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1.
Int J Mol Med ; 44(3): 939-948, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524247

RESUMO

Chemokine C­X3­C motif ligand 1 (CX3CL1) and its sole receptor, CX3CR1, are known to be involved in neuronal damage/death following brain ischemia. In the present study, time­dependent expression changes of CX3CL1 and CX3CR1 proteins were investigated in the hippocampal CA1 field following 5 min of transient global cerebral ischemia (tgCI) in gerbils. To induce tgCI in gerbils, bilateral common carotid arteries were occluded for 5 min using aneurysm clips. Expression changes of CX3CL1 and CX3CR1 proteins were assessed at 1, 2 and 5 days after tgCI using western blotting and immunohistochemistry. CX3CL1 immunoreactivity was strong in the CA1 pyramidal cells of animals in the sham operation group. Weak CX3CL1 immunoreactivity was detected at 6 h after tgCI, recovered at 1 day after tgCI and disappeared from 5 days after tgCI. CX3CR1 immunoreactivity was very weak in CA1 pyramidal cells of the sham animals. CX3CR1 immunoreactivity in CA1 pyramidal cells was significantly increased at 1 days after tgCI and gradually decreased thereafter. On the other hand, CX3CR1 immunoreactivity was significantly increased in microglia from 5 days after tgCI. These results showed that CX3CL1 and CX3CR1 protein expression levels in pyramidal cells and microglia in the hippocampal CA1 field following tgCI were changed, indicating that tgCI­induced expression changes of CX3CL1 and CX3CR1 proteins might be closely associated with tgCI­induced delayed neuronal death and microglial activation.


Assuntos
Isquemia Encefálica/metabolismo , Região CA1 Hipocampal/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Receptor 1 de Quimiocina CX3C/genética , Morte Celular , Quimiocina CX3CL1/genética , Expressão Gênica , Gerbillinae , Imuno-Histoquímica , Masculino , Microglia/metabolismo , Neurônios/metabolismo
2.
BMC Res Notes ; 12(1): 496, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399137

RESUMO

OBJECTIVE: We recently reported that curcumin supplementation in a metabolically (i.e., Western diet [WD]) and chemically (i.e., CCl4) induced female rat model of non-alcoholic steatohepatitis (NASH) was associated with lower liver pathology scores and molecular markers of inflammation. This occurred when curcumin was given during induction of disease (preventative arm; 8-week WD with or without curcumin [8WD + C vs. 8WD]) as well as when given after disease development (treatment arm; 12-week WD with or without curcumin during weeks 9-12 [12WD + C vs. 12WD]). Herein, we sought to extend our findings from that study by determining the effects of curcumin supplementation on cytokine/chemokine expression in serum collected from these same rats. RESULTS: 24 cytokines/chemokines were assayed. IL-2 (+ 80%) and IL-13 (+ 83%) were greater with curcumin supplementation in the prevention arm. IL-2 (+ 192%), IL-13 (+ 87%), IL-17A (+ 81%) and fractalkine (+ 121%) were higher while RANTES was lower (- 22%) with curcumin supplementation in the treatment arm (p < 0.05 for all). RANTES concentrations also correlated significantly with hepatic pathology scores of inflammation (r = 0.417, p = 0.008). Select serum cytokines/chemokines were affected with curcumin supplementation in this female rat model of NASH. Moreover, curcumin's effect(s) on RANTES and its association with liver disease pathogenesis and progression may warrant further investigation.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Animais , Tetracloreto de Carbono/administração & dosagem , Quimiocina CCL5/sangue , Quimiocina CCL5/genética , Quimiocina CX3CL1/sangue , Quimiocina CX3CL1/genética , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Humanos , Interleucina-13/sangue , Interleucina-13/genética , Interleucina-17/sangue , Interleucina-17/genética , Interleucina-2/sangue , Interleucina-2/genética , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Ratos , Ratos Wistar , Resultado do Tratamento
3.
Medicine (Baltimore) ; 98(34): e16706, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441843

