β-1,3-Glucan given orally modulates immunomyelopoietic activity and enhances the resistance of tumour-bearing mice

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PREVENTION OF AORTIC ELASTIC LAMINA DEFECTS BY LOSARTAN IN APOLIPOPROTEIN E-DEFICIENT MOUSE

• 1 In a previous study, we identified prevalent internal elastic lamina (IEL) defects in the aorta of hyperlipidaemic apolipoprotein E (ApoE)‐deficient mice that are thought to provide a structural basis for the development of atherosclerosis and intimal thickening. In the present study, we examined the effects of losartan, an angiotensin AT₁ receptor antagonist, on the development of IEL defects.
• 2 Male 18‐week‐old ApoE‐deficient mice (maintained on a normal diet) were treated with losartan (3 or 30 mg/kg per day) for 10 weeks via the drinking water. The IEL defects were quantified histologically by measuring the continuity of the IEL within the inner curvature of the aortic arch.
• 3 In untreated animals, there was an age‐dependent increase in IEL defects from 7.2 ± 2.1% at 18 weeks to 13.8 ± 4.0% at 28 weeks. Treatment with the high dose of losartan significantly prevented the development of IEL defects (4.7 ± 1.3% at 28 weeks; P < 0.05 vs untreated). This effect was independent of changes in blood pressure or plasma lipid levels. Using quantitative real‐time polymerase chain reaction, we found that the effects of losartan were not associated with changes in levels of matrix metalloproteinase (MMP)‐2 and MMP‐9, tissue inhibitor of matrix metalloproteinase‐1 or inflammatory markers in the aorta.
• 4 The results suggest that the renin–angiotensin system may contribute to the development of aortic IEL defects in a blood pressure‐independent manner.

     

Role of α1D‐adrenoceptors in vascular wall hypertrophy during angiotensin II‐induced hypertension

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In vivo studies on the immunotoxic effects of microcystins on rabbit

Microcystins (MCs) are the toxic molecules produced by common cyanobacterium in freshwater blooms. Their toxicities raise severe health issues in livestock and human beings. In current study, the immunotoxic effects of MC‐LR were investigated in rabbit through evaluating the dynamics of white blood cell (WBC) numbers and cytokine production such as interleukin‐3 (IL‐3), IL‐4, IL‐6, interferon‐γ (IFN‐γ), tumor necrosis factor‐α (TNF‐α). MCs at the high dose (50 μg MC‐LReq kg^?1) significantly induced increase in the WBC number but decrease in the Th1 (IFN‐γ, TNF‐α) and Th2 (IL‐3, IL‐4, IL‐6) production. In the low dose group(12.5 μg MC‐LReq kg^?1), the number of WBC and the production of IFN‐γ, IFN‐α, IL‐4, IL‐3, and IL‐6 increased gradually in first 12 h, reach the peaks at 12 h, and dropped after 24 h. Significantly positive correlations were found between the cytokines production of IL‐4 and IL‐6, IFN‐γ and IFN‐α, or IL‐4 and IFN‐γ. In conclusion, MC‐LR is able to disturb the rabbit immune system and there exists time‐dose response relationship in the MC‐LR‐eliciting perturbation, which probably give a better insight into investigating the immunotoxicity mechanisms of MCs in vivo. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

