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1.
Arthritis Res Ther ; 23(1): 216, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412663

RESUMO

BACKGROUND: Excessive osteoclast activity, which is strongly stimulated by pro-inflammatory mediators, results in bone and cartilage degeneration as central features of many arthritides. Levels of the alarmin S100A8/A9 and interleukin (IL)-1ß are both increased in arthritis patients and correlate with disease activity and progression of tissue erosion. We previously presented S100A8/A9 as a good biomarker for joint inflammation and arthritis pathology under circumstances of high IL-1 signaling in mice that lack the gene encoding IL-1 receptor antagonist (Il1rn-/- mice). Here, we investigated whether S100A8/A9 is also actively involved in the development of joint inflammation and both cartilage and bone pathology under these conditions by comparing Il1rn-/- mice with mice that have an additional deficiency for S100a9 (Il1rn-/-XS100a9-/-). METHODS: Il1rn-/-XS100a9-/- on a BALB/c background were obtained by crossing S100a9-/- mice and Il1rn-/- mice. Arthritis incidence and severity were macroscopically scored. Myeloid cell populations in the bone marrow and spleen were determined using flow cytometry. In vitro osteoclastogenesis of bone marrow cells was evaluated with TRAP staining. Microscopic joint inflammation, cartilage degeneration, and bone destruction were evaluated using histology of ankle joints of 12- and 20-week-old mice. RESULTS: Macroscopically scored arthritis severity was comparable between Il1rn-/- and Il1rn-/-XS100a9-/- mice. Inflammation, cartilage erosion, and bone erosion were clearly present in 12-week-old mice of both strains lacking Il1rn-/-, but not significantly different between Il1rn-/-XS100a9-/- and Il1rn-/-. Moreover, we observed that the numbers of neutrophils and monocytes were increased by the absence of Il1rn, which was affected by the absence of S100a9 only in the spleen but not in the bone marrow. In line with our other findings, the absence of S100a9 did not affect the osteoclastogenic potential of osteoclast precursors in the absence of Il1rn. Finally, in agreement with the findings in early arthritis development in 12-week-old mice, cartilage and bone erosion in 20-week-old mice was significantly higher in both Il1rn-/- strains, but the additional absence of S100a9 did not further affect tissue pathology. CONCLUSION: S100A8/A9 deficiency does not significantly affect inflammation and joint destruction in mice with high IL1ß signaling suggesting that S100A8/A9 is not essential for the development of arthritis under these conditions.


Assuntos
Artrite Experimental , Calgranulina A , Calgranulina B , Proteína Antagonista do Receptor de Interleucina 1 , Animais , Artrite Experimental/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Humanos , Inflamação/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
2.
Sci Rep ; 11(1): 16212, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376762

RESUMO

During 2020, understanding the molecular mechanism of SARS-CoV-2 infection (the cause of COVID-19) became a scientific priority due to the devastating effects of the COVID-19. Many researchers have studied the effect of this viral infection on lung epithelial transcriptomes and deposited data in public repositories. Comprehensive analysis of such data could pave the way for development of efficient vaccines and effective drugs. In the current study, we obtained high-throughput gene expression data associated with human lung epithelial cells infected with respiratory viruses such as SARS-CoV-2, SARS, H1N1, avian influenza, rhinovirus and Dhori, then performed comparative transcriptome analysis to identify SARS-CoV-2 exclusive genes. The analysis yielded seven SARS-CoV-2 specific genes including CSF2 [GM-CSF] (colony-stimulating factor 2) and calcium-binding proteins (such as S100A8 and S100A9), which are known to be involved in respiratory diseases. The analyses showed that genes involved in inflammation are commonly altered by infection of SARS-CoV-2 and influenza viruses. Furthermore, results of protein-protein interaction analyses were consistent with a functional role of CSF2 and S100A9 in COVID-19 disease. In conclusion, our analysis revealed cellular genes associated with SARS-CoV-2 infection of the human lung epithelium; these are potential therapeutic targets.


