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Ethnopharmacological relevance Fritillariae Bulbus (Beimu in Chinese) is derived from the bulbus of many Fritillaria species (family Liliaceae ), which has been used as an antitussive herb in traditional Chinese medicine for more than 2000 years. Due to the complexity of plant origins and significant variations in chemical profiles, the characterization of the profile of the major bioactive constituents and its association with pharmacological activity are important for the quality control of Beimu herbs from different origins. Aim of the study This study aims to investigate the distribution of major bioactive isosteroidal alkaloids in Beimu herbs of different origins and its correlation with the tracheobronchial relaxant activity. Methods Quantification of 7 main bioactive 5 α -cevanine isosteroidal alkaloids, including ebeiedine, ebeiedinone, hupehenine, isoverticine, verticine, verticinone and imperialine, in 23 Fritillaria species was performed using gas chromatography. The relaxant effect of different extracts of 4 commonly used Beimu herbs, namely Zhe-Beimu ( F. thunbergii Miq.), Chuan-Beimu ( F. cirrhosa D. Don), Hubei-Beimu ( F. hupehensis Hsiao et K. C. Hsia) and Yi-Beimu ( F. pallidiflora Schrenk), was evaluated using rat isolated tracheal and bronchial preparations pre-contracted with carbachol, the well established in vitro antitussive model. Results Amongst 23 Fritillaria species detected, significant variations of the types and quantities of 7 major isosteroidal alkaloids were determined, which served as an important indicator for the classification of different Beimu herbs with distinct geographic distributions. Based on the type and quantity of these alkaloids, different origins of Beimu could be clearly clustered into several subgroups by principal component analysis. Furthermore, both crude alkaloid and water extracts of all 4 Beimu herbs showed a dose-dependent tracheobronchial relaxation with different potencies. The total content of alkaloids (weight adjusted based on the activity of individual alkaloids) in Beimu extracts significantly correlated with their tracheobronchial relaxation effects ( r 2 > 0.9, p < 0.001). Conclusions The results demonstrated that the differences in chemical profile of major bioactive isosteroidal alkaloids and pharmacological activity of Beimu could be incorporated into a simple and unified method for quality control and potential prediction of activity of Beimu herbs from different origins. [ABSTRACT FROM AUTHOR]

This study aims at examining the hypolipidemic effect of piceatannol on high fat diet (HFD)-induced hypercholesterolemic Sprague-Dawley rats and serum metabolite changes. Piceatannol supplement significantly lowered the total cholesterols, low density lipoprotein cholesterol levels and the atherogenic index as compared to the HFD model which only have increased dietary cholesterol intake. Using untargeted mass spectrometry-based metabolomic platforms, multivariate statistics revealed that HFD significantly perturbed fatty acids, lysophospholipids, bile acids and conjugated bile acids. Reduced CYP7A1 protein expression and increase in glycocholate and taurodeoxycholate after piceatannol treatment suggested the conjugated bile acid might contribute to the cholesterol-lowering effect. For lipid profiles, lysoPC (20:2) and lysoPC (20:0) were decreased while the ratio of esterified arachidonic acid to esterified dihomo-γ linoleic acid was up-regulated for rats after piceatannol supplement. These results indicated that the therapeutic effect of piceatannol is associated with bile acid and fatty acid metabolisms and reduced absorption of dietary cholesterols. [ABSTRACT FROM AUTHOR]

Lycium barbarum fruit (Goji or wolfberry) is widely used as a functional food as well as an herb in Chinese medicine. The polysaccharides of L. barbarum (LBPs) are well-known for immunomodulation and antioxidant activities. This study evaluated the yields, properties and bioactivities of LBPs extracted from L. barbarum fruit by different methods including hot water (HWE 100 °C), ultrasonic water (UWE 30–40 °C), subcritical water (SWE 110 °C), and ultrasound-enhanced subcritical water extraction (USWE 110 °C). The total LBP yield (80 min extraction followed by ethanol precipitation) was the highest from USWE (14% w/w) and the lowest from HWE (7.6%). The LBP from USWE also showed the highest protein (27.9%) and phenolic content (5.3%, w/w), and the highest antioxidant activities (scavenging radicals by DPPH and trolox equivalent antioxidant capacity assays; ferric reducing power). It also showed the highest immunoactivities in activating the phagocytosis and NO production of RAW264.7 macrophages. USWE was proven the most efficient method for extraction of LBPs. Temperature and ultrasound were two chief factors affecting the extraction yield, chemical properties and bioactivities of LBP. [ABSTRACT FROM AUTHOR]

