Редактирование: CXCL2 (раздел)

==Publications==

{{medline-entry
|title=Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33041998
|abstract=Alzheimer's Disease (AD) is associated with neuropathological changes, including aggregation of tau neurofibrillary tangles (NFTs) and amyloid-beta plaques. Mounting evidence indicates that vascular dysfunction also plays a key role in the pathogenesis and progression of AD, in part through endothelial dysfunction. Based on findings in animal models that tau pathology induces vascular abnormalities and cellular senescence, we hypothesized that tau pathology in the human AD brain leads to vascular senescence. To explore this hypothesis, we isolated intact microvessels from the dorsolateral prefrontal cortex (PFC, BA9) from 16 subjects with advanced Braak stages (Braak V/VI, B3) and 12 control subjects (Braak 0/I/II, B1), and quantified expression of 42 genes associated with senescence, cell adhesion, and various endothelial cell functions. Genes associated with endothelial senescence and leukocyte adhesion, including [[SERPINE1]] (PAI-1), [[CXCL8]] (IL8), [[CXCL1]], [[CXCL2]], ICAM-2, and [[TIE1]], were significantly upregulated in B3 microvessels after adjusting for sex and cerebrovascular pathology. In particular, the senescence-associated secretory phenotype genes [[SERPINE1]] and [[CXCL8]] were upregulated by more than 2-fold in B3 microvessels after adjusting for sex, cerebrovascular pathology, and age at death. Protein quantification data from longitudinal plasma samples for a subset of 13 ([i]n[/i] = 9 B3, [i]n[/i] = 4 B1) subjects showed no significant differences in plasma senescence or adhesion-associated protein levels, suggesting that these changes were not associated with systemic vascular alterations. Future investigations of senescence biomarkers in both the peripheral and cortical vasculature could further elucidate links between tau pathology and vascular changes in human AD.

|keywords=* Alzheimer's disease
* endothelial senescence
* gene expression
* neurofibrillary tangles
* plasma biomarkers
* tau pathology
* vascular dysfunction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525127
}}
{{medline-entry
|title=Inflammatory and Senescent Phenotype of Pancreatic Stellate Cells Induced by Sqstm1 Downregulation Facilitates Pancreatic Cancer Progression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31182922
|abstract=Pancreatic ductal adenocarcinoma (PDAC) has unique microenvironment with extensive infiltration of fibroblasts, which are mainly derived from the resident pancreatic stellate cells (PaSCs). As activated PaSCs constitute a major contributor to pancreatic cancer progression, the mechanisms underlying their activation have been being intensively studied. Previous studies showed that Sequestosome-1 (sqstm1) can modulate the functional status of fibroblasts in cancer. Here, we further delineated the role of sqstm1 in PaSCs. The analysis of PDAC patient samples revealed reduction of sqstm1 expression in activated PaSCs in both mRNA and protein level. Downregulated sqstm1 via shRNA in PaSCs led to an inflammatory and senescent phenotype with increased IL8, [[CXCL1]], and [[CXCL2]] expression. Further analysis demonstrated that increased intracellular reactive oxygen species level contributed to the senescence in sqstm1-downregulated PaSCs. This was mediated via impaired NRF2 activity since reduced sqstm1 resulted in accumulation of [[KEAP1]]. Meanwhile, we found that sqstm1 degradation caused by enhanced autophagy was not associated with transformation of senescent phenotype. At last, the data revealed that sqstm1-downregulated PaSCs promoted pancreatic tumor cell growth, invasion, and macrophage phenotype transformation. Collectively, the current study indicated that sqstm1 controlled transformation of senescent phenotype of PaSCs, which in turn is pro-tumorigenic.
|mesh-terms=* Animals
* Carcinoma, Pancreatic Ductal
* Cell Line, Tumor
* Chemokine CXCL1
* Chemokine CXCL2
* Female
* Fluorescent Antibody Technique
* Humans
* Immunoblotting
* Immunohistochemistry
* Interleukin-8
* Mice
* Mice, Inbred BALB C
* Mice, Nude
* Pancreatic Neoplasms
* Pancreatic Stellate Cells
* RNA, Small Interfering
* Reactive Oxygen Species
* Real-Time Polymerase Chain Reaction
* Sequestosome-1 Protein
|keywords=* pancreatic adenocarcinoma
* pancreatic stellate cells
* reactive oxygen species
* senescence
* sqstm1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535784
}}
{{medline-entry
|title=Long-term every-other-day administration of DMAMCL has little effect on aging and age-associated physiological decline in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31048563
|abstract=The activation of transcription factor NF-κB is currently identified as one of the driving forces to the aging process. Genetic impairment of NF-κB signaling pathway or pharmacological inhibition of NF-κB activity has been shown to extend healthspan and lifespan in animal models, and delay or reduce many age-related symptoms. However, the aging intervention strategies based on NF-κB inhibition by the suitable small molecular compound is currently still lacking. The water-soluble dimethylaminomicheliolide (DMAMCL), can inhibit NF-κB activity and is currently undergoing clinical trials. In this study, we showed that 15 months of DMAMCL administration started in 1-year old male mice was well-tolerated and safe, and improved or had little effect on some age-associated symptoms, such as neurobehavioral phenotypes, physical performance, cardiac function, hematological parameters, immune aging phenotypes, clinical chemistry parameters, and glucose homeostasis. At the molecular level, DMAMCL administration mitigated serum levels of several age-associated inflammatory cytokines, including IL-6, IL-1α, IL-1β, [[TNF]]-α, IFN-γ, and [[CXCL2]], and inhibited NF-κB activity in several aged tissues. Collectively, our results indicate that current strategy of DMAMCL administration may has little effect on aging process in mice, and provide basic clues to further exploit the possibility of DMAMCL-based aging intervention to promote healthy aging.
