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1.
Ann Otol Rhinol Laryngol ; 129(3): 245-255, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31646875

RESUMO

OBJECTIVES: Diesel exhaust particles (DEP)s are notorious ambient pollutants composed of a complex mixture of a carbon core and diverse chemical irritants. Several studies have demonstrated significant relationships between DEP exposure and serious nasal inflammatory response in vitro, but available information regarding underlying networks in terms of gene expression changes has not sufficiently explained potential mechanisms of DEP-induced nasal damage, especially in vivo. METHODS: In the present study, we identified DEP-induced gene expression profiles under short-term and long-term exposure, and identified signaling pathways based on microarray data for understanding effects of DEP exposure in the mouse nasal cavity. RESULTS: Alteration in gene expression due to DEP exposure provokes an imbalance of the immune system via dysregulated inflammatory markers, predicted to disrupt protective responses against harmful exogenous substances in the body. Several candidate markers were identified after validation using qRT-PCR, including S100A9, CAMP, IL20, and S100A8. CONCLUSIONS: Although further mechanistic studies are required for verifying the utility of the potential biomarkers suggested by the present study, our in vivo results may provide meaningful suggestions for understanding the complex cellular signaling pathways involved in DEP-induced nasal damages.


Assuntos
Expressão Gênica , Rinite/induzido quimicamente , Emissões de Veículos/toxicidade , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Biomarcadores/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Camundongos Endogâmicos BALB C , Modelos Animais , Testes de Provocação Nasal , Análise de Sequência com Séries de Oligonucleotídeos , RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Rinite/metabolismo , Transdução de Sinais , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 845-851, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694095

RESUMO

Objective: To explore the role of S100A8, the receptor for advanced glycation endproducts (RAGE) and Caveolin-1 in neutrophilic asthmatic rats, and to further study the intervention of roxithromycin and the possible mechanisms. Methods: Male Brown Norway rats were randomly assigned to a control group, an asthma group and a Roxithromycin group. The asthmatic rat model was established by intraperitoneal injection of ovalbumin (OVA) and Freund's complete adjuvant (FCA) mixture, and aerosol inhalation of OVA. Rats in the Roxithromycin group were given roxithromycin injection 30 mg/kg 30 minutes before each challenge. Rats in the control and the asthma groups were replaced with equal volumes of saline, respectively. Bronchoalveolar lavage fluid (BALF) neutrophil percentage (Neu%) and pathological changes of pulmonary tissue (hematoxylin-eosin, HE staining) were measured to confirm the establishment of asthmatic models. The concentration of inflammatory cytokines and S100A8 were quantified by enzyme-linked immunosorbent assay (ELISA), and the expression of Caveolin-1 and RAGE at protein levels were detected by immunohistochemistry and Western blot. Results: Neu% in BALF of the asthma group was significantly higher than those of the control group, and Neu% in the Roxithromycin group was lower than the asthma group (all P<0.01). Pulmonary histology revealed that there were a large number of inflammatory cells infiltrated in the bronchial and perivascular, pulmonary interstitial and alveolar spaces, and the bronchial wall and smooth muscles were thickened obviously in the asthma group. Rats in the Roxithromycin group showed milder inflammation and airway remodeling change than the asthma group. There was no obvious pathological damage in the control group. The concentration of IL-6 and IL-17 in BALF and serum of rats in the asthma group were significantly higher than those in the control group (P<0.01), and Roxithromycin inhibited the high expression of these cytokines (P<0.05). The expression of S100A8 and RAGE in the asthma group were significantly higher than those in the control group [(20.6±4.4) vs (7.1±2.0) ng/L; (885±118) vs (462±102) ng/L; (14.2±1.7) vs (7.6±1.8) ng/L; (774±166) vs (406±69) ng/L, all P<0.05], and Roxithromycin inhibited the high expression of these proteins [(14.3±3.7) vs (20.6±4.4) ng/L; (650±53) vs (885±118) ng/L; (10.4±1.2) vs (14.2±1.7) ng/L; (560±64) vs (728±72) ng/L] (all P<0.05). Meanwhile, the expression of Caveolin-1 in the asthma group was significantly lower than that in the control group (P<0.01), and Roxithromycin up-regulated its expression (P<0.01). Correlation analysis showed that there was a significantly positive correlation between the expression of S100A8 and RAGE (r=0.706, P<0.01), while there was a significantly negative correlation between the expression of S100A8 and Caveolin-1 (r=-0.775, P<0.01), and between the expression of Caveolin-1 and RAGE (r=-0.919, P<0.01). Conclusion: S100A8 and Caveolin-1 may play an important role in neutrophilic asthma via RAGE, and Roxithromycin may exerts anti-inflammatory effects and inhibition of airway remodeling partly through this signaling pathway.


Assuntos
Antibacterianos/farmacologia , Asma/tratamento farmacológico , Calgranulina A/efeitos dos fármacos , Caveolina 1/efeitos dos fármacos , Roxitromicina/farmacologia , Remodelação das Vias Aéreas , Animais , Antibacterianos/administração & dosagem , Western Blotting , Líquido da Lavagem Broncoalveolar , Calgranulina A/metabolismo , Caveolina 1/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Pulmão/fisiopatologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ovalbumina , Ratos , Receptor para Produtos Finais de Glicação Avançada , Roxitromicina/administração & dosagem
3.
Anticancer Res ; 39(9): 4681-4685, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519567

