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41.
THE MICROCOCCI OF MILK 总被引:1,自引:1,他引:0
42.
Herraiz C Journé F Abdel-Malek Z Ghanem G Jiménez-Cervantes C García-Borrón JC 《Molecular endocrinology (Baltimore, Md.)》2011,25(1):138-156
Melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor expressed in melanocytes, is a major determinant of skin pigmentation, phototype and cancer risk. Upon stimulation by αMSH, MC1R triggers the cAMP and ERK1/ERK2 MAPK pathways. In mouse melanocytes, ERK activation by αMSH binding to Mc1r depends on cAMP, and melanocytes are considered a paradigm for cAMP-dependent ERK activation. However, human MC1R variants associated with red hair, fair skin [red hair color (RHC) phenotype], and increased skin cancer risk display reduced cAMP signaling but activate ERKs as efficiently as wild type in heterologous cells, suggesting independent signaling to ERKs and cAMP in human melanocytes. We show that MC1R signaling activated the ERK pathway in normal human melanocytes and melanoma cells expressing physiological levels of endogenous RHC variants. ERK activation was comparable for wild-type and mutant MC1R and was independent on cAMP because it was neither triggered by stimulation of cAMP synthesis with forskolin nor blocked by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine. Stimulation of MC1R with αMSH did not lead to protein kinase C activation and ERK activation was unaffected by protein kinase C inhibitors. Conversely, pharmacological interference, small interfering RNA studies, expression profiles, and functional reconstitution experiments showed that αMSH-induced ERK activation resulted from Src tyrosine kinase-mediated transactivation of the stem cell factor receptor, a receptor tyrosine kinase essential for proliferation, differentiation, and survival of melanocyte precursors, thus demonstrating a functional link between the stem cell factor receptor and MC1R. Moreover, this transactivation phenomenon is unique because it is unaffected by natural mutations impairing canonical MC1R signaling through the cAMP pathway. 相似文献
43.
Background
Despite the impact of sodium valproate and dexamethasone on migraine headache, the efficacy of the two drugs has not been properly investigated and compared. This trial compared the effect of the two drugs on acute migraine headache.Methods
This double blind randomized clinical trial was conducted on patients aged 18 to 65 years with acute migraine headache who referred to the emergency departments of Beasat and Farshchian Hospitals in Hamadan, Iran, from April 2012 to June 2014. Patients were randomly assigned to receive a single-dose of either 400 mg sodium valproate or 16 mg dexamethasone plus 50 ml saline normal solution within 15 min intravenously. The severity of headache in the two groups was evaluated at baseline, 0.5 and 2 hours later using the Visual Analog Scale (VAS) on a scale of 0 to 10.Results
Of 104 patients enrolled, 72 patients remained for analysis. The effect of both sodium valproate and dexamethasone on acute migraine headache was statistically significant at 0.5 and 2 hours post-treatment compared to pre-treatment (P=0.001). The severity of headache based on VAS reduced form 8.20 (7.72, 8.68) before treatment to 5.31 (4.74, 5.89) and 3.66 (2.99, 4.33) at 0.5 and 2 hours after treatment, respectively, in patients receiving sodium valproate and from 8.46 (8.05, 8.86) before treatment to 5.46 (4.81, 6.11) and 3.59 (2.84, 4.35) at 0.5 and 2 hours after treatment, respectively, in patients receiving dexamethasone. Both drugs were highly effective in improvement of acute headache in patients without aura. However, sodium valproate significantly improved the acute headache in patients with aura but dexamethasone did not. The severity of headache based on VAS reduced form 8.50 (7.40, 9.60) before treatment to 4.67 (2.40, 6.93) and 3.50 (1.78, 5.22) at 0.5 and 2 hours after treatment, respectively, in patients with aura receiving sodium valproate and from 8.80 (7.76, 9.84) before treatment to 7.20 (4.98, 9.42) and 6.20 (2.43, 9.97) at 0.5 and 2 hours after treatment, respectively, in patients with aura receiving dexamethasone.Conclusions
This trial indicated that, in overall, intravenous sodium valproate is not superior to intravenous dexamethasone in treatment of acute migraine attacks. However, in patients with aura, only sodium valproate but not dexamethasone is effective in headache relief. This issue needs further investigations.Trial Registration
ClinicalTrials.gov IRCT201202199014N1 相似文献44.
