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Subsequent Activation (subsequent + activation)
Selected AbstractsBinding characteristics of chondroitin sulfate proteoglycans and laminin-1, and correlative neurite outgrowth behaviors in a standard tissue culture choice assayDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2002Diane M. Snow Abstract Neuronal growth cones are capable of sophisticated discrimination of environmental cues, on cell surfaces and in the extracellular matrix, to accomplish navigation during development (generation) and following nervous system injury (regeneration). Choices made by growth cones are commonly examined using tissue culture paradigms in which molecules of interest are purified and substratum-bound. From observations of growth cone behaviors using these paradigms, assertions are made about choices neuronal growth cones may make in vivo. However, in many cases, the binding, interactions, and conformations of these molecules have not been determined. In the present study, we investigated the binding characteristics of two commonly studied outgrowth regulatory molecules: chondroitin sulfate proteoglycans (CSPGs), which are typically inhibitory to neurite outgrowth during development and following nervous system injury, and laminin, which is typically outgrowth promoting for many neuronal types. Using a novel combination of radiolabeling and quantitative fluorescence, we determined the precise concentrations of CSPGs and laminin-1 that were bound separately and together in a variety of choice assays. For identically prepared cultures, we correlated neurite outgrowth behaviors with binding characteristics. The data support our working hypothesis that neuronal growth cones are guided by the ratio of outgrowth-promoting to outgrowth-inhibiting influences in their environment, i.e., they summate local molecular cues. The response of growth cones to these molecular combinations is most likely mediated by integrins and subsequent activation of signal transduction cascades in growth cones. © 2002 Wiley Periodicals, Inc. J Neurobiol 51: 285,301, 2002 [source] Hypertrophic cardiomyopathy: from genetics to treatmentEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2010Ali J. Marian Eur J Clin Invest 2010; 40 (4): 360,369 Abstract Background, Hypertrophic cardiomyopathy (HCM) is the prototypic form of pathological cardiac hypertrophy. HCM is an important cause of sudden cardiac death in the young and a major cause of morbidity in the elderly. Design, We discuss the clinical implications of recent advances in the molecular genetics of HCM. Results, The current diagnosis of HCM is neither adequately sensitive nor specific. Partial elucidation of the molecular genetic basis of HCM has raised interest in genetic-based diagnosis and management. Over a dozen causal genes have been identified. MYH7 and MYBPC3 mutations account for about 50% of cases. The remaining known causal genes are uncommon and some are rare. Advances in DNA sequencing techniques have made genetic screening practical. The difficulty, particularly in the sporadic cases and in small families, is to discern the causal from the non-causal variants. Overall, the causal mutations alone have limited implications in risk stratification and prognostication, as the clinical phenotype arises from complex and often non-linear interactions between various determinants. Conclusions, The clinical phenotype of ,HCM' results from mutations in sarcomeric proteins and subsequent activation of multiple cellular constituents including signal transducers. We advocate that HCM, despite its current recognition and management as a single disease entity, involves multiple partially independent mechanisms, despite similarity in the ensuing phenotype. To treat HCM effectively, it is necessary to delineate the underlying fundamental mechanisms that govern the pathogenesis of the phenotype and apply these principles to the treatment of each subset of clinically recognized HCM. [source] Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006Alessio Nencioni Dr. Abstract Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X,protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level. [source] In vitro inhibitory effect of gossypol