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Cell Entry (cell + entry)
Selected AbstractsBK Polyoma Virus Allograft Nephropathy: Ultrastructural Features from Viral Cell Entry to LysisAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2003Cinthia B Drachenberg BK virions must enter the host cell and target their genome to the nucleus in order to complete their life cycle. The mechanisms by which the virions accomplish these tasks are not known. In this morphological study we found that BK virions localized beneath the host cell cytoplasmic membrane in 60,70-nm, smooth (non-coated) monopinocytotic vesicles similar to, or consistent with, caveolae. In the cytoplasm, the monopinocytotic vesicles carrying virions appeared to fuse with a system of smooth, vesicles and tubules that communicated with the rough endoplasmic reticulum and was continuous with the Golgi system. Membrane-bound single virions and large tubulo-reticular complexes loaded with virions accumulated in paranuclear locations. Occasional nuclei displayed virions within the perinuclear cisterna in association to the perinuclear viral accumulations. Tubular cells with mature productive infection had large nuclei, distended by daughter virions, whereas they lacked significant numbers of cytoplasmic virions. In addition to virally induced cell necrosis, there was extensive tubular cell damage (apoptosis and necrosis) in morphologically non-infected tubules. The observed ultrastructural interactions between the BK virions and host cells are remarkably similar to viral cell entry and nuclear targeting described for SV40 virus. [source] HeLa Cell Entry by Guanidinium-Rich ,-Peptides: Importance of Specific Cation,Cell Surface InteractionsCHEMBIOCHEM, Issue 8 2007Terra B. Potocky Abstract Short cationic oligomers, including arginine-rich peptides and analogous ,-amino acid oligomers (", -peptides"), can enter the cytoplasm and nucleus of a living cell from the extracellular medium. It seems increasingly clear that multiple entry pathways are possible, depending upon the structure of the guanidinium-rich molecule, the type of cell, and other factors. We have previously shown that conformational stability and spatial clustering of guanidinium groups increase the HeLa cell entry efficiency of short helical , -peptides bearing six guanidinium groups, results that suggest that these , -peptides could be useful tools for studying the entry process. Here we describe studies intended to identify the point in the entry process at which helix stability and spatial arrangement of guanidinium groups exert their effect. Our results suggest that key distinctions involve the mode of interaction between different guanidinium-rich ,-peptides and the HeLa cell surface. A specific guanidinium display appears to be required for proper engagement of cell-surface heparan sulfate proteoglycans and concomitant induction of endocytic uptake. [source] Cell entry by human pathogenic arenavirusesCELLULAR MICROBIOLOGY, Issue 4 2008Jillian M. Rojek Summary The arenaviruses Lassa virus (LASV) in Africa and Machupo (MACV), Guanarito (GTOV) and Junin viruses (JUNV) in South America cause severe haemorrhagic fevers in humans with fatality rates of 15,35%. The present review focuses on the first steps of infection with human pathogenic arenaviruses, the interaction with their cellular receptor molecules and subsequent entry into the host cell. While similarities exist in genomic organization, structure and clinical disease caused by pathogenic Old World and New World arenaviruses these pathogens use different primary receptors. The Old World arenaviruses employ ,-dystroglycan, a cellular receptor for proteins of the extracellular matrix, and the human pathogenic New World arenaviruses use the cellular cargo receptor transferrin receptor 1. While the New World arenavirus JUNV enters cells via clathrin-dependent endocytosis, evidence occurred for clathrin-independent entry of the prototypic Old World arenavirus lymphocytic choriomeningitis virus. Upon internalization, arenaviruses are delivered to the endosome, where pH-dependent membrane fusion is mediated by the envelope glycoprotein (GP). While arenavirus GPs share characteristics with class I fusion GPs of other enveloped viruses, unusual mechanistic features of GP-mediated membrane fusion have recently been discovered for arenaviruses with important implications for viral entry. [source] Acquisition of regulatory function by human CD8+ T cells treated with anti-CD3 antibody requires TNFEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Vitaly Ablamunits Abstract Anti-CD3 mAb can modulate graft rejection and attenuate autoimmune diseases but their mechanism(s) of action remain unclear. CD8+ T cells with regulatory function are induced in vitro by Teplizumab, a humanized anti-CD3 antibody and inhibit responses