Highlights: [•] Shan Zha’s hypocholesterolaemic and vasoprotective effects were investigated. [•] Shan Zha 80% ethanolic extract improved lipid profile in hypercholesterolaemic rats. [•] Endothelium-mediated aortic relaxation was enhanced in Shan Zha treated rats. [•] Shan Zha could provide its effect by up-regulating hepatic CYP7A1 mRNA expression. [•] Shan Zha may be used to treat hypercholesterolaemia-related complications. [Copyright &y& Elsevier]

Highlights: [•] Investigate the hypocholesterolaemic and vascular protective effects of PNS. [•] 28-Day treatment of PNS improved lipid profile in hypercholesterolaemic rats. [•] PNS improved endothelium-mediated aortic relaxation. [•] PNS gave its effect by changing the hepatic CYP7A1 and PPARα expressions. [•] This study provides mechanistic explanation of PNS’s beneficial effects. [Copyright &y& Elsevier]

Abstract: Gui-ling-gao (GLG), also known as turtle jelly, is a popular medicinal Chinese health/functional food prepared from several traditional Chinese medicinal herbs. The present study aimed at examining and explaining the anti-inflammatory properties of GLG by using lipopolysaccharide (LPS)-induced inflammation in splenocytes isolated from BALB/c mice. Additionally, the effects of GLG on mRNA and protein expressions of inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines in LPS-stimulated splenocyte proliferation were evaluated by real-time RT-PCR and Western blot assays. We demonstrated that GLG significantly inhibited LPS-induced splenocyte proliferation in a concentration-dependent manner. LPS-mediated up-regulations in the gene and protein expressions of iNOS, interleukin-1β (IL-1β) and tumour necrosis factor-alpha (TNF-α) were suppressed by GLG. These findings suggest for the first time that GLG exerts anti-inflammatory effects by inhibiting the expression of iNOS and pro-inflammatory cytokines such as IL-1β and TNF-α. The current study provides strong scientific evidence for the health-beneficial claim that consumption of GLG could help the body to modulate the immune system. [Copyright &y& Elsevier]

Abstract: Some of the major components of Danshen (Salvia miltiorrhiza), a widely used Chinese herbal medicine rich in phenolic acids, are thermosensitive and may degrade to other phenolic acids during extractions with heating. The chemical profiles of Danshen water-extract may vary with different heat water extraction at different temperatures, affecting the composition and bioactivity of the extracts. In this study, six water-extracts of Danshen obtained from heat reflux water extraction and microwave-assisted extraction with water (MAE-W) at different temperatures were tested for their composition and pharmacological effects. Among these extracts, the third-round MAE-W (100°C) extract had the highest phenolic acids and tanshinones contents, with the strongest antioxidant activity in 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay and ferric reducing/antioxidant potential (FRAP) assay. This extract also showed the strongest inhibitory effects on 2,2′-azobis-2-amidinopropane (AAPH)-induced hemolysis in human red blood cells, hydrogen peroxide-induced apoptosis in rat heart H9c2 cells and the highest relaxation effects on rat basilar artery. The antioxidant effects of Danshen water-extracts linearly correlated to their relaxation effects (r =0.895–0.977). Through multiple linear regression analysis, danshensu was found to be the most significant marker in the antioxidant and vasodilation effects of Danshen water-extract, while tanshinone IIA as the marker on hydrogen peroxide-induced apoptosis in rat heart H9c2 cells. Danshensu is, therefore, a useful marker for the quality control of Danshen water-extracts in antioxidant and vasodilation, while tanshinone IIA for anti-apoptotic potential of different extracts. [Copyright &y& Elsevier]