Assuntos
Células Epiteliais Alveolares/metabolismo , COVID-19/genética , Transcriptoma , Células Epiteliais Alveolares/virologia , COVID-19/metabolismo , COVID-19/virologia , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , SARS-CoV-2/patogenicidade
3.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445548

RESUMO

S100A9, a Ca2+-binding protein, is tightly associated to neutrophil pro-inflammatory functions when forming a heterodimer with its S100A8 partner. Upon secretion into the extracellular environment, these proteins behave like damage-associated molecular pattern molecules, which actively participate in the amplification of the inflammation process by recruitment and activation of pro-inflammatory cells. Intracellular functions have also been attributed to the S100A8/A9 complex, notably its ability to regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. However, the complete functional spectrum of S100A8/A9 at the intracellular level is far from being understood. In this context, we here investigated the possibility that the absence of intracellular S100A8/A9 is involved in cytokine secretion. To overcome the difficulty of genetically modifying neutrophils, we used murine neutrophils derived from wild-type and S100A9-/- Hoxb8 immortalized myeloid progenitors. After confirming that differentiated Hoxb8 neutrophil-like cells are a suitable model to study neutrophil functions, our data show that absence of S100A8/A9 led to a dysregulation of cytokine secretion after lipopolysaccharide (LPS) stimulation. Furthermore, we demonstrate that S100A8/A9-induced cytokine secretion was regulated by the nuclear factor kappa B (NF-κB) pathway. These results were confirmed in human differentiated HL-60 cells, in which S100A9 was inhibited by shRNAs. Finally, our results indicate that the degranulation process could be involved in the regulation of cytokine secretion by S100A8/A9.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Citocinas/metabolismo , Proteínas de Homeodomínio/metabolismo , Neutrófilos/imunologia , Células-Tronco/imunologia , Animais , Calgranulina A/genética , Calgranulina B/genética , Estrogênios/farmacologia , Células HL-60 , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias , Neutrófilos/citologia , Neutrófilos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo
4.
Commun Biol ; 4(1): 865, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257370

RESUMO

A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease. To study a possible tumor protection effect by the Ncf1 mutation in a manner dependent on cell types, we used experimental mouse models of lung colonization assay by B16F10 melanoma cells. We observed fewer tumor foci in Ncf1 mutant mice, irrespective of αßT, γδT, B-cell deficiencies, or of a functional Ncf1 expression in CD68-positive monocytes/macrophages. The susceptibility to tumor colonization was restored by the human S100A8 (MRP8) promoter directing a functional Ncf1 expression to granulocytes. This effect was associated with an increase of both ROS and interleukin 1 beta (IL-1ß) production from lung neutrophils. Moreover, neutrophil depletion by anti-Ly6G antibodies increased tumor colonization in wild type but failed in the Ncf1 mutant mice. In conclusion, tumor colonization is counteracted by ROS-activated and IL-1ß-secreting tissue neutrophils.


Assuntos
Regulação Neoplásica da Expressão Gênica , NADPH Oxidases/genética , Neoplasias/genética , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Calgranulina A/genética , Calgranulina A/metabolismo , Linhagem Celular Tumoral , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , NADPH Oxidases/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único
5.
Nat Immunol ; 22(9): 1118-1126, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34326534

RESUMO

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.


Assuntos
Proteínas de Ligação a DNA/genética , Doenças Hereditárias Autoinflamatórias/genética , Doenças Inflamatórias Intestinais/genética , Macrófagos/imunologia , Fatores de Transcrição/genética , Animais , Calgranulina A/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Lipocalina-2/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th17/imunologia , Transcrição Genética/genética , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo
6.
Aging (Albany NY) ; 13(11): 15523-15537, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099591