from gossypol-acetic acid, and (+)- and (,)-isomers of gossypol on the growth of Edwardsiella ictaluriJOURNAL OF APPLIED MICROBIOLOGY, Issue 1 2004M. Yildirim-Aksoy Abstract Aim:, This study was conducted to evaluate the toxic effect of gossypol from gossypol-acetic acid, and (+)- and (,)-isomers of gossypol on the growth of Edwardsiella ictaluri. Methods and Results:, Inhibitory effect of various concentrations of gossypol on the growth of E. ictaluri was determined. Bacterial recovery was performed by preincubation of bacteria in medium containing various concentrations of gossypol and subsequent activation of bacteria by inoculating on gossypol-free plates. Concentrations of racemic gossypol, (+)-gossypol and (,)-gossypol of 1·5 ,g ml,1 or higher significantly reduced the number of bacterial colonies compared with that of the control. The growth of E. ictaluri was completely inhibited on agar plates supplemented with 3 ,g ml,1, regardless of the forms of gossypol. The inhibitory effect of (+)-gossypol was higher than that of (,)-gossypol or gossypol-acetic acid. Recovery of E. ictaluri was <50% for all three forms of gossypol at concentrations of 5 ,g ml,1. Bacterial recovery remained relatively constant (6·5%) at gossypol concentrations from 10 to 100 ,g ml,1. Complete killing of E. ictaluri was not reached at gossypol levels up to 100 ,g ml,1. Conclusion:, Gossypol-acetic acid, and (+)- and (,)-optical isomers have anti-bacterial effect against E. ictaluri. The results suggest the action is bacteriostatic rather than bactericidal. Significance and Impact of the Study:, The therapeutic effect of gossypol against E. ictaluri may be useful in controlling enteric septicaemia of catfish. [source] Epac1-induced cellular proliferation in prostate cancer cells is mediated by B-Raf/ERK and mTOR signaling cascadesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2009Uma Kant Misra Abstract cAMP-dependent, PKA-independent effects on cell proliferation are mediated by cAMP binding to EPAC and activation of Rap signaling. In this report, we employed the analogue 8-CPT-2-O-Me-cAMP to study binding to EPAC and subsequent activation of B-Raf/ERK and mTOR signaling in human cancer cells. This compound significantly stimulated DNA synthesis, protein synthesis, and cellular proliferation of human 1-LN prostate cancer cells. By study of phosphorylation-dependent activation, we demonstrate that EPAC-mediated cellular effects require activation of the B-Raf/ERK and mTOR signaling cascades. RNAi directed against EPAC gene expression as well as inhibitors of ERK, PI 3-kinase, and mTOR were employed to further demonstrate the role of these pathways in regulating prostate cancer cell proliferation. These studies were then extended to several other human prostate cancer cell lines and melanoma cells with comparable results. We conclude that B-Raf/ERK and mTOR signaling play an essential role in cAMP-dependent, but PKA-independent, proliferation of cancer cells. J. Cell. Biochem. 108: 998,1011, 2009. © 2009 Wiley-Liss, Inc. [source] Fragile X mental retardation protein is required for chemically-induced long-term potentiation of the hippocampus in adult miceJOURNAL OF NEUROCHEMISTRY, Issue 3 2009Yuze Shang Abstract Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout mice, have deficits in the Morris water maze and trace fear memory tests, showing impairment in hippocampus-dependent learning and memory. However, results for synaptic long-term potentiation (LTP), a key cellular model for learning and memory, remain inconclusive in the hippocampus of Fmr1 knockout mice. Here, we demonstrate that FMRP is required for glycine induced LTP (Gly-LTP) in the CA1 of hippocampus. This form of LTP requires activation of post-synaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Genetic deletion of FMRP interrupted the phosphorylation of ERK1/2, suggesting the possible role of FMRP in the regulation of the activity of ERK1/2. Our study provide strong evidences that FMRP participates in Gly-LTP in the hippocampus by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS. [source] Interactions between surface proteins of Streptococcus pyogenes and coagulation factors modulate clotting of human plasmaJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2003H. Herwald