RESUMO

OBJECTIVE: Postoperative chronic pain is characterized by high incidence, long duration, and complex pathogenesis. The purpose of this study was to investigate the correlation between the single nucleotide polymorphisms of the CCL2 gene rs4586 (g.5974T>C), CALCA rs3781719 (-692T>C), CX3CL1 rs614230 (2342C>T), and the risk of postoperative chronic pain in Chinese Han women. METHODS: We analyzed the CCL2 gene rs4586, CALCA rs3781719, CX3CL1 rs614230 single nucleotide polymorphism (SNPs) of 350 Chinese Han women with chronic postsurgical pain (CPSP) 6 months after cesarean section and 350 healthy women without chronic pain (HC). The levels of CCL2, CALCA, and CX3CL1 in serum were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The CCL2 rs4586 T allele and the CX3CL1 gene rs614230C allele were protective factors for CPSP risk (adjusted OR = 0.766, 95% CI: 0.675-0.865 and OR = 0.336, 95% CI: 0.644-0.835). The CALCA gene rs3781719C allele was a risk factor for CPSP (adjusted OR = 1.273, 95% CI: 1.125-1.424). CCL2 rs4586, CX3CL1 gene rs614230, and CALCA gene rs3781719 locus gene polymorphisms were associated with serum CCL2, CX3CL1, and CALCA protein levels. CONCLUSION: Our results support that CCL2 gene rs4586, CALCA rs3781719, CX3CL1 rs614230 gene polymorphism are associated with the occurrence of chronic pain after cesarean section in Chinese Han women.


Assuntos
Cesárea/efeitos adversos , Dor Crônica/etiologia , Dor Crônica/genética , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Peptídeo Relacionado com Gene de Calcitonina/genética , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CX3CL1/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
4.
J Ovarian Res ; 12(1): 42, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077234

RESUMO

BACKGROUND: Chemokines are involved in the homing of various cancer cells, including those of ovarian cancer (OvCa), to distant organs. They may also promote or inhibit cancer progression and metastasis. Hypoxia, a common phenomenon in malignant tumors, promotes cell proliferation regulated by HIF-1α. Hypoxia-induced genes are involved in metastasis-associated functions and in the epithelial-to-mesenchymal transition (EMT). RESULTS: Tissue microarrays of human OvCa showed elevated expression of CX3CR1 and HIF-1α compared to normal cells, and their levels were higher in adenocarcinoma stages II and III. To substantiate these observations, we performed studies using OvCa cells. Following exposure to hypoxia, OVCAR-3, SW 626, and TOV-112D cells showed high expression of CX3CR1, a transmembrane protein involved in the adhesion and migration of leukocytes, causing an increased chemotactic response to CX3CL1, the ligand for CX3CR1. As determined by flow cytometry, immunofluorescence, RT-PCR, and western blots, there were higher expressions of CX3CR1 and HIF-1α in OvCa cell lines exposed to hypoxia. Further, OvCa cells expressing CX3CR1 were sensitive to the CX3CL1 ligand. Chemotaxis based on chemokine receptors was influential in elevating the expression of EMT markers and matrix metalloproteinases, which are involved in the progression and metastasis of cancer cells. CONCLUSIONS: In OvCa cells, CX3CR1 was upregulated in a process involving hypoxia-mediated regulation of HIF-1α. The elevated levels of CX3CR1, which were sensitive to CX3CL1, increased EMT markers that led to the progression and metastasis of OvCa. Thus, CX3CR1 and HIF-1α are suitable targets for treatment of OvCa.


Assuntos
Receptor 1 de Quimiocina CX3C/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor 1 de Quimiocina CX3C/genética , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Quimiocina CX3CL1/biossíntese , Quimiocina CX3CL1/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Invasividade Neoplásica , Neoplasias Ovarianas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
J Neuroinflammation ; 16(1): 30, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744705

RESUMO

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder, and the most common form of dementia. As the understanding of AD has progressed, it is now believed that AD is an amyloid-initiated tauopathy with neuroinflammation serving as the link between amyloid deposition, tau pathology, and neurodegeneration. As microglia are the main immune effectors in the central nervous system, they have been the focus of attention in studies investigating the neuroinflammatory component of AD. Therefore, recent work has focused on immunomodulators, which can alter microglial activation without suppressing activity, as potential therapeutics for AD. Fractalkine (CX3CL1; FKN), a unique chemokine with a one-to-one relationship with its receptor, signals through its cognate receptor (CX3CR1) to reduce expression of pro-inflammatory genes in activated microglia. Disrupting FKN signaling has opposing effects on the two hallmark pathologies of AD, but over-expressing a soluble FKN has been shown to reduce tau pathology while not altering amyloid pathology. Recently, differential signaling has been reported when comparing two cleavage variants of soluble FKN. These differential effects may explain recent studies reporting seemingly conflicting results regarding the effect of FKN over expression on AD pathologies.


