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The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies. 相似文献
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Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Myocardial dysfunction, often termed sepsis-induced cardiomyopathy, is a frequent complication and is associated with worse outcomes. Numerous mechanisms contribute to sepsis-induced cardiomyopathy and a growing body of evidence suggests that bioenergetic and metabolic derangements play a central role in its development; however, there are significant discrepancies in the literature, perhaps reflecting variability in the experimental models employed or in the host response to sepsis. The condition is characterised by lack of significant cell death, normal tissue oxygen levels and, in survivors, reversibility of organ dysfunction. The functional changes observed in cardiac tissue may represent an adaptive response to prolonged stress that limits cell death, improving the potential for recovery. In this review, we describe our current understanding of the pathophysiology underlying myocardial dysfunction in sepsis, with a focus on disrupted mitochondrial processes. 相似文献
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Sepsis is a syndrome of life-threatening multiorgan dysfunction caused by host response dysregulation to infection. Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide-induced sepsis. However, little is known about the mechanism underlying its effects on sepsis. In the current study, we investigated the protective effect of UTI on liver injury in a cecal ligation and puncture (CLP)-induced sepsis of C57BL/6 mouse model and explored the possible mechanisms. Mice underwent CLP as sepsis models and were randomized into five groups including the sham group, UTI group, CLP group, UTI-L group, and UTI-H group. UTI was intraperitoneally administered at doses of UTI 1500 U/100 g (UTI-L group) or 3000 U/100 g (UTI-H group), before CLP. The mice were killed, and immunohistochemical changes, cytokine levels, and antioxidant enzyme activities were detected. Our results showed that UTI ameliorated CLP-mediated increases in serum aspartate aminotransferase and alanine aminotransferase activities, histological activity index, degenerative region ratio, and infiltrated inflammatory cell numbers. Moreover, UTI also decreased nitrotyrosine and 4-hydroxynonenal, activated caspase-3, and activated poly (ADP-ribose) polymerase (PARP) levels and inhibited the mitogen-activated protein kinase pathway activation in liver tissues. Our results indicated that UTI could inhibit CLP-induced liver injury by suppressing inflammation and oxidation. Our results indicated that UTI may serve as a potential therapeutic agent for sepsis. 相似文献
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Machado RA Constantino L Martins MR de Albuquerque IM Menna-Barreto S Streck E Quevedo J Dal-Pizzol F 《Cell biology international》2007,31(9):1036-1041
Central nervous system dopaminergic mechanisms have been implicated in the cytokine response to stress and sepsis. We here describe the effects of haloperidol or clozapine in the treatment of sepsis induced by cecal ligation and puncture. Male Wistar rats were subjected to the CLP procedure were treated with haloperidol or clozapine and plasma cytokines, myeloperoxidase activity, markers of organ injury and survival was analyzed. The addition of haloperidol or clozapine to basic support did not diminished hepatic, renal, pancreatic or muscular damage observed after sepsis. Neither haloperidol, nor clozapine, modulates pro and antiinflammatory cytokines after sepsis induction. In addition, haloperidol treatment did not diminished myeloperoxidase activity in the kidney, lung or liver, or altered BALF markers of lung damage or inflammatory infiltration. Our data did not support a role of haloperidol or clozapine as an immunomodulator agent in the treatment of sepsis in an animal model of peritonitis. 相似文献
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Melanie J. StablesDerek W. Gilroy 《Progress in lipid research》2011,50(1):35-51
Originally regarded as just membrane constituents and energy storing molecules, lipids are now recognised as potent signalling molecules that regulate a multitude of cellular responses via receptor-mediated pathways, including cell growth and death, and inflammation/infection. Derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), each lipid displays unique properties, thus making their role in inflammation distinct from that of other lipids derived from the same PUFA. The diversity of their actions arises because such metabolites are synthesised via discrete enzymatic pathways and because they elicit their response via different receptors. This review will collate the bioactive lipid research to date and summarise the findings in terms of the major pathways involved in their biosynthesis and their role in inflammation and its resolution. It will include lipids derived from AA (prostanoids, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, lipoxins and epoxyeicosatrienoic acids), EPA (E-series resolvins), and DHA (D-series resolvins, protectins and maresins). 相似文献
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Endothelial cell protein C receptor (EPCR) plays important roles in blood coagulation and inflammation. EPCR activity is markedly changed by ectodomain cleavage and release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Oroxylin A (OroA), a major component of Scutellaria baicalensis Georgi, is known to exhibit anti-angiogenic, antiinflammation, and anti-invasive activities. However, little is known about the effects of OroA on EPCR shedding. Data showed that OroA induced potent inhibition of phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and on cecal ligation and puncture (CLP)-induced EPCR shedding through suppression of TACE expression and activity. In addition, treatment with OroA resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of OroA as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding. [BMB Reports 2014; 47(6): 336-341] 相似文献
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Miehe U Kadyrov M Neumaier-Wagner P Bartz C Rath W Huppertz B 《Histochemistry and cell biology》2006,126(4):465-471
Differentiation processes in the trophoblast comprise polarization, cell fusion and migration. All these processes involve dramatic reorganizations of cytoskeletal proteins such as intermediate filaments or actin. Due to very restricted knowledge on cytoskeletal changes in trophoblast, we analyzed the protein expression of an actin stress fiber-associated protein, the carboxy-terminal LIM domain protein (CLP36). CLP36 belongs to the enigma family of proteins, binds to α-actinin and is involved in the cytoskeletal reorganization and signal transduction of a variety of cells. CLP36 protein was found to be exclusively expressed in the cytotrophoblast layer. Colocalization of CLP36 with Mib-1 revealed that CLP36 protein expression is restricted to proliferative and early post-proliferative trophoblast cells. Blockage of syncytial fusion by culture of villous explants in the presence of caspase 8 inhibitors further supported this notion since CLP36 was only found in the basal and proliferative layer of the multilayered cytotrophoblast. We present evidence for the exclusive protein expression of CLP36 in proliferative and early post-proliferative trophoblast cells. Pathological pregnancy syndromes such as preeclampsia are driven by alterations of trophoblast differentiation and turnover, where it needs to be elucidated whether CLP36 is involved in these alterations. 相似文献
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Agkisacutacin, a C-type lectin-like protein (CLP) isolated from Agkistrodon acutus venom, had been previously identified as an antagonist of platelet aggregation induced by ristocetin, as well as a certain extent fibrinogenlytic activity. In this study, agkisacutacin was further purified by three-step chromatography, and its biological functions were characterized. Agkisacutacin after further purification retained the effect on ristocetin-induced, von Willebrand factor-dependent platelet aggregation, while it lost the fibrinogenlytic activity. FACS and ELISA assays showed that agkisacutacin belongs to membrane glycoprotein Ib-binding protein (GPIb-bp) for it could block and inhibit the binding of anti-GPIb antibody to GPIb. Especially, agkisacutacin exhibits anti-coagulant activity and the function as IX/X-binding protein was confirmed by PAGE and ELISA. So, agkisacutacin is the first reported CLP that binds to both platelet membrane receptors and coagulation factors. 相似文献