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Sökning: WFRF:(Rahman Milladur)

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1.
  • Abdulla, Aree, et al. (författare)
  • Platelets play an important role in acute pancreatitis
  • 2010
  • Ingår i: 45th Congress of the European-Society-for-Surgical-Research,Geneva, Switzerland,2010-06-09 - 2010-06-12. - John Wiley and Sons Inc..
  • Konferensbidrag (refereegranskat)
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2.
  • Abdulla, Aree, et al. (författare)
  • Role of platelets in experimental acute pancreatitis.
  • 2011
  • Ingår i: British Journal of Surgery. - John Wiley and Sons Inc.. - 1365-2168. ; 98, s. 93-103
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:: Platelets not only control thrombosis and haemostasis but may also regulate inflammatory processes. Acute pancreatitis (AP) is characterized by changes in both coagulation and proinflammatory activities. The role of platelets in AP is not yet known. METHODS:: AP was induced in C57BL/6 mice by repeated caerulein administration (50 µg/kg intraperitoneally). Mice received a platelet-depleting or control antibody before caerulein challenge. Neutrophil infiltration, myeloperoxidase (MPO) and macrophage inflammatory protein (MIP) 2 levels, acinar cell necrosis and haemorrhage in the pancreas, as well as serum amylase activity, were determined 24 h after caerulein injection. In an alternative model of pancreatitis, L-arginine (4 g/kg intraperitoneally) was given twice with an interval of 1 h and tissue samples were taken after 72 h [Correction added after online publication 29 September 2010: in the preceding sentence, 4 mg/kg was corrected to 4 g/kg]. RESULTS:: Caerulein administration increased acinar cell necrosis, neutrophil infiltration, focal haemorrhage and serum amylase levels. Platelet depletion reduced acinar cell necrosis, haemorrhage and serum amylase levels in AP. Depletion of platelets decreased caerulein-induced MPO levels and neutrophil recruitment in the pancreas. Platelet depletion abolished caerulein-induced MIP-2 generation in the pancreas and circulation. The effects of platelet depletion on necrosis, neutrophils and MPO levels were confirmed in L-arginine-induced pancreatitis. CONCLUSION:: Platelets play a crucial role in AP by regulating neutrophil infiltration, most likely mediated by MIP-2 production in the pancreas. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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3.
  • Al-Haidari, Amr A., et al. (författare)
  • Neutrophil extracellular traps promote peritoneal metastasis of colon cancer cells
  • 2019
  • Ingår i: Oncotarget. - Impact Journals, LLC. - 1949-2553. ; 10:12, s. 1238-1249
  • Tidskriftsartikel (refereegranskat)abstract
    • Cytoreductive surgery is the only curative option for patients with peritoneal carcinomatosis, however, intraperitoneal recurrence rate is high making new ways to prevent cancer recurrence an urgent need. Recent evidence suggests that neutrophils are involved in cancer progression. The purpose of our study was to examine the role of neutrophils in the spread of colon cancer cells in the peritoneal cavity. The number of metastatic noduli in the peritoneal cavity was quantified in mice injected with murine colon cancer cells (CT-26) intraperitoneally after surgical laparotomy and treated with a neutrophil depleting antibody or DNase I. In addition, peritoneal metastases were harvested from patients with peritoneal carcinomatosis. Scanning and transmission electron microscopy showed extensive neutrophil extracellular trap (NET) formation in peritoneal colon cancer metastases in mice and patients. Neutrophil depletion markedly reduced the number of metastases in laparotomised animals. Administration of DNase I decreased the number of metastatic nodules by 88% in laparotomised animals as well as NET-induced chemokinedependent colon cancer cell migration and adhesion in vitro. Finally, CT-26 cancer cells were found to express the avβ3 integrin and inhibition of av integrin abolished NET-induced adhesion of colon cancer cells to vitronectin. Taken together, our data show that NETs play an important role in colon cancer cell metastasis in the peritoneal cavity and regulate colon cancer cell migration and adhesion to extracellular matrix proteins. These novel findings suggest that targeting NETs might be an effective strategy to antagonize intrabdominal recurrences of colon cancer after cytoreductive surgery in patients with peritoneal carcinomatosis.
4.
  • Awla, Darbaz, et al. (författare)
  • Rho-kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis.