Assuntos
Doença de Alzheimer/patologia , Quimiocina CX3CL1/genética , Inflamação/patologia , Transdução de Sinais , Doença de Alzheimer/genética , Animais , Humanos , Inflamação/genética
6.
Int J Mol Sci ; 20(3)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717334

RESUMO

CX3CL1, which is a chemokine involved in many aspects of human pregnancy, is a membrane-bound chemokine shed into circulation as a soluble isoform. Placental CX3CL1 is induced by inflammatory cytokines and is upregulated in severe early-onset preeclampsia. In this study, the hypothesis was addressed whether angiotensin II can deregulate placental CX3CL1 expression, and whether CX3CL1 can promote a pro-inflammatory status of monocytes. qPCR analysis of human placenta samples (n = 45) showed stable expression of CX3CL1 and the angiotensin II receptor AGTR1 throughout the first trimester, but did not show a correlation between both or any influence of maternal age, BMI, and gestational age. Angiotensin II incubation of placental explants transiently deregulated CX3CL1 expression, while the angiotensin II receptor antagonist candesartan reversed this effect. Overexpression of recombinant human CX3CL1 in SGHPL-4 trophoblasts increased adhesion of THP-1 monocytes and significantly increased IL8, CCL19, and CCL13 in co-cultures with human primary monocytes. Incubation of primary monocytes with CX3CL1 and subsequent global transcriptome analysis of CD16⁺ subsets revealed 81 upregulated genes, including clusterin, lipocalin-2, and the leptin receptor. Aldosterone synthase, osteopontin, and cortisone reductase were some of the 66 downregulated genes present. These data suggest that maternal angiotensin II levels influence placental CX3CL1 expression, which, in turn, can affect monocyte to trophoblast adhesion. Release of placental CX3CL1 could promote the pro-inflammatory status of the CD16⁺ subset of maternal monocytes.


Assuntos
Angiotensina II/metabolismo , Comunicação Celular , Quimiocina CX3CL1/genética , Regulação da Expressão Gênica , Monócitos/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismo , Adulto , Linhagem Celular , Quimiocina CX3CL1/metabolismo , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Idade Gestacional , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Gravidez , RNA Mensageiro , Transcriptoma , Adulto Jovem
7.
Mol Metab ; 20: 89-101, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30553772

RESUMO

OBJECTIVE: Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand-receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis. We sought to reduce atherosclerosis by preventing monocyte-endothelial cell interactions through use of a long-acting CX3CR1 agonist. METHODS: In this study, the chemokine domain of CX3CL1 was fused to the mouse Fc region to generate a long-acting soluble form of CX3CL1 suitable for chronic studies. CX3CL1-Fc or saline was injected twice a week (30 mg/kg) for 4 months into Ldlr knockout (KO) mice on an atherogenic western diet. RESULTS: CX3CL1-Fc-treated Ldlr KO mice showed decreased en face aortic lesion surface area and reduced aortic root lesion size with decreased necrotic core area. Flow cytometry analyses of CX3CL1-Fc-treated aortic wall cell digests revealed a decrease in M1-like polarized macrophages and T cells. Moreover, CX3CL1-Fc administration reduced diet-induced atherosclerosis after switching from an atherogenic to a normal chow diet. In vitro monocyte adhesion studies revealed that CX3CL1-Fc treatment caused fewer monocytes to adhere to a human umbilical vein endothelial cell monolayer. Furthermore, a dorsal window chamber model demonstrated that CX3CL1-Fc treatment decreased in vivo leukocyte adhesion and rolling in live capillaries after short-term ischemia-reperfusion. CONCLUSION: These results indicate that CX3CL1-Fc can inhibit monocyte/endothelial cell adhesion as well as reduce atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Quimiocina CX3CL1/uso terapêutico , Placa Aterosclerótica/tratamento farmacológico , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/prevenção & controle , Células Cultivadas , Quimiocina CX3CL1/genética , Fragmentos Fc das Imunoglobulinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/prevenção & controle , Receptores de LDL/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico
8.
Immunol Cell Biol ; 97(5): 457-469, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30575118