Summary., Invasive and toxic infections caused by Streptococcus pyogenes are connected with high morbidity and mortality. Typical symptoms of these infections are hypotension, edema formation, tissue necrosis, and bleeding disorders. Here we report that components of the coagulation system including fibrinogen, factors V, XI, and XII, and H-kininogen, are assembled at the surface of S. pyogenes through specific interactions with bacterial surface proteins. In plasma environment, absorption of fibrinogen by S. pyogenes causes a hypocoagulatory state resulting in prolonged clotting times and impaired fibrin network formation. Moreover, the binding of coagulation factors and the subsequent activation of the coagulation system at the bacterial surface lead to the formation of a fibrin network covering S. pyogenes bacteria adhering to epithelial cells. The results suggest that interactions between S. pyogenes and components of the coagulation system contribute to some of the symptoms seen in severe infections caused by this important human pathogen. [source] Co-regulation of B-Myb expression by E2F1 and EGF receptor,MOLECULAR CARCINOGENESIS, Issue 1 2006Norihisa Hanada Abstract Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is frequently over-expressed in human cancers and is associated with tumorigenesis, and increased tumor proliferation and progression. Also found in breast tumors with high levels is B-Myb, a transcription factor whose expression is activated by E2F1/3 at the late G1 phase and the level is sustained through the S phase. Recent reports suggest a casual correlation between EGFR and B-Myb expression in primary breast carcinomas. However, the mechanism for such co-expression remains un-investigated. Here, we report that EGFR is important for B-Myb expression and the underlying mechanism involves cooperated effects from EGFR and E2F1. EGF stimulation and forced expression of EGFR significantly increase B-Myb gene activity and such increase occurs in the G1 phase. EGF-induced B-Myb expression was not significantly suppressed following inhibition of PI-3K and ERK, two major EGFR downstream pathways. In contrast, we observed EGF-induced in vivo association of nuclear EGFR to the B-Myb promoter and the association is only detected at the G1/S phase and is abolished by EGFR kinase inhibitor. As EGFR lacks DNA-binding domain but contains transactivational activity and E2F1 activates B-Myb expression in the G1/S phase, we further reasoned that nuclear EGFR might cooperate with E2F1 leading to activation of B-Myb. Indeed, we found that EGFR co-immunoprecipitated with E2F1 in an EGF-dependent manner and that EGF activated in vivo binding of E2F1 to the B-Myb promoter. Consistently, forced expression of both EGFR and E2F1 in EGFR-null CHO cells greatly enhanced B-Myb promoter activity, compared to the vector control and expression of EGFR or E2F1 alone. Promoter mutagenesis studies showed that EGF-induced activation of B-Myb promoter required both E2F and EGFR target sites. In summary, our data suggest that deregulated EGFR signaling pathway facilitate tumor cell proliferation partly via EGFR interaction with E2F1 and subsequent activation of B-Myb gene expression. © 2005 Wiley-Liss, Inc. [source] Activation of the redox sensor Pap1 by hydrogen peroxide requires modulation of the intracellular oxidant concentrationMOLECULAR MICROBIOLOGY, Issue 5 2004Ana P. Vivancos Summary The transcription factor Pap1 and the MAP kinase Sty1 are key regulators of hydrogen peroxide-induced responses in Schizosaccharomyces pombe. Pap1 can be activated quickly at low, but not high, hydrogen peroxide concentrations. The MAP kinase Sty1 has been reported to participate in Pap1 activation by the oxidant. Here, we provide biochemical and genetic evidence for the in vivo formation of a hydrogen peroxide-induced disulphide bond in Pap1, which precedes the rapid and reversible nuclear accumulation of the transcription factor. We show that activation of the Sty1 cascade before the oxidative insult, or overexpression of the Sty1-regulated genes ctt1 (encoding catalase) or gpx1 (encoding glutathione peroxidase), can accelerate Pap1 entry even at high doses of hydrogen peroxide. In fact, the