of autologous and allogeneic T cells. They inhibit CD4+ T-cell proliferation by mechanisms involving TNF and CCL4, and by blocking target cell entry into G2/M phase of cell cycle but neither kill them, nor compete for IL-2. CD8+ Treg can be isolated from peripheral blood following treatment of patients with Type 1 diabetes with Teplizumab, but not from untreated patients. The induction of CD8+ Treg by anti-CD3 mAb requires TNF and signaling through the NF-,B cascade. The CD8+ Treg express CD25, glucocorticoid-induced TNF receptor family, CTLA-4, Foxp3, and TNFR2, and the combined expression of TNFR2 and CD25 identifies a potent subpopulation of CD8+ Treg. These studies have identified a novel mechanism of immune regulation by anti-CD3 mAb and markers that may be used to track inducible CD8+ Treg in settings such as chronic inflammation or immune therapy. [source] Multifunctional host defense peptides: intracellular-targeting antimicrobial peptidesFEBS JOURNAL, Issue 22 2009Pierre Nicolas There is widespread acceptance that cationic antimicrobial peptides, apart from their membrane-permeabilizing/disrupting properties, also operate through interactions with intracellular targets, or disruption of key cellular processes. Examples of intracellular activity include inhibition of DNA and protein synthesis, inhibition of chaperone-assisted protein folding and enzymatic activity, and inhibition of cytoplasmic membrane septum formation and cell wall synthesis. The purpose of this minireview is to question some widely held views about intracellular-targeting antimicrobial peptides. In particular, I focus on the relative contributions of intracellular targeting and membrane disruption to the overall killing strategy of antimicrobial peptides, as well as on mechanisms whereby some peptides are able to translocate spontaneously across the plasma membrane. Currently, there are no more than three peptides that have been convincingly demonstrated to enter microbial cells without the involvement of stereospecific interactions with a receptor/docking molecule and, once in the cell, to interfere with cellular functions. From the limited data currently available, it seems unlikely that this property, which is isolated in particular peptide families, is also shared by the hundreds of naturally occurring antimicrobial peptides that differ in length, amino acid composition, sequence, hydrophobicity, amphipathicity, and membrane-bound conformation. Microbial cell entry and/or membrane damage associated with membrane phase/transient pore or long-lived transitions could be a feature common to intracellular-targeting antimicrobial peptides and mammalian cell-penetrating peptides that have an overrepresentation of one or two amino acids, i.e. Trp and Pro, His, or Arg. Differences in membrane lipid composition, as well as differential lipid recruitment by peptides, may provide a basis for microbial cell killing on one hand, and mammalian cell passage on the other. [source] Structure,function relationship of novel X4 HIV-1 entry inhibitors , L- and D-arginine peptide-aminoglycoside conjugatesFEBS JOURNAL, Issue 24 2007Ravi Hegde We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers d - and l -arginine peptides (APACs). The d -APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective l -APACs. d -arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their l -arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1, (SDF-1,)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. d -APACs readily concentrate in the nucleus, whereas the l -APACs do not. 9-mer- d -arginine analogues are more efficient inhibitors than the 6-mer- d -arginine conjugates and the neomycin- d -polymers are better inhibitors than their respective neamine conjugates. This and further structure,function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors. [source] The second phase activation of protein kinase C , at late G1 is required for DNA synthesis in serum-induced cell cycle progressionGENES TO CELLS, Issue 4 2003Koichi Kitamura Background: Cell lines that stably over-express protein kinase C (PKC) , frequently show a decrease in growth rate and saturation density, leading to the hypothesis that PKC, has a negative effect on cell proliferation. However, the mode of PKC, activation, the cell cycle stage requiring PKC, activity, and the exact role of PKC, at that stage remains unknown. Results: Here we show that the treatment of quiescent fibroblasts with serum activates PKC, at two distinct time points, within 10 min after serum treatment, and for a longer duration between 6 and 10 h. This biphasic activation correlates with the phosphorylation of Thr-505 at the activation loop of PKC,. Importantly, an inhibitor of PKC,, rottlerin, suppresses the biphasic activation of PKC,, and suppression of the second phase of PKC, activation is sufficient