RESUMO

Mutations in the isocitrate dehydrogenase (IDH) 1 gene, especially the R132H mutation, have been reported to be associated with a better prognosis in glioma patients. However, the underlying molecular mechanisms are not yet well understood. Many factors may contribute to differences in the survival of IDH1 wild-type and IDH1 mutant glioma patients, in which immune components play a potentially important role. In this study, we analyzed The Cancer Genome Atlas (TCGA), and the Chinese Glioma Genome Atlas (CGGA) databases, as well as glioma patient-derived tumor samples. We found that there was a higher infiltration of natural killer (NK) cells in IDH1 mutant glioma patients, and this was correlated with a better prognosis. We also showed that IDH1-R132 tumor cells had higher expression levels of the chemokine CX3CL1. This arises as a result of the conversion of α-ketoglutarate to R(-)-2-hydroxyglutarate by the IDH1 mutant and the resultant phosphorylation of nuclear factor kappa B. Knockdown of CX3CL1 decreased the migration of NK cells. In addition, the high levels of expression of CX3CL1 were positively correlated with glioma patient survival in the TCGA and CGGA databases, and in the clinical samples. Overall, our data have identified a novel mechanism in which R132H mutation of the IDH1 gene serves as a tumor suppressor by promoting the recruitment of NK cells through CX3CL1/CX3CR1 chemotaxis.


Assuntos
Receptor 1 de Quimiocina CX3C/imunologia , Quimiocina CX3CL1/imunologia , Quimiotaxia , Regulação Neoplásica da Expressão Gênica/imunologia , Glioma , Isocitrato Desidrogenase , Células Matadoras Naturais/imunologia , Mutação de Sentido Incorreto , Proteínas Supressoras de Tumor , Substituição de Aminoácidos , Receptor 1 de Quimiocina CX3C/genética , Linhagem Celular Tumoral , Quimiocina CX3CL1/genética , Quimiotaxia/genética , Quimiotaxia/imunologia , Feminino , Glioma/genética , Glioma/imunologia , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/imunologia , Células Matadoras Naturais/patologia , Masculino , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia
9.
Eur Rev Med Pharmacol Sci ; 22(21): 7197-7204, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30468463

RESUMO

OBJECTIVE: To investigate the potential effect of miR-485-5p on the development of osteosarcoma (OA) and its relevant mechanism. PATIENTS AND METHODS: The expression level of miR-485-5p was detected in OA tissues and cells (MG-63) comparing with corresponding adjacent normal tissues and normal human osteoblastic cell lines (Hfob1.19), respectively. Luciferase assay was performed to evaluate the interaction between miR-485-5p and CX3CL1, the effects of miR-485-5p on MG-63 cells were determined by subsequent experiments including cell proliferation, expression level of CX3CL1, detection of invasion and migration capacities. RESULTS: In our present research, miR-485-5p was down-regulated in OA tissues and we got the same result in OA cells. In order to obtain potential target of miR-485-5p, we checked it in three publicly available algorithms, TargetScan, miRDB and microRNA. We found that CX3CL1 is a direct target of miR-485-5p, and Luciferase assays confirmed our hypothesis. The results showed that decreased expression of CX3CL1 resulting from the up-regulation of miR-485-5p could decelerate cell proliferation, invasion and migration in OA cells. CONCLUSIONS: We showed the suppressor function of miR-485-5p in OA by targeting CX3CL1, indicating that miR-485-5p/CX3CL1 axis might be a potential therapeutic target for the treatment of OA.


Assuntos
Neoplasias Ósseas/metabolismo , Movimento Celular , Proliferação de Células , Quimiocina CX3CL1/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , Regiões 3' não Traduzidas , Sítios de Ligação , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Quimiocina CX3CL1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Metástase Neoplásica , Osteossarcoma/genética , Osteossarcoma/patologia , Transdução de Sinais
10.
PLoS One ; 13(11): e0207085, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30399192

RESUMO

Preterm labor (PTL) is the most common cause of neonatal death and long-term adverse outcome. The pharmacological agents for PTL prevention are palliative and frequently fail to prevent PTL and improve neonatal outcome. It is essential to fully understand the molecular mechanisms of PTL in order to develop novel therapeutic methods against PTL. Several lines of evidence indicate some chemokines are expressed in gestational tissues during labor or PTL. To reveal the pathophysiological roles of the CX3CL1-CX3CR1 axis in PTL, we performed present study using LPS-induced PTL mice model in CX3CR1-deficient (Cx3cr1-/-) mice. We indicated that PTL was suppressed in Cx3cr1-/- mice and immunoneutralization of CX3CL1 in WT mice. From immunohistochemical and the gene expression analyses, the CX3CL1-CX3CR1 axis has detrimental roles in PTL through intrauterine recruitment of macrophages and the enhancement of macrophage-derived inflammatory mediators. Thus, the CX3CL1-CX3CR1 axis may be a good molecular target for preventing PTL.