  • 2011
  • Ingår i: British Journal of Pharmacology. - The British Pharmacological Society. - 1476-5381. ; 162, s. 648-658
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho-kinase is a potent regulator of specific cellular processes effecting several pro-inflammatory activities. Herein, we examined the role of Rho-kinase signalling in acute pancreatitis. Experimental approach: Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho-kinase inhibitor Y-27632 (0.5-5 mg kg(-1) ) before induction of pancreatitis. Key results: Taurocholate infusion caused a clear-cut increase in serum amylase, pancreatic neutrophil infiltration, acinar cell necrosis and oedema formation in the pancreas. Levels of pancreatic myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), trypsinogen activation peptide (TAP) and lung MPO were significantly increased, indicating local and systemic disease. Inhibition of Rho-kinase activity dose-dependently protected against pancreatitis. For example, 5 mg kg(-1) Y-27632 reduced acinar cell necrosis, leucocyte infiltration and pancreatic oedema by 90%, 89% and 58% respectively as well as tissue levels of MPO by 75% and MIP-2 by 84%. Moreover, Rho-kinase inhibition decreased lung MPO by 75% and serum amylase by 83%. Pancreatitis-induced TAP levels were reduced by 61% in Y-27632-treated mice. Inhibition of Rho-kinase abolished secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. Conclusions and Implications: Our novel data suggest that Rho-kinase signalling plays an important role in acute pancreatitis by regulating trypsinogen activation and subsequent CXC chemokine formation, neutrophil infiltration and tissue injury. Thus, these results indicate that Rho-kinase may constitute a novel target in the management of SAP.
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5.
  • Chew, Michelle, et al. (författare)
  • Soluble CD40L (CD154) is increased in patients with shock.
  • 2010
  • Ingår i: Inflammation Research. - Birkhäuser Verlag. - 1420-908X. ; 59, s. 979-982
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Recent data suggest that soluble CD40L (sCD40L) plays an important role in murine sepsis. The aim of the present study was to determine plasma levels of CD40L in critically ill patients with systemic inflammatory response syndrome (SIRS) and shock, with and without sepsis. DESIGN: A prospective observational one-centre cohort study in a mixed-bed ICU of an university hospital. Fifty-three consecutive patients fulfilling the criteria for SIRS with shock as well as seven age-matched controls were included. ELISA was used to determine sCD40L in the plasma. RESULTS: The level of sCD40L in plasma from healthy controls was 0.18 +/- 0.03 ng/ml. It was found that sCD40L levels were significantly higher in patients with non-septic shock (0.72 +/- 0.18 ng/ml) and septic shock (0.50 +/- 0.1 ng/ml). However, the levels of sCD40L were not different between these two groups of patients, or in those with low and high APACHE scores. CONCLUSION: Our data show that sCD40L is increased in patients with shock from septic and non-septic etiologies. However, further studies are needed to delineate the functional significance of sCD40L in the clinical outcome in shock patients.
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6.
  • Hasan, Zirak, et al. (författare)
  • Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury
  • 2013
  • Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - American Physiological Society. - 1522-1504. ; 304:4, s. 221-229
  • Tidskriftsartikel (refereegranskat)abstract
    • Hasan Z, Rahman M, Palani K, Syk I, Jeppsson B, Thorlacius H. Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury. Am J Physiol Lung Cell Mol Physiol 304: L221-L229, 2013. First published December 14, 2012; doi:10.1152/ajplung.00199.2012.-Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-alpha (TNF-alpha), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-alpha, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.
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7.
  • Hasan, Zirak, et al. (författare)
  • Rho-kinase regulates induction of T-cell immune dysfunction in abdominal sepsis.
  • 2013
  • Ingår i: Infection and Immunity. - American Society for Microbiology. - 1098-5522. ; 81:7, s. 2499-2506
  • Tidskriftsartikel (refereegranskat)abstract
    • T-cell dysfunction increases susceptibility to infections in patients with sepsis. In the present study, we hypothesized that Rho-kinase signaling might regulate induction of T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were treated with the specific Rho-kinase inhibitor Y-27632 (5 mg/kg) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation and regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) were determined by flow cytometry. Formation of IFN-γ and IL-4 in the spleen and plasma levels of HMBG1 and IL-6 were quantified by use of ELISA. It was found that CLP evoked apoptosis and decreased proliferation in splenic CD4 T-cells. Inhibition of Rho-kinase activity decreased apoptosis and enhanced proliferation of CD4 T-cells in septic animals. In addition, CLP-evoked induction of regulatory T-cells in the spleen was abolished by Rho-kinase inhibition. CLP reduced the levels of IFN-γ and IL-4 in the spleen. Pretreatment with Y-27632 inhibited the sepsis-induced decrease in IFN-γ but not IL-4 formation in the spleen. CLP increased plasma levels of HMGB1 by 20-fold and IL-6 by 19-fold. Inhibition of Rho-kinase decreased this CLP-evoked increase of HMGB1, IL-6 and IL-17 levels in the plasma by more than 60%, suggesting that Rho-kinase regulates systemic inflammation in sepsis. Moreover, we observed that pretreatment with Y-27632 abolished CLP-induced bacteremia. Together, our novel findings indicate that Rho-kinase is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, targeting Rho-kinase signaling might be a useful strategy to improve T-cell immunity in patients with abdominal sepsis.
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8.
  • Hasan, Zirak, et al. (författare)
  • Rho-Kinase Signaling Regulates Pulmonary Infiltration of Neutrophils in Abdominal Sepsis via Attenuation of CXC Chemokine Formation and Mac-1 Expression on Neutrophils.