lack of Sty1 impedes Pap1 nuclear localization, but only at high doses of the oxidant. We propose that, whereas low doses of hydrogen peroxide lead directly to Pap1 oxidation-activation, high concentrations of the oxidant initially activate the Sty1 pathway, with the consequent increase in scavenging enzymes, which in turn helps to decompose the excess of hydrogen peroxide and achieve an appropriate concentration for the subsequent activation of Pap1. Our results also suggest that activation of Sty1 at high doses of hydrogen peroxide may also be required to trigger other antioxidant activities such as those reverting the overoxidation of cysteine residues at the Pap1 pathway. [source] Nitrergic,purinergic interactions in rat distal colon motilityNEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2004K. Van Crombruggen Abstract, Responses of rat distal colon circular muscle strips to exogenous nitric oxide (NO) and adenosine 5,-triphosphate (ATP) and to electrical field stimulation (EFS) were assessed in the absence/presence of various agents that interfere with nitrergic,purinergic pathways. Exogenous NO (10,6 to 10,4 mol L,1) elicited concentration-dependent, tetrodotoxin (TTX)-insensitive relaxations. The soluble guanylyl-cyclase (sGC) inhibitor 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced duration and amplitude; the small conductance Ca2+ -sensitive K+ (SK)-channel blocker apamin (APA) only shortened the relaxations. ODQ + APA showed a marked inhibitory effect on duration and amplitude. TTX, APA, the NO-synthase inhibitor N(omega)-nitro- l -arginine methyl ester (l -NAME) and the purinergic receptor P2Y antagonist Reactive Blue 2 (RB2) shortened the relaxations by exogenous ATP (10,3 mol L,1) but did not influence the amplitude. ODQ had no effect. TTX + l -NAME did not yield a more pronounced inhibitory effect than TTX alone. The effect of ATP- , -S was similar to that of ATP. Electrical field stimulation (EFS) (40 V, 0.05 ms, 0.5,4 Hz for 30 s) yielded TTX-sensitive relaxations that were not altered by l -NAME, ODQ or RB2. APA shortened the relaxations. l -NAME + APA nearly abolished these relaxations. ODQ + APA and RB2 +l -NAME reduced the duration. These results suggest that distinct sets of small conductance SK-channels are involved in the amplitude and the duration of the relaxations and that NO increases their sensitivity to NO and ATP via guanosine 3,,5,-cyclic monophosphate (cGMP). ATP elicits relaxations via P2Y receptors with subsequent activation of SK-channels and induces neuronal release of NO. Both nitrergic and purinergic pathways must be blocked to inhibit EFS-induced relaxations. [source] Rapid Control of Wound Infections by Targeted Photodynamic Therapy Monitored by In Vivo Bioluminescence Imaging,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2002Michael R. Hamblin ABSTRACT The worldwide rise in antibiotic resistance necessitates the development of novel antimicrobial strategies. In this study we report on the first use of a photochemical approach to destroy bacteria infecting a wound in an animal model. Following topical application, a targeted polycationic photosensitizer conjugate between poly- l -lysine and chlorine6 penetrated the Gram (,) outer bacterial membrane, and subsequent activation with 660 nm laser light rapidly killed Escherichia coli infecting excisional wounds in mice. To facilitate real-time monitoring of infection, we used bacteria that expressed the lux operon from Photorhabdus luminescens; these cells emitted a bioluminescent signal that allowed the infection to be rapidly quantified, using a low-light imaging system. There was a light-dose dependent loss of luminescence in the wound treated with conjugate and light, not seen in untreated wounds. Treated wounds healed as well as control wounds, showing that the photodynamic treatment did not damage the host tissue. Our study points to the possible use of this methodology in the rapid control of wounds and other localized infections. [source] Activity-dependent regulation of voltage-gated Na+ channel expression in Mat-LyLu rat prostate cancer cell lineTHE JOURNAL OF PHYSIOLOGY, Issue 2 2006William J. Brackenbury We have shown previously that voltage-gated Na+ channels (VGSCs) are up-regulated