Compelling evidence suggests that the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell-mediated T helper (Th)2 ...response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell-mediated, TSLP-dependent activation of MCs may play a central role in "intrinsic" forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.
Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral ...sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood-spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS.
In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, ...neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.
From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure−activity relationship studies were performed ...focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.
In Alzheimer disease (AD), amyloid beta peptide (Abeta) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Abeta-induced perturbations in cerebral ...vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Abeta binding to the V domain of RAGE and inhibited Abeta40- and Abeta42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Abeta-precursor protein, a transgenic mouse model of AD with established Abeta pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Abeta40 and Abeta42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited beta-secretase activity and Abeta production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Abeta40 and Abeta42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Abeta-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.
Background: The importance of the electronic health record today signifies the approach that is being used in meaningful use and what it means for the adoption of the electronic health record. ...Electronic health records can provide many benefits for providers and their patients, but the benefits depend on how they're used. Meaningful use is the set of standards defined by the Centers for Medicare and Medicaid Services (CMS) Incentive Programs that governs the use of electronic health records and allows eligible providers and hospitals to earn incentive payments by meeting specific criteria (HealthIT.gov 2013). The problem that is being presented is the lack of patient engagement in the electronic health record. With the adoption of meaningful use, patients are confused with the types of services that are available to them, how they can improve their health outcomes and how they can be more involved in the decision aspects of quality care. Methodology: In order to explore the interest of patients on the use of the portal, a verbal sampling of patients' opinion on their interest for portal use was conducted for about four months during clinic visit after getting proper permission from the executive team. Results/conclusion: If providers really want to engage their patients in their healthcare, implementing a patient portal will improve the hospitals efficiency in providing quality care (Kressly, 2013). Patients are customers, who look for value and remain loyal based on the suite of services they receive for their care provider (Murphy, 2012). The business of healthcare requires that providers and organizations care about its patients as beneficiaries of their care as well as consumers (Murphy, 2012). If patient portals lead to happier patients, then the outcome is likely to be good for business (Murphy, 2012).
Recent evidence suggests that hepatic stellate cells function as liver‐specific pericytes that are highly contractile in response to endothelin‐1 (ET‐1). Liver injury has been shown to lead to ...“activation” of stellate cells producing a phenotypic change to a more myofibroblastic cell type including loss of vitamin A and increased contractility. The present study was undertaken to test the effects of short‐term chronic ethanol consumption (36% of total calories for 5 weeks according to the Lieber‐DeCarli protocol) on hepatic vitamin A storage, expression of smooth muscle α‐actin, and sinusoidal contractility in Sprague‐Dawley rats. Using in vivo epifluorescence video microscopy, we quantified the number of sites of vitamin A fluorescence (purportedly stellate cells) and assessed sinusoidal microhemodynamics at baseline and during a 20‐minute infusion period of ET‐1 (1 pmol* 100 g body weight bw−1*min−1). Retinol and retinyl palmitate were measured after the experiment by means of high‐pressure liquid chromatography (HPLC). A highly significant decrease in liver retinyl palmitate level (control: 622.5 ± 50.9; ethanol: 273.0 ± 38.0 μg/g liver; P < .001) was found that correlated with a decrease in sites of vitamin A fluorescence (control: 531.4 ± 76.1; ethanol: 141.1 ± 30.2* mm−2; r = .82, P < .001). Concomitantly scattered expression of smooth muscle α‐actin in sinusoids was observed. Although sinusoidal hemodynamics were not affected at baseline, a significant increase in sinusoidal contractility on endothelin‐1 infusion (e.g., sinusoidal resistance % of baseline value: control: 10 minutes: 288.7 ± 71.7, 20 minutes: 200.5 ± 46.9; ethanol: 10 minutes: 1,916.0 ± 701.7, 20 minutes: 656.8 ± 103.3; P < .05 and .01, respectively) was observed. These data indicate that chronic ethanol consumption in this moderate model initiates stellate cell activation. Increased sinusoidal responsiveness to the vasoconstrictor ET‐1 in vivo may contribute to the increased susceptibility of ethanol‐fed rats to secondary stresses that increase ET‐1 expression, such as endotoxemia. (Hepatology 1995; 22:1565–1576).