Abstract: The hypocholesterolemic and atheroscleroprotective potentials of dietary consumption of hawthorn (dried fruit of Crataegus pinnatifida, Shan Zha) were investigated by monitoring plasma lipid profiles and aortic relaxation in Sprague–Dawley rats fed with either normal diet, high-cholesterol diet (HCD) or HCD supplemented with hawthorn powder (2%, w/w) (4weeks). In HCD-fed rats, an increased plasma total cholesterol and LDL-cholesterol with a decreased HDL-cholesterol was observed, and consumption of hawthorn markedly suppressed the elevated total cholesterol and LDL-lipoprotein levels plus an increased HDL-cholesterol level. The blunted acetylcholine-induced, endothelium-dependent relaxation of isolated aortas of HCD-fed rats was improved by hawthorn. The development of fatty liver, an increased nitric oxide synthase (NOS) activity and an elevated oxidative stress (as estimated by the attenuated levels of anti-oxidant enzymes) associated with HCD were attenuated by hawthorn. Thus, the results demonstrated that hawthorn consumption provides overall beneficial effects on reversing HCD associated detrimental changes. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Rheum officinale Baill. (Da Huang) is one of the herbs commonly used in traditional Chinese medicine formulae against cancer. The traditional decoction is similar to the water extract used in the present study. Aim of the study: The water extract of Da Huang was investigated to see if it possesses anticancer effects through apoptotic pathways. Materials and methods: Human lung adenocarcinoma A549 and human breast cancer MCF-7 cell lines were treated with different concentrations of Da Huang water extract at different time intervals. Growth inhibition was detected by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] and colony formation assays; apoptosis was detected by cell morphologic analysis, DNA fragmentation analysis and COMET assay. Results: Da Huang water extract was found to have significant growth inhibitory effects on both A549 and MCF-7 cell lines with IC50 values 620±12.7 and 515±10.1μg/ml, respectively. Growth inhibitory effects were dose- and time-dependent. A significant decrease in cell number, DNA fragmentation and single DNA strand breakages were observed in the Da Huang water extract treated A549 and MCF-7 cells. Conclusions: This suggests that the water extract of Da Huang exerts potential anticancer activity through growth inhibition and apoptosis on MCF-7 and A549 cells lines. [Copyright &y& Elsevier]

Abstract: Hypercholesterolemia is a dominant risk factor for the development and progression of atherosclerosis and cardiovascular diseases. Natural compounds have been proved to be useful in lowering serum cholesterol to slow down the progression of cardiovascular diseases. Pueraria lobata is employed clinically to treat cardiovascular diseases in China. In the present study, the atheroscleroprotective potential of the herb''s major active compound, puerarin, was investigated by monitoring serum lipid profile and major enzyme expressions on cholesterol homeostasis in Sprague–Dawley rats fed with control diet, hypercholesterolmic diet or hypercholesterolmic diet plus administration of puerarin (300 mg/kg/day, p.o.) for 4 weeks. Puerarin markedly attenuated the increased total cholesterol induced by hypercholesterolmic diet in both serum and liver. It caused a significant reduction in the atherogenic index. Expression of mRNA for hepatic 7α-hydroxylase (CYP7A1) was significantly enhanced but not for those of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and lanosterol 14α-demethylase (CYP51). To further explore the atheroscleroprotective potential of puerarin, acetylcholine induced endothelium-dependent vasorelaxation and endothelial nitric oxide synthase (eNOS) expression on isolated thoracic aortas were analyzed. Animals administered with puerarin suppressed the hypercholesterolemic diet induced impairment of eNOS expression, whereas there was no significant difference in the endothelium-dependent vasorelaxation among various groups of animals. These data indicated that puerarin reduced the atherogenic properties of dietary cholesterol in rats. Its hypocholesterolemic function may be due to the promotion of cholesterol and bile acids excretion in liver. Whether puerarin targets directly on cholesterol homeostasis or both cholesterol homeostasis and endothelial function remains to be determined. [Copyright &y& Elsevier]