ACUTE EFFECTS OF NICOTINE ON ARTERIAL STIFFNESS AND WAVE REFLECTION IN HEALTHY YOUNG NON-SMOKERS

• 1 Recently, we have demonstrated that cigarette smoke exposure proportionally increases plasma nicotine levels and arterial wave reflection to the aorta. However, the exact contribution of nicotine to the smoke‐induced enhancement of wave reflection and the potential underlying mechanisms have not been fully investigated.
• 2 The present study was a prospective study in 15 healthy male non‐smokers. All received a placebo and a 2 mg nicotine tablet, according to a randomized double‐blind cross‐over study design. Each subject underwent repeated measurements at baseline and for 1 h after nicotine or placebo intake, using carotid–femoral pulse wave velocity (PWV) to assess arterial compliance. Concurrently, aortic pressures and the augmentation index were evaluated using applanation tonometry.
• 3 Plasma nicotine concentrations achieved 1 h after intake of the nicotine tablet reached comparable levels to those achieved after 1 h exposure to passive smoke (3.6 ± 0.4 vs 3.2 ± 0.4 ng/mL, respectively; P = 0.4).
• 4 Nicotine enhanced arterial wave reflection to the aorta, as assessed by the augmentation index corrected for heart rate (4.2 ± 1.3 vs–0.7 ± 0.8% with placebo; P = 0.001). In addition, a progressive increase in carotid–femoral PWV was noted after nicotine administration (0.3 ± 0.1 vs–0.02 ± 0.1 m/s with placebo; P = 0.04). This remained significant even after adjustment for changes in mean blood pressure and heart rate (P = 0.01).
• 5 Plasma nicotine concentrations comparable to those achieved after exposure to passive smoke enhance arterial wave reflection to the aorta. This is accompanied by an increase in carotid–femoral PWV, denoting a deterioration of arterial compliance by nicotine.

     

Curcumin ameliorates high glucose‐induced acute vascular endothelial dysfunction in rat thoracic aorta

• 1 The aims of the present study were to explore the protective effect of curcumin against the acute vascular endothelial dysfunction induced by high glucose and to investigate the possible role of heme oxygenase (HO)‐1 in this protective action.
• 2 Thoracic aortic rings, with or without endothelium, obtained from male Sprague‐Dawley rats were mounted in an organ bath. Isometric contraction of the rings was recorded. After completion of the organ bath studies, rings were homogenized and centrifuged (30 000 g, 4°C, 15 min) and HO activity was determined in the supernatant.
• 3 After 2 h incubation of aortic rings in the presence of high glucose (44 mmol/L), the relaxation evoked by acetylcholine (3 × 10^?8 to 3 × 10^?5 mol/L) was significantly decreased only in rings with an intact endothelium. When rings were coincubated in the presence of curcumin (10^?13 to 10^?11 mol/L) and high glucose, curcumin reversed the vasodilator dysfunction induced by high glucose dose dependently.
• 4 Curcumin (10^?11 mol/L) increased HO activity in the aortic rings compared with activity in control rings (63.1 ± 3.6 vs control 43.2 ± 2.9 pmol/mg per h, respectively; P < 0.01). Protoporphyrin IX zinc (10^?6 mol/L), an inhibitor of HO‐1, offset the protective effects of curcumin. In addition, the non‐selective guanylate cyclase (GC) inhibitor methylene blue (10^?6 mol/L) completely abolished the protective effects of curcumin.
• 5 In conclusion, the results of the present study show that curcumin alleviates the acute endothelium‐dependent vasodilator dysfunction induced by high glucose in rat aortic rings. Increased HO‐1 activity and stimulation of GC may be involved in the protective effects of curcumin.

     

SMOKING AND CORONARY ATHEROSCLEROSIS: FOLLOW-UP STUDY IN CHINA

• 1 The aim of the present study was to explore the association between the total number of cigarettes smoked in life and the severity of and mortality due to coronary atherosclerosis.
• 2 The study population comprised 1096 consecutive patients (820 men and 276 women) who underwent coronary angiography for suspected or known coronary atherosclerosis. Anthropometric and plasma measurements (body mass index, blood pressure and blood lipid, blood glucose and pro‐insulin levels) were made. The number of cigarettes smoked during previous years was estimated. The severity of coronary atherosclerosis was defined by the Gensini score system.
• 3 At baseline, a significant positive association was observed between the number of cigarettes smoked and Gensini score (r = 0.213; P = 0.000), pro‐insulin (r = 0.072; P = 0.017), total leucocyte count (r = 0.179; P = 0.000) and neutrophil count (r = 0.164; P = 0.000), whereas an inverse correlation was found between the number of cigarettes smoked and High‐density lipoprotein–cholesterol (r = ?0.150; P = 0.000).
• 4 When participants were divided into five categories based on the baseline number of cigarettes smoked, an independent association between baseline number of cigarettes smoked and all‐cause mortality was observed in a multivariate analysis of Cox proportional hazards models, with a hazard ratio (95% confidence interval) of 1.328 (1.086–1.623; P = 0.006) during a median follow up of 2.86 years.
• 5 The number of cigarettes smoked was a highly significant predictor of coronary atherosclerosis and an independent risk factor for mortality in subjects with atherosclerosis in this Chinese population.