RESUMO

S100 calcium-binding protein A8 (S100A8) and S100A9 are small molecular weight calcium-binding regulatory proteins that have been involved in multiple chronic inflammatory diseases. However, the role of S100A8 and S100A9 in keratinocytes in wounded skin and how they are regulated during this process are still unclear. Here, we found that S100A8 and S100A9 were both upregulated in burn-wounded skins in vivo and thermal-stimulated epidermal keratinocytes in vitro, accompanied by increased levels of epithelial-mesenchymal transition (EMT). Then, we demonstrated that upregulation of S100A8 and S100A9 alone or together enhanced characteristics of EMT in normal keratinocytes, manifested by excessive proliferation rate, abnormal ability of cell invasion, and high expression levels of EMT marker proteins. The transcription factor PU box-binding protein (PU.1) bound to the promoter regions and transcriptionally promoted the expression of S100A8 and S100A9 both in the human and mice, and it had strong positive correlations with both S100A8 and S100A9 protein levels in burned skin in vivo. Moreover, PU.1 positively regulated expression of S100A8 and S100A9 in a dose-dependent manner, and enhanced EMT of keratinocytes in vitro. Finally, through the burn mouse model, we found that PU.1-/- mice displayed a lower ability of scar formation, manifested by smaller scar volume, thickness, and collagen content, which could be enhanced by S100A8 and S100A9. In conclusion, PU.1 transcriptionally promotes expression of S100A8 and S100A9, thus positively regulating epithelial-mesenchymal transformation (EMT) and invasive growth of dermal keratinocytes during scar formation post burn.


Assuntos
Queimaduras/patologia , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Movimento Celular , Cicatriz/patologia , Transição Epitelial-Mesenquimal , Queratinócitos/patologia , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Adulto , Animais , Proliferação de Células , Modelos Animais de Doenças , Feminino , Temperatura Alta , Humanos , Masculino , Camundongos Endogâmicos BALB C , Regulação para Cima/genética
7.
Am J Physiol Gastrointest Liver Physiol ; 321(2): G157-G170, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132111

RESUMO

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.NEW & NOTEWORTHY Obese Zucker rats, which are resistant to leptin, exhibit a diminished inflammatory response in the trinitrobenzenesulfonic acid (TNBS) model of colitis, suggesting leptin role is proinflammatory. At the same time, obese Zucker rats present a debilitated intestinal barrier function, with increased translocation of LPS. Zucker rats present a dual response in the TNBS model of rat colitis.


Assuntos
Colite Ulcerativa/metabolismo , Mucosa Intestinal/metabolismo , Leptina/metabolismo , Lipopolissacarídeos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Calgranulina A/metabolismo , Quimiocina CXCL1/metabolismo , Colite Ulcerativa/etiologia , Colite Ulcerativa/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Absorção Intestinal , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Zucker , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Fator de Transcrição STAT3/metabolismo , Proteínas de Junções Íntimas/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Front Immunol ; 12: 635569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868260

RESUMO

While there is convincing evidence on the role of Aire-positive medullary thymic epithelial cells (mTEC) in the induction of central tolerance, the nature and function of post-Aire mTECs and Hassall's corpuscles have remained enigmatic. Here we summarize the existing data on these late stages of mTEC differentiation with special focus on their potential to contribute to central tolerance induction by triggering the unique pro-inflammatory microenvironment in the thymus. In order to complement the existing evidence that has been obtained from mouse models, we performed proteomic analysis on microdissected samples from human thymic medullary areas at different differentiation stages. The analysis confirms that at the post-Aire stages, the mTECs lose their nuclei but maintain machinery required for translation and exocytosis and also upregulate proteins specific to keratinocyte differentiation and cornification. In addition, at the late stages of differentiation, the human mTECs display a distinct pro-inflammatory signature, including upregulation of the potent endogenous TLR4 agonist S100A8/S100A9. Collectively, the study suggests a novel mechanism by which the post-Aire mTECs and Hassall's corpuscles contribute to the thymic microenvironment with potential cues on the induction of central tolerance.


