Редактирование: CXCR4

C-X-C chemokine receptor type 4 (CXC-R4) (CXCR-4) (FB22) (Fusin) (HM89) (LCR1) (Leukocyte-derived seven transmembrane domain receptor) (LESTR) (Lipopolysaccharide-associated protein 3) (LAP-3) (LPS-associated protein 3) (NPYRL) (Stromal cell-derived factor 1 receptor) (SDF-1 receptor) (CD184 antigen)

==Publications==

{{medline-entry
|title=The IMMENSE Study: The Interplay Between iMMune and ENdothelial Cells in Mediating Cardiovascular Risk in Systemic Lupus Erythematosus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33193356
|abstract=Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3 CD31 [[CXCR4]]  T cells (T ), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a T  subset with immunosenescent features, such as the loss of [[CD28]]. Therefore, the aim of this study was to elucidate the interplay between T  subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients and 10 healthy controls (HCs) were recruited. Flow cytometric analysis of endothelial progenitor cells (EPCs) and T  subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)-[i]γ[/i] were measured. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects' serum stimulation were also evaluated. Results showed that the percentage of T  and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent [[CD28]]  cells among T  subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to T  cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of T  and inversely related to the [[CD28]]  T  subsets. We indirectly evaluated the role of the T  subset on the endothelium upon stimulation with serum from subjects with a low percentage of T  CD3  cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of T  compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the [[CD28]]  subset exerts detrimental role over the T  phenotype, where T  could exert an anti-inflammatory effect on endothelial cells and might orchestrate [i]via[/i] IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.

|keywords=* angiogenic T cells
* cardiovascular risk
* endothelial progenitor cells
* immunosenescence
* systemic lupus erythematosus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658008
}}
{{medline-entry
|title=Co-option of Neutrophil Fates by Tissue Environments.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33098771
|abstract=Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in [[CXCL12]]-rich areas and relied on [[CXCR4]]. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.

|keywords=* angiogenesis
* immune heterogeneity
* immune niche
* innate immunity
* neutrophil lifespan
* neutrophils
* single-cell analysis
* tissue-resident cells
|full-text-url=https://sci-hub.do/10.1016/j.cell.2020.10.003
}}
{{medline-entry
|title=Postsynaptic damage and microglial activation in AD patients could be linked [[CXCR4]]/[[CXCL12]] expression levels.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32949560
|abstract=Alzheimer's disease (AD) is one of the most common forms of dementia with still unknown pathogenesis. Several cytokines and chemokines are involved in the pathogenesis of AD. Among the chemokines, the [[CXCR4]]/[[CXCL12]] complex has been shown to play an important role in the pathogenetic development of AD. We investigated the expression levels of [[CXCR4]] / [[CXCL12]] in fifteen brain regions of healthy non-demented subjects (NDHC) (2139 sample) and AD patients (1170 sample) stratified according to sex and age. Furthermore, we correlated their expressions with the Neurogranin (NRGN) and [[CHI3L1]] levels, two inflamm-aging markers. We highlighted that [[CXCR4]] gene expression levels were age-correlated in the brain of NDHC subjects and that AD nullified this correlation. A similar trend, but diametrically opposite was observed for [[CXCL12]]. Its expression was decreased during the aging in both sexes, and in the brains of AD patients, it underwent an inversion of the trend, only and exclusively in females. Brains of AD patients expressed high [[CXCR4]] and [[CHI3L1]], and low [[CXCL12]] and Neurogranin levels compared to NDHC subjects. Both [[CXCR4]] and [[CXCL12]] correlated significantly with [[CHI3L1]] and Neurogranin expression levels, regardless of disease. Furthermore, we showed a selective modulation of [[CXCL12]] and [[CXCR4]] only in specific brain regions. Taken together our results demonstrate that [[CXCL12]] and [[CXCR4]] are linked to Neurogranin and [[CHI3L1]] expression levels and the relationship between postsynaptic damage and microglial activation in AD could be shown using all these genes. Further confirmations are needed to demonstrate the close link between these genes.