Equilibrative nucleoside transporters (ENTs) play a crucial role in the transport of nucleoside and nucleoside analogues, which are important for nucleotide synthesis and chemotherapy. In addition, ENTs regulate extracellular adenosine levels in the vicinity of its receptors and hence influence adenosine-related functions. The clinical applications of ENT inhibitors in the treatment of cardiovascular diseases and cancer therapy have been explored in numerous studies. However, all ENT inhibitors to date are selective for ENT1 but not ENT2. In the present study, we investigated the novel compound 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino- N -(naphthalen-2-yl)-1,3,5-triazin-2-amine (FPMINT) as an inhibitor of ENT1 and ENT2. Nucleoside transporter-deficient PK15NTD cells stably expressing ENT1 and ENT2 showed that FPMINT inhibited [ 3 H]uridine and [ 3 H]adenosine transport through both ENT1 and ENT2 in a concentration-dependent manner. The IC 50 value of FPMINT for ENT2 was 5-10-fold less than for ENT1, and FPMINT could not be displaced with excess washing. Kinetic studies revealed that FPMINT reduced V max of [ 3 H]uridine transport in ENT1 and ENT2 without affecting K M . Therefore, we conclude that FPMINT inhibits ENTs in an irreversible and non-competitive manner. Although already selective for ENT2 over ENT1, further modification of the chemical structure of FPMINT may lead to even better ENT2-selective inhibitors of potential clinical, physiological and pharmacological importance. [ABSTRACT FROM AUTHOR]

The safety of ready-to-eat foods is an important issue. Improper storage and handling of ready-to-eat items may lead to foodborne disease outbreaks. In this study, raw salmon finger sushi (nigiri) was selected as a target ready-to-eat food for microbiological surveillance. The aim of this study was to evaluate the microbiological quality of take-away sushi sold in the licensed sushi shops in Hong Kong. Sushi samples were collected from 120 randomly selected licensed sushi shops in the 19 districts in Hong Kong from 1 st June to 30 th July 2014. They were tested for aerobic colony count (ACC), Escherichia coli and Staphylococcus aureus counts as well as the presence of Salmonella spp. to evaluate their overall hygienic quality. None of the samples was found to contain Salmonella spp. and 1.7% of the collected samples were classified as unsatisfactory for containing more than 100 CFU/g of E. coli indicating the overall hygienic quality of take-away sushi in Hong Kong was good. There was no significant difference between samples purchased from chain stores and those from self-hosted business, suggesting that microbiological quality of take-away sushi was not affected by these two types of business models. Based on the current findings, it was suggested that the government should have more frequent routine inspections and provide food hygiene education to the workers in the sushi shops in Hong Kong so as to minimize the risk of foodborne disease outbreaks. [ABSTRACT FROM AUTHOR]

In this study, we evaluated the anabolic effect and the underlying cellular mechanisms involved of vitamin K 2 (10 nM) and 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) (10 nM), alone and in combination, on primary osteoblasts harvested from the iliac crests of C57BL/KsJ lean ( +/+ ) and obese/diabetic ( db/db ) mice. A lower alkaline phosphatase (ALP) activity plus a reduced expression of bone anabolic markers and bone formation transcription factors (osteocalcin, Runx2, Dlx5, ATF4 and OSX) were consistently detected in osteoblasts of db/db mice compared to lean mice. A significantly higher calcium deposits formation in osteoblasts was observed in lean mice when compared to db/db mice. Co-administration of vitamin K 2 (10 nM) and 1,25(OH) 2 D 3 (10 nM) caused an enhancement of calcium deposits in osteoblasts in both strains of mice. Vitamins K 2 and 1,25(OH) 2 D 3 co-administration time-dependently (7, 14 and 21 days) increased the levels of bone anabolic markers and bone formation transcription factors, with a greater magnitude of increase observed in osteoblasts of db/db mice. Combined vitamins K 2 plus 1,25(OH) 2 D 3 treatment significantly enhanced migration and the re-appearance of surface microvilli and ruffles of osteoblasts of db/db mice. Thus, our results illustrate that vitamins K 2 plus D 3 combination could be a novel therapeutic strategy in treating diabetes-associated osteoporosis. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The fruit of Schisandra chinensis ( Turcz. ) Baill , has been traditionally used in management of liver diseases and ageing associated neurodegeneration. The bioactive compound from this medicinal plant would be valuable for its potential use in prevention and treatment of Parkinson׳s disease. Aim of the study The overall objective of the present study was to understand the neuroprotective effect of schisantherin A, a dibenzocyclooctadiene lignan from the fruit of S. chinensis ( Turcz. ) Baill , and to elucidate its underlying mechanism of action. Material and methods This study investigated the protective effect of schisantherin A against selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced neural damage in human neuroblastoma SH-SY5Y cells and zebrafish models. Oxidative stress and related signaling pathways underlying the neuroprotective effect were determined by multiple biochemical assays and Western blot. Results Pretreatment with schisantherin A offered neuroprotection against 6-OHDA-induced SH-SY5Y cytotoxicity. Moreover, schisantherin A could prevent 6-OHDA-stimulated dopaminergic neuron loss in zebrafish. Our mechanistic study showed that schisantherin A can regulate intracellular ROS accumulation, and inhibit NO overproduction by down-regulating the over-expression of iNOS in 6-OHDA treated SH-SY5Y cells. Schisantherin A also protects against 6-OHDA-mediated activation of MAPKs, PI3K/Akt and GSK3β. Conclusion These findings demonstrate that schisantherin A may have potential therapeutic value for neurodegenerative diseases associated with abnormal oxidative stress such as Parkinson׳s disease. [ABSTRACT FROM AUTHOR]