Assuntos
Diferenciação Celular , Microambiente Celular , Tolerância Central , Células Epiteliais/metabolismo , Mediadores da Inflamação/metabolismo , Timo/metabolismo , Fatores de Transcrição/metabolismo , Animais , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Pré-Escolar , Células Epiteliais/imunologia , Humanos , Lactente , Camundongos , Proteoma , Proteômica , Timo/imunologia , Receptor 4 Toll-Like/metabolismo
9.
Molecules ; 26(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801279

RESUMO

Deregulations of the expression of the S100A8 and S100A9 genes and/or proteins, as well as changes in their plasma levels or their levels of secretion in the bone marrow microenvironment, are frequently observed in acute myeloblastic leukemias (AML) and acute lymphoblastic leukemias (ALL). These deregulations impact the prognosis of patients through various mechanisms of cellular or extracellular regulation of the viability of leukemic cells. In particular, S100A8 and S100A9 in monomeric, homodimeric, or heterodimeric forms are able to modulate the survival and the sensitivity to chemotherapy of leukemic clones through their action on the regulation of intracellular calcium, on oxidative stress, on the activation of apoptosis, and thanks to their implications, on cell death regulation by autophagy and pyroptosis. Moreover, biologic effects of S100A8/9 via both TLR4 and RAGE on hematopoietic stem cells contribute to the selection and expansion of leukemic clones by excretion of proinflammatory cytokines and/or immune regulation. Hence, the therapeutic targeting of S100A8 and S100A9 appears to be a promising way to improve treatment efficiency in acute leukemias.


Assuntos
Antineoplásicos/farmacologia , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Animais , Calgranulina A/antagonistas & inibidores , Calgranulina B/química , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Transdução de Sinais
10.
J Biol Chem ; 296: 100538, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33722610

RESUMO

The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a "multiple gear" regulatory mechanism, in which different activators (e.g., insulin receptor substrate-1 and CagA), oncogenic mutations (e.g., E76A), and allosteric inhibitors (e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.


Assuntos
Calgranulina A/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Piperidinas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/metabolismo , Regulação Alostérica , Humanos , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
11.
Front Immunol ; 12: 553911, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717058

RESUMO

Intra-abdominal infection (peritonitis) is a leading cause of severe disease in surgical intensive care units, as over 70% of patients diagnosed with peritonitis develop septic shock. A critical role of the immune system is to return to homeostasis after combating infection. S100A8/A9 (calprotectin) is an antimicrobial and pro-inflammatory protein complex used as a biomarker for diagnosis of numerous inflammatory disorders. Here we describe the role of S100A8/A9 in inflammatory collateral tissue damage (ICTD). Using a mouse model of disseminated intra-abdominal candidiasis (IAC) in wild-type and S100A8/A9-deficient mice in the presence or absence of S100A9 inhibitor paquinimod, the role of S100A8/A9 during ICTD and fungal clearance were investigated. S100A8/A9-deficient mice developed less ICTD than wild-type mice. Restoration of S100A8/A9 in knockout mice by injection of recombinant protein resulted in increased ICTD and fungal clearance comparable to wild-type levels. Treatment with paquinimod abolished ICTD and S100A9-deficient mice showed increased survival compared to wild-type littermates. The data indicates that S100A8/A9 controls ICTD levels and antimicrobial activity during IAC and that targeting of S100A8/A9 could serve as promising adjunct therapy against this challenging disease.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Micoses/etiologia , Micoses/metabolismo , Peritonite/etiologia , Peritonite/metabolismo , Animais , Biomarcadores , Contagem de Colônia Microbiana , Citocinas/metabolismo , Modelos Animais de Doenças , Resistência à Doença/genética , Resistência à Doença/imunologia , Suscetibilidade a Doenças , Imunomodulação , Mediadores da Inflamação , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Micoses/mortalidade , Micoses/patologia , Peritonite/mortalidade , Peritonite/patologia , Prognóstico
12.
Clin Lab ; 67(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33616330