  • 2012
  • Ingår i: Shock. - Lippincott Williams & Wilkins. - 1540-0514. ; 37:3, s. 282-288
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACT: Excessive neutrophil infiltration is a major component in septic lung injury, although the signaling mechanisms behind pulmonary recruitment of neutrophils in polymicrobial sepsis remain elusive. Herein, we hypothesized that Rho-kinase activity may play a significant role in pulmonary neutrophil recruitment and tissue damage in abdominal sepsis. Male C57BL/6 mice were treated with the Rho-kinase inhibitor Y-27632 (0.5 or 5 mg/kg) before cecal ligation and puncture. Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets as well as soluble CD40L and metalloproteinase-9 (MMP-9) in plasma. CLP triggered significant pulmonary damage characterized by neutrophil infiltration, increased levels of CXC chemokines, and edema formation in the lung. Furthermore, CLP up-regulated Mac-1 expression on neutrophils, decreased CD40L on platelets and increased soluble CD40L and MMP-9 in the circulation. Interestingly, inhibition of Rho-kinase dose-dependently decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration and tissue damage in the lung. Moreover, Rho-kinase inhibition significantly reduced sepsis-provoked gene-expression of CXC chemokines in alveolar macrophages. In contrast, Rho-kinase inhibition had no effect on platelet shedding of CD40L or plasma levels of MMP-9 in septic mice. In conclusion, these data demonstrate that the Rho-kinase signaling pathway plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of CXC chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis.
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9.
  • Hasan, Zirak, et al. (författare)
  • Targeting CD44 Expressed on Neutrophils Inhibits Lung Damage in Abdominal Sepsis.
  • 2011
  • Ingår i: Shock. - Lippincott Williams & Wilkins. - 1540-0514. ; 35, s. 567-572
  • Tidskriftsartikel (refereegranskat)abstract
    • Neutrophil infiltration is an insidious feature in septic lung injury, although the specific adhesive mechanisms regulating pulmonary recruitment of neutrophils in polymicrobial sepsis remain elusive. The aim of this present study was to define the role of CD44 in sepsis-induced neutrophil infiltration and lung damage. Mice were treated with a monoclonal antibody against CD44 before cecal ligation and puncture (CLP) induction. Edema formation, bronchoalveolar accumulation of neutrophils, myeloperoxidase activity, and macrophage inflammatory protein-2 (MIP-2) levels in the lung were determined after CLP. Expression of Mac-1 and CD44 on neutrophils was quantified by using flow cytometry. In separate experiments, fluorescent-labeled neutrophils co-incubated with an anti-CD44 antibody were adoptively transferred to CLP mice. CLP triggered clear-cut lung damage characterized by edema formation, neutrophil infiltration, and increased levels of MIP-2 in the lung. Notably, immunoneutralization of CD44 reduced CLP-induced pulmonary accumulation of neutrophils. In addition, functional inhibition of CD44 decreased CLP-induced lung damage and edema. However, formation of MIP-2 in the lung and neutrophil expression of Mac-1 were intact in septic mice pretreated with the anti-CD44 antibody. Adoptive transfer experiments revealed that neutrophil rather than lung CD44 mediates neutrophil accumulation in septic lung injury. Moreover, administration of hyaluronidase had no effect on CLP-induced neutrophil recruitment and tissue damage in the lung. Our data demonstrate that CD44 contributes to pulmonary infiltration of neutrophils and lung damage associated with abdominal sepsis. Thus, these novel findings suggest that CD44 may serve as a target to protect against lung injury in polymicrobial sepsis.
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10.
  • Hawez, Avin, et al. (författare)
  • MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
  • 2019
  • Ingår i: Frontiers in Immunology. - Frontiers Media S. A.. - 1664-3224. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Accumulating data suggest that neutrophil extracellular traps (NETs) exert a key function in several diseases. Peptidylarginine deiminase 4 (PAD4) regulates NET formation via citrullination of histones. The aim of this study was to examine the role of miR-155 in controlling PAD4-dependent generation of NETs. Bone marrow neutrophils were stimulated with PMA and MIP-2. Pre-incubation of neutrophils with translational inhibitors (cycloheximide or puromycin) markedly decreased NET formation induced by PMA or MIP-2. Neutrophil transfection with a mimic miR-155 increased PMA-induced PAD4 mRNA expression and NET formation. In contrast, transfection with an antagomiR-155 decreased induction of PAD4 mRNA and NETs in response to PMA challenge. Bioinformatical examination of PAD4 revealed a potential binding site in AU-rich elements at the 3′-UTR region. MiR-155 binding to PAD4 was examined by use of target site blockers and RNA immunoprecipitation, revealing that miR-155 regulation of PAD4 mRNA is mediated via AU-rich elements in the 3′-UTR region. In conclusion, our findings demonstrate that miR-155 positively regulates neutrophil expression of PAD4 and expulsion of extracellular traps. Thus, our novel results indicate that targeting miR-155 might be useful to inhibit exaggerated NET generation in inflammatory diseases.
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