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Concept: Vasodilation


Oxidative stress is one of the most critical factors implicated in disease conditions. Buchanania lanzan Spr. (Anacardiaceae) bark powder preparation has been reported for treating an inflammatory condition in the Ayurvedic Pharmacopoeia of India.

Concepts: Carbon dioxide, Oxidative stress, Nitrogen, Radical, Endothelium, Nitric oxide, Vasodilation, Nitric oxide synthase


Diospyros kaki Thunb. is widely distributed in East Asian countries, its leaves being mainly used for making tea. In this study, coussaric acid (CA) and betulinic acid (BA), both triterpenoid compounds, were obtained from D. kaki leaf extracts through bioassay-guided isolation. CA and BA showed anti-inflammatory effects via inhibition of the nuclear factor-κB (NF-κB) pathway, providing important information on their anti-inflammatory mechanism. Furthermore, they markedly inhibited nitric oxide (NO) and prostaglandin E₂ (PGE₂) production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages, and suppressed tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) levels. Furthermore, they decreased protein expression of inducible nitric oxide synthase and cyclooxygenase-2. Pre-treatment with CA and BA inhibited LPS-induced NF-κB. We further examined the effects of CA and BA on heme oxygenase (HO)-1 expression in RAW 264.7 macrophages: BA induced HO-1 protein expression in a dose-dependent manner, while CA had no effect. We also investigated whether BA treatment induced nuclear translocation of Nrf2. BA inhibited LPS-induced NF-κB-binding activity, as well as pro-inflammatory mediator and cytokine production (e.g., NO, PGE₂, TNF-α, IL-1β, IL-6), by partial reversal of this effect by SnPP, an inhibitor of HO-1. These findings further elucidate the anti-inflammatory mechanism of CA and BA isolated from D. kaki.

Concepts: Endothelium, Nitric oxide, Vasodilation, Persimmon, Nitric oxide synthase, Heme oxygenase, Betulinic acid


A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

Concepts: Protein, Neurology, Endothelium, Cardiovascular system, Endothelial dysfunction, Nitric oxide, Vasodilation, Nitric oxide synthase


Changes in the gut microbiota may underpin many human diseases, but the mechanisms that are responsible for altering microbial communities remain poorly understood. Antibiotic usage elevates the risk of contracting gastroenteritis caused by Salmonella enterica serovars, increases the duration for which patients shed the pathogen in their faeces, and may on occasion produce a bacteriologic and symptomatic relapse. These antibiotic-induced changes in the gut microbiota can be studied in mice, in which the disruption of a balanced microbial community by treatment with the antibiotic streptomycin leads to an expansion of S. enterica serovars in the large bowel. However, the mechanisms by which streptomycin treatment drives an expansion of S. enterica serovars are not fully resolved. Here we show that host-mediated oxidation of galactose and glucose promotes post-antibiotic expansion of S. enterica serovar Typhimurium (S. Typhimurium). By elevating expression of the gene encoding inducible nitric oxide synthase (iNOS) in the caecal mucosa, streptomycin treatment increased post-antibiotic availability of the oxidation products galactarate and glucarate in the murine caecum. S. Typhimurium used galactarate and glucarate within the gut lumen of streptomycin pre-treated mice, and genetic ablation of the respective catabolic pathways reduced S. Typhimurium competitiveness. Our results identify host-mediated oxidation of carbohydrates in the gut as a mechanism for post-antibiotic pathogen expansion.

Concepts: Bacteria, Gut flora, Microbiology, Nitric oxide, Vasodilation, Salmonella enterica, Salmonella, Nitric oxide synthase


Magnolia bark contains several compounds such as magnolol, honokiol, 4-O-methylhonokiol, obovatol, and other neolignan compounds. These compounds have been reported to have various beneficial effects in various diseases. There is sufficient possibility that ethanol extract of Magnolia officinalis is more effective in amyloidogenesis via synergism of these ingredients. Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer’s disease (AD). We investigated whether the ethanol extract of M. officinalis (10 mg/ kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis in AD mouse model by intraperitoneal lipopolysaccharide (LPS, 250 µg/ kg/day for seven times) injection. We found that ethanol extract of M. officinalis prevented LPS-induced memory deficiency as well as inhibited the LPS-induced elevation of inflammatory proteins, such as inducible nitric oxide synthase and cyclooxygenase 2, and activation of astrocytes and microglia. In particular, administration of M. officinalis ethanol extract inhibited LPS-induced amyloidogenesis, which resulted in the inhibition of amyloid precursor protein, beta-site amyloid-precursor-protein-cleaving enzyme 1 and C99. Thus, this study shows that ethanol extract of M. officinalis prevents LPS-induced memory impairment as well as amyloidogenesis via inhibition of neuroinflammation and suggests that ethanol extract of M. officinalis might be a useful intervention for neuroinflammation-associated diseases such as AD. Copyright © 2012 John Wiley & Sons, Ltd.