RESUMO

BACKGROUND: The current study aims to evaluate the expression and clinical significance of myeloid-related protein (MRP) 8/14 in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: The levels of MRP8/14, TNF-α, and IL-1ß in the serum of the patients with AECOPD were determined using ELISA assay. The correlation between the expression of MRP8/14 and TNF-α, IL-1ß, forced expiratory volume in one second FEV1 % pred in AECOPD patients was analyzed using Pearson's correlation assay. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of serum MRP8/14 in AECOPD patients. RESULTS: The levels of MRP8/14, TNF-α, and IL-1ß in the serum of the patients with AECOPD were significantly higher than those in the control group. Furthermore, the expression of MRP8/14 was positively correlated with TNF-α, IL-1ß, and negatively correlated with FEV1 % pred. In addition, the level of serum MRP8/14 in GOLD 3-4 patients was higher than that in GOLD 1 - 2 patients. Meanwhile, the level of serum MRP8/14 in AECOPD patients with mMRC 3 - 4 was higher than that in patients with mMRC 0 - 2. ROC analysis showed that serum MRP8/14 could differentiate AECOPD patients from healthy controls. CONCLUSIONS: Altogether, elevated serum MRP8/14 level plays a key role in chronic airway inflammation and may be a useful marker in the diagnosis of AECOPD patients.


Assuntos
Calgranulina A/análise , Calgranulina A/metabolismo , Doença Pulmonar Obstrutiva Crônica , Biomarcadores , Estudos de Casos e Controles , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Testes de Função Respiratória , Fator de Necrose Tumoral alfa
13.
Biosci Biotechnol Biochem ; 85(5): 1215-1226, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33587104

RESUMO

We examined whether peripheral leukocytes of mice derived from in vitro αMEM-cultured embryos and exhibiting type 2 diabetes had higher expression of inflammatory-related genes associated with the development of atherosclerosis. Also, we examined the impact of a barley diet on inflammatory gene expression. Adult mice were produced by embryo transfer, after culturing two-cell embryos for 48 h in either α minimal essential media (α-MEM) or potassium simplex optimized medium control media. Mice were fed either a barley or rice diet for 10 weeks. Postprandial blood glucose and mRNA levels of several inflammatory genes, including Tnfa and Nox2, in blood leukocytes were significantly higher in MEM mice fed a rice diet compared with control mice. Barley intake reduced expression of S100a8 and Nox2. In summary, MEM mice exhibited postprandial hyperglycemia and peripheral leukocytes with higher expression of genes related to the development of atherosclerosis, and barley intake reduced some gene expression.


Assuntos
Aterosclerose/dietoterapia , Blastocisto/efeitos dos fármacos , Dieta/métodos , Hordeum/química , Hiperglicemia/dietoterapia , Efeitos Tardios da Exposição Pré-Natal/dietoterapia , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Blastocisto/metabolismo , Blastocisto/patologia , Glicemia/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Transferência Embrionária , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Camundongos , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , Compostos Orgânicos/efeitos adversos , Oryza/química , Período Pós-Prandial , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530496

RESUMO

S100 calcium-binding protein A8 (S100A8), a danger-associated molecular pattern, has emerged as an important mediator of the pro-inflammatory response. Some S100 proteins play a prominent role in neuroinflammatory disorders and increase the secretion of pro-inflammatory cytokines in microglial cells. The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action. In this study, we reported that the S100A8 protein expression was increased in mouse neuronal and microglial cells when exposed to hypoxia, and induced neuroinflammation and neuronal apoptosis. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia. Also, phosphorylation of ERK via the TLR4 receptor induced the priming of the NLRP3 inflammasome. The changes in Cyclooxygenase-2 (COX-2) expression, a well-known inflammatory activator, were regulated by the S100A8 expression in microglial cells. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia. These results suggested that S100A8 may be an important molecule for bidirectional microglia-neuron communication and a new therapeutic target for neurological disorders caused by microglial inflammation during hypoxia.


Assuntos
Apoptose/genética , Calgranulina A/genética , Regulação da Expressão Gênica , Hipóxia/genética , Hipóxia/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Animais , Biomarcadores , Calgranulina A/metabolismo , Linhagem Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Fosforilação
15.
Cancer Commun (Lond) ; 41(2): 154-170, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33389821