     

Influence of ketanserin on the effects of methylenedioxymethamphetamine on body temperature in the mouse

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Semiquinone glucoside derivative provides protection against γ‐radiation by modulation of immune response in murine model

Present study was undertaken to evaluate radioprotective and immunomodulatory activities of a novel semiquinone glucoside derivative (SQGD) isolated from Bacillus sp. INM‐1 in C₅₇BL/6 mice. Whole body survival study was performed to evaluate in vivo radioprotective efficacy of SQGD. To observe effect of SQGD on immunostimulation, Circulatory cytokine (i.e., interleukin‐2 (IL‐2), IFN‐γ, IL‐10, granulocyte colony stimulating factor (G‐CSF), granulocyte macrophage colony stimulating factor (GM‐CSF), and macrophage colony stimulating factor (M‐CSF) expression was analyzed in serum of irradiated and SQGD treated mice at different time intervals using ELISA assay. Results of the present investigation indicated that SQGD pre‐treatment (‐2 h) to lethally irradiated mice provide ～83% whole body survival compared with irradiated mice where no survival was observed at 30^th post irradiation day. Significant (p < 0.05) induction in IL‐2 and IFN‐γ expression was observed at all tested time intervals with SQGD pre‐treated irradiated mice as compared with irradiated mice alone. However, sharp increase in IL‐10 expression was observed in irradiated mice which were found to be subsidized in irradiated mice pre‐treated with SQGD. Similarly, significant (p < 0.05%) induction in G‐CSF, M‐CSF and GM‐CSF expression was observed in irradiated mice treated with SQGD as compared with irradiated control mice at tested time intervals. In conclusion, SQGD pre‐treatment to irradiated mice enhanced expression of IL‐12 and IFN‐γ while down‐regulated IL‐10 expression and thus modulates cytoprotective pro‐inflammatory TH₁ type immune response in irradiated mice. Further, SQGD pre‐treatment to irradiated mice accelerate G‐CSF, GM‐CSF and M‐CSF expression suggesting improved haematopoiesis and enhanced cellular immune response in immuno‐compromised irradiated mice that may contribute to in vivo radiation protection. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 478–488, 2016.     

Anti‐viral activity of jatrophone against RSV‐induced respiratory infection via increase in interferon‐γ generating dendritic cells

Respiratory syncytial virus (RSV), a member of Paramyxoviridae family is responsible for bronchiolitis and pneumonia. The present study investigated anti‐viral and anti‐inflammatory activities of jatrophone against RSV‐infection in pulmonary epithelial cells in vitro and in mice model in vivo. The changes in viabilities of RSV infected cells by jatrophone treatment were determined by MTT assay. The fluorescence associated with production of ROS was evaluated by fluorescence microscopy using H2DCFDA dye. The IFN‐γ secreting cells were detected in mice BALF by stimulation with phorbol myristate acetate and ionomycin. The reduction of BEAS‐2B cell viability by RSV was alleviated on treatment with jatrophone in dose based manner. The cytopathogenic changes by RSV infection were prevented and viral growth inhibited by jatrophone in BEAS‐2B cells. Jatrophone treatment significantly alleviated RSV mediated overproduction of IL‐6/‐8 and suppressed ROS generation in the cells. The pulmonary viral titers were found to be markedly lower in mice treated with jatrophone relative to untreated group. The jatrophone treated mice also showed reduced IL‐4/‐5/‐13 levels and elevated IFN‐γ level in BALF relative to untreated RSV infected mice. Flow cytometry revealed elevated count of IFN‐γ generating cells in RSV infected mice on treatment with jatrophone. Thus jatrophone inhibits viral growth and oxidative damage by RSV in pulmonary epithelial cells. In RSV infected mice jatrophone increased immunity for viral infection by modulating cell phenotype for promotion of anti‐viral IFN‐γ. Thus jatrophone acts as potential anti‐viral compound and may be developed for treatment of respiratory treat infection.     