for the suppression of DNA synthesis. Consistent with this, the transient over-expression of PKC, mutant molecules lacking kinase activity suppresses serum-induced DNA synthesis. These results imply that PKC, plays a positive role in cell cycle progression. While the over-expression of PKC, enhances serum-induced DNA synthesis, this was not observed for PKC,. Similar experiments using a series of PKC,/, chimeras showed that the carboxyl-terminal 51 amino acids of PKC, are responsible for the stimulatory effect. On the other hand, the over-expression of PKC, suppresses cell entry into M-phase, being consistent with the previous studies based on stable over-expressors. Conclusions: We conclude that PKC, plays a role in the late-G1 phase through the positive regulation of cell-cycle progression, in addition to negative regulation of the entry into M-phase. [source] Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus,HEPATOLOGY, Issue 2 2005Dimitri Lavillette Because of the lack of a robust cell culture system, relatively little is known about the molecular details of the cell entry mechanism for hepatitis C virus (HCV). Recently, we described infectious HCV pseudo-particles (HCVpp) that were generated by incorporating unmodified HCV E1E2 glycoproteins into the membrane of retroviral core particles. These initial studies, performed with E1E2 glycoproteins of genotype 1, noted that HCVpp closely mimic the cell entry and neutralization properties of parental HCV. Because sequence variations in E1 and E2 may account for differences in tropism, replication properties, neutralization, and response to treatment in patients infected with different genotypes, we investigated the functional properties of HCV envelope glycoproteins from different genotypes/subtypes. Our studies indicate that hepatocytes were preferential targets of infection in vitro, although HCV replication in extrahepatic sites has been reported in vivo. Receptor competition assays using antibodies against the CD81 ectodomain as well as ectopic expression of CD81 in CD81-deficient HepG2 cells indicated that CD81 is used by all the different genotypes/subtypes analyzed to enter the cells. However, by silencing RNA (siRNA) interference assays, our results show that the level of Scavenger Receptor Class-B Type-I (SR-BI) needed for efficient infection varies between genotypes and subtypes. Finally, sera from chronic HCV carriers were found to exhibit broadly reactive activities that inhibited HCVpp cell entry, but failed to neutralize all the different genotypes. In conclusion, we characterize common steps in the cell entry pathways of the major HCV genotypes that should provide clues for the development of cell entry inhibitors and vaccines. (HEPATOLOGY 2005;41:265,274.) [source] Effect of cytofectins on the immune response of murine macrophages to mammalian DNAIMMUNOLOGY, Issue 2 2003Fu-Gang Zhu Summary DNA, depending on base sequence, can induce a wide range of immune responses. While bacterial DNA is stimulatory, mammalian DNA is inactive alone and can, moreover, inhibit the response to bacterial DNA. To determine whether the mode of cell entry affects the immune properties of mammalian DNA, we have investigated the effects of the cytofectin agents Fugene 6 (Roche Diagnostics Corp., Indianapolis, IN), Lipofectin and Lipofectamine (Life Technologies, Grand Island, NY) on the responses of murine macrophages to DNA from calf thymus and human placenta. Whereas calf thymus and human placenta DNA alone failed to stimulate J774 or RAW264·7 cell lines or bone marrow-derived macrophages, these DNAs in complexes with cytofectin agents stimulated macrophages to produce nitric oxide but not interleukin 12. Both single-stranded and double-stranded DNAs were active in the presence of cytofectins. Macrophage activation by the DNA,cytofectin complexes was reduced by chloroquine, suggesting a role of endosomal acidification in activation. As shown by flow cytometry and confocal microscopy, the cytofectins caused an increase in the uptake of DNA into cells. Our findings indicate that macrophages vary in their response to DNA depending on uptake pathway, suggesting that activation by DNA reflects not only sequence but also context or intracellular location. [source] Combining adenoviral oncolysis with temozolomide improves cell killing of melanoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 12 2007Christina Quirin Abstract Oncolytic Adenoviruses are emerging agents for treatment of cancer by tumor-restricted virus replication, cell lysis and virus spread. Clinical studies with first generation oncolytic adenoviruses have revealed that an increased potency is warranted in order to achieve therapeutic efficacy. One approach towards this end is to combine adenoviral oncolysis with chemotherapy. Here, a fundamental requirement is that chemotherapy