Mehri Shahir Seyed Mahmoud Hashemi Ali Asadirad Mohammad Varahram Mehdi Kazempour-Dizaji Gert Folkerts Johan Garssen Ian Adcock Esmaeil Mortaz 《Journal of cellular physiology》2020,235(10):7043-7055
Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T-cell activation via direct cell–cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) help maintain immunological tolerance through the induction of T-cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC-derived exosomes on the induction of mouse tolDCs, murine adipose-derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick-TC kits. BM-derived DCs (BMDCs) were prepared and cocultured with MSCs-derived exosomes (100 μg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS; 0.1μg/ml) at Day 8 for 24 hr. The study groups were divided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester-labeled BALB/C-derived splenocytes p. Interleukin-6 (IL-6), IL-10, and transforming growth factor-β (TGF-β) release were measured by enzyme-linked immunosorbent assay. MSC-derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC-derived exosomes decrease IL-6 release but augment IL-10 and TGF-β release (p ≤ .05). Lymphocyte proliferation was decreased (p ≤ .05) in the presence of DCs treated with MSC-derived exosomes. CMSC-derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC-induced immune responses. 相似文献
45.
Faisal Ali Mustafa Zakkar Kersti Karu Elaine A. Lidington Shahir S. Hamdulay Joseph J. Boyle Mire Zloh Andrea Bauer Dorian O. Haskard Paul C. Evans Justin C. Mason 《The Journal of biological chemistry》2009,284(28):18882-18892
In addition to cholesterol-lowering properties, statins exhibit lipid-independent immunomodulatory, anti-inflammatory actions. However, high concentrations are typically required to induce these effects in vitro, raising questions concerning therapeutic relevance. We present evidence that endothelial cell sensitivity to statins depends upon shear stress. Using heme oxygenase-1 expression as a model, we demonstrate differential heme oxygenase-1 induction by atorvastatin in atheroresistant compared with atheroprone sites of the murine aorta. In vitro, exposure of human endothelial cells to laminar shear stress significantly reduced the statin concentration required to induce heme oxygenase-1 and protect against H2O2-mediated injury. Synergy was observed between laminar shear stress and atorvastatin, resulting in optimal expression of heme oxygenase-1 and resistance to oxidative stress, a response inhibited by heme oxygenase-1 small interfering RNA. Moreover, treatment of laminar shear stress-exposed endothelial cells resulted in a significant fall in intracellular cholesterol. Mechanistically, synergy required Akt phosphorylation, activation of Kruppel-like factor 2, NF-E2-related factor-2 (Nrf2), increased nitric-oxide synthase activity, and enhanced HO-1 mRNA stability. In contrast, heme oxygenase-1 induction by atorvastatin in endothelial cells exposed to oscillatory flow was markedly attenuated. We have identified a novel relationship between laminar shear stress and statins, demonstrating that atorvastatin-mediated heme oxygenase-1-dependent antioxidant effects are laminar shear stress-dependent, proving the principle that biomechanical signaling contributes significantly to endothelial responsiveness to pharmacological agents. Our findings suggest statin pleiotropy may be suboptimal at disturbed flow atherosusceptible sites, emphasizing the need for more specific therapeutic agents, such as those targeting Kruppel-like factor 2 or Nrf2.The efficacy of 3-hydroxy-3-methylglutaryl-coenzyme A reductase antagonists (statins) in reducing low density lipoprotein cholesterol, cardiovascular morbidity, and mortality is widely recognized (1). The observation that beneficial actions of statins on vascular function are detectable prior to any fall in serum