EFFECTS OF ANTI-HYPERTENSIVE DRUGS ON PRODUCTION OF SOLUBLE FMS-LIKE TYROSINE KINASE 1 AND SOLUBLE ENDOGLIN FROM HUMAN NORMAL AND PRE-ECLAMPTIC PLACENTAS IN VITRO

• 1 Increases in soluble fms‐like tyrosine kinase 1 (sFlt‐1) and soluble endoglin (sEng) contribute to the pathogenesis of pre‐eclampsia. Soluble Flt‐1 binds to circulating free vascular endothelial growth factor and placenta growth factor and this is associated with endothelial dysfunction. Soluble endoglin, a transforming growth factor (TGF)‐β coreceptor, was reported to synergize with sFlt‐1 to amplify endothelial dysfunction by inhibiting TGF‐β1‐mediated vasorelaxation.
• 2 The aim of the present study was to examine whether the antihypertensive drugs clonidine (0.08–1.3 µg/mL), diazoxide (25–300 µg/mL), frusemide (60–1000 µg/mL) and hydralazine (6.3–100 µg/mL) have any effect on placental production of sFlt‐1 and sEng in placentas from normal and pre‐eclamptic pregnancies.
• 3 Explants were taken from non‐laboured term placentas of normal pregnancy (n = 5) and women with pre‐eclampsia (n = 5). Villous explants were cultured with increasing doses of antihypertensive drugs. Placental sFlt‐1 and sEng production was examined using ELISA.
• 4 Baseline sFlt‐1 production was higher in placentas from women with pre‐eclampsia than from normal pregnancy (4.5 ± 1.4 vs 3.2 ± 0.6 ng/mg of total protein, respectively; P < 0.001), as was sEng production (9.0 ± 2.3 vs 4.1 ± 0.6 ng/mg of total protein, respectively; P < 0.001). With the exception of frusemide, none of the antihypertensive drugs tested had any effect on sFlt‐1 and sEng production from placental explants of normal pregnancy and women with pre‐eclampsia. Increasing frusemide concentrations were correlated with increased sEng production in normal pregnancy (P < 0.005).
• 5 In conclusion, placental sFlt‐1 and sEng production was higher in pre‐eclampsia and antihypertensive drugs had no effect on placental production of sFlt‐1 and sEng in vitro.

     

Dissecting the T-cell response to hordeins in coeliac disease can develop barley with reduced immunotoxicity

Aliment Pharmacol Ther 2010; 32: 1184–1191

Summary

Background Wheat, rye and barley prolamins are toxic to patients with coeliac disease. Barley is diploid with pure inbred cultivars available, and is attractive for genetic approaches to detoxification. Aim To identify barley hordein fractions which activated the interferon‐γ (IFN‐γ) secreting peripheral blood T‐cells from coeliac volunteers, and compare immunotoxicity of hordeins from experimental barley lines. Methods To reactivate a T‐cell response to hordein, volunteers underwent a 3‐day oral barley challenge. Peripheral blood mononuclear cells (PBMC) were isolated from twenty‐one HLA DQ2⁺ patients with confirmed coeliac disease. IFN‐γ ELISpot assays enumerated T‐cells activated by purified prolamins and positive controls. Results Hordein‐specific T‐cells were induced by oral barley challenge. All prolamin fractions were immunotoxic, but D‐ and C‐hordeins were most active. Barley lines lacking B‐ and C‐hordeins had a 5‐fold reduced hordein‐content, and immunotoxicity of hordein extracts were reduced 20‐fold compared with wild‐type barley. Conclusions In vivo oral barley challenge offers a convenient and rapid approach to test the immunotoxicity of small amounts of purified hordeins using fresh T‐cells from patients in high throughput overnight assays. Barley lines that did not accumulate B‐ and C‐hordeins were viable, yet had substantially reduced immunotoxicity. Creation of hordein‐free barley may therefore be possible.     