does not interfere with adenovirus replication in cancer cells. We have previously developed a melanoma-targeted oncolytic adenovirus, Ad5/3.2xTyr, which features tyrosinase promoter regulated replication and enhanced cell entry into melanoma cells. In this study, we investigated a combination treatment of melanoma cells with Ad5/3.2xTyr and temozolomide (TMZ), which produces the same active metabolite as Dacarbazine/DTIC, the standard chemotherapy for advanced melanoma. We report that TMZ does not inhibit adenovirus replication in melanoma cells. Additive or synergistic cell killing of melanoma cells, dependent on the cell line used, was observed. Enhanced cell binding was not responsible for synergism of adenoviral oncolysis and TMZ treatment. We rather observed that higher numbers of virus genomes are produced in TMZ-treated cells, which also showed a cell cycle arrest in the G2 phase. Our results have important implications for the clinical implementation of adenoviral oncolysis for treatment of malignant melanoma. It suggests that such studies are feasible in the presence of TMZ or DTIC chemotherapy and recommends the investigation of a viro-chemo combination therapy. © 2007 Wiley-Liss, Inc. [source] Co-chaperone BAG3 and adenovirus penton base protein partnershipJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2010E. Gout Abstract The BAG family of Hsp70/Hsc70 co-chaperones is characterised by the presence of a conserved BAG domain at the carboxyl-terminus. BAG3 protein is the only member of this family containing also the N-terminally located WW domain. We describe here the identification of adenovirus (Ad) penton base protein as the first BAG3 partner recognising BAG3 WW domain. Ad penton base is the viral capsid constituent responsible for virus internalisation. It contains in the N-terminal part two conserved PPxY motifs, known ligands of WW domains. In cells producing Ad penton base protein, cytoplasmic endogenous BAG3 interacts with it and co-migrates to the nucleus. Preincubation of BAG3 with Ad base protein results in only slight modulation of BAG3 co-chaperone activity, suggesting that this interaction is not related to the classical BAG3 co-chaperone function. However, depletion of BAG3 impairs the cell entry of the virus and viral progeny production in Ad-infected cells, suggesting that the interaction between virus penton base protein and cellular co-chaperone BAG3 positively influences virus life cycle. These results thus demonstrate a novel host,pathogen interaction, which contributes to the successful infectious life cycle of adenoviruses. In addition, these data enrich our knowledge about the multifunctionality of the BAG3 co-chaperone. J. Cell. Biochem. 111: 699,708, 2010. © 2010 Wiley-Liss, Inc. [source] Role of mathematical modeling on the optimal control of HIV-1 pathogenesisAICHE JOURNAL, Issue 3 2006Marcel Joly Abstract Mathematical modeling of HIV-1 infection has proven to be instrumental for the modern understanding basis of the AIDS pathogenesis, since it offers the unique means to adequately pose hypotheses concerning AIDS dynamics and treatment protocols. Focusing on the HIV-1 subtype-B epidemic, a comprehensive review and discussion of the state-of-the-art in the area is presented. Based on recent results, this multidisciplinary study is then extended to a more in-depth view at the cellular and molecular biology levels that address key issues concerned with the natural history of AIDS, as the basic human anatomic model, the host cell entry of HIV-1, the quantification the HIV-1 infectivity in terms of viral coreceptor specificity, as well as regulation and expression of CCR5 and CXCR4 molecules on the target cell, the T-lymphocyte generation and infection models, and the immune response model. In the sequence, modeling techniques for AIDS pathogenesis are revised and models concerned with either the general HIV-1 dynamics or specifically related to the HIV-1 primary infection are discussed. Ultimately, a general framework for the real-world problem of optimizing the highly active antiretroviral therapy (HAART) benefits is proposed regarding the important questions associated with the drug chemotherapy resistance, side effects and costs. © 2005 American Institute of Chemical Engineers AIChE J, 2006 [source] Latest news and product developmentsPRESCRIBER, Issue 23-24 2007Article first published online: 8 JAN 200 Cervical cancer risk falls after COC use ends Combined oral contraceptives (COCs) are associated with a slight increase in the risk of cervical cancer but this diminishes with time after use ends, an international study has shown (Lancet 2007;370:1609,21). Analysis of data for 16 573 women with and 35 509 women without cervical cancer confirmed that using a COC for 10 years between the ages of 20 and 30 increases the incidence of invasive cervical cancer