cholesterol, extend to normocholesterolemic patients and exceed those of other lipid-lowering drugs despite comparable falls in total cholesterol (2, 3), suggest the existence of low density lipoprotein-cholesterol-independent effects (4, 5). Judging from in vitro studies, these may include immunomodulatory, anti-inflammatory, anti-adhesive, anti-thrombotic, and cytoprotective actions (6). However, the experimental work demonstrating these pleiotropic effects has predominantly used statin concentrations exceeding those achieved by therapeutic dosing, raising questions concerning clinical relevance (4).Heme oxygenase-1 (HO-1)2 acts as the rate-limiting factor in the catabolism of heme into biliverdin, releasing free iron and carbon monoxide (CO). Biliverdin is subsequently converted to bilirubin by biliverdin reductase, whereas intracellular iron induces expression of heavy chain-ferritin and the opening of Fe2+ export channels (7). The biologic activity of HO-1 represents an important adaptive response in cellular homeostasis, as revealed by widespread inflammation and persistent endothelial injury in human HO-1 deficiency (8).Expression of HO-1 in atherosclerotic lesions, and its ability to inhibit vascular smooth muscle cell proliferation, exert anti-inflammatory, antioxidant, and antithrombotic effects, suggests a protective role during atherogenesis (9, 10). HMOX1 promoter polymorphisms affecting HO-1 expression may influence susceptibility to intimal hyperplasia and coronary artery disease, whereas a low serum bilirubin constitutes a cardiovascular risk factor (11). Moreover, overexpression of HO-1 inhibited atherogenesis, whereas Hmox1−/− mice bred onto an ApoE−/− background developed more extensive and complex atherosclerotic plaques (12, 13).Recent interest has focused on the therapeutic potential of HO-1 and its products, with probucol, statins, rapamycin, nitric oxide donors, and aspirin being shown to induce HO-1 (reviewed in Ref. 10). Indeed, induction of HO-1 may represent an important component of the vasculoprotective profile of statins, with simvastatin, atorvastatin, and rosuvastatin variously shown to increase HMOX1 promoter activity and mRNA levels, to induce enzyme activity and increase antioxidant capacity in human endothelial cells (EC) (14–18). However, induction of HO-1 in vascular EC in vivo has not yet been demonstrated.Vascular endothelium exposed to unidirectional, pulsatile laminar shear stress (LSS) >10 dynes/cm2 is relatively protected against atherogenesis. LSS increases nitric oxide (NO) biosynthesis, prolongs EC survival, and generates an anticoagulant, anti-adhesive cell surface. In contrast, endothelium exposed to disturbed blood flow, with low shear reversing or oscillatory flow patterns, such as that located at arterial branch points and curvatures, is atheroprone. Thus endothelial cells exposed to disturbed blood flow exhibit reduced levels of endothelial nitric-oxide synthase (eNOS), increased apoptosis, oxidative stress, permeability to low density lipoprotein, and leukocyte adhesion (19).The atheroprotective influence of unidirectional LSS and the overlap between these actions and those of statins led us to hypothesize that LSS increases endothelial responsiveness to statins. We demonstrate for the first time that treatment of mice with atorvastatin induces HO-1 expression in the aortic endothelium and that this occurs preferentially at sites exposed to LSS. In vitro, pre-conditioning human EC with an atheroprotective, but not an atheroprone waveform, significantly reduces the concentration of atorvastatin required to enhance HO-1-mediated cytoprotection against oxidant-induced injury. A synergistic relationship between LSS and statins is revealed, resulting in maximal Akt phosphorylation and dependence upon eNOS, Kruppel-like factor 2 (KLF2), and NF-E2-related factor-2 (Nrf2) activation. 相似文献
46.