Chlamydia pneumoniae induces a pro-inflammatory phenotype in murine vascular smooth muscle cells independently of elevating reactive oxygen species

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DIRECT EFFECT OF DEXMEDETOMIDINE ON RAT ISOLATED AORTA INVOLVES ENDOTHELIAL NITRIC OXIDE SYNTHESIS AND ACTIVATION OF THE LIPOXYGENASE PATHWAY

• 1 The aims of the present in vitro study were to examine the roles of pathways associated with arachidonic acid metabolism in dexmedetomidine‐induced contraction and to determine which endothelium‐derived vasodilators are involved in the endothelium‐dependent attenuation of vasoconstriction elicited by dexmedetomidine.
• 2 Dexmedetomidine (10^?9–10^?6 mol/L) concentration–response curves were constructed in: (i) aortic rings with no drug pretreatment; (ii) endothelium‐denuded aortic rings pretreated with either 2 × 10^?5 mol/L quinacrine dihydrochloride, 10^?5 mol/L nordihydroguaiaretic acid (NDGA), 3 × 10^?5 mol/L indomethacin or 10^?5 mol/L fluconazole; and (iii) endothelium‐intact aortic rings pretreated with either 5 × 10^?5 mol/L N^G‐nitro‐l‐ arginine methyl ester (l ‐NAME), 10^?5 mol/L fluconazole, 10^?5 mol/L indomethacin, 10^?5 mol/L glibenclamide, 5 × 10^?3 mol/L tetraethylammonium or 5 × 10^?5 mol/L l ‐NAME plus rauwolscine (10^?5, 10^?6 mol/L). The production of nitric oxide (NO) metabolites was determined in human umbilical vein endothelial cells treated with dexmedetomidine.
• 3 Quinacrine dihydrochloride, NDGA and indomethacin attenuated the dexmedetomidine‐induced contraction of endothelium‐denuded rings. Dexmedetomidine (10^?7–10^?6 mol/L)‐induced contractions of endothelium‐denuded rings were enhanced compared with those of endothelium‐intact rings, as were dexmedetomidine‐induced contractions of endothelium‐intact rings pretreated with l ‐NAME or tetraethylammonium. Rauwolscine attenuated dexmedetomidine‐induced contractions in endothelium‐intact rings pretreated with l ‐NAME. Dexmedetomidine (10^?6 mol/L) was found to activate NO production.
• 4 Taken together, the results indicate that dexmedetomidine‐induced contraction of aortic rings involves activation of the lipoxygenase and cyclo‐oxygenase pathways and is attenuated by increased NO production following stimulation of endothelial α₂‐adrenoceptors by dexmedetomidine.

     

Effect of the Arg389Gly β(1) -adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype-dependent response to metoprolol treatment

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EFFECTS OF SODIUM FERULATE ON HUMAN OSTEOARTHRITIC CHONDROCYTES AND OSTEOARTHRITIS IN RATS

• 1 Oxidation, inflammation and apoptosis are involved in the aetiology and pathology of osteoarthritis (OA). Sodium ferulate (SF) has been demonstrated to have anti‐oxidant, anti‐inflammatory and anti‐apoptotic actions in cardiovascular, hepatic and diabetic disorders. These findings suggest that SF may have beneficial effects on OA. Therefore, present study investigated the effects of SF in an in vivo rat OA model, as well as in vitro in human OA chondrocytes.
• 2 Rats were divided into the following groups: (i) an untreated control group; (ii) papain‐induced OA; (iii) OA rats treated with 0.1 or 0.5% SF; and (iv) normal rats injected with 0.5% SF intra‐articularly. Human chondrocytes from OA patients were cultured before being stimulated with 2 ng/mL interleukin‐1β and subsequently treated with SF (125, 250 and 500 µmol/L). The effects of SF were evaluated both in vivo and in vitro.
• 3 In OA rats, SF treatment dose‐dependently reversed pathological changes in OA cartilage, decreased BAX‐immunopositive chondrocytes and increased Bcl‐2‐immunopositive chondrocytes. Both in vivo and in vitro analyses demonstrated a significant decrease in matrix metalloproteinase‐1 and an increase in tissue‐specific inhibitor of metalloproteinase‐1. In vitro, SF enhanced chondrocyte proliferation and decreased nitric oxide production and apoptosis.
• 4 The results demonstrate that SF dose‐dependently suppresses pathological processes in both in vitro and in vivo OA models. Thus, SF could be a therapeutic strategy for the treatment of OA.