in human metastatic disease (prostate, breast and small-cell lung cancers), and that VGSC activity potentiates metastatic cell behaviours. However, the mechanism(s) regulating functional VGSC expression in cancer cells remains unknown. We investigated the possibility of activity-dependent (auto)regulation of VGSC functional expression in the strongly metastatic Mat-LyLu model of rat prostate cancer. Pretreatment with tetrodotoxin (TTX) for 24,72 h subsequently suppressed peak VGSC current density without affecting voltage dependence. The hypothesis was tested that the VGSC auto-regulation occurred via VGSC-mediated Na+ influx and subsequent activation of protein kinase A (PKA). Indeed, TTX pretreatment reduced the level of phosphorylated PKA, and the PKA inhibitor KT5720 decreased, whilst the adenylate cyclase activator forskolin and the Na+ ionophore monensin both increased the peak VGSC current density. TTX reduced the mRNA level of Nav1.7, predominant in these cells, and VGSC protein expression at the plasma membrane, although the total VGSC protein level remained unchanged. TTX pretreatment eliminated the VGSC-dependent component of the cells' migration in Transwell assays. We concluded that the VGSC activity in Mat-LyLu rat prostate cancer cells was up-regulated in steady-state via a positive feedback mechanism involving PKA, and this enhanced the cells' migratory potential. [source] The oncogenic potential of a prostate cancer-derived androgen receptor mutantTHE PROSTATE, Issue 6 2007Xu-Bao Shi Abstract BACKGROUND The role of androgen receptor (AR) mutations in the initiation of prostate cancer (CaP) remains unclear. The purpose of this study was to assess the influence of an AR mutation on prostate tumorigenesis and to determine the resulting molecular alterations. METHODS Wild-type AR (ARWT) or the CaP-derived K580R AR (ARK580R) mutant was stably transfected into SV40-immortalized human prostate epithelial pRNS-1-1 cells that lack AR expression and fail to grow in nude mice. The ability of these AR-transfected cell lines to form tumor was investigated in vitro and in vivo. Additionally, gene expression profiling of these cell lines was performed. RESULTS Compared with the ARWT, the ARK580R induced greater than sixfold increase in colony formation in soft agar. In vivo studies confirmed that the ARK580R -transfected pRNS-1-1 cells were able to form tumors in nude mice. Using a combination of microarray and RT-PCR, 29 differentially expressed genes were identified in ARK580R cells. It was found that silencing the expression of placental alkaline phosphatase (ALPP) that was upregulated in ARK580R cells resulted in significant inhibition of cell growth. Furthermore, the ARK580R -transfected pRNS-1-1 cells expressed markedly increased p-Akt and p-p70 S6K. CONCLUSION The ARK580R mutation promoted the malignant transformation of prostate epithelial cells. This was associated with upregulation of ALPP and subsequent activation of the Akt signaling pathway. Prostate 67: 591,602, 2007. © 2007 Wiley-Liss, Inc. [source] Selenium improves the antioxidant ability against aluminium-induced oxidative stress in ryegrass rootsANNALS OF APPLIED BIOLOGY, Issue 2 2010P. Cartes We investigated the role of selenium (Se) against aluminium (Al) stress in ryegrass by evaluating the growth responses and the antioxidant properties of plants cultured hydroponically with Al (0 or 0.2 mM) and selenite (0,10 µM Se). Al addition significantly reduced the yield and length of shoots and roots, and most Al was accumulated in the roots. Al also enhanced lipid peroxidation and activated the peroxidase (POD), ascorbate peroxidase (APX) and superoxide dismutase (SOD) enzymes in the roots. Se application up to 2 µM improved root growth and steadily decreased thiobarbituric acid reactive substances (TBARS) accumulation in plants treated with 0 and 0.2 mM Al. However, above 2 µM, Se induced stress in plants grown with or without Al. Significant changes in antioxidant enzymes activities were also found as a result of the added Se. At low Se addition levels POD was activated, whereas APX activity decreased irrespective of added Al. Furthermore, Se supplied up to 2 µM greatly decreased root SOD activity in Al-stressed plants. Our study provides