Assuntos
Receptor 1 de Quimiocina CX3C/deficiência , Quimiocina CX3CL1/deficiência , Inflamação/metabolismo , Trabalho de Parto Prematuro/metabolismo , Adulto , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/metabolismo , Modelos Animais de Doenças , Escherichia coli , Feminino , Expressão Gênica , Humanos , Inflamação/patologia , Lipopolissacarídeos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Trabalho de Parto Prematuro/patologia , Placenta/metabolismo , Placenta/patologia , Gravidez , Proteínas Recombinantes/metabolismo
11.
Cell Death Dis ; 9(10): 962, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237497

RESUMO

Tumor growth is modulated by crosstalk between cancer cells and the tumor microenvironment. Recent advances have shown that miRNA dysfunction in tumor cells can modulate the tumor microenvironment to indirectly determine their progression. However, this process is poorly understood in testicular germ cell tumors (TGCTs). We reported here that miR-125b was repressed in TGCT samples by epigenetic modifications rather than genetic alternations. Furthermore, miR-125b overexpression significantly alleviated the tumor growth in two NCCIT human embryonic carcinoma xenograft models in vivo, whereas miR-125b did not stimulate autonomous tumor cell growth in vitro. Notably, forced expression of miR-125b in NCCIT embryonic carcinoma cells decreased the abundance of host tumor-associated macrophages (TAMs) within tumor microenvironment. Selective deletion of host macrophages by clodronate abolished the anti-tumoral ability of miR-125b in xenograft models. By RNA profiling, Western blot and luciferase reporter assay, we further observed that miR-125b directly regulated tumor cell-derived chemokine CSF1 and CX3CL1, which are known to control the recruitment of TAMs to tumor sites. Lastly, we found that one set of miRNAs, which are under the regulation of miR-125b, might convergently target CSF1/CX3CL1 in NCCIT cells using miRNA profiling. These findings uncover the anticancer effect of miR-125b via mediating tumor-stroma crosstalk in xenograft models of TGCTs and raise the possibility of targeting miR-125b as miRNA therapeutics.


Assuntos
Quimiocina CX3CL1/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , MicroRNAs/metabolismo , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Testiculares/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Quimiocina CX3CL1/genética , Ensaio de Imunoadsorção Enzimática , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Marcação In Situ das Extremidades Cortadas , Fator Estimulador de Colônias de Macrófagos/genética , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Embrionárias de Células Germinativas/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Neoplasias Testiculares/genética , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
12.
J Neuroinflammation ; 15(1): 278, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30253780

RESUMO

BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1-/-) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1-/-, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.


Assuntos
Quimiocina CX3CL1/genética , Regulação da Expressão Gênica/genética , Microglia/metabolismo , Tauopatias/patologia , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Quimiocina CX3CL1/metabolismo , Transtornos Cognitivos/etiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Mutação/genética , Tauopatias/complicações , Tauopatias/genética , Proteínas tau/genética , Proteínas tau/metabolismo
13.
Exp Physiol ; 103(9): 1192-1199, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29920821