|keywords=* Aging
* Alzheimer’s disease
* Bioinformatics
* CHI3L1
* Chitinase
* NRGN
|full-text-url=https://sci-hub.do/10.1016/j.brainres.2020.147127
}}
{{medline-entry
|title=Aging-Related Reduced Expression of [[CXCR4]] on Bone Marrow Mesenchymal Stromal Cells Contributes to Hematopoietic Stem and Progenitor Cell Defects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32418119
|abstract=Aging impairs the regenerative potential of hematopoietic stem cells (HSC) and skews differentiation towards the myeloid lineage. The bone marrow (BM) microenvironment has recently been suggested to influence HSC aging, however the mechanisms whereby BM stromal cells mediate this effect is unknown. Here we show that aging-associated decreased expression of [[CXCR4]] expression on BM mesenchymal stem cells ([[MSC]]) plays a crucial role in the development of the hematopoietic stem and progenitor cells (HSPC) aging phenotype. The BM [[MSC]] from old mice was sufficient to drive a premature aging phenotype of young HSPC when cultured together ex vivo. The impaired ability of old [[MSC]] to support HSPC function is associated with reduced expression of [[CXCR4]] on BM [[MSC]] of old mice. Deletion of the [[CXCR4]] gene in young [[MSC]] accelerates an aging phenotype in these cells characterized by increased production of reactive oxygen species (ROS), DNA damage, senescence, and reduced proliferation. Culture of HSPC from young mice with [[CXCR4]] deficient [[MSC]] also from young mice led to a premature aging phenotype in the young HSPC, as evidenced by reduced hematopoietic regeneration and enhanced myeloid differentiation. Mechanistically, [[CXCR4]] signaling prevents BM [[MSC]] dysfunction by suppressing oxidative stress, as treatment of old or [[CXCR4]] deficient [[MSC]] with N-acetyl-L-cysteine (NAC), improved their niche supporting activity, and attenuated the HSPC aging phenotype. Our studies suggest that age-associated reduction in [[CXCR4]] expression on BM [[MSC]] impairs hematopoietic niche activity with increased ROS production, driving an HSC aging phenotype. Thus, modulation of the SDF-1/[[CXCR4]] axis in [[MSC]] may lead to novel interventions to alleviate the age-associated decline in immune/hematopoietic function.

|keywords=* Aging
* CXCR4 and ROS
* HSPC
* MSC
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395885
}}
{{medline-entry
|title=Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the SDF-1/[[CXCR4]] signalling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32384208
|abstract=Homozygosity for a four-missense single-nucleotide polymorphism haplotype of the human [[BPIFB4]] gene is enriched in long-living individuals. Delivery of this longevity-associated variant (LAV) improved revascularisation and reduced endothelial dysfunction and atherosclerosis in mice through a mechanism involving the stromal cell-derived factor-1 (SDF-1). Here, we investigated if delivery of the LAV-[[BPIFB4]] gene may attenuate the progression of diabetic cardiomyopathy. Compared with age-matched lean controls, diabetic db/db mice showed altered echocardiographic indices of diastolic and systolic function and histological evidence of microvascular rarefaction, lipid accumulation, and fibrosis in the myocardium. All these alterations, as well as endothelial dysfunction, were prevented by systemic LAV-[[BPIFB4]] gene therapy using an adeno-associated viral vector serotype 9 (AAV9). In contrast, AAV9 wild-type-[[BPIFB4]] exerted no benefit. Interestingly, LAV-[[BPIFB4]]-treated mice showed increased SDF-1 levels in peripheral blood and myocardium and up-regulation of the cardiac myosin heavy chain isoform alpha, a contractile protein that was reduced in diabetic hearts. SDF-1 up-regulation was instrumental to LAV-[[BPIFB4]]-induced benefit as both haemodynamic and structural improvements were inhibited by an orally active antagonist of the SDF-1 [[CXCR4]] receptor. In mice with type-2 diabetes, LAV-[[BPIFB4]] gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes-induced stress. These results support the viability of transferring healthy characteristics of longevity to attenuate diabetic cardiac disease.