RESUMO

BACKGROUND: The transforming growth factor-ß (TGF-ß) pathway plays a pivotal role in inducing epithelial-mesenchymal transition (EMT), which is a key step in cancer invasion and metastasis. However, the regulatory mechanism of TGF-ß in inducing EMT in colorectal cancer (CRC) has not been fully elucidated. In previous studies, it was found that S100A8 may regulate EMT. This study aimed to clarify the role of S100A8 in TGF-ß-induced EMT and explore the underlying mechanism in CRC. METHODS: S100A8 and upstream transcription factor 2 (USF2) expression was detected by immunohistochemistry in 412 CRC tissues. Kaplan-Meier survival analysis was performed. In vitro, Western blot, and migration and invasion assays were performed to investigate the effects of S100A8 and USF2 on TGF-ß-induced EMT. Mouse metastasis models were used to determine in vivo metastasis ability. Luciferase reporter and chromatin immunoprecipitation assay were used to explore the role of USF2 on S100A8 transcription. RESULTS: During TGF-ß-induced EMT in CRC cells, S100A8 and the transcription factor USF2 were upregulated. S100A8 promoted cell migration and invasion and EMT. USF2 transcriptionally regulated S100A8 expression by directly binding to its promoter region. Furthermore, TGF-ß enhanced the USF2/S100A8 signaling axis of CRC cells whereas extracellular S100A8 inhibited the USF2/S100A8 axis of CRC cells. S100A8 expression in tumor cells was associated with poor overall survival in CRC. USF2 expression was positively related to S100A8 expression in tumor cells but negatively related to S100A8-positive stromal cells. CONCLUSIONS: TGF-ß was found to promote EMT and metastasis through the USF2/S100A8 axis in CRC while extracellular S100A8 suppressed the USF2/S100A8 axis. USF2 was identified as an important switch on the intracellular and extracellular S100A8 feedback loop.


Assuntos
Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Animais , Calgranulina A/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Fator de Crescimento Transformador beta/metabolismo , Fatores Estimuladores Upstream
16.
Sci Rep ; 11(1): 1337, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446797

RESUMO

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Direct co-culture showed most distinct phenotype changes in MCF10A cells followed by conditioned media treatment and indirect co-culture. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.


Assuntos
Neoplasias da Mama/metabolismo , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Comunicação Celular , Células Epiteliais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Epiteliais/patologia , Feminino , Humanos , Glândulas Mamárias Humanas/patologia , Camundongos , Camundongos Endogâmicos BALB C
18.
Molecules ; 26(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466593

RESUMO

S100 proteins are involved in the pathogenesis of sporadic colorectal carcinoma through different mechanisms. The aim of our study was to assess tissue mRNA encoding S100 proteins in patients with non-advanced and advanced colorectal adenoma. Mucosal biopsies were taken from the caecum, transverse colon and rectum during diagnostic and/or therapeutic colonoscopy. Another biopsy was obtained from adenomatous tissue in the advanced adenoma group. The tissue mRNA for each S100 protein (S100A4, S100A6, S100A8, S100A9, S100A11 and S100P) was investigated. Eighteen biopsies were obtained from the healthy mucosa in controls and the non-advanced adenoma group (six individuals in each group) and thirty biopsies in the advanced adenoma group (ten patients). Nine biopsies were obtained from advanced adenoma tissue (9/10 patients). Significant differences in mRNA investigated in the healthy mucosa were identified between (1) controls and the advanced adenoma group for S100A6 (p = 0.012), (2) controls and the non-advanced adenoma group for S100A8 (p = 0.033) and (3) controls and the advanced adenoma group for S100A11 (p = 0.005). In the advanced adenoma group, differences between the healthy mucosa and adenomatous tissue were found in S100A6 (p = 0.002), S100A8 (p = 0.002), S100A9 (p = 0.021) and S100A11 (p = 0.029). Abnormal mRNA expression for different S100 proteins was identified in the pathological adenomatous tissue as well as in the morphologically normal large intestinal mucosa.