|mesh-terms=* Aging
* Animals
* Cytokines
* Drug Administration Schedule
* Gene Expression Regulation
* Male
* Mice
* Mice, Inbred C57BL
* Musculoskeletal Physiological Phenomena
* Sesquiterpenes, Guaiane
|keywords=* DMAMCL
* NF-κB
* age-associated physiological decline
* inflammaging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535057
}}
{{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=Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30617300
|abstract=Neutrophils clear viruses, but excessive neutrophil responses induce tissue injury and worsen disease. Aging increases mortality to influenza infection; however, whether this is due to impaired viral clearance or a pathological host immune response is unknown. Here we show that aged mice have higher levels of lung neutrophils than younger mice after influenza viral infection. Depleting neutrophils after, but not before, infection substantially improves the survival of aged mice without altering viral clearance. Aged alveolar epithelial cells (AECs) have a higher frequency of senescence and secrete higher levels of the neutrophil-attracting chemokines [[CXCL1]] and [[CXCL2]] during influenza infection. These chemokines are required for age-enhanced neutrophil chemotaxis in vitro. Our work suggests that aging increases mortality from influenza in part because senescent AECs secrete more chemokines, leading to excessive neutrophil recruitment. Therapies that mitigate this pathological immune response in the elderly might improve outcomes of influenza and other respiratory infections.
|mesh-terms=* Aging
* Animals
* Cell Count
* Cellular Senescence
* Chemokine CXCL1
* Chemokine CXCL2
* Chemotaxis
* Epithelial Cells
* Humans
* Influenza, Human
* Lung
* Mice
* Mice, Inbred C57BL
* Mortality
* Neutrophils
* Survival Analysis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375784
}}
{{medline-entry
|title=Time-Dependent Changes in Local and Serum Levels of Inflammatory Cytokines as Markers for Incised Wound Aging of Skeletal Muscles.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29760352
|abstract=Wound age estimation is an important research field in forensic pathology. The expression levels of cytokines in the incised skeletal muscle were analyzed using a mouse model to explore the applicability for wound aging. A 5-mm long incisional wound was made at the biceps femoris muscle, and the muscle and serum were sampled at 6, 12, 24 and 48 hours after injury. Using a multiplex bead-based immunoassay, we measured the tissue levels of nine cytokines (IL-1β, IL-6, IL-7, [[CCL2]], [[CCL3]], [[CCL4]], [[CXCL1]], [[CXCL2]], and [[CXCL1]]0), which are all involved in the pathways of inflammatory response and tissue injury. Immunoassay of post-injury muscle samples revealed significant increases in the levels of six cytokines, except for [[CCL3]], [[CCL4]] and IL-7, at 6 hours after injury. The elevated tissue levels of these six cytokines were maintained during 48 hours after injury, although the levels of IL-6 and [[CXCL1]] were significantly decreased at 12 hours. In case of [[CCL3]], its tissue levels were increased only at 12 hours. By contrast, [[CCL4]] and IL-7 levels were increased only at 48 hours. Moreover, serum levels of most cytokines, except for [[CXCL1]], remained unchanged during 24 hours after injury, followed by significant increases at 48 hours. Serum [[CXCL1]] levels were increased at 6 hours and then decreased to the basal levels. Thus, the significant increase in the muscle levels of [[CXCL1]] and IL-7 was observed at 6 and 48 hours after injury, respectively. Measuring muscle [[CXCL1]] and IL-7 levels is helpful for estimating incised wound aging.