evidence that Se alleviated the Al-induced oxidative stress in ryegrass roots through the enhancement of the spontaneous dismutation of superoxide radicals and the subsequent activation of POD enzyme. [source] Sperm motility in the steelhead Oncorhynchus mykiss (Walbaum): influence of the composition of the incubation and activation mediaAQUACULTURE RESEARCH, Issue 3 2006Joshua Woolsey Abstract This study examined the pH sensitivity of steelhead, Oncorhynchus mykiss (Walbaum), sperm motility relative to the composition of incubation and activation media. The percentage of sperm that initiated motility following incubation in a sperm immobilizing solution (SI) titrated to different pH values and subsequent activation by dilution in buffered swimming medium (SM) at pH 8.5 or 50% ovarian fluid (OF) showed little or no pH sensitivity; sperm diluted in de-ionized water (DI) showed no motility after incubation at any pH. In contrast, motility of sperm diluted in tap water (TAP) was highly sensitive to the pH of the incubation medium. Sperm incubated with buffered seminal plasma at high, but not low pH demonstrated high percent motility when diluted with DI. Sperm incubated in low-pH SI demonstrated high motility only when diluted into high-pH SM. The effects of the composition of incubation and activation media on sperm motility were generally reflected in comparable effects on fertility. Therefore, these data indicate that the pH sensitivity of sperm motility and fertility depends on the composition of commonly used incubation as well as activation media. [source] Cover Picture: Biotechnology Journal 6/2006BIOTECHNOLOGY JOURNAL, Issue 6 2006Article first published online: 14 JUN 200 Cover illustration: Foreground photographs show transmission and photon light images of human CD4 T cells in culture following three days after infection by HIV-1-luciferase and subsequent activation (from Sáez-Cirión et al., current issue); Background photograph by Shelley Spray (with permission Institut Pasteur, Paris); Montage by M. Marchand and S. Shorte, http://www.pfid.org. Image ,Self-Diagnosis' © Artville/Getty Images. [source] Effects of mood stabilizers on the inhibition of adenylate cyclase via dopamine D2 -like receptorsBIPOLAR DISORDERS, Issue 3 2007Liliana P Montezinho Objective:, The mood stabilizing drugs lithium, carbamazepine and valproate modulate brain adenosine monophosphate (cAMP) levels, which are assumed to be elevated in bipolar disorder patients. The aim of this work was to investigate how these three mood stabilizing agents affect the regulation of cAMP levels by dopamine D2 -like receptors in vitro in rat cortical neurons in culture and in vivo in the rat prefrontal cortex. Methods:, The production of cAMP was measured in the cultured cortical neurons or in microdialysis samples collected from the prefrontal cortex of freely moving rats using the [8- 3H] and [125I] radioimmunoassay kits. Results:,In vitro and in vivo data showed that the treatment with the mood stabilizing drugs had no effect on basal cAMP levels in vitro, but had differential effects in vivo. Direct stimulation of adenylate cyclase (AC) with forskolin increased cAMP levels both in vitro and in vivo, and this effect was significantly inhibited by all three mood stabilizers. Activation of dopamine D2 -like receptors with quinpirole partially inhibited forskolin-induced increase in cAMP in untreated cultures, but no effect was observed in cortical neuron cultures treated with the mood stabilizing drugs. Similar results were obtained by chronic treatment with lithium and valproate in the prefrontal cortex in vivo. However, surprisingly, in carbamazepine-treated rats the activation of dopamine D2 -like receptors enhanced the responsiveness of AC to subsequent activation by forskolin, possibly as a consequence of chronic inhibition of the activity of the enzyme. Conclusions:, It was shown that each of these drugs affects basal- and forskolin-evoked cAMP levels in a distinct way, resulting in differential responses to dopamine D2 -like receptors activation. [source] Immune response profiles in human skinBRITISH JOURNAL OF DERMATOLOGY, Issue 2007T. Meyer Summary In addition to the function as a physical barrier human skin has been shown to