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Efficient Neutrophil Extracellular Trap Induction Requires Mobilization of Both Intracellular and Extracellular Calcium Pools and Is Modulated by Cyclosporine A  [PDF]
Anurag Kumar Gupta, Stavros Giaglis, Paul Hasler, Sinuhe Hahn
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097088
Abstract: Excessive or aberrant generation of neutrophil extracellular traps (NETs) has recently become implicated in the underlying aetiology of a number of human pathologies including preeclampsia, systemic lupus erythromatosus, rheumatoid arthritis, auto-antibody induced small vessel vasculitis, coagulopathies such as deep vein thrombosis or pulmonary complications. These results imply that effective pharmacological therapeutic strategies will need to be developed to counter overt NETosis in these and other inflammatory disorders. As calcium flux is implicated in the generation of reactive oxygen species and histone citrullination, two key events in NETosis, we analysed the roles of both extra- and intracellular calcium pools and their modulation by pharmacological agents in the NETotic process in detail. Interleukin-8 (IL-8) was used as a physiological stimulus of NETosis. Our data demonstrate that efficient induction of NETosis requires mobilisation of both extracellular and intracellular calcium pools. Since modulation of the calcineurin pathway by cyclosporine A has been described in neutrophils, we investigated its influence on NETosis. Our data indicate that IL-8 induced NETosis is reduced by ascomycin and cyclosporine A, antagonists of the calcineurin pathway, but not following treatment with rapamycin, which utilizes the mTOR pathway. The action of the G protein coupled receptor phospholipase C pathway appears to be essential for the induction of NETs by IL-8, as NETosis was diminished by treatment with either pertussis toxin, a G-protein inhibitor, the phospholipase C inhibitor, U73122, or staurosporine, an inhibitor of protein kinase C. The data regarding the calcineurin antagonists, ascomycin and cyclosporine A, open the possibility to therapeutically supress or modulate NETosis. They also provide new insight into the mechanism whereby such immune suppressive drugs render transplant patients susceptible to opportunistic fungal infections.
Cadmium Induces Transcription Independently of Intracellular Calcium Mobilization  [PDF]
Brooke E. Tvermoes,Gary S. Bird,Jonathan H. Freedman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020542
Abstract: Exposure to cadmium is associated with human pathologies and altered gene expression. The molecular mechanisms by which cadmium affects transcription remain unclear. It has been proposed that cadmium activates transcription by altering intracellular calcium concentration ([Ca2+]i) and disrupting calcium-mediated intracellular signaling processes. This hypothesis is based on several studies that may be technically problematic; including the use of BAPTA chelators, BAPTA-based fluorescent sensors, and cytotoxic concentrations of metal.
IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17
Brian W Booth, Tracy Sandifer, Erika L Martin, Linda D Martin
Respiratory Research , 2007, DOI: 10.1186/1465-9921-8-51
Abstract: In this study, normal human bronchial epithelial (NHBE) cells grown in air/liquid interface (ALI) culture were used to examine the mechanisms whereby IL-13 induces release of TGFα and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFα and ADAM17 were visualized by confocal microscopy.IL-13 was found to induce proliferation of NHBE cells, and release of TGFα, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFα expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation.Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFα shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine (IL-13) induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGFα to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGFα, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma.Growth factors and cytokines serve integral functions in physiological processes as diverse as proliferation, differentiation, angiogenesis, immune responses and disease progression [1-3]. In a process impacting many cell types such as an immune response, the relationship between cytokines and growth factors can influence the response of tissues that become surrounded by an inflammatory milieu [3]. Similarly, cytokines and growth factors serve to ultimately enhance or resolve inflammation-induced changes in
Effect of cholestasis on Bromocriptine-induced yawning
Parviz M,Karimian M,Dehpour A,KeshvarzM
Tehran University Medical Journal , 1998,
Abstract: The purpose of this study was investigation of effect of cholestasis on bromocriptine-induced yawning in male rats. Bromocriptine, the agonist of dopamine receptors (especially "D2"), causes yawning in male intact rats. In the present study, cholestasis was produced in male rats by surgery and ligation of common bile duct. The number of yawning induced by intraperitoneal injection of bromocriptine (11 mg/kg) was compared in cholestatic rats with sham operated and control groups. Immediately after injection of the drug and putting animals on the frame of behavioral study, the number of yawning was determined in a period of one hour. Obtained results, indicated significant difference in the number of bromocriptine-induced yawning between cholestatic rats and the other two groups. There wasn't significant difference between sham and control rats. These results indicate that some changes occur in cholestatic rats which increase sensitivity and response of dopamine receptors. Since it is proved that dopamine agonist-induced yawning is mediated via nitric oxide, and also level of nitric oxide is increased in cholestasis, it can be supposed that the mentioned response may be due to elevated level of nitric oxide. On the other hand, increased number of yawning in cholestatic rats may be due to increased level of endogenous opioids in these animals.
