Inhibition of in Vitro and in Vivo HIV Replication by a Distamycin Analogue That Interferes with Chemokine Receptor Function:  A Candidate for Chemotherapeutic and Microbicidal Application

1998 ◽  
Vol 41 (13) ◽  
pp. 2184-2193 ◽  
Author(s):  
O. M. Z. Howard ◽  
J. J. Oppenheim ◽  
Melinda G. Hollingshead ◽  
Joseph M. Covey ◽  
J. Bigelow ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Receptor Function ◽  
Hiv Replication

Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity

2007 ◽  
Vol 26 (4) ◽  
pp. 333-338 ◽  
Author(s):  
Anna Forsby ◽  
Bas Blaauboer
Keyword(s):  
Exposure Period ◽  
Cellular Protein ◽  
In Vitro Toxicity ◽  
Target Tissue ◽  
Receptor Function ◽  
Human Neuroblastoma ◽  
Protein Levels ◽  
Effective Doses

Risk assessment of neurotoxicity is mainly based on in vivo exposure, followed by tests on behaviour, physiology and pathology. In this study, an attempt to estimate lowest observed neurotoxic doses after single or repeated dose exposure was performed. Differentiated human neuroblastoma SH-SY5Y cells were exposed to acrylamide, lindane, parathion, paraoxon, phenytoin, diazepam or caffeine for 72 hours. The effects on protein synthesis and intracellular free Ca2+concentration were studied as physiological endpoints. Voltage operated Ca2 +channel function, acetylcholine receptor function and neurite degenerative effects were investigated as neurospecific endpoints for excitability, cholinergic signal transduction and axonopathy, respectively. The general cytotoxicity, determined as the total cellular protein levels after the 72 hours exposure period, was used for comparison to the specific endpoints and for estimation of acute lethality. The lowest concentration that induced 20% effect (EC 20) obtained for each compound, was used as a surrogate for the lowest neurotoxic level (LOEL) at the target site in vivo. The LOELs were integrated with data on adsorption, distribution, metabolism and excretion of the compounds in physiologically-based biokinetic (PBBK) models of the rat and the lowest observed effective doses (LOEDs) were estimated for the test compounds. A good correlation was observed between the estimated LOEDs and experimental LOEDs found in literature for rat for all test compounds, except for diazepam. However, when using in vitro data from the literature on diazepam's effect on gamma-amino butyric acid (GABA)A receptor function for the estimation of LOED, the correlation between the estimated and experimental LOEDs was improved from a 10 000-fold to a 10-fold difference. Our results indicate that it is possible to estimate LOEDs by integrating in vitro toxicity data as surrogates for lowest observed target tissue levels with PBBK models, provided that some knowledge about toxic mechanisms is known. Human & Experimental Toxicology (2007) 26, 333—338

scholarly journals Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 161-167 ◽  
Author(s):  
Nicholas T. Funderburg ◽  
Elizabeth Mayne ◽  
Scott F. Sieg ◽  
Robert Asaad ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Tissue Factor ◽  
Immune Activation ◽  
Interleukin 6 ◽  
Plasma Levels ◽  
Thrombus Formation ◽  
Hiv Replication ◽  
Increased Risk

Abstract HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV+ patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.

scholarly journals Cc Chemokine Receptor (Ccr)3/Eotaxin Is Followed by Ccr4/Monocyte-Derived Chemokine in Mediating Pulmonary T Helper Lymphocyte Type 2 Recruitment after Serial Antigen Challenge in Vivo

2000 ◽  
Vol 191 (2) ◽  
pp. 265-274 ◽  
Author(s):  
Clare M. Lloyd ◽  
Tracy Delaney ◽  
Trang Nguyen ◽  
Jane Tian ◽  
Carlos Martinez-A ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Progressive Increase ◽  
Allergic Airway Disease ◽  
Antigen Challenge ◽  
Th2 Cells ◽  
T Helper ◽  
Cc Chemokine

Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

scholarly journals Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1160-1167 ◽  
Author(s):  
G. Angus McQuibban ◽  
Jiang-Hong Gong ◽  
Julie P. Wong ◽  
John L. Wallace ◽  
Ian Clark-Lewis ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Leukemic Cell ◽  
Proteolytic Processing ◽  
Cc Chemokine ◽  
Monocyte Chemoattractant ◽  
The Matrix