from 3.8 to 4.5 per 1000 by age 50. However, the excess risk disappears 10 years after cessation of use. , A new analysis of the US Nurses' Health Study suggests that protection against ovarian cancer does not persist beyond 20 years after cessation of COC use. This study also showed that tubal ligation is associated with reduced risk of ovarian cancer (Am J Epidemiol 2007; 166;894,901). Pharmaceutical services fund moves to PCTs The ,global sum' that provides central funding for NHS pharmaceutical services is being shifted to PCTs. The Government has included legislation for the change in the recent Health and Social Care Bill. The fund pays the fees and allowances for pharmacy contractors and appliance contractors. The Government says this is a ,natural progression and in keeping with moves to devolve NHS funds to the frontline' that will enable PCTs to manage pharmacy services better by ,encouraging best prescribing practice'. Fewer fluoroquinolones in the community Restricting prescribing of fluoroquinolone antibacterials does not increase hospital admissions for infection among older people, say Canadian researchers (Am J Med 2007;120:893,900). Their analysis of an Ontario medical database shows that, in a community where fluoroquinolones were the most widely prescribed antibacterials, a one-third reduction in prescribing was not followed by an increase in hospital admissions for infectious episodes in the over,65s. On the contrary, there was a 32 per cent reduction in admissions for gastrointestinal conditions. FDA reports increased TB risk with infliximab The US Food and Drug Administration has published an analysis of cases of TB associated with infliximab (Remicade) detected via its spontaneous adverse event reporting scheme (Ann Intern Med 2007;147: 699,702). In 2001 the FDA placed a warning about the risk of TB on product labelling for infliximab and advised testing for TB before initiating treatment. This analysis of 130 cases of TB since reported in patients treated with infliximab found that 45 per cent had developed extra-pulmonary disease; risk factors included use of immunosuppressants (including methotrexate), a history of TB and time spent in an endemic area. Of 67 cases in which treatment was initiated after the warning was issued, 34 with a negative tuberculin skin test developed TB after receiving infliximab. MHRA announces anticounterfeit strategy The UK is a transit point, distribution hub and end-user of counterfeit medicines, says the MHRA in its first anti-counterfeiting strategy (www.mhra.gov.uk). Counterfeits have been detected in the legitimate supply chain with increasing frequency since 2004, resulting in nine batch recalls and a further five incidents detected at wholesale level. The MHRA's proposed approach includes: communication to raise awareness of the risk and facilitate reporting, collaboration with the WHO, the industry and law enforcement agencies, and targeted surveillance, prosecution and regulation. Evidence lacking for choosing DMARD There is insufficient evidence to choose one DMARD or biological agent over another in patients with RA, US investigators say (www.annals.org/cgi/content/abstract/0000605,20080115000192v1). Their systematic review of meta-analyses and intervention and observational trials found no evidence of differences among DMARDs or anti-TNF agents. Mono-therapy with an anti-TNF agent was associated with superior radiographic but not clinical outcomes; methotrexate plus an anti-TNF agent was superior in clinical and functional terms to either drug given alone. Be alert to psychiatric ADRs with rimonabant Clinicians should remain alert for the development of anxiety, depression and an increased risk of suicide with rimonabant (Acomplia), say Danish investigators (Lancet 2007;370:1706,13). Their meta-analysis of four randomised trials involving a total of 4105 patients showed that rimonabant was associated with an increased risk of serious adverse events (odds ratio 1.4; number needed to harm, NNH, 59), including a 2.5,fold increased risk of depression (NNH 49) and a threefold increased risk of anxiety (NNH 166). Following a warning from the FDA of an increased risk of suicide with rimonabant, the authors say their findings indicate a need for ,increased alertness by physicians to these potentially severe psychiatric adverse reactions'. New strategy for NHS medicines information The UK Medicines Information Service (www.ukmi.nhs.uk) has published its new management strategy setting out how it will respond to recent developments in the NHS. Developments include greater access to information for patients, support for nontraditional prescribers and new commissioning arrangements. New antiretroviral Maraviroc (Celsentri) is the first CCR5 antagonist to be introduced for the treatment of HIV infection. CCR5 is one of two co-receptors to which