|keywords=* BPIFB4
* Cardiomyopathy
* Diabetes
* Gene therapy
* Longevity
|full-text-url=https://sci-hub.do/10.1002/ejhf.1840
}}
{{medline-entry
|title=Regenerative and protective effects of dMSC-sEVs on high-glucose-induced senescent fibroblasts by suppressing RAGE pathway and activating Smad pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32349787
|abstract=Fibroblasts are crucial for supporting normal wound healing. However, the functional state of these cells is impaired in diabetics because of a high-glucose (HG) microenvironment. Small extracellular vesicles (sEVs) have emerged as a promising tool for skin wound treatment. The aim of this study was to investigate the effects of sEVs derived from human decidua-derived mesenchymal stem cells (dMSC-sEVs) on HG-induced human dermal fibroblast (HDF) senescence and diabetic wound healing and explore the underlying mechanism. We first created a HDF senescent model induced by HG in vitro. dMSC-conditioned medium (dMSC-CM) and dMSC-sEVs were collected and applied to treat the HG-induced HDFs. We then examined the proliferation, migration, differentiation, and senescence of these fibroblasts. At the same time, the expressions of RAGE, p21 RAS, Smad2/3, and pSmad2/3 were also analyzed. Furthermore, pSmad2/3 inhibitor (SB431542) was used to block the expression of pSmad2/3 to determine whether dMSC-sEVs improved HDF senescence by activating Smad pathway. Finally, we assessed the effect of dMSC-sEVs on diabetic wound healing. The HG microenvironment impaired the proliferation, migration, and differentiation abilities of the HDFs and accelerated their senescence. dMSC-CM containing sEVs improved the proliferation and migration abilities of the HG-induced fibroblasts. dMSC-sEVs internalized by HG-induced HDFs not only significantly promoted HDF proliferation, migration, and differentiation, but also improved the senescent state. Furthermore, dMSC-sEVs inhibited the expression of RAGE and stimulated the activation of Smad signaling pathway in these cells. However, SB431542 (pSmad2/3 inhibitor) could partially alleviate the anti-senescent effects of dMSC-sEVs on HG-induced HDFs. Moreover, the local application of dMSC-sEVs accelerated collagen deposition and led to enhanced wound healing in diabetic mice. The detection of [[PCNA]], [[CXCR4]], α-SMA, and p21 showed that dMSC-sEVs could enhance HDF proliferation, migration, and differentiation abilities and improve HDF senescent state in vivo. dMSC-sEVs have regenerative and protective effects on HG-induced senescent fibroblasts by suppressing RAGE pathway and activating Smad pathway, thereby accelerating diabetic wound healing. This indicates that dMSC-sEVs may be a promising candidate for diabetic wound treatment.

|keywords=* Diabetic wounds
* Fibroblasts
* High-glucose
* Senescence
* Small extracellular vesicles
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191792
}}
{{medline-entry
|title=Stromal Cell-Derived Factor 1 Protects Brain Vascular Endothelial Cells from Radiation-Induced Brain Damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31658727
|abstract=Stromal cell-derived factor 1 (SDF-1) and its main receptor, CXC chemokine receptor 4 ([[CXCR4]]), play a critical role in endothelial cell function regulation during cardiogenesis, angiogenesis, and reendothelialization after injury. The expression of [[CXCR4]] and SDF-1 in brain endothelial cells decreases due to ionizing radiation treatment and aging. SDF-1 protein treatment in the senescent and radiation-damaged cells reduced several senescence phenotypes, such as decreased cell proliferation, upregulated p53 and p21 expression, and increased senescence-associated beta-galactosidase (SA-β-gal) activity, through [[CXCR4]]-dependent signaling. By inhibiting extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription protein 3 (STAT3), we confirmed that activation of both is important in recovery by SDF-1-related mechanisms. A [[CXCR4]] agonist, ATI2341, protected brain endothelial cells from radiation-induced damage. In irradiation-damaged tissue, ATI2341 treatment inhibited cell death in the villi of the small intestine and decreased SA-β-gal activity in arterial tissue. An ischemic injury experiment revealed no decrease in blood flow by irradiation in ATI2341-administrated mice. ATI2341 treatment specifically affected [[CXCR4]] action in mouse brain vessels and partially restored normal cognitive ability in irradiated mice. These results demonstrate that SDF-1 and ATI2341 may offer potential therapeutic approaches to recover tissues damaged during chemotherapy or radiotherapy, particularly by protecting vascular endothelial cells.