RESUMO

NEW FINDINGS: What is the central question of the study? Does neonatal stress, in the form of neonatal maternal separation, influence the maturation of microglial density, morphology and neuronal signalling in medullary regions regulating cardiorespiratory function in rat pups? What is the main finding and its importance? Using Iba-1 immunohistochemistry, we show that neonatal maternal separation augments microglial density and the proportion of cells with an amoeboid morphology in the medulla. Although the current understanding of the effect of early life stress on medullary development is relatively limited, these data show that within this area, microglia are affected by neonatal stress. Microglia could therefore be important effectors in cardiorespiratory disorders resulting from maternal separation. ABSTRACT: Neonatal stress has wide-ranging consequences for the developing brain, including the medullary cardiorespiratory network. In rat pups, the reflexive cardiorespiratory inhibition triggered by the presence of liquids near the larynx is augmented by neonatal maternal separation (NMS), especially in males. Sex-specific enhancement of synaptic connectivity by NMS might explain this cardiorespiratory dysfunction. Microglia influence the formation, maturation, activity and elimination of developing synapses, but their role in the wiring of medullary networks is unknown. Owing to their sensitivity to sex hormones and stress hormones, microglial dysfunction could contribute to the abnormal cardiorespiratory phenotype observed in NMS pups. Here, we first used ionized calcium-binding adapter molecule-1 (Iba-1) immunolabelling to compare the density and morphology of microglia in the medulla of male versus female rat pups (14-15 days old) that were either undisturbed or subjected to NMS (3 h day-1 ; postnatal days 3-12). Neonatal maternal separation augmented the density of Iba-1+ cells (caudal region of the NTS), increased the size of the soma and reduced the arborization area (especially in the dorsal motor nucleus of the vagus). Sex-based differences were not observed. Given that the actions of microglia are regulated by neuronal fractalkine (CX3 CL1 ), we then used western blot analysis to compare the expression of CX3 CL1 and its microglial receptor (CX3 CR1 ) in medullary homogenates from control and NMS pups. Although CX3 CR1 expression was 59% greater in males versus females, NMS had no effect on CX3 CL1 /CX3 CR1 signalling. Given that an amoeboid morphology reflects an immature phenotype in developing microglia, NMS could interfere with synaptic pruning via a different mechanism.


Assuntos
Animais Recém-Nascidos , Bulbo/patologia , Microglia/patologia , Estresse Psicológico/patologia , Animais , Ansiedade de Separação/patologia , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/metabolismo , Feminino , Masculino , Privação Materna , Proteínas dos Microfilamentos/metabolismo , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Transdução de Sinais , Sinapses/patologia
14.
Glia ; 66(8): 1752-1762, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29624735

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons of the substantia nigra and the accumulation of protein aggregates, called Lewy bodies, where the most abundant is alpha-synuclein (α-SYN). Mutations of the gene that codes for α-SYN (SNCA), such as the A53T mutation, and duplications of the gene generate cases of PD with autosomal dominant inheritance. As a result of the association of inflammation with the neurodegeneration of PD, we analyzed whether overexpression of wild-type α-SYN (α-SYNWT ) or mutated α-SYN (α-SYNA53T ) are involved in the neuronal dopaminergic loss and inflammation process, along with the role of the chemokine fractalkine (CX3CL1) and its receptor (CX3CR1). We generated in vivo murine models overexpressing human α-SYNWT or α-SYNA53T in wild type (Cx3cr1+/+ ) or deficient (Cx3cr1-/- ) mice for CX3CR1 using unilateral intracerebral injection of adeno-associated viral vectors. No changes in CX3CL1 levels were observed by immunofluorescence or analysis by qRT-PCR in this model. Interestingly, the expression α-SYNWT induced dopaminergic neuronal death to a similar degree in both genotypes. However, the expression of α-SYNA53T produced an exacerbated neurodegeneration, enhanced in the Cx3cr1-/- mice. This neurodegeneration was accompanied by an increase in neuroinflammation and microgliosis as well as the production of pro-inflammatory markers, which were exacerbated in Cx3cr1-/- mice overexpressing α-SYNA53T . Furthermore, we observed that in primary microglia CX3CR1 was a critical factor in the modulation of microglial dynamics in response to α-SYNWT or α-SYNA53T . Altogether, our study reveals that CX3CR1 plays an essential role in neuroinflammation induced by α-SYNA53T .


Assuntos
Quimiocina CX3CL1/deficiência , Doenças Neurodegenerativas/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Quimiocina CX3CL1/genética , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Camundongos Knockout , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/genética , Substância Negra/metabolismo
15.
J Clin Invest ; 128(4): 1458-1470, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29504946

RESUMO

We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and ß cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased ß cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased α cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered ß cell action potential (AP) firing and decreased α cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin-sensitive manner. Together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.


Assuntos
Glicemia/metabolismo , Quimiocina CX3CL1/farmacologia , Fragmentos Fc das Imunoglobulinas/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Animais , Glicemia/genética , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Quimiocina CX3CL1/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Fragmentos Fc das Imunoglobulinas/genética , Secreção de Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Transgênicos , Proteínas Recombinantes de Fusão/genética
16.
Georgian Med News ; (274): 125-130, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29461240