Bromocriptine Does Not Alter Speed–Accuracy Tradeoff  [PDF]
Jasper Winkel,Leendert van Maanen,Martine R. van Schouwenburg,Roshan Cools,Birte U. Forstmann
Frontiers in Neuroscience , 2012, DOI: 10.3389/fnins.2012.00126
Abstract: Being quick often comes at the expense of being accurate. This speed–accuracy tradeoff is a central feature of many types of decision making. It has been proposed that dopamine plays an important role in adjusting responses between fast and accurate behavior. In the current study we investigated the role of dopamine in perceptual decision making in humans, focusing on speed–accuracy tradeoff. Using a cued version of the random dot motion task, we instructed subjects to either make a fast or an accurate decision. We investigated decision making behavior in subjects who were given bromocriptine (a dopamine receptor agonist) or placebo. We analyzed the behavioral data using two accumulator models, the drift diffusion model, and the linear ballistic accumulator model. On a behavioral level, there were clear differences in decision threshold between speed and accuracy focus, but decision threshold did not differ between the drug and placebo sessions. Bayesian analyses support the null hypothesis that there is no effect of bromocriptine on decision threshold. On the neural level, we replicate previous findings that the striatum and pre-supplementary motor area are active when preparing for speed, compared with accurate decisions. We do not find an effect of bromocriptine on this activation. Therefore, we conclude that bromocriptine does not alter speed–accuracy tradeoff.
Neutrophil Secretion Induced by an Intracellular Ca Rise and Followed by Whole-Cell Patch-Clamp Recordings Occurs Without any Selective Mobilization of Different Granule Populations
Daniel Granfeldt,Olle Harbecke, se Bj rstad,Anna Karlsson,Claes Dahlgren
Journal of Biomedicine and Biotechnology , 2006, DOI: 10.1155/jbb/2006/97803
Abstract: We have investigated calcium-induced secretion in human neutrophils, using a whole-cell patch-clamp technique. Mobilization of subcellular granules to the cell membrane was followed as the change in membrane capacitance (△Cm). Both the magnitude and the kinetics of the response differed between low and high concentrations of Ca2
Cyclosporine and Hepatitis C  [PDF]
Ryan Caballes, Mark W. Russo
Open Journal of Organ Transplant Surgery (OJOTS) , 2012, DOI: 10.4236/ojots.2012.24009
Abstract: End stage liver disease from hepatitis C is a leading indication for liver transplantation. Recurrent hepatitis C after liver transplant may lead to cirrhosis and graft failure in up to 25% of recipients five years after liver transplantation. Anti-viral therapy is challenging after liver transplantation due to increased side effects including cytopenias and decreased efficacy compared to the nontransplant population. Tacrolimus and cyclosporine are the most common immunosuppressants used to prevent graft rejection. Tacrolimus is more potent than cyclosporine and may be preferred to cyclosporine. However, cyclosporine may have activity against hepatitis C and may have a theoretical advantage to tacrolimus in hepatitis liver transplant recipients. Cyclosporine may inhibit NS5B and NS5A protein complexes and increase endogenous interferon activity. Cyclophilin inhibitors without immunosuppressive properties are under development and represent a novel mechanisms for inhibiting HCV replication.
Bromocriptine in Central Hyperthermia after Severe Traumatic Brain Injury  [PDF]
Tamer Zakhary, Ahmed Sabry
Open Journal of Emergency Medicine (OJEM) , 2017, DOI: 10.4236/ojem.2017.53010
Abstract: Strong evidence showed that fever after traumatic brain injury TBI is associated with increased mortality. In this study, we tried to evaluate the role of Bromocriptine in central hyperthermia in patients with severe TBI. This prospective controlled study was conducted on 50 severe TBI patients who admitted to the critical care department and confirmed on Computed Tomography (CT) of the brain and GCS of less than 9 at admission. Then, they were randomly assigned into 2 groups. Bromocriptine group (25) received bromocriptine 7.5 mg/day during 24 hours from admission through a naso-gastric (NG) feeding tube. Control group (25) received conventional treatment only. Temperature was measured every 2 hours. The antipyretic measures used were the same across all patients enrolled. The primary outcome was number of patients diagnosed with central hyperthermia. After the discharge of all patients, there was a statistically significant difference between the 2 groups in number of patients diagnosed with central hyperthermia (6 (24%) in bromocriptine group Vs 18 (72%) in control, p = 0.002). There were no differences in hospital length of stay (p = 0.904) or mortality (p = 0.393). Early administration of bromocriptine in severe TBI may be associated with lower incidence of central hyperthermia with no effect on length of stay or mortality.