Kinderlerer AR Ali F Johns M Lidington EA Leung V Boyle JJ Hamdulay SS Evans PC Haskard DO Mason JC 《The Journal of biological chemistry》2008,283(21):14636-14644
Complement activation may predispose to vascular injury and atherogenesis. The atheroprotective actions of unidirectional laminar shear stress led us to explore its influence on endothelial cell expression of complement inhibitory proteins CD59 and decay-accelerating factor. Human umbilical vein and aortic endothelial cells were exposed to laminar shear stress (12 dynes/cm(2)) or disturbed flow (+/- 5 dynes/cm(2) at 1Hz) in a parallel plate flow chamber. Laminar shear induced a flow rate-dependent increase in steady-state CD59 mRNA, reaching 4-fold at 12 dynes/cm(2). Following 24-48 h of laminar shear stress, cell surface expression of CD59 was up-regulated by 100%, whereas decay-accelerating factor expression was unchanged. The increase in CD59 following laminar shear was functionally significant, reducing C9 deposition and complement-mediated lysis of flow-conditioned endothelial cells by 50%. Although CD59 induction was independent of PI3-K, ERK1/2 and nitric oxide, an RNA interference approach demonstrated dependence upon an ERK5/KLF2 signaling pathway. In contrast to laminar shear stress, disturbed flow failed to induce endothelial cell CD59 protein expression. Likewise, CD59 expression on vascular endothelium was significantly higher in atheroresistant regions of the murine aorta exposed to unidirectional laminar shear stress, when compared with atheroprone areas exposed to disturbed flow. We propose that up-regulation of CD59 via ERK5/KLF2 activation leads to endothelial resistance to complement-mediated injury and protects from atherogenesis in regions of laminar shear stress. 相似文献
47.
Abdel-Malek Hebbachi Geoffrey F Gibbons 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》1999,1441(1):36-50
The requirements for microsomal triglyceride transfer protein (MTP) during the turnover and transfer of glycerolipids from intracellular compartments into secretory very low-density lipoprotein (VLDL) were studied by pre-labelling lipids with [3H]glycerol and [14C]oleate in primary cultures of rat hepatocytes. The intracellular redistribution of pre-labelled glycerolipids was then compared at the end of subsequent chase periods during which the MTP inhibitor BMS-200150 was either present or absent in the medium. Inhibition of MTP resulted in a decreased output of VLDL triacylglycerol (TAG) and a delayed removal of labelled TAG from the cytosol and from the membranes of the smooth endoplasmic reticulum (SER), the cis- and the trans-Golgi. Inactivation of MTP did not decrease the bulk lipolytic turnover of cellular TAG as reflected by changes in its [3H]glycerol:[14C]oleate ratios. However, a larger proportion of the resultant TAG fatty acids was re-esterified and remained with the membranes of the various subcellular fractions rather than emerging as VLDL. The effects of BMS-200150 on the pattern of phospholipid (PL) mechanism and redistribution suggested that inhibition of MTP prevented the normal lipolytic transfer of PL-derived fatty acids out of the SER, cis- and trans-Golgi membrane pools. Finally, changes in the 14C specific radioactivities of the cytosolic and membrane pools of TAG suggested that inhibition of MTP prevented a normal influx of relatively unlabelled fatty acids into these pools during the chase period. 相似文献
48.
Potratz J Yang J Abdel-Malek K Peña Pitarch E Grosland N 《Journal of biomechanical engineering》2005,127(6):934-945
This paper presents the design and prototyping of an inherently compliant lightweight hand mechanism. The hand mechanism itself has 15 degrees of freedom and five fingers. Although the degrees of freedom in each finger are coupled, reducing the number of independent degrees of freedom to 5, the 15 degrees of freedom of the hand could potentially be individually actuated. Each joint consists of a novel flexing mechanism that is based on the loading of a compression spring in the axial and transverse direction via a cable and conduit system. Currently, a bench top version of the prototype is being developed; the three joints of each finger are coupled together to simplify the control system. The current control scheme under investigation simulates a control scheme where myoelectric signals in the wrist flexor and extensor muscles are converted in to x and y coordinates on a control scheme chart. Static load-deformation analysis of finger segments is studied based on a 3-dimensional model without taking the stiffener into account, and the experiment validates the simulation. 相似文献
49.
