ(2)-hydroxido-di-µ(3)-oxido-bis-(2-phenyl-acetato)tetra-tin(IV).

The asymmetric unit of the title compound, [Sn(4)(C(7)H(6)Cl)(8)(C(8)H(7)O(2))(2)O(2)(OH)(2)], comprises one-half of the centrosymmetric tin(IV) complex. µ(3)-Oxide and µ(2)-hydroxide bridges link the four five-coordinate Sn(IV) atoms to generate three fused four-membered Sn-O-Sn-O rings in a ladder-like structure. The two endocyclic Sn atoms each bind to two µ(3)-oxide anions and a µ(2)-hydroxide ligand, together with two 2-chloro-benzyl groups. The exocyclic Sn atoms each carry a monodentate phenyl-acetate ligand, two 2-chloro-benzyl groups, and µ(3)-oxide and µ(2)-hydroxide ligands. Both types of Sn atoms adopt a distorted trigonal-bipyramidal coordination geometry. The mol-ecular conformation is stabilized by intra-molecular O-H⋯O inter-actions involving the µ(2)-hydroxide ligands and the C=O group of the phenyl-acetate ligand.

Cytotoxic neo-clerodane diterpenoid alkaloids from Scutellaria barbata.

Six new neo-clerodane diterpenoid alkaloids, named scutehenanines A-D (1, 4, 5, 6), 6-O-acetylscutehenanine A (2), and 6-O-(2-carbonyl-3-methylbutanoyl)scutehenanine A (3), were isolated from the whole plant of Scutellaria barbata. Their structures were established on the basis of detailed physical data analyses. In vitro, the six new isolated compounds showed cytotoxic activities against three human cancer lines (HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells) and gave IC50 values in the range 2.8-6.4 microM.

Two new neo-clerodane diterpenoid alkaloids from Scutellaria barbata with cytotoxic activities.

Two new neo-clerodane diterpenoid alkaloids, scutebarbatine O (1) and 6-O-nicotinoylscutebarbatine G (2), were isolated from the whole plant of Scutellaria barbata. Their structures were elucidated by spectroscopic methods including extensive 1D and 2D NMR analyses. In vitro, compounds 1 and 2 showed cytotoxic activities against three human tumor cell lines, namely, HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells, and with IC(50) values in the range of 2.1-5.7 microM.

Uptake of oleoyl-chitosan nanoparticles by A549 cells.

The aim of the present study was to evaluate cellular uptake of oleoyl-chitosan (OCH) nanoparticles by using A549 cells, a human lung carcinoma cell line, for drug and gene delivery applications. In this study, self-assembled OCH nanoparticles encapsulating a fluorescent marker molecule, fluorescein isothiocyanate (FITC), were prepared and characterized. The effects of particle size, concentration, and incubation time on the cellular uptake of the nanoparticles (FITC-OCH nanoparticles) were quantified by spectrofluorometric measurement and confirmed using fluorescence microscopy studies. The nanoparticles were taken up by the cells, and levels of binding and uptake increased with the decrease of particle size and the increase of particle concentration and incubation time. These results implied that the OCH nanoparticles have great potential to be applied as a drug carrier system to deliver drugs into the cells.

Minor Prenylated Flavonoids from the Twigs of Macarangaadenantha and Their Cytotoxic Activity.

Three new minor prenylated flavonoids, named macadenanthins A-C (1-3), together with three known ones (4-6), were isolated from the twigs of Macaranga adenantha. Their structures were elucidated on the basis of extensive spectroscopic analysis including NMR, UV and MS. The prenyl moieties in compounds 1-3 were further modified by cyclization and hydroxylation. The new compounds were tested for their cytotoxicity against four cancer cell lines (MCF-7, Hep G2, Hela and P388) and showed IC50 values in the range of 13.76-22.27 µM.

Three new prenylated flavonoids from Macaranga denticulata and their anticancer effects.

One rare flavonoid-diterpene heterodimer, denticulatain C (1), one modified geranyl-type side chain substituted flavonoid, denticulatain D (2) and one geranylated flavonoid, denticulatain E (3), as well as 11 known compounds (4-14) were isolated from the fronds of Macaranga denticulata. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 4 and 8 inhibited the proliferation of A-549 cell line with IC50 values of 48.6 and 20.2 µg/mL, respectively. Compounds 3, 6, and 8 exhibited significant antiangiogenic activity on a zebrafish model with IC50 values of 9.78, 0.34, and 2.55 µg/mL, respectively.

Cytotoxic prenylated flavonoids from Macaranga indica.

Three new prenylated flavonoids, macarindicins A-C (1-3), as well as seven known compounds (4-10) were isolated from the twigs of Macaranga indica. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 2 and 3 enriched the diversity of prenyl moiety in genus Macaranga especially in the aspect of various lengths of prenyl chain. All the known compounds were isolated from M. indica for the first time and this plant was found to contain large number of ellagic acid. Compounds 1-10 were tested for their cytotoxicity against four cancer cell lines (MCF-7, Hep G2, Hela and P388) and showed IC50 values in the range of 2.61-20.35 µg/mL.

Cytotoxic prenylated bibenzyls and flavonoids from Macaranga kurzii.

One unique prenylated bibenzyl, kurzphenol A (1), two new prenylated flavonoids, kurzphenols B and C (2 and 3), as well as fourteen known compounds (4-17) were isolated from the twigs of Macaranga kurzii. Compound 1 was the first example of prenylated bibenzyl which possesses a benzofuran ring. All the known compounds were isolated from M. kurzii for the first time. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 1-17 were tested for their cytotoxicity against A-549 and Hep G2 cancer cell lines and showed IC50 values in the range of 9.76-30.14 µg/mL.

Chemical constituents from Euphorbia stracheyi and their biological activities.

Three new diterpenoids, stracheyioids A-C (1-3), as well as 36 known compounds (4-39) were isolated from the whole plants of Euphorbia stracheyi. Compound 1 was a rare 13-deoxy tigliane diterpenoid and compound 2 was an ingenol diterpenoid characterized by an unique 2Z,4Z-decadienoyl acidic moieties. All the known compounds were isolated from E. stracheyi for the first time. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 1-39 were tested for their cytotoxicity against five cancer cell lines (A-549, MCF-7, Hep G2, Hela and P388) and showed IC50 values in the range 6.64-42.86 µM. The antiangiogenic activities of the isolated compounds were also evaluated using a zebrafish model.

New norditerpenoid alkaloids from Scutellaria barbata with cytotoxic activities.

Two new norditerpenoid alkaloids, named scutebarbatines M-N (1 and 2), were isolated from the whole plant of Scutellaria barbata D. Don. Their structures were established on the basis of detailed spectral analyses. In vitro, two new compounds showed significant cytotoxic activities against three human cancer lines (HONE-1 nasopharyngeal, KB oral epidermoid carcinoma and HT29 colorectal carcinoma cells), and gave IC50 values in the range of 3.5-6.3 µM.