     

SUBENDOCARDIAL VIABILITY INDEX IS RELATED TO THE DIASTOLIC/SYSTOLIC TIME RATIO AND LEFT VENTRICULAR FILLING PRESSURE, NOT TO AORTIC PRESSURE: AN INVASIVE STUDY IN RESTING HUMANS

• 1 The myocardial perfusion relative to left ventricular (LV) workload may be estimated by the subendocardial viability index (SVI). The SVI is a pressure–time integral ratio: the numerator is the area between aortic and LV pressures during diastolic time (DT) and the denominator is the area under the LV pressure curve during systolic time (ST). New non‐invasive tonometric devices allow estimation of SVI but neglect LV end‐diastolic pressure (LVEDP) in the calculation. The aim of the present study was to determine the haemodynamic correlates of SVI and to test the effects of neglecting LVEDP on SVI estimation.
• 2 High‐fidelity pressures were recorded at rest at the aortic root and LV level in 38 subjects (33 men/five women; mean (±SD) age 47 ± 14 years; nine controls and 29 patients with various cardiac diseases). The SVI (1.16 ± 0.28) was positively correlated with the DT/ST ratio (1.71 ± 0.35; r² = 0.81) and was negatively correlated with LVEDP (15 ± 7 mmHg; multiple r² = 0.94). The SVI was not related to aortic pressure (mean, pulse, mean systolic, mean diastolic). In 17 patients with LVEDP > 14 mmHg, the SVI calculated assuming zero LVEDP was 33 ± 15% higher (range 16–70%) than the actual SVI.
• 3 The DT/ST ratio was the main determinant of the myocardial perfusion relative to cardiac workload and accounted for 81% of SVI variability, whereas aortic pressure did not contribute. Although LVEDP accounted for only 13% of SVI variability, it should be taken into account in the non‐invasive calculation of SVI in patients with known or suspected increases in LV filling pressure.

     

CALCITONIN GENE-RELATED PEPTIDE MEDIATES THE CARDIOPROTECTIVE EFFECTS OF RUTAECARPINE AGAINST ISCHAEMIA–REPERFUSION INJURY IN SPONTANEOUSLY HYPERTENSIVE RATS

• 1 It has been shown that calcitonin gene‐related peptide (CGRP) plays an important role in mediating the cardioprotection exerted by rutaecarpine in normal animals. The aim of the present study was to determine whether rutaecarpine is able to decrease the susceptibility of hypertensive animals to ischaemia–reperfusion injury by stimulating CGRP release.
• 2 Spontaneously hypertensive rats (SHR) were pretreated with rutaecarpine (20 or 40 mg/kg per day, i.g.) for 18 days and then the heart and thoracic aorta were isolated for cardiac function and vascular relaxation analysis. Blood samples and coronary effluent were collected to measure CGRP levels and creatine kinase activity, respectively. The effect of 10 or 30 µmol/L rutaecarpine on CGRP release was also examined in isolated aortic rings set up in a homeothermal organ bath.
• 3 Rutaecarpine treatment resulted in a hypotensive effect in SHR concomitant with increases in plasma CGRP levels. In addition, rutaecarpine significantly stimulated the release of CGRP from aortic rings. Twenty minutes ischaemia and 30 min reperfusion resulted in a marked decrease in myocardial function and a significant increase in the release of creatine kinase in normal control (Wistar‐Kyoto) rats, an effect that was exacerbated in SHR. Similarly, the decreased vasodilator response to acetylcholine (3 ? 10^?9 to 10^?6 mol/L) in isolated aortic rings from Wistar‐Kyoto rats was also aggravated in SHR. Both cardiac function and vasodilator responses were significantly improved in SHR after pretreatment with rutaecarpine.
• 4 The results of the present study suggest that the increased cardiac susceptibility to ischaemia–reperfusion injury in SHR is related to decreased plasma CGRP levels and that antihypertensive therapy with rutaecarpine reverses cardiac susceptibility to reperfusion injury by stimulating CGRP release.