Glycosaminoglycan from Ostrea rivularis attenuates hyperlipidemia and regulates gut microbiota in high-cholesterol diet-fed zebrafish.

Hyperlipidemia an immense group of acquired or genetic metabolic disorders that is characterized by an excess of lipids in the bloodstream. Altogether, they have a high prevalence worldwide and constitute a major threat to human health. Glycosaminoglycans (GAG) are natural biomolecules that have hypolipidemic activity. The purpose of this study was to investigate the potential hypolipidemic effect of glycosaminoglycans extracted from Ostrea rivularis (OGAG) on hyperlipidemic zebrafish, as well as the possible underlying mechanism of such effect. Dietary supplementation with OGAG during 4 weeks significantly reduced the serum and hepatic lipid levels and the hepatosomatic index in hyperlipidemic zebrafish. In addition, histopathological showed that OGAG supplementation decreases the volume and number of lipid droplets in hepatocytes. Transcriptome and real-time quantitative polymerase chain reaction analysis revealed that the gene expression levels of PPARγ, SCD, HMGRA, ACAT2, HMGCS, and HMGCR were significantly downregulated by OGAG treatment in hepatocytes, whereas those of CD36, FABP2, FABP6, ABCG5, and CYP7A1 were significantly upregulated. This suggests that the hypolipidemic effect of OGAG relies on increasing the ketogenic metabolism of fatty acids, inhibiting cholesterol synthesis, and enhancing the transformation of cholesterol to bile acid. Furthermore, OGAG treatment improved gut microbiota imbalance by reducing the Firmicutes-to-Bacteroidetes ratio, increasing the relative abundance of beneficial bacteria (Bacteroidetes, Verrucomicrobia, Acidobacteria, and Sphingomonas), and reducing the relative abundance of harmful bacteria (Proteobacteria, Cohaesibacter, Vibrio, and Terrisporobacter). These findings highlight the potential benefit of implementing OGAG as a dietary supplement to prevent and treat hyperlipidemia.

Discovery of 2-(3,4-dialkoxyphenyl)-2-(substituted pyridazin-3-yl)acetonitriles as phosphodiesterase 4 inhibitors with anti-neuroinflammation potential based on three-dimensional quantitative structure-activity relationship study.

Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti-neuroinflammation activities, reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross-validated coefficient (q2 ), conventional coefficient (r2 ), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2-(3,4-dialkoxyphenyl)-2-(substituted pyridazin-3-yl) acetonitriles 16a-i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid-nanomolar IC50 values and potential anti-neuroinflammation activity in BV-2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a "V-shaped" conformation, extending the side chain to S-pocket.

[Role of cAMP/CREB/BDNF signaling pathway in anti-depressive effect of vortioxetine in mice].

OBJECTIVE: To investigate the effects of vortioxetine on cAMP/CREB/BDNF signal pathway. METHODS: Forty Kunming mice were randomized into control group and chronic unpredictable mild stress (CUMS) group. After establishment of depressive models verified by sucrose preference test, the mice in CUMS group were divided into model group, fluoxetine group and vortioxetine group. The antidepressive effect of vortioxetine was analyzed by tail suspension test, forced swim test and open field test. The levels of cAMP were detected using a commercial ELISA kit, and the expressions of pCREB and brain-derived neurotrophic factor (BDNF) were evaluated with Western blotting. RESULTS: Vortioxetine significantly shortened the immobility time of the depressive mice in tail suspension test and forced swim test without affecting the locomotor activity of the mice in open fields, suggesting the antidepressive effect of against depression in mice. Vortioxetine significantly increased the levels of cAMP and promoted the expression of pCREB and BDNF in the hippocampus of the mice (P<0.01). CONCLUSION: Vortioxetine improves the behaviors of mice with depression possibly by affecting the cAMP/CREB/BDNF signal pathway.

Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings.

In this study, catecholamides (7a-l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.

Subcritical water extraction of antioxidant phenolic compounds from XiLan olive fruit dreg.

Olive fruit dreg (OFD), waste from olive softdrink processing, has caused disposal problems. Nevertheless, OFD is a good source of functional ingredients, such as phenolic compounds. This study investigated the extraction conditions of phenolic compounds from OFD by using subcritical water (SCW) extraction method, antioxidant activity of SCW extracts, and components of phenolic compounds by LC-MS. SCW extraction experiments were performed in a batch stainless steel reactor at temperatures ranging from 100 to 180 °C at residence time of 5 to 60 min, and at solid-to-liquid ratio of 1:20 to 1:60. Higher recoveries of phenolic compounds [37.52 ± 0.87 mg gallic acid equivalents (GAE)/g, dry weight (DW)] were obtained at 160 °C, solid-to-liquid ratio of 1:50, and extract time of 30 min than at 2 h extraction with methanol (1.21 ± 0.16 mg GAE/g DW), ethanol (0.24 ± 0.07 mg GAE/g DW), and acetone (0.34 ± 0.01 mg GAE/g DW). The antioxidant activities of the SCW extracts were significantly stronger than those in methanol extracts at the same concentration of total phenolic contents. LC-MS analysis results indicated that SCW extracts contained higher amounts of phenolic compounds, such as chlorogenic acid, homovanillic acid, gallic acid, hydroxytyrosol, quercetin, and syringic acid. SCW at 160 °C, 30 min, and solid-to-liquid ratio of 1:50 may be a good substitute of organic solvents, such as methanol, ethanol, and acetone to recover phenolic compounds from OFD.

[Prokaryotic expression of SARS coronavirus spike protein and construction of its DNA vaccine].

OBJECTIVE: To study the immunological characteristics of the spike (S) protein of SARS coronavirus (SARS-CoV) and analyze the feasibility of using this protein as the component for SARS vaccine development. METHODS: The two truncated fragments of S gene were separately cloned into the prokaryotic expression vector pET-15b and expressed in E.coli. The resulting recombinant proteins, rS(a) and rS(b), were purified by affinity chromatography. The full-length S gene was cloned into the eukaryotic expression plasmid pSecTagB to prepare recombinant plasmid pSecS as the DNA vaccine to immunize BALB/c mice for inducing the secretion of anti-SARS-CoV protein. The immunological effect of anti-SARS-CoV antibody was tested with purified rS(a) and rS(b) proteins by enzyme-linked immunosorbent assay (ELISA). RESULTS: Both the truncated recombinant proteins were expressed in soluble forms and reacted specifically with the sera from immunized pSecS mice and clinically diagnosed SARS patients. The prokaryotically expressed recombinant truncated S protein had similar antigenicity with SARS-CoV S protein. CONCLUSION: The recombinant protein could be used as an antigen for detecting the serum of SARS CoV-infected patients. The SARS-CoV S gene vaccine could induce the production of specific antibody, which offers clues for the research of SARS DNA vaccine.