Background The role of Kdr (VEGFR-2/Flk-1) in vascular formation has been well described, but the role of Flt1 (VEGFR-1) is not well studied and is generally considered as a decoy receptor for trapping VEGF. Methods The effects of VEGFR1/2 kinase inhibitor (VRI) and calycosin on Flt1 tyrosine kinase (TK) activity were evaluated by molecular docking, enzymatic inhibition assay, protein co-immunoprecipitation and siRNA gene knock-down analysis in HUVECs. Toxicities of the chemicals were examined using HUVECs viability. Their effects on angiogenesis and vessel formation were furthered studied in HUVECs in vitro and Tg ( fli-1 : EGFP ) zebrafish in vivo . The gene and protein expression of VEGF and VEGF receptors were investigated by quantitative RT-PCR and Western blot. Results VRI strongly inhibited physiological functions of both VEGF receptors and suppressed endothelial cell survival. This resulted in blood vessel loss in zebrafish embryos. Interestingly, calycosin co-treatment impeded VRI-induced blood vessel loss. Docking and kinase inhibition assay revealed that calycosin competed with VRI for the tyrosine kinase domain of Flt1 without affecting ATP binding. On the contrary, calycosin did not affect the interaction between VRI and Kdr-TK. Consistent with these results, calycosin counteracted the inhibition of Flt1-TK and PI3K phosphorylation induced by VRI in HUVECs. Further studies in vitro and in vivo showed that the minimizing effect of calycosin on VRI-mediated endothelial cytotoxicity was blocked by wortmannin (a PI3K inhibitor). The impeding effect of calycosin on VRI-induced blood vessel loss was absent in zebrafish embryos injected with Flt1 MO. Conclusions Flt1-tyrosine kinase (TK) activity contributed significantly in endothelial cells survival and vascular development during embryo angiogenesis in zebrafish by engaging PI3K/Akt pathway. General significance The roles of Flt1 activity in endothelial cell survival in physiological vascular formation may have been previously under-appreciated. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The hip of Rosa multiflora Thunb. (HRM) has been traditionally used as a dietary supplement and a herbal remedy for the treatment of various diseases, including inflammation, osteoarthritis, rheumatoid arthritis and chronic pain, in China. The current study was to evaluate the therapeutic efficacy of the petroleum ether extractive of HRM (PEE) on type II collagen-induced rheumatoid arthritis (CIA) in male Wistar rats. In addition, the anti-inflammatory mechanism(s) of PEE on type II CIA was explored. Materials and methods Rheumatoid arthritis (RA) was induced by intradermal injection of bovine type II collagen on Day 1 and Day 8. Starting from Day 13, normal rats were treated with vehicle (serving as the control group); the CIA rats were treated with vehicle (CIA group), dexamethasone (0.25 mg/kg bw per day, p.o.) (a positive control), lei-gong-teng (LGT: 10 mg/kg bw per day, p.o.) (a clinically used Chinese patent medicine in RA therapy) or PEE (12, 36 or 120 mg/kg bw per day, p.o.) for 28 days. Results and conclusions PEE (120 mg/kg bw per day) efficiently attenuated the severity of arthritis in the CIA rats by reducing the mean arthritis severity scores and the fore/hind paw swelling as well as reduced histological changes by decreasing the cartilage surface erosion and cartilage proteoglan depletion. PEE׳s therapeutic effect in RA may involve the inhibition of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, in serum and/or the elevation of the activities of hepatic anti-oxidative enzymes including SOD, CAT and GSH-Px. However, the detailed anti-inflammatory mechanism, the main effective components and the interaction between different ingredients in PEE are still not clear and require more studies. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Semen Astragali Complanati (SAC), the dried ripe seed of Flatstem Milkvetch (Astragalus complanatus Bunge) (Leguminosae), is commonly used in traditional Chinese medicine (TCM) for treating muscle, liver, kidney, blood, skin and reproductive system diseases. Materials and methods Relevant information about SAC was gathered via "Google Scholar", "ISI Web of Knowledge", "PubMed", "ScienceDirect", "Medline Plus", "ACS", "CNKI" and "Wiley Online Library" and from books in local libraries. Results The major contents of SAC include fatty acids, amino acids, polysaccharides, flavonoids, triterpene glycosides and trace elements. Previous scientific studies have reported that SAC exhibits a number of therapeutic effects on chronic diseases such as cardiovascular diseases, diabetes mellitus and cancers. It has been found that flavonoids are the main bioactive component in SAC. However most of the previous studies have shown the effects brought by the total flavonoid fraction extracted from SAC only; further studies are warranted for the biological effects produced by individual components. There are only a few studies on the toxicity of SAC and the overall results show that its toxicity is quite low or even non-existent. Conclusions SAC is a valuable TCM herb with multiple pharmacological effects for treating some chronic diseases. More studies on SAC will help us to have a better understanding of its pharmacological mechanisms so as to provide more scientific evidence to explain its traditional uses, identify its therapeutic potential on other diseases and understand its possible harmful effects. Based on previous studies, it is easy to identify that antioxidant effect of SAC might play an important role on its pharmacological effects. Studying the effects of SAC on handling intracellular reactive oxygen species may be a potential direction to help understanding the molecular mechanisms of SAC on preventing and/or treating chronic diseases. [ABSTRACT FROM AUTHOR]