RESUMO

To improve the effectiveness of diagnosis and prediction of adverse asthma comorbid conditions based on research of clinical manifestations features, functional disorders of the airways and endothelial dysfunction. 79 patients were selected for the study. All the patients were divided into 3 groups: group 1 - patients with asthma (n-22); group II (n-24) - patients with asthma + diabetes mellitus type 2; group III (n-33) - patients with asthma + obesity + arterial hypertension (AH) and control group (n-17) - healthy people. All the patients underwent clinical examination. Spirography indicators were tested, and full patients' examination was conducted. The levels of fractalkine (CX3CL1) and Monocyte Chemoattractant Protein - 1(MCP-1) were determined by Enzyme-linked immunosorbent assay (ELISA) test using Ray Bio® Human Fractalkine system manufactured by Ray Biotech, Inc., USA; "Human MCP-1" (eBioscience, Austria), respectively. Statistical processing of parameters of endothelial function, МСР-1 andCX3CL1, depending on comorbid pathology, has identified statistically significant elevated level of the separametersinall studied groups. The most pronounced changes of both parameters were registered in group 2 patients, indicative of the most significant manifestations of endothelial dysfunction in this patient group.Assessment of endothelium dysfunction markers depending on external respiration function was performed. It has been found out that МСР-1 affects vital pulmonary capacity (χ2=14.466; р=0.002) and forced expiratory volume in 1 second (FEV1) (χ2=8.471; р=0.037). Besides, CX3CL1 exerts influence on these parameters as well (χ2=19.385, р=0.001); (χ2=11.476, р=0.009), respectively. The decrease in rate parameters, in particular, FEV1, MEF 25, MEF 50, and MEF 75, was identified in all patient groups. Based on these data, we can assume that patients with a combination of asthma and diabetes mellitus type 2 demonstrate more cases of endothelial malfunction, leading to the worsening of respiratory function, compared to the group with asthma, obesity and arterial hypertension and a group without comorbidity.


Assuntos
Asma/genética , Quimiocina CCL2/genética , Quimiocina CX3CL1/genética , Diabetes Mellitus Tipo 2/genética , Hipertensão/genética , Obesidade/genética , Adulto , Asma/complicações , Asma/metabolismo , Asma/fisiopatologia , Estudos de Casos e Controles , Quimiocina CCL2/metabolismo , Quimiocina CX3CL1/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Progressão da Doença , Feminino , Fluxo Expiratório Forçado/fisiologia , Volume Expiratório Forçado/fisiologia , Regulação da Expressão Gênica , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Prognóstico , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiopatologia , Espirometria
17.
Blood Coagul Fibrinolysis ; 29(4): 361-368, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29406386

RESUMO

: Fractalkine (FKN) is a cytokine which plays an important role in atherosclerosis and other inflammatory diseases. Studies have shown that FKN induces integrin-independent leukocyte adhesion to primary endothelial cells under physiological flow conditions. Further, increased expression of FKN has been demonstrated in atherosclerotic lesions induced by low shear stress. However, the signal transduction mechanisms involved in low shear stress-induced FKN upregulation are not well characterized. In this study, EA.hy926 cells were subjected to varying intensity of fluid shear stress for different time durations. Further, mRNA and protein expressions of FKN were assessed by quantitative real-time PCR and Western blotting, respectively. Upregulation of FKN expression, which was induced via activation of mitogen-activated protein kinases signaling pathway under conditions of low shear stress, was studied both in the presence and absence of inhibitors. Low shear stress (∼4.58 dyne/cm) for more than 1 h promoted FKN expression and activated the extracellular signal-regulated kinase (ERK)1/2, p38, and Jun N-terminal kinase (JNK) mitogen-activated protein kinases signaling pathways by their phosphorylation. Inhibitors of ERK1/2, p38, and JNK pathways downregulated the FKN expression. In this study, fluid shear stress affected FKN expression in endothelial cells via activation of ERK1/2, p38, and JNK in a time-dependent manner. Our findings serve to advance the theoretical basis for prevention and treatment of atherosclerosis.


Assuntos
Quimiocina CX3CL1/metabolismo , Células Endoteliais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Mecânico , Aterosclerose/prevenção & controle , Linhagem Celular , Quimiocina CX3CL1/genética , Células Endoteliais/enzimologia , Humanos , Fosforilação , RNA Mensageiro/metabolismo , Transdução de Sinais , Regulação para Cima
18.
Cytokine ; 104: 23-28, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29414322