Recent evidence suggests that hepatic stellate cells function as liver-specific pericytes that are highly contractile in response to endothelin-1 (ET-1). Liver injury has been shown to lead to ...“activation” of stellate cells producing a phenotypic change to a more myofibroblastic cell type including loss of vitamin A and increased contractility. The present study was undertaken to test the effects of short-term chronic ethanol consumption (36% of total calories for 5 weeks according to the Lieber-DeCarli protocol) on hepatic vitamin A storage, expression of smooth muscle α-actin, and sinusoidal contractility in Sprague-Dawley rats. Using
in vivo epifluorescence video microscopy, we quantified the number of sites of vitamin A fluorescence (purportedly stellate cells) and assessed sinusoidal microhemodynamics at baseline and during a 20-minute infusion period of ET1 (1 pmol ∗ 100 g body weight bw
−1∗min
−1). Retinol and retinyl palmitate were measured after the experiment by means of high-pressure liquid chromatography (HPLC). A highly significant decrease in liver retinyl palmitate level (control: 622.5 ± 50.9; ethanol: 273.0 ± 38.0 μg/g liver;
P < .001) was found that correlated with a decrease in sites of vitamin A fluorescence (control: 531.4 ± 76.1; ethanol: 141.1 ± 30.2∗mm
2;
r = .82,
P < .001). Concomitantly scattered expression of smooth muscle α-actin in sinusoids was observed. Although sinusoidal hemodynamics were not affected at baseline, a significant increase in sinusoidal contractility on endothelin-1 infusion (e.g., sinusoidal resistance % of baseline value: control: 10 minutes: 288.7 ± 71.7, 20 minutes: 200.5 ± 46.9; ethanol: 10 minutes: 1,916.0 ± 701.7, 20 minutes: 656.8 ± 103.3;
P < .05 and .01, respectively) was observed. These data indicate that chronic ethanol consumption in this moderate model initiates stellate cell activation. Increased sinusoidal responsiveness to the vasoconstrictor ET-1
in vivo may contribute to the increased susceptibility of ethanol-fed rats to secondary stresses that increase ET-1 expression, such as endotoxemia.
Vitamin A deficiency enhances ozone-induced lung injury Paquette, N.C. (Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD.); Zhang, L.Y; Ellis, W.A ...
The American journal of physiology,
03/1996, Letnik:
270, Številka:
3
Journal Article
Recenzirano
The present study determined the effects of vitamin A (vA) deficiency on the responses to ozone (O3) challenges in two inbred strains of mice that are differentially susceptible to O3-induced lung ...inflammation. Susceptible C57BL/6J (B6) and resistant C3H/HeJ (C3) dams at 2 wk gestation were fed test diets containing either 0 or 10 microgram retinol/g diet. In mice that were maintained on vA-sufficient (vA+) diet, lung and liver, tissue concentrations of vA and retinyl palmitate (RP) were significantly (P 0.05) lower in the B6 strain compared with C3, as measured by high-performance liquid chromatography techniques. vA and RP levels were significantly (P 0.05) reduced in lung and liver tissues of 8-wk-old B6 and C3 mice that were maintained on a vA deficient (vA-) diet. vA+ and vA- mice of both strains were exposed to air or 0.3 ppm O3/72 h, and lung injury was assessed by differential cell count and total protein concentration in bronchoalveolar ravage (BAL) returns. O3 exposure caused significantly (P 0.05) greater increases in inflammatory cells and total protein in BAL returns of vA+ B6 mice than vA+ C3 mice. vA deficiency significantly (P 0.05) enhanced O3-induced increases in polymorphonuclear leukocytes in C3 mice and epithelial cell loss in both strains. Compared with vA+ mice, lung permeability was also significantly (P 0.05) enhanced in vA- mice of both strains exposed to O3. vA replacement partially reversed the O3-induced lung injury that was enhanced by vA- diet. Results indicate that vA may have an important role in the pathogenesis of O3-induced lung injury in differentially susceptible inbred strains of mice
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