Abstract: The safety of ready-to-eat food is an important issue. Improper handling of ready-to-eat food items may result in foodborne outbreaks. In this study, Chinese barbecued pork (Char Siu in Chinese) was selected as the target ready-to-eat food item for a microbial survey. The aim of this study was to evaluate the microbiological quality of Chinese barbecued pork sold in licensed Siu Mei and Lo Mei shops in Hong Kong. A total of 115 samples were collected from supermarkets or wet markets in the 18 districts. They were tested for aerobic plate counts (APC), Escherichia coli and Staphylococcus aureus counts, and the presence of Salmonella spp. for assessing their safety level. Results showed APC ranging from 1.97 to 6.84 log CFU/g, with a mean of 5.05 log CFU/g; E. coli counts ranging from none detected to 3.10 log CFU/g, with a mean of 1.78 log CFU/g; and S. aureus counts ranging from none detected to 1.42 log CFU/g, with a mean of 0.15 log CFU/g. The mean APC and E. coli counts of samples from supermarkets were found to be significantly lower than those from wet markets (p < 0.05) indicating that supermarkets had better microbiological quality than wet markets. Salmonella spp. were isolated from 39% of the samples analyzed, indicating that cross-contamination was quite a serious problem in Siu Mei and Lo Mei shops in Hong Kong. Based on these results, recommendations such as routine inspections and training of vendors were suggested to improve the microbiological quality of products sold in licensed Siu Mei and Lo Mei shops in Hong Kong so as to minimize risks of foodborne outbreaks. [Copyright &y& Elsevier]

Abstract: Epoxyeicosatrienoic acids (EETs) induce vasorelaxation, probably through G protein-coupled receptors. The identity of these receptors is unclear, but it has been reported that EETs may bind to peroxisome proliferator activated receptors (PPARs) and E-prostanoid (EP) receptors. Therefore, we studied whether PPARs or EP receptors were involved in 14,15-EET-induced vasorelaxation. Isometric tensions of rat mesenteric arteries were measured. The vasorelaxant effect of 14,15-EET was inhibited by NF449 (Gs-protein inhibitor), Rp-cAMP (cAMP antagonist) and KT5720 (PKA inhibitor), suggesting that the effect of 14,15-EET was mediated through Gs protein-coupled receptors which were linked to the cAMP/PKA-dependent pathway. Pretreatments with MK886 (PPARα antagonist) and GW9662 (PPARγ antagonist) did not influence 14,15-EET-induced vasorelaxation. The vasorelaxant effect of 14,15-EET was inhibited by AH6809 (EP2 receptor antagonist), whereas SC19220 (EP1 receptor antagonist), L798106 (EP3 receptor antagonist) and GW627368X (EP4 receptor antagonist) had no effect. The effect of 14,15-EET and the mechanism involved was mimicked by prostaglandin E2 (an EP2 receptor agonist). The 14,15-EET-induced relaxation was slightly potentiated in the presence of indomethacin (cyclooxygenase inhibitor which block PGE2 synthesis). Binding study showed that the amount of 14,15-EET bound to the cell membrane of rat mesenteric arterial smooth muscle cells was much higher than that bound to the nuclear membrane. The binding of 14,15-EET to the cell membrane was attenuated by AH6809 and siRNA against EP2 receptors. In conclusion, our study has demonstrated that 14,15-EET exerts relaxant effects on rat mesenteric arteries, at least partly via the stimulation of EP2 receptors. This subsequently leads to activation of cAMP/PKA-dependent pathway in vascular smooth muscle cells. [Copyright &y& Elsevier]