Effect of Bromocriptine on Insulin Resistance in Patients with PCO  [PDF]
Zivar Shirinpour, Bahman Ghaderian, Homeira Rashidi, Armaghan Moravej Aleali, Seyed Peyman Payami
Open Journal of Endocrine and Metabolic Diseases (OJEMD) , 2014, DOI: 10.4236/ojemd.2014.412026
Abstract: Introduction: Poly cystic ovary (PCO) is one of the most common endocrine disorders in women. All patients with PCO are at risk of insulin resistance, IFG and diabetes. Recently, bromocriptine is used in treatment of diabetes mellitus type II to improve insulin resistance. Objective: The aim of this study is the evaluation of bromocriptine on insulin resistance in PCO people. Patients and Methods: In this single-blind controlled clinical trial with placebo, 44 patients with PCO referring to endocrinology clinic were evaluated. Inclusion criteria were BMI > 25 kg/m2 and diagnosed PCO patients according to Rotterdam criteria and rule out other causes. Blood samples were obtained for FBS, Fasting Insulin, Prolactin, TSH and 17(OH)P. They divided two groups: Case group was given bromocriptine 2.5 mg daily and placebo was given to control group. Patients were treated for 8 days and in day 9th blood sample was obtained for FBS, Fasting insulin, HOMA-IR index. Mann-Whitney method is used for mean comparison. Results: Data analysis using showed in pre diabetes range, mean changes of FBS, insulin level and IR in Groups 1 and 2 had significant differences(P = 0.004), but no significant different was found in FBS < 100 mg/dl (P = 0.92). In group with BMI < 30 kg/m2, no significant differences were found in changes in FBS < insulin level and IR (P = 0.13, 0.13, and 0.11 respectively). In group with BMI ≥ 30 kg/m2, no significant differences were found in changes in insulin level and IR (P = 0.69, 0.089 respectively). Mean systolic blood pressure changes in Group 1 and 2 in FBS > 100 mg/dl with (P = 0.036) were significant, but no significant difference showed in mean change of diastolic blood pressure in FBS > 100 mg/dl (P = 0.99). In FBS < 100 mg/dl mean changes in systolic and diastolic blood pressures were not significant (P = 0.6). Age showed no difference changes in effect on treatment in Groups 1 and 2 (P = 0.1). Conclusion: Our study showed, even in the short-term consumption, bromocriptine reduced FBS and insulin levels and insulin resistance in PCO patients with pre-diabetes range.
Cyclosporine: A Review  [PDF]
Dustin Tedesco,Lukas Haragsim
Journal of Transplantation , 2012, DOI: 10.1155/2012/230386
Abstract: The discovery and use of cyclosporine since its inception into clinical use in the late 1970s has played a major role in the advancement of transplant medicine. While it has improved rates of acute rejection and early graft survival, data on long-term survival of renal allografts is less convincing. The finding of acute reversible nephrotoxicity and nephrotoxicity in nonrenal transplants has since led to the widely accepted view that there is a chronic more irreversible component to this agent as well. Since that time, there has been intense interest in finding protocols which seek to minimize and even avoid the use of calcineurin inhibitors altogether. We seek to review cyclosporine in terms of its mechanism of action, pathophysiologic, and histologic features associated with acute and chronic nephrotoxicity and recent studies looking to avoid its toxic side effects. 1. Introduction Discovered in the lab of Sandoz in Switzerland in 1972, cyclosporine (CsA) has since revolutionized transplant medicine. Initially discovered while searching for novel antifungal agents, it was found to have many immunologic properties that made it an attractive agent for immunosuppression following renal and other solid organ transplants. With the premise that cell-mediated immunity was involved in autoimmune and chronic inflammatory conditions, Borel set up a series of experiments using antiinflammatory, immunosuppressant, and antimitotic medications to examine their effects on lymphocyte-mediated lysis of presensitized and na?ve effector cells. In these experiments, it was found that cyclosporine inhibited both in vitro cell-mediated lysis as well as lymphocyte sensitization by allogeneic target cells [1]. It was this work and others by Borel that exhibited the cell-mediated specificity of cyclosporine, theoretically lending itself to a far better side effect profile than the current immunosuppressive agents in use at that time. Subsequently, a European multicenter trial demonstrated one-year graft survival of 72% and 52% in recipients of cadaveric renal transplants allocated to receive either cyclosporine or azathioprine and steroids, respectively, for immunosuppression. Such promising results helped lead to clinical approval of CsA for use in the early 1980s [2]. With improved rates of acute rejection and one-year graft survival, cyclosporine has become a mainstay for immune suppression of renal and other solid organ transplants. A review from Hariharan et al. published in 2000 looking at graft survival in more than 93,000 transplants from 1988 to 1996 revealed
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