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Caroline Schmutz Alison Cartwright Helen Williams Oliver Haworth John HH Williams Andrew Filer Mike Salmon Christopher D Buckley Jim Middleton 《Arthritis research & therapy》2010,12(4):R161
Introduction
Monocytes/macrophages accumulate in the rheumatoid (RA) synovium where they play a central role in inflammation and joint destruction. Identification of molecules involved in their accumulation and differentiation is important to inform therapeutic strategies. This study investigated the expression and function of chemokine receptor CCR9 in the peripheral blood (PB) and synovium of RA, non-RA patients and healthy volunteers. 相似文献47.
Mary S. Pampusch Hadia M. Abdelaal Emily K. Cartwright Jhomary S. Molden Brianna C. Davey Jordan D. Sauve Emily N. Sevcik Aaron K. Rendahl Eva G. Rakasz Elizabeth Connick Edward A. Berger Pamela J. Skinner 《PLoS pathogens》2022,18(2)
During chronic human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection prior to AIDS progression, the vast majority of viral replication is concentrated within B cell follicles of secondary lymphoid tissues. We investigated whether infusion of T cells expressing an SIV-specific chimeric antigen receptor (CAR) and the follicular homing receptor, CXCR5, could successfully kill viral-RNA+ cells in targeted lymphoid follicles in SIV-infected rhesus macaques. In this study, CD4 and CD8 T cells from rhesus macaques were genetically modified to express antiviral CAR and CXCR5 moieties (generating CAR/CXCR5-T cells) and autologously infused into a chronically infected animal. At 2 days post-treatment, the CAR/CXCR5-T cells were located primarily in spleen and lymph nodes both inside and outside of lymphoid follicles. Few CAR/CXCR5-T cells were detected in the ileum, rectum, and lung, and no cells were detected in the bone marrow, liver, or brain. Within follicles, CAR/CXCR5-T cells were found in direct contact with SIV-viral RNA+ cells. We next infused CAR/CXCR5-T cells into ART-suppressed SIV-infected rhesus macaques, in which the animals were released from ART at the time of infusion. These CAR/CXCR5-T cells replicated in vivo within both the extrafollicular and follicular regions of lymph nodes and accumulated within lymphoid follicles. CAR/CXR5-T cell concentrations in follicles peaked during the first week post-infusion but declined to undetectable levels after 2 to 4 weeks. Overall, CAR/CXCR5-T cell-treated animals maintained lower viral loads and follicular viral RNA levels than untreated control animals, and no outstanding adverse reactions were noted. These findings indicate that CAR/CXCR5-T cell treatment is safe and holds promise as a future treatment for the durable remission of HIV. 相似文献
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Tamer M. A. Mohamed Delvac Oceandy Sukhpal Prehar Nasser Alatwi Zeinab Hegab Florence M. Baudoin Adam Pickard Aly O. Zaki Raja Nadif Elizabeth J. Cartwright Ludwig Neyses 《The Journal of biological chemistry》2009,284(18):12091-12098
The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a
modulator of cardiac contractility. We have demonstrated previously that
isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart
and that this complex regulates β-adrenergic signal transmission in
vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a
specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG)
showed a significant reduction in nNOS and total NOS activities as well as in
cGMP levels in the heart compared with their wild type (WT) littermates. In
contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with
the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a
3-fold increase in Ser16 phospholamban (PLB) phosphorylation as
well as Ser22 and Ser23 cardiac troponin I (cTnI)
phosphorylation at base line compared with the WT. In addition, the relative
induction of PLB phosphorylation and cTnI phosphorylation following
isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining
the blunted physiological response to the β-adrenergic stimulation. In
keeping with the data from the transgenic animals, neonatal rat cardiomyocytes
overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP
levels. This was accompanied by an increase in cAMP levels, which led to an
increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP
levels were likely due to the modulation of cardiac phosphodiesterase, which
determined the balance between cGMP and cAMP following PMCA4b overexpression.
In conclusion, these results showed that the nNOS-PMCA4b complex regulates
contractility via cAMP and phosphorylation of both PLB and cTnI.Neuronal nitric-oxide synthase
(nNOS)5 is involved in
a number of key processes in cardiomyocytes including calcium cycling
(1), the β-adrenergic
contractile response (2,
3), post-infarct left
ventricular remodeling (4), and
the regulation of redox equilibrium
(5). Moreover, a polymorphism
in an nNOS-interacting protein, CAPON, has been found to form a quantitative
trait for the determination of the QT interval in humans
(6), whereas a mutation in
α1-syntrophin (SNTA1), another interacting partner of nNOS, has been
associated with long QT syndrome
(7). The signaling events
downstream of the nNOS-CAPON
(8) and nNOS-SNTA1
(7) complexes, which are
responsible for mediating cardiac repolarization and sodium current
respectively, have been elucidated. The nNOS-containing protein complex is
therefore of immediate relevance to human pathology.In recent years, we have shown that the sarcolemmal calcium pump, which
ejects calcium to the extracellular compartment (reviewed in Refs.
9 and
10), is an important molecule
involved in signal regulation and transmission in the heart
(11). We have demonstrated
that isoform 4b of the sarcolemmal calcium pump (also known as PMCA4b for
plasma membrane calcium/calmodulin-dependent
ATPase 4b) modulates signaling through a tight molecular
interaction with nNOS, leading to the modulation of β-adrenergic
responsiveness in the heart
(12). However, the events
following signaling through the PMCA4b-nNOS complex remain unknown.In myocardial cells, nNOS has been localized to the sarcolemma
(13), sarcoplasmic reticulum
(2), and mitochondria
(14), and translocation
between compartments has been demonstrated
(15). It has been speculated
that these various localizations provide specificity to NO signaling, but the
exact mechanisms have yet to be elucidated. In this study, we show a mechanism
by which one fraction of nNOS serves highly specific functions through binding
to PMCA4b. As PMCA4b is confined to the sarcolemma and is a calcium pump, it
is the first identified protein to fulfill these aggregate functions. 1) It
acts as an anchoring protein; 2) it regulates nNOS activity; and 3) it
modulates a process at the plasma membrane, i.e. β-adrenergic
signaling. 相似文献
50.
Dietary fats are efficiently absorbed in the small intestine and transported into the blood via the lymph as chylomicrons, despite enormous variations in the amount and composition of the dietary lipid. The aim of the present study was to investigate how enterocytes respond to increased dietary fats of different composition. Rabbits were fed a low fat chow diet, and chow supplemented with sunflower oil (high n-6 polyunsaturated fatty acids), fish oil (high n-3 polyunsaturated fatty acids), or an oil mixture of a composition similar to that of the typical western diet. Feeding fat for 2 weeks markedly stimulated the ability of the isolated enterocytes to synthesize and secrete apolipoprotein B48, triacylglycerol, and cholesteryl ester (up to 18-, 50-, and 80-fold, respectively) in particles of chylomicron density. The magnitude of stimulation was sunflower oil > western diet lipid > fish oil. Single doses of lipid given 18 h prior to isolation of enterocytes stimulated chylomicron secretion by only 10% of that observed after 2 weeks of dietary supplementation. Enterocytes are replaced rapidly (half-life 1-2 days) by cells which move from the crypts to the tips of the villi, where absorption of nutrients takes place.Our observations suggest that dietary lipids modulate the function of enterocytes as they move from the crypts, so that the cells are 'turned-on' to lipid absorption. The results also show that diets of different fatty acid composition vary in their effects. 相似文献