|mesh-terms=* Animals
* Blood Vessels
* Brain
* Cell Line
* Cellular Senescence
* Chemokine CXCL12
* Cranial Irradiation
* Disease Models, Animal
* Down-Regulation
* Endothelial Cells
* Female
* Gene Expression Regulation
* Humans
* Lipopeptides
* Mice
* Receptors, CXCR4
* Signal Transduction
|keywords=* CXCR4
* SDF-1
* brain disorder
* endothelial dysfunction
* ionizing radiation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830118
}}
{{medline-entry
|title=A Neutrophil Timer Coordinates Immune Defense and Vascular Protection.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30709741
|abstract=Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine [[CXCL2]] to induce chemokine receptor [[CXCR2]]-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by [[CXCR4]] (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.
|mesh-terms=* Animals
* Blood Vessels
* Candida albicans
* Cells, Cultured
* Cellular Senescence
* Chemokine CXCL2
* Circadian Rhythm
* Host-Pathogen Interactions
* Humans
* Inflammation
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Neutrophil Infiltration
* Neutrophils
* Phagocytosis
* Receptors, CXCR4
* Time Factors
|keywords=* Bmal1
* CXCR2
* CXCR4
* Candida albicans
* Neutrophil
* circadian clock
* infection
* inflammation
* myocardial infarction
* neutrophil aging
|full-text-url=https://sci-hub.do/10.1016/j.immuni.2019.01.002
}}
{{medline-entry
|title=Novel molecular mechanisms for the adaptogenic effects of herbal extracts on isolated brain cells using systems biology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30466987
|abstract=Adaptogens are natural compounds or plant extracts that increase adaptability and survival of organisms under stress. Adaptogens stimulate cellular and organismal defense systems by activating intracellular and extracellular signaling pathways and expression of stress-activated proteins and neuropeptides. The effects adaptogens on mediators of adaptive stress response and longevity signaling pathways have been reported, but their stress-protective mechanisms are still not fully understood. The aim of this study was to identify key molecular mechanisms of adaptogenic plants traditionally used to treat stress and aging-related disorders, i.e., Rhodiola rosea, Eleutherococcus senticosus, Withania somnifera, Rhaponticum carthamoides, and Bryonia alba. To investigate the underlying molecular mechanisms of adaptogens, we conducted RNA sequencing to profile gene expression alterations in T98G neuroglia cells upon treatment of adaptogens and analyzed the relevance of deregulated genes to adaptive stress-response signaling pathways using in silico pathway analysis software. At least 88 of the 3516 genes regulated by adaptogens were closely associated with adaptive stress response and adaptive stress-response signaling pathways (ASRSPs), including neuronal signaling related to corticotropin-releasing hormone, cAMP-mediated, protein kinase A, and CREB; pathways related to signaling involving [[CXCR4]], melatonin, nitric oxide synthase, [[GP6]], Gαs, MAPK, neuroinflammation, neuropathic pain, opioids, renin-angiotensin, AMPK, calcium, and synapses; and pathways associated with dendritic cell maturation and G-coupled protein receptor-mediated nutrient sensing in enteroendocrine cells. All samples tested showed significant effects on the expression of genes encoding neurohormones [[CRH]], GNRH, [[UCN]], G-protein-coupled and other transmembrane receptors [[TLR9]], [[PRLR]], [[CHRNE]], [[GP1BA]], [[PLXNA4]], a ligand-dependent nuclear receptor [[RORA]], transmembrane channels, transcription regulators [[FOS]], [[FOXO6]], [[SCX]], [[STAT5A]], [[ZFPM2]], [[ZNF396]], [[ZNF467]], protein kinases [[MAPK10]], [[MAPK13]], [[MERTK]], [[FLT1]], [[PRKCH]], [[ROS1]], [[TTN]]), phosphatases [[PTPRD]], [[PTPRR]], peptidases, metabolic enzymes, a chaperone (HSPA6), and other proteins, all of which modulate numerous life processes, playing key roles in several canonical pathways involved in defense response and regulation of homeostasis in organisms. It is for the first time we report that the molecular mechanism of actions of melatonin and plant adaptogens are alike, all adaptogens tested activated the melatonin signaling pathway by acting through two G-protein-coupled membrane receptors MT1 and MT2 and upregulation of the ligand-specific nuclear receptor [[RORA]], which plays a role in intellectual disability, neurological disorders, retinopathy, hypertension, dyslipidemia, and cancer, which are common in aging. Furthermore, melatonin activated adaptive signaling pathways and upregulated expression of [[UCN]], [[GNRH1]], [[TLR9]], [[GP1BA]], [[PLXNA4]], [[CHRM4]], [[GPR19]], [[VIPR2]], [[RORA]], [[STAT5A]], [[ZFPM2]], [[ZNF396]], [[FLT1]], [[MAPK10]], [[MERTK]], [[PRKCH]], and [[TTN]], which were commonly regulated by all adaptogens tested. We conclude that melatonin is an adaptation hormone playing an important role in regulation of homeostasis. Adaptogens presumably worked as eustressors ("stress-vaccines") to activate the cellular adaptive system by inducing the expression of ASRSPs, which then reciprocally protected cells from damage caused by distress. Functional investigation by interactive pathways analysis demonstrated that adaptogens activated ASRSPs associated with stress-induced and aging-related disorders such as chronic inflammation, cardiovascular health, neurodegenerative cognitive impairment, metabolic disorders, and cancer. This study has elucidated the genome-wide effects of several adaptogenic herbal extracts in brain cells culture. These data highlight the consistent activation of ASRSPs by adaptogens in T98G neuroglia cells. The extracts affected many genes playing key roles in modulation of adaptive homeostasis, indicating their ability to modify gene expression to prevent stress-induced and aging-related disorders. Overall, this study provides a comprehensive look at the molecular mechanisms by which adaptogens exerts stress-protective effects.
|mesh-terms=* Adaptation, Physiological
* Brain
* Bryonia
* Cell Line, Tumor
* Eleutherococcus
* Glioblastoma
* Humans
* Leuzea
* Longevity
* Neuroglia
* Plant Extracts
* Rhodiola
* Signal Transduction
* Systems Biology
* Withania
|keywords=* Adaptogen
* Melatonin
* Pathway analysis
* RNA sequencing
* Rhodiola
* Withania
|full-text-url=https://sci-hub.do/10.1016/j.phymed.2018.09.204
}}
{{medline-entry
|title=Reducing [[CXCR4]] Resulted in Impairing Proliferation and Promoting Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30080220
|abstract=Alzheimer's disease (AD) is one of the most common and devastating aging related neurodegenerative diseases. Aging is a natural physiological process, a progressive deterioration of the overall homeostatic brain mechanisms, accompanied by cognitive decline. [[CXCL12]]/[[CXCR4]] chemokine signaling plays a critical role in modulating various nervous system developmental processes and in regulating synaptic plasticity. In this article, we have firstly shown that [[CXCR4]] is critical for cell proliferation and cytotoxicity in the SH-SY5Y cell model. Moreover, it has been firstly demonstrated that [[CXCR4]] colocalized with AKT on the membrane and regulated the AKT activation to prevent aging and AD. In a word, we supply a novel pathway that [[CXCR4]] pathway stimulated by [[CXCL12]] regulated AKT activation, CREB phosphorylation and P53 level to affect the process of aging and AD. Therefore, [[CXCR4]] may be a novel target and biomarker for the diagnosis and treatment of AD and aging.