Concepts: Alzheimer's disease, Endothelium, Nitric oxide, Vasodilation, Nitric oxide synthase, Memory loss, Magnolia, Magnolol


The effects of particulate matter (PM) on endothelial cells have been evaluated in vitro by exposing isolated endothelial cells to different types of PM. Although some of the findings from these experiments have been corroborated by in vivo studies, an in vitro model that assesses the interaction among different cell types is necessary to achieve more realistic assays. We developed an in vitro model that mimics the alveolar-capillary interface, and we challenged the model using TiO(2) nanoparticles (TiO2-NPs). Human umbilical endothelial cells (HUVECs) were cultured on the basolateral side of a membrane and pneumocytes (A549) on the apical side. Confluent co-cultures were exposed on the apical side to 10 μg/cm(2) of TiO2-NPs or 10 ng/mL of TNFα for 24 h. Unexposed cultures were used as negative controls. We evaluated monocyte adhesion to HUVECs, adhesion molecule expression, nitric oxide concentration and proinflammatory cytokine release. The TiO2-NPs added to the pneumocytes induced a 3- to 4-fold increase in monocyte adhesion to the HUVECs and significant increases in the expression of adhesion molecules (4-fold for P-selectin at 8 h, and about 8 to 10-fold for E-selectin, ICAM-1, VCAM-1 and PECAM-1 at 24 h). Nitric oxide production also increased significantly (2-fold). These results indicate that exposing pneumocytes to TiO2-NPs causes endothelial cell activation.

Concepts: Inflammation, Atherosclerosis, Blood vessel, In vivo, Endothelium, Nitric oxide, Vasodilation, VCAM-1


OBJECTIVES:: In our previous research the antihypertensive properties of lycopene-containing tomato oleoresin have been revealed. The present study was aimed to assess if oleoresin interferes in the inflammatory signalling in endothelial cells, imitating reduction of inflammatory processes in the vessel wall and in this way to propose the mechanism for the reduction of blood pressure by oleoresin. METHODS AND RESULTS:: A wide number of functional and inflammatory markers were investigated in two cultured endothelial cell models [EA.hy926 and human umbilical vein endothelial cell (HUVEC)], exposed to oleoresin and carotenoids lycopene and lutein. All the carotenoids significantly improved basic endothelial function as measured by increased nitric oxide and decreased endothelin (ET-1) release. They were effective in attenuation of inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling: decrease of tumour necrosis factor-alpha (TNF-α)-induced leukocytes adhesion, expression of adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and nuclear translocation of NF-κB components as well as some revert of inhibitor of kappa B (IκB) ubiquitination. In addition, the carotenoids were able to inhibit NF-κB activation in transfected endothelial cells. When combined with lutein, oleoresin exerted synergistic effect on preclusion of leukocytes adhesion. CONCLUSIONS:: Prevention of over-expression of adhesion molecules through inhibition of NF-κB signalling may be one of the main mechanisms driving carotenoids to attenuate inflammatory leukocyte adhesion to endothelium. This is the first profound study on the mechanisms involved in the positive action of natural tomato products in endothelial cells.

Concepts: Inflammation, Atherosclerosis, Blood vessel, Cell adhesion molecule, Endothelium, Nitric oxide, Vasodilation, VCAM-1


We recently showed that inducible nitric oxide synthase conformational intermediates can be resolved via FMN fluorescence lifetimes. Here we show that neuronal NOS activation by calmodulin removes constraints favoring a closed ‘input state’, increasing occupation of other states and facilitating conformational transitions. The 90 ps FMN input state lifetime distinguishes it from ∼4 ns ‘open’ states in which FMN does not interact strongly with other groups, or 0.9 ns output states in which FMN interacts with ferriheme. Enablement of the conformational cycle is an important paradigm for control in nNOS and related enzymes, and may extend to other control modalities.

Concepts: Endothelium, Nitric oxide, Vasodilation, Nitric oxide synthase, NOS1, Biological functions of nitric oxide


In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 μM lovastatin for three days prior to addition of Tumor necrosis factor - α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.

Concepts: Inflammation, Blood, Mesenchymal stem cell, Bone marrow, Blood vessel, Endothelium, Nitric oxide, Vasodilation


This study evaluates the effect of wild blueberry (WB) consumption on the biomechanical properties of the aorta in the obese Zucker rat (OZR), a model of the metabolic syndrome. Thirty-six OZRs and 36 lean controls (lean Zucker rats) were placed either on a WB-enriched or a control © diet for 8 weeks. Phenylephrine (Phe)-mediated vasoconstriction and acetylcholine (Ach)-mediated vasorelaxation in the aortic vessel were investigated, as well as the contribution of the nitric oxide synthase and cyclooxygenase (COX) pathways in each of the above responses by using specific inhibitors. Obese Zucker rats exhibited a reduced vasocontstrictor response to Phe and an exaggerated vasorelaxant response to Ach. The WB diet partially restored Phe-induced constrictor responses and attenuated Ach-induced relaxant responses in OZR. Plasma nitric oxide was significantly attenuated (22.1 ± 1.1 μmol·L(-1), WB vs 25.6 ± 1.4 μmol·L(-1), C, p ≤ 0.05) with the WB diet. Thromboxane A2 levels in the aortic effluent were not significantly affected in the WB diet group, while PGI2 concentration significantly increased (766.5 ± 92.2 pg·mg(-1) aorta in the WB vs 571.7 ± 37.8 pg·g(-1) aorta in the C group, p ≤ 0.05). Downregulation of inducible nitric oxide synthase and COX2 expression in the OZR aorta was observed in the WB diet group. In conclusion, WB consumption altered the biomechanical properties of the OZR aorta by partially restoring the impaired Phe-induced constrictor responses and attenuating the exaggerated response to Ach-induced vasorelaxation.

Concepts: Nutrition, Endothelium, Nitric oxide, Vasodilation, Aorta, Nitric oxide synthase