RESUMO

OBJECTIVE: To investigate the expression levels of fractalkine (FKN) mRNA in peripheral blood mononuclear cells (PBMCs) and FKN protein in serum of patients with lupus nephritis (LN) from China, and to evaluate the associations between the expression of FKN and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K), anti-double-stranded DNA and complement proteins in LN patients. METHODS: Real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were used to detect the expression levels of FKN mRNA in PBMCs and FKN protein in serum separately from 105 patients with LN and 52 healthy controls. RESULTS: Serum level and mRNA level of FKN were significantly increased in LN patients when compared to controls (P < 0.001). Higher FKN levels were found in active LN patients and LN patients with renal damage when compared with inactive LN patients and LN patients without renal damage (P < 0.001). Higher serum FKN levels were detected in inactive LN patients in comparison with healthy controls (Z = -7.165, P < 0.001). The FKN expression levels were positively correlated with SLEDAI-2 K, and was associated with the presence of autoantibodies and negatively correlated with complement proteins C3 and C4 in LN patients. CONCLUSIONS: The results suggest that upregulation of FKN is associated with the pathogenesis and activity of LN in Chinese patients.


Assuntos
Grupo com Ancestrais do Continente Asiático , Quimiocina CX3CL1/genética , Nefrite Lúpica/genética , Regulação para Cima/genética , Adulto , Estudos de Casos e Controles , Quimiocina CX3CL1/sangue , Humanos , Leucócitos Mononucleares/metabolismo , Nefrite Lúpica/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença
19.
Cytokine Growth Factor Rev ; 39: 116-123, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29290570

RESUMO

Inflammation and angiogenesis are two interdependent processes underlying pathogenesis of cardiovascular disorders. The initiation and progression of atherosclerosis strongly depends on specific patterns of cytokine expression. In this review, we analyze correlation between expression of two members of the cytokine family and the processes of inflammation and angiogenesis related to atherosclerosis. Placental growth factor and chemokine CX3XL1 (fractalkine) promote inflammatory cell infiltration, angiogenesis and plaque rupture. Because these cytokines share similar roles during atherosclerotic development, their combined value as a predictor or indicator of inflammation and vascular healing may be extremely useful.


Assuntos
Indutores da Angiogênese/imunologia , Doenças Cardiovasculares/imunologia , Quimiocina CX3CL1/imunologia , Inflamação/patologia , Neovascularização Patológica , Fator de Crescimento Placentário/imunologia , Animais , Quimiocina CX3CL1/genética , Humanos , Camundongos , Fator de Crescimento Placentário/genética
20.
Biochem J ; 475(4): 723-732, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29301984

RESUMO

Leukocyte arrest on the endothelial cell surface during leukocyte extravasation is induced by rapid integrin activation by chemokines. We recently reported that fractalkine induces integrin activation without its receptor CX3CR1 through binding to the allosteric site (site 2) of integrins. Peptides from site 2 bound to fractalkine and suppressed integrin activation by fractalkine. We hypothesized that this is not limited to membrane-bound fractalkine. We studied whether stromal cell-derived factor-1 (SDF1), another chemokine that plays a critical role in leukocyte arrest, activates integrins through binding to site 2. We describe here that (1) SDF1 activated soluble integrin αvß3 in cell-free conditions, suggesting that SDF1 can activate αvß3 without CXCR4; (2) site 2 peptide bound to SDF1, suggesting that SDF1 binds to site 2; (3) SDF1 activated integrins αvß3, α4ß1, and α5ß1 on CHO cells (CXCR4-negative) and site 2 peptide suppressed the activation; (4) A CXCR4 antagonist AMD3100 did not affect the site 2-mediated integrin activation by SDF1; (5) Cell-surface integrins were fully activated in 1 min (much faster than activation of soluble αvß3) and the activation lasted at least for 1 h. We propose that the binding of SDF1 to cell-surface proteoglycan facilitates the allosteric activation process; (6) Mutations in the predicted site 2-binding site in SDF1 suppressed integrin activation. These results suggest that SDF1 (e.g. presented on proteoglycans) can rapidly activate integrins in an allosteric manner by binding to site 2 in the absence of CXCR4. The allosteric integrin activation by SDF1 is a novel target for drug discovery.


Assuntos
Quimiocina CXCL12/química , Integrinas/química , Receptores CXCR4/química , Sítio Alostérico , Animais , Sítios de Ligação , Células CHO , Sistema Livre de Células , Quimiocina CX3CL1/química , Quimiocina CX3CL1/genética , Quimiocina CXCL12/genética , Cricetulus , Humanos , Integrinas/genética , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Receptores CXCR4/genética , Transdução de Sinais/genética
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