|mesh-terms=* Aging
* Animals
* Biomarkers
* Cytokines
* Gene Expression Regulation
* Immunoassay
* Inflammation Mediators
* Male
* Mice, Inbred BALB C
* Muscle, Skeletal
* RNA, Messenger
* Time Factors
* Wounds and Injuries
|keywords=* bead-based immunoassay
* cytokines
* sharp force injury
* skeletal muscle
* wound aging
|full-text-url=https://sci-hub.do/10.1620/tjem.245.29
}}
{{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=Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27845246
|abstract=Palmitate triggers inflammatory responses in several cell types, but its effects on cardiac fibroblasts are at present unknown. The aims of the study were to (1) assess the potential of palmitate to promote inflammatory signaling in cardiac fibroblasts through [[TLR4]] and the [[NLRP3]] inflammasome and (2) characterize the cellular phenotype of cardiac fibroblasts exposed to palmitate. We examined whether palmitate induces inflammatory responses in cardiac fibroblasts from WT, [[NLRP3]]  and ASC mice (C57BL/6 background). Exposure to palmitate caused production of [[TNF]], IL-6 and [[CXCL2]] via [[TLR4]] activation. [[NLRP3]] inflammasomes are activated in a two-step manner. Whereas palmitate did not prime the [[NLRP3]] inflammasome, it induced activation in LPS-primed cardiac fibroblasts as indicated by IL-1β, IL-18 production and [[NLRP3]]-ASC co-localization. Palmitate-induced [[NLRP3]] inflammasome activation in LPS-primed cardiac fibroblasts was associated with reduced AMPK activity, mitochondrial reactive oxygen species production and mitochondrial dysfunction. The cardiac fibroblast phenotype caused by palmitate, in an LPS and [[NLRP3]] independent manner, was characterized by decreased cellular proliferation, contractility, collagen and MMP-2 expression, as well as increased senescence-associated β-galactosidase activity, and consistent with a state of cellular senescence. This study establishes that in vitro palmitate exposure of cardiac fibroblasts provides inflammatory responses via [[TLR4]] and [[NLRP3]] inflammasome activation. Palmitate also modulates cardiac fibroblast functionality, in a [[NLRP3]] independent manner, resulting in a phenotype related to cellular senescence. These effects of palmitate could be of importance for myocardial dysfunction in obese and diabetic patients.
|mesh-terms=* Animals
* Apoptosis Regulatory Proteins
* Cellular Senescence
* Chemokine CXCL2
* Fibroblasts
* Heart
* Inflammasomes
* Inflammation
* Interleukin-18
* Interleukin-1beta
* Interleukin-6
* Lipopolysaccharides
* Mice
* Mice, Inbred C57BL
* NLR Family, Pyrin Domain-Containing 3 Protein
* Palmitates
* Signal Transduction
* Toll-Like Receptor 4
* beta-Galactosidase
|keywords=* Cardiac fibroblast
* Cellular senescence
* Inflammation
* NLRP3
* Palmitate
* TLR4
|full-text-url=https://sci-hub.do/10.1016/j.bbalip.2016.11.003
}}
{{medline-entry
|title=Mice with heterozygous deficiency of manganese superoxide dismutase ([[SOD2]]) have a skin immune system with features of "inflamm-aging".
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23856836
|abstract=Dendritic cells (DC) are central in regulating skin immunity. Immunosenescence is associated with a chronic inflammatory state. Little is known about the contribution of DC to "inflamm-aging". When determining langerhans cell (LC) numbers, we found a 60 % reduction of LC in aged epidermis. Reactive oxygen species(ROS) are linked with aging. The mitochondrial manganese superoxide dismutase ([[SOD2]]) is in the first line of antioxidant defense. We investigated the function of DC from [[SOD2]] heterozygous mice ([[SOD2]] /-) and found that at 4 months of age LC numbers are not altered, but activated LC have impaired expression of MHC-II and [[CD44]]. Immature [[SOD2]] /- DC produced increased proinflammatory IL-6 and chemokines [[CXCL1]] and [[CXCL2]]. Upon challenge [[SOD2]] /- DC accumulated ROS. When activating [[SOD2]] /- DC by LPS they less efficiently upregulated MHC-II, [[CD86]] and [[CD44]]. Surprisingly, in vivo contact hypersensitivity (CHS) was enhanced in [[SOD2]] /- mice although [[SOD2]] /- DC were less potent in stimulating wt T cells. However, [[SOD2]] /- T cells showed increased proliferation, even when stimulated with [[SOD2]] /- DC, possibly explaining the increased CHS. Our findings suggest that [[SOD2]] is a molecular candidate in the regulation of "inflamm-aging" conveying both immunosuppressive and proinflammatory signals through alteration of DC and T cell functions.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Animals
* B7-2 Antigen
* Cell Differentiation
* Cells, Cultured
* Chemokine CXCL1
* Chemokine CXCL2
* Dendritic Cells
* Dermatitis, Contact
* Heterozygote
* Histocompatibility Antigens Class II
* Humans
* Hyaluronan Receptors
* Inflammation
* Interleukin-6
* Lymphocyte Activation
* Mice
* Mice, Inbred C57BL
* Mice, Mutant Strains
* Reactive Oxygen Species
* Superoxide Dismutase
* T-Lymphocytes
* Young Adult

|full-text-url=https://sci-hub.do/10.1007/s00403-013-1389-7
}}