The use of proteins or nucleic acids as therapeutic agents has been severely hampered by their intrinsic inability to cross the cell membrane. Moreover, common techniques for driving the delivery of macromolecules lack the ability to distinguish between healthy and diseased tissue, precluding their clinical use. Recently, receptor-mediated delivery (RMD) has emerged as a technology with the potential to circumvent the obstacles associated with the delivery of drug targets by utilizing the natural endocytosis of a ligand upon binding to its receptor. Here, we describe the synthesis of variants of substance P (SP), an eleven amino acid neuropeptide ligand of the neurokinin type 1 receptor (NK1R), for the delivery of various types of cargo. The variants of SP were synthesized with an N-terminal maleimide moiety that allows conjugation to surface thiols, resulting in a nonreducible thioether. Cargos lacking an available thiol are conjugated to SP using commercially available cross-linkers. In addition to the delivery of proteins, we expand the use of SP to include nuclear delivery of DNA fragments that are actively expressed in the target cells. We also show that SP can be used to deliver whole bacteriophage particles as well as polystyrene beads up to 1 μm in diameter. The results show the ability of SP to deliver cargo of various sizes and chemical properties that retain their function within the cell. Furthermore, the overexpression of the NK1R in many tumors provides the potential for developing targeted delivery reagents that are specific toward diseased tissue. 相似文献
50.
Mitogenic, melanogenic, and cAMP responses of cultured neonatal human melanocytes to commonly used mitogens. 总被引:13,自引:0,他引:13
Z Abdel-Malek V B Swope J Pallas K Krug J J Nordlund 《Journal of cellular physiology》1992,150(2):416-425
The following studies have been undertaken to compare and correlate the effects of 12-O-tetradecanoylphorbol acetate (TPA), basic fibroblast growth factor (bFGF), cholera toxin (CT), and isobutyl methylxanthine (IBMX) on neonatal human melanocyte (NHM) proliferation, tyrosinase activity, and cyclic adenosine monophosphate (cAMP) concentration. NHM proliferated at a maximal rate in medium containing 8 nM TPA, 200 ng/ml CT, and 10(-4) M IBMX. TPA alone did not result in optimal melanocyte proliferation, and, as previously shown, its mitogenic effect was greatly enhanced by the addition of CT and IBMX individually or concomitantly. Human recombinant (hr) bFGF could replace TPA in the NHM growth medium. Maximal proliferation was achieved using 3 ng/ml hrbFGF, 20 ng/ml CT, and 10(-4) M IBMX. The mitogenic effect of 1.2 ng/ml hrbFGF was potentiated in the concomitant but not individual presence of CT and IBMX. TPA alone in the absence of CT and IBMX caused a dose-dependent stimulation of tyrosinase activity. Maximal tyrosinase activity was obtained in the presence of 0.8 nM TPA, 20 ng/ml CT, and 10(-4) M IBMX. Unlike TPA, hrbFGF alone resulted in inhibition of tyrosinase activity. In the presence of hrbFGF, tyrosinase activity was potentiated by CT and IBMX, but not by CT alone. Neither TPA nor hrbFGF alone could increase intracellular cAMP levels. The effects of CT and IBMX on intracellular cAMP concentration were enhanced to a greater extent by TPA than by hrbFGF. Under our experimental conditions, in the presence of hrbFGF, CT but not IBMX resulted in a dose-dependent increase in cAMP concentration. Further studies on NHM will be aimed at determining the exact role of protein kinase C (PKC) in regulating proliferation and melanogenesis and the mechanism(s) activated by hrbFGF. 相似文献