|mesh-terms=* Aging
* Alzheimer Disease
* Biomarkers
* Cell Line
* Cell Proliferation
* Chemokine CXCL12
* Cyclic AMP Response Element-Binding Protein
* Humans
* Phosphorylation
* Protein Transport
* Proto-Oncogene Proteins c-akt
* RNA Interference
* RNA, Small Interfering
* Receptors, CXCR4
* Signal Transduction
* Tumor Suppressor Protein p53
|keywords=* AKT
* Alzheimer’s disease (AD)
* CXCR4
* SH-SY5Y
* aging
|full-text-url=https://sci-hub.do/10.1007/s12603-018-1013-9
}}
{{medline-entry
|title=Targeting junctional adhesion molecule-C ameliorates sepsis-induced acute lung injury by decreasing [[CXCR4]]  aged neutrophils.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30088666
|abstract=Sepsis is a severe inflammatory condition associated with high mortality. Transmigration of neutrophils into tissues increases their lifespan to promote deleterious function. Junctional adhesion molecule-C (JAM-C) plays a pivotal role in neutrophil transmigration into tissues. We aim to study the role of JAM-C on the aging of neutrophils to cause sepsis-induced acute lung injury (ALI). Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP) and JAM-C expression in serum was assessed. Bone marrow-derived neutrophils (BMDN) were treated with recombinant mouse JAM-C (rmJAM-C) ex vivo and their viability was assessed. CLP-operated animals were administrated with either isotype IgG or anti-JAM-C Ab at a concentration of 3 mg/kg and after 20 h, aged neutrophils ([[CXCR4]]  ) were assessed in blood and lungs and correlated with systemic injury and inflammatory markers. Soluble JAM-C level in serum was up-regulated during sepsis. Treatment with rmJAM-C inhibited BMDN apoptosis, thereby increasing their lifespan. CLP increased the frequencies of [[CXCR4]]  neutrophils in blood and lungs, while treatment with anti-JAM-C Ab significantly reduced the frequencies of [[CXCR4]]  aged neutrophils. Treatment with anti-JAM-C Ab significantly reduced systemic injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as systemic and lung inflammatory cytokines (IL-6 and IL-1β) and chemokine (macrophage inflammatory protein-2). The blockade of JAM-C improved lung histology and reduced neutrophil contents in lungs of septic mice. Thus, reduction of the pro-inflammatory aged neutrophils by blockade of JAM-C has a novel therapeutic potential in sepsis-induced ALI.