be an important immune organ displaying various defense mechanisms, which can be divided into three major functional compartiments: (i) Epithelial defense, which is characterized by antimicrobial peptides and proteins (AP) and which can be induced in inflammatory lesions but also in the absence of inflammation. (ii) Innate-inflammatory immunity, which involves recognition of microbial compounds by particular receptors like Toll-like receptors (TLR) and subsequent activation of signalling pathways resulting in expression of pro-inflammatory cytokines and interferons, as well as genes of adaptive immunity. Interferon , (IFN,) produced by plasmacytoid dendritic cells (DC) may stimulate myeloid DC to produce IL-12 resulting in classical T-cell activation or to produce IL-23 activating IL-17 producing T-cells (IL-23/IL-17 pathway). (iii) Adaptive immunity, which is based on antigen presenting cells, T-cells and B-cells and which is characterized by specificity and memory. In contrast to epithelial defense and innate-inflammatory immunity, adaptive immune functions provide slowly reacting protection. Recent improvements of our knowledge of dysregulated immune pathways associated with inflammatory skin diseases represent an important basis of novel immunomodulatory treatment modalities. [source] Continued need of appropriate betalactam-derived skin test reagents for the management of allergy to betalactamsCLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2007M. Blanca Summary Immediate allergic reactions to betalactams (BLs) are due to IgE antibodies that recognize the ring-derived penicilloyl determinant or side-chain structures of common BLs. The presence of specific IgE antibodies can be demonstrated by skin testing, the determination of specific IgE antibodies in sera or their binding to basophils with subsequent activation upon contact with penicillins in vitro. Skin tests are still the most sensitive technique followed by in vitro tests, which may sometimes yield useful complementary information. The diversity of the response to BLs has meant that in some instances, in addition to benzylpenicillin-derived determinants, testing for amoxycillin, cephalosporins or other BLs may also be required to establish the diagnosis. The recent withdrawal from the market of BL-derived materials for skin testing will have a serious effect on public health, resulting in a return to the pre-1960 era before these reagents became available. Because of their greater sensitivity, these skin tests cannot yet be replaced by in vitro tests. Furthermore, skin tests are the most readily available form of allergy testing for physicians. This paper reviews the results of skin tests in BL allergy and provides evidence for their continued need. [source] INVOLVEMENT OF BOTH ENDOPLASMIC RETICULUM- AND MITOCHONDRIA-DEPENDENT PATHWAYS IN CARDIOTOXIN III-INDUCED APOPTOSIS IN HL-60 CELLSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2008Ching-Ming Chien SUMMARY 1Cardiotoxin (CTX) III, a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. In the present study, we investigated the mechanisms underlying the anticancer activity of CTX III in human leukaemia (HL-60 cells). 2Cardiotoxin III activated the endoplasmic reticulum (ER) pathway of apoptosis in HL-60 cells, as indicated by increased levels of calcium and glucose-related protein 78 (Grp78), and triggered the subsequent activation of µ-calpain and caspase 12. 3In addition, CTX III initiated the mitochondrial apoptotic pathway in HL-60 cells, as evidenced by an increased Bax/Bcl-2 ratio, the release of cytochrome c and activation of caspase 9. 4In the presence of 50 µmol/L Z-ATAD-FMK (a caspase 12 inhibitor) and 100 µmol/L Z-LEHD-FMK (a caspase 9 inhibitor), the CTX III-mediated activation of caspase 9 and caspase 3 was significantly reduced. There was no significant effect of the caspase 12 inhibitor Z-ATAD-FMK on mitochondrial cytochrome c release. 5Cardiotoxin III-mediated activation of caspase 12 was not abrogated in the presence of the caspase 9 inhibitor Z-LEHD-FMK, indicating that caspase 12 activation was not downstream of caspase 9. 6These results indicate that CTX III induces cell apoptosis via both ER stress and a mitochondrial death pathway. [source] | |||||||||||||