the HIV virus must attach to achieve cell entry. Maraviroc is licensed for use by treatment-experienced patients in whom only CCR5-tropic HIV-1 is detectable. The recommended dose ranges from 150 to 600mg twice daily depending on interactions with concurrent medication. Dimeticone superior Dimeticone 4 per cent lotion (Hedrin) is superior to malathion 0.5 per cent in the eradication of head lice, a UK study in 58 children and 15 adults has shown (PLoS ONE 2007;2: e1127. doi:10.1371/journal.pone. 0001127). Two applications of dimeticone lotion one week apart cleared active infestation in 70 per cent of participants compared with 33 per cent in those who used a single application of malathion. Copyright © 2007 Wiley Interface Ltd. [source] BK Polyoma Virus Allograft Nephropathy: Ultrastructural Features from Viral Cell Entry to LysisAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2003Cinthia B Drachenberg BK virions must enter the host cell and target their genome to the nucleus in order to complete their life cycle. The mechanisms by which the virions accomplish these tasks are not known. In this morphological study we found that BK virions localized beneath the host cell cytoplasmic membrane in 60,70-nm, smooth (non-coated) monopinocytotic vesicles similar to, or consistent with, caveolae. In the cytoplasm, the monopinocytotic vesicles carrying virions appeared to fuse with a system of smooth, vesicles and tubules that communicated with the rough endoplasmic reticulum and was continuous with the Golgi system. Membrane-bound single virions and large tubulo-reticular complexes loaded with virions accumulated in paranuclear locations. Occasional nuclei displayed virions within the perinuclear cisterna in association to the perinuclear viral accumulations. Tubular cells with mature productive infection had large nuclei, distended by daughter virions, whereas they lacked significant numbers of cytoplasmic virions. In addition to virally induced cell necrosis, there was extensive tubular cell damage (apoptosis and necrosis) in morphologically non-infected tubules. The observed ultrastructural interactions between the BK virions and host cells are remarkably similar to viral cell entry and nuclear targeting described for SV40 virus. [source] Angiotensin I-Converting Enzyme And Metabolism Of The Haematological Peptide N -Acetyl-Seryl-Aspartyl-Lysyl-ProlineCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2001Michel Azizi SUMMARY 1. Angiotensin I-converting enzyme (ACE) has two homologous active N- and C-terminal domains and displays activity towards a broad range of substrates. The tetrapeptide N -acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) has been shown to be hydrolysed in vitro by ACE and to be a preferential substrate for its N-terminal active site. This peptide reversibly prevents the recruitment of pluripotent haematopoietic stem cells and normal early progenitors into the S-phase. 2. Angiotensin I-converting enzyme inhibitors, given as a single dose to normal subjects or during long-term treatment in hypertensive patients, result in plasma AcSDKP levels five- to six-fold higher and urine concentrations 40-fold higher than those of control subjects and/or patients. Thus, AcSDKP is a natural peptide hydrolysed by the N-terminal domain of ACE in vivo. In addition, ACE may be implicated in the process of haematopoietic stem cell regulation by permanently degrading this natural circulating inhibitor of cell entry into the S-phase. 3. Besides hydrolysis by ACE, the second very effective mechanism by which AcSDKP is cleared from plasma is glomerular filtration. Because of its high sensitivity and specificity, the measurement of AcSDKP in plasma and urine provides a valuable tool in screening specific inhibitors of the N-terminal domain of ACE and in monitoring ACE inhibition during chronic treatment. 4. The long-term consequences of AcSDKP accumulation are not known. During chronic ACE inhibition in rats, AcSDKP levels slightly increase in organs with high ACE content (kidneys, lungs). To significantly increase its concentration in target haematopoietic organs (the extracellular fraction of bone marrow), AcSDKP has to be infused on top of a captopril-based treatment. 5. A selective inhibitor of the N-domain of ACE in vitro and in vivo has been identified recently. The phosphinic peptide RXP 407 does not interfere with blood pressure regulation, but does increase, dose dependently, plasma concentrations of AcSDKP in mice, in contrast with lisinopril, which affects the metabolism of both AcSDKP and angiotensin I. N-Terminal-selective ACE inhibitors may be used to selectively control AcSDKP metabolism in target haematopoietic organs. This new therapeutic strategy may be of value for protecting haematopoietic cells from the toxicity of cancer chemotherapy. [source] | ||||||||||||||||