|mesh-terms=* Acute Lung Injury
* Animals
* Antibodies
* Antibody Specificity
* Apoptosis
* Cell Adhesion Molecules
* Cellular Senescence
* Cytokines
* Immunoglobulin G
* Immunoglobulins
* Lung
* Macrophage-1 Antigen
* Male
* Mice
* Mice, Inbred C57BL
* Molecular Targeted Therapy
* Neutrophils
* Real-Time Polymerase Chain Reaction
* Receptors, CXCR4
* Recombinant Proteins
* Sepsis
* Transendothelial and Transepithelial Migration
|keywords=* CXCR4
* acute lung injury
* apoptosis
* junctional adhesion molecule-C
* neutrophil aging
* sepsis
* transmigration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258282
}}
{{medline-entry
|title=Tumor microenvironment in functional adrenocortical adenomas: immune cell infiltration in cortisol-producing adrenocortical adenoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29596893
|abstract=The tumor microenvironment plays pivotal roles in various human neoplasms. However, that of benign tumor, particularly hormone-secreting endocrine tumors, has remained virtually unknown. Therefore, we firstly attempted to analyze the tumor microenvironment of autonomous hormone-secreting adrenocortical adenomas. We first histologically evaluated 21 cortisol-producing adrenocortical adenoma (CPA) and 13 aldosterone-producing adrenocortical adenoma (APA) cases. Quantitative histologic analysis revealed that intratumoral immune cell infiltration (ICI) was more pronounced in CPAs than in APAs. We then evaluated the cytokine and chemokine profiles using polymerase chain reaction arrays in APAs and CPAs. Angiogenic chemokines, C-X-C motif chemokine ligand (CXCL) 1 and [[CXCL2]], were significantly more abundant in CPAs than in APAs using subsequent quantitative polymerase chain reaction and immunohistochemical analyses. We then examined the vascular density between these 2 adenomas, and the density was significantly higher in overt CPAs than in APAs. Of particular interest, [[CXCL12]]-positive vessels were detected predominantly in CPAs, and their infiltrating immune cells were C-X-C motif chemokine receptor 4 ([[CXCR4]]) positive. These results above indicated that [[CXCL12]]-[[CXCR4]] signaling could partly account for ICI detected predominantly in CPAs. We then further explored the etiology of ICI in CPAs by evaluating the senescence of tumor cells possibly caused by excessive cortisol in CPAs. The status of senescence markers, p16 and p21, was significantly more abundant in CPAs than in APAs. In addition, all CPA cases examined were positive for senescence-associated β-galactosidase. These results all indicated that exposure to local excessive cortisol could result in senescence of tumors cells and play essential roles in constituting the characteristic tissue microenvironment of CPAs.
|mesh-terms=* Adenoma
* Adrenal Cortex Neoplasms
* Adrenocortical Adenoma
* Adult
* Aldosterone
* Female
* Gene Expression Regulation, Neoplastic
* Humans
* Male
* Middle Aged
* RNA, Messenger
* Tumor Microenvironment
|keywords=* Adrenocortical adenoma
* Cellular senescence
* Immune cell infiltration
* Steroids
* Tumor microenvironment
|full-text-url=https://sci-hub.do/10.1016/j.humpath.2018.03.016
}}
{{medline-entry
|title=Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29167123
|abstract=Aging is associated with a dysfunctional endothelial phenotype as well as reduced angiogenic capabilities. Exercise exerts beneficial effects on the cardiovascular system, possibly by increasing/maintaining the number and/or function of circulating angiogenic cells (CACs), which are known to decline with age. However, the relationship between cardiorespiratory fitness (CRF) and age-related changes in the frequency of CACs, as well as the exercise-induced responsiveness of CACs in older individuals, has not yet been determined. One-hundred seven healthy male volunteers, aged 18-75 yr, participated in study 1. CRF was estimated using a submaximal cycling ergometer test. Circulating endothelial progenitor cells (EPCs), angiogenic T cells (T ), and their chemokine (C-X-C motif) receptor 4 ([[CXCR4]]) cell surface receptor expression were enumerated by flow cytometry using peripheral blood samples obtained under resting conditions before the exercise test. In study 2, 17 healthy men (8 young men, 18-25 yr; 9 older men, 60-75 yr) were recruited, and these participants undertook a 30-min cycling exercise bout at 70% maximal O  consumption, with CACs enumerated before and immediately after exercise. Age was inversely associated with both [[CD34]]  progenitor cells ( r  = -0.140, P = 0.000) and T  ( r  = -0.176, P = 0.000) cells as well as [[CXCR4]]-expressing CACs ([[CD34]] : r  = -0.167, P = 0.000; EPCs: r  = -0.098, P = 0.001; T : r  = -0.053, P = 0.015). However, after correcting for age, CRF had no relationship with either CAC subset. In addition, older individuals displayed attenuated exercise-induced increases in [[CD34]]  progenitor cells, T , [[CD4]] , T , and CD8 [[CXCR4]]  T  cells. Older men display lower CAC levels, which may contribute to increased risk of cardiovascular disease, and older adults display an impaired exercise-induced responsiveness of these cells. NEW