Assuntos
Adenoma/patologia , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/patologia , RNA Mensageiro/metabolismo , Proteína A6 Ligante de Cálcio S100/metabolismo , Proteínas S100/metabolismo , Adenoma/genética , Adenoma/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Calgranulina A/genética , Calgranulina B/genética , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Projetos Piloto , Prognóstico , RNA Mensageiro/genética , Proteína A6 Ligante de Cálcio S100/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Proteínas S100/genética
19.
Cancer Immunol Immunother ; 70(5): 1365-1378, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33146829

RESUMO

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor progression through both immunologic and non-immunologic mechanisms. This study was conducted to evaluate the expression of S100A8, a well-known MDSC marker, and the significance of its expression in pre-invasive and invasive breast cancers. S100A8 expression in tumor cells (TCs) and immune cells (ICs) was assessed by immunohistochemistry, and its association with clinicopathologic features and infiltration of other IC subsets including CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocytes (TILs) and PD-L1+ ICs was evaluated. S100A8 expression in TCs and ICs showed a positive correlation in pre-invasive carcinoma and invasive carcinoma. S100A8+ ICs, but not S100A8+ TCs, were significantly higher in number in invasive carcinoma than in pre-invasive carcinoma. Infiltration of S100A8+ ICs was revealed as a poor prognostic indicator in pre-invasive and invasive carcinomas, especially in hormone receptor-positive subgroup. Infiltration of CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ ICs was significantly higher in S100A8+ IC (+) group than in S100A8+ IC (-) group. Combined analyses of IC subset infiltration revealed that infiltration of S100A8+ ICs was associated with poor clinical outcome in the PD-L1+ IC (-), CD8+ TIL-low, and FOXP3+ TIL-low subgroups. In conclusion, S100A8+ ICs seem to undergo a dynamic change during breast cancer progression in association with other IC subset infiltration. The prognostic impact of S100A8+ IC infiltration was greater in less immunogenic tumors.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Linfócitos T CD8-Positivos/imunologia , Calgranulina A/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Células Supressoras Mieloides/imunologia , Subpopulações de Linfócitos T/imunologia , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Carcinogênese , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Invasividade Neoplásica
20.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33215218

RESUMO

S100a8 serves an important role in cell differentiation and is abnormally expressed in common tumors, but there are few studies on the association between S100a8 and brain I/R injury. The present study aimed to investigate the role of S100a8 in oxygen­glucose deprivation and reoxygenation (OGD/R)­induced BV2 microglia cell injury, and to elucidate the potential underlying molecular mechanisms. BV2 cells were exposed to OGD/R to mimic ischemia/reperfusion (I/R) injury in vitro. S100a8 expression was detected via reverse transcription­quantitative PCR and western blot analyses. Following transfection with short hairpin RNAs targeting S100a8, the levels of inflammatory cytokines and oxidative stress­related factors were determined using commercial kits. Apoptosis was assessed using flow cytometric analysis and the expression levels of apoptosis­related proteins were determined using western blot analysis. Subsequently, the mRNA and protein levels of Grb2­associated binder 1 (GAB1) were assessed following S100a8 silencing. Immunoprecipitation (IP) was performed to verify the association between S100a8 and GAB1. The levels of inflammation, oxidative stress and apoptosis were assessed following GAB1 silencing, along with S100a8 silencing in BV2 cells subjected to OGD/R. The results indicated that exposure to OGD/R markedly upregulated S100a8 expression in BV2 cells. S100a8 silencing inhibited inflammation, oxidative stress and apoptosis, accompanied by changes in the expression of related proteins. The IP assay revealed a strong interaction between GAB1 and S100a8. In addition, GAB1 silencing reversed the inhibitory effects of S100a8 silencing on inflammation, oxidative stress and apoptosis in OGD/R­stimulated BV2 cells. Taken together, the results of the present study demonstrated that S100a8 silencing alleviated inflammation, oxidative stress and the apoptosis of BV2 cells induced by OGD/R, partly by upregulating the expression of GAB1. Thus, these findings may potentially provide a novel direction to develop therapeutic strategies for cerebral I/R injury.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Calgranulina A/metabolismo , Inflamação/metabolismo , Estresse Oxidativo , Traumatismo por Reperfusão/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/genética , Calgranulina A/genética , Linhagem Celular , Inativação Gênica , Glucose/metabolismo , Glutationa Peroxidase/metabolismo , Inflamação/genética , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Camundongos , Microglia/metabolismo , Estresse Oxidativo/genética , Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
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