Monocyte chemoattractant protein (MCP)–3 is inactivated upon cleavage by the matrix metalloproteinase (MMP) gelatinase A (MMP-2). We investigated the susceptibility to proteolytic processing of the 4 human MCPs by 8 recombinant MMPs to determine whether MCP-3 is an isolated example or represents a general susceptibility of chemokines to proteolytic inactivation by these important inflammatory proteases. In addition to MMP-2, MCP-3 is efficiently cleaved by membrane type 1 (MT1)–MMP, the cellular activator of MMP-2, and by collagenase-1 and collagenase-3 (MMP-1, MMP-13) and stromelysin-1 (MMP-3). Specificity was shown by absence of cleavage by matrilysin (MMP-7) and the leukocytic MMPs neutrophil collagenase (MMP-8) and gelatinase B (MMP-9). The closely related chemokines MCP-1, MCP-2, and MCP-4 were not cleaved by MMP-2 or MT1-MMP, but were cleaved by MMP-1 and MMP-3 with varying efficiency. MCPs were typically cleaved between residues 4 and 5, but MCP-4 was further processed at Val7-Pro8. Synthetic MCP analogs corresponding to the MMP-cleaved forms bound CC chemokine receptor (CCR)–2 and CCR-3, but lacked chemoattractant activity in pre-B cells transfected with CCR-2 and CCR-3 or in THP-1 monocytic cells, a transformed leukemic cell line. Moreover, the truncated products of MCP-2 and MCP-4, like MCP-3, were potent antagonists of their cognate CC chemokine receptors in transwell cell migration assays in vitro. When they were injected 24 hours after the initiation of carrageenan-induced inflammation in rat paws, their in vivo antagonist activities were revealed by a greater than 66% reduction in inflammatory edema progression after 12 hours. We propose that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.

scholarly journals Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tong-Cui Ma ◽  
Run-Hong Zhou ◽  
Xu Wang ◽  
Jie-Liang Li ◽  
Ming Sang ◽  
...  
Keyword(s):  
Cost Effective ◽  
Peripheral Blood Monocyte ◽  
Type I ◽  
Restriction Factors ◽  
Oligoadenylate Synthetase ◽  
Hiv Replication ◽  
Inhibitory Protein ◽  
Anti Hiv

Abstract The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2′,5′-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product.

LPS-induced expression of a novel chemokine receptor (L-CCR) in mouse glial cells in vitro and in vivo

Glia ◽  
2003 ◽  
Vol 41 (4) ◽  
pp. 327-336 ◽  
Author(s):  
Mike W. Zuurman ◽  
Joost Heeroma ◽  
Nieske Brouwer ◽  
Hendrikus W.G.M. Boddeke ◽  
Knut Biber
Keyword(s):  
Glial Cells ◽  
Chemokine Receptor ◽  
Induced Expression

Expression of CC chemokine receptor 3 on human keratinocytes in vivo and in vitro — upregulation by RANTES

2001 ◽  
Vol 25 (3) ◽  
pp. 229-235 ◽  
Author(s):  
Motoshi Wakugawa ◽  
Koichiro Nakamura ◽  
Masahiro Akatsuka ◽  
Shin Su Kim ◽  
Yoshitsugu Yamada ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Human Keratinocytes ◽  
Cc Chemokine

Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 413-421 ◽  
Author(s):  
Taoyong Chen ◽  
Jun Guo ◽  
Mingjin Yang ◽  
Chaofeng Han ◽  
Minghui Zhang ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Chemokine Receptor ◽  
Cyclooxygenase 2 ◽  
Lymphoid Organs ◽  
Receptor Expression ◽  
Chemokine Receptor Expression ◽  
Cox 2 ◽  
Secondary Lymphoid Organs

Abstract Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow–derived DCs toward macrophage inflammatory protein-3β (MIP-3β) and induces them to retain responsiveness to MIP-1α after lipopolysaccharide (LPS)–stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor–κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.

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