Abstract: Folic acid supplementation provides beneficial effects on endothelial functions in patients with hyperhomocysteinemia. However, its effects on vascular functions under diabetic conditions are largely unknown. Therefore, the effect(s) of folic acid (5.7 and 71 μg/kg/day for 4 weeks) on aortic relaxation was investigated using obese/diabetic (+db/+db) mice and lean littermate (+db/+m) mice. Acetylcholine-induced relaxation in +db/+db mice was less than that observed in +db/+m mice. The reduced relaxation in +db/+db mice was restored by consumption of 71 μg/kg folic acid. Acetylcholine-induced relaxation (with and without folic acid treatment) was sensitive to N G-nitro-l-arginine methyl ester, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, geldanamycin and triciribine. In addition, acetylcholine-induced relaxation was attenuated by resistin. The plasma level of resistin in +db/+db mice was sevenfold higher than that measured in +db/+m mice, and the elevated plasma level of resistin in +db/+db mice was reduced by 25% after treatment with 71 μg/kg folic acid. Folic acid slightly increased the ratio of reduced glutathione to oxidized glutathione in +db/+db mice. Moreover, folic acid caused a reduction in PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression, an increase in the phosphorylation of endothelial nitric oxide synthase (eNOSSer1177) and AktSer473, and an enhanced interaction of heat shock protein 90 (HSP90) with eNOS in both strains, with greater magnitude observed in +db/+db mice. In conclusion, folic acid consumption improved blunted acetylcholine-induced relaxation in +db/+db mice. The mechanism may be, at least partly, attributed to enhancement of PI3K/HSP90/eNOS/Akt cascade, reduction in plasma resistin level, down-regulation of PTEN and slight modification of oxidative state. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the vasorelaxation effects of formononetin, an isoflavone/phytoestrogen found abundantly in Astragalus mongholicus Bunge, on rat isolated aorta and the underlying mechanisms involved. Cumulative administration of formononetin, genistein, daidzein and biochanin A relaxed phenylephrine-preconstricted aorta. Formononetin and biochanin A caused a similar magnitude of relaxation whereas daidzein was least potent. Mechanical removal of endothelium, L-NAME (100 μM) and methylene blue (10 μM) suppressed formononetin-induced relaxation. Formononetin increased endothelial nitric oxide (NO) synthase (eNOS), but not inducible NO synthase, activity with an up-regulation of eNOS mRNA and p-eNOSSer1177 protein expression. In endothelium-denuded preparations, formononetin-induced vasorelaxation was significantly reduced by glibenclamide (3 μM) and iberiotoxin (100 nM), and a combination of glibenclamide (3 μM) plus iberiotoxin (100 nM) abolished the relaxation. In contrast, formononetin-elicited endothelium-independent relaxation was not altered by ICI 182,780 (10 μM, an estrogen receptor (ERα/ERβ) antagonist) or mifepristone (10 μM, a progesterone receptor antagonist). In single aortic smooth muscle cells, formononetin caused opening of iberiotoxin-sensitive Ca2+-activated K+ (BKCa) channels and glibenclamide-sensitive adenosine triphosphate (ATP)-dependent K+ (KATP) channels. Thus, our results suggest that formononetin caused vascular relaxation via endothelium/NO-dependent mechanism and endothelium-independent mechanism which involves the activation of BKCa and KATP channels. [Copyright &y& Elsevier]