RESUMO

BACKGROUND/AIM: S100A8 is a chemoattractant known to be associated with metastatic niche formation. Herein, we evaluated the prognostic value of S100A8 in patients with clear cell renal cell carcinoma (CCRCC). MATERIALS AND METHODS: A total of 152 CCRCC patients who have undergone nephrectomy were enrolled. The expression of S100A8 was assessed immunohistochemically using tissue microarray (TMA) blocks of CCRCC. Using statistical analysis, the relationship between S100A8 expression and clinicopathological factors was evaluated. RESULTS: Among 152 TMA cores, 21 (6.9%) showed higher S100A8 expression. S100A8 expression was significantly increased in cores of patients with higher T stage (≥2, p<0.001) and higher Fuhrman nuclear grade (≥3, p<0.001). Multivariate analysis confirmed that high expression of S100A8 was significantly correlated to poor disease-free survival (hazard ratio, 2.601; 95% confidence interval (CI), 1.020-6.628; p-value=0.045). CONCLUSION: S100A8 expression may have a prognostic value in CCRCC reflecting TNM staging and Fuhrman nuclear grade.


Assuntos
Biomarcadores Tumorais , Calgranulina A/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Expressão Gênica , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Calgranulina A/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico
4.
BMC Cancer ; 19(1): 597, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208368

RESUMO

BACKGROUND: S100A8 and S100A9, two heterodimer-forming members of the S100 family, aberrantly express in a variety of cancer types. However, little is known about the mechanism that regulates S100A8/S100A9 co-expression in cancer cells. METHODS: The expression level of S100A8/S100A9 measured in three squamous cell carcinomas (SCC) cell lines and their corresponding xenografts, as well as in 257 SCC tissues. The correlation between S100A8/S100A9, Hippo pathway and F-actin cytoskeleton were evaluated using western blot, qPCR, ChIP and Immunofluorescence staining tests. IncuCyte ZOOM long time live cell image monitoring system, qPCR and Flow Cytometry measured the effects of S100A8/S100A9 and YAP on cell proliferation, cell differentiation and apoptosis. RESULTS: Here, we report that through activation of the Hippo pathway, suspension and dense culture significantly induce S100A8/S100A9 co-expression and co-localization in SCC cells. Furthermore, these expressional characteristics of S100A8/S100A9 also observed in the xenografts derived from the corresponding SCC cells. Importantly, Co-expression of S100A8/S100A9 detected in 257 SCC specimens derived from five types of SCC tissues. Activation of the Hippo pathway by overexpression of Lats1, knockdown of YAP, as well as disruption of F-actin indeed obviously results in S100A8/S100A9 co-expression in attached SCC cells. Conversely, inhibition of the Hippo pathway leads to S100A8/S100A9 co-expression in a manner opposite of cell suspension and dense. In addition, we found that TEAD1 is required for YAP-induced S100A8/S100A9-expressions. The functional studies provide evidence that knockdown of S100A8/S100A9 together significantly inhibit cell proliferation but promote squamous differentiation and apoptosis. CONCLUSIONS: Our findings demonstrate for the first time that the expression of S100A8/S100A9 is inducible by changes of cell shape and density through activation of the Hippo pathway in SCC cells. Induced S100A8/S100A9 promoted cell proliferation, inhibit cell differentiation and apoptosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Fatores de Transcrição/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Animais , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Serina-Treonina Quinases/metabolismo
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(4): 359-364, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31014429

RESUMO

OBJECTIVE: To study the association between S100A8 expression and prognosis in children with acute lymphoblastic leukemia (ALL). METHODS: The clinical data of 377 children with ALL who were treated with the CCLG-2008-ALL regimen were retrospectively reviewed. ELISA and PCR were used to measure serum protein levels and mRNA expression of S100A8. The Kaplan-Meier method was used for survival analysis and a Cox regression analysis was also performed. RESULTS: The children were followed up for 56 months, and the overall survival rate of the 377 children was 89.1%. The prednisone good response group had significantly lower S100A8 protein and mRNA levels than the prednisone poor response group (P<0.01). In the children with standard or median risk, both S100A8 protein and mRNA levels were associated with event-free survival rate (P<0.05). There were significant differences in S100A8 protein and mRNA levels between the children with different risk stratifications (P<0.01). The children who experienced events had significantly higher S100A8 protein and mRNA levels than those who did not (P<0.01). The Kaplan-Meier survival analysis and the Cox regression model suggested that S100A8 overexpression was an independent risk factor for the prognosis of children with ALL. CONCLUSIONS: High S100A8 expression may be associated with the poor prognosis of children with ALL and is promising as a new marker for individualized precise treatment of children with ALL.


Assuntos
Calgranulina A/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Intervalo Livre de Doença , Humanos , Prognóstico , Estudos Retrospectivos
6.
Nat Commun ; 10(1): 1685, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30976008

RESUMO

Neonatal sepsis is characterized by hyperinflammation causing enhanced morbidity and mortality compared to adults. This suggests differences in the response towards invading threats. Here we investigate activated cord blood macrophages (CBMΦ) in comparison to adult macrophages (PBMΦ), indicating incomplete interferon gamma (IFN-γ) and interleukin 10 (IL-10)-induced activation of CBMΦ. CBMΦ show reduced expression of phagocytosis receptors and cytokine expression in addition to altered energy metabolism. In particular, IFN-γ as well as IL-10-activated CBMΦ completely fail to increase glycolysis and furthermore show reduced activation of the mTOR pathway, which is important for survival in sepsis. MTOR inhibition by rapamycin equalizes cytokine production in CBMΦ and PBMΦ. Finally, incubation of PBMΦ with cord blood serum or S100A8/A9, which is highly expressed in neonates, suppresses mTOR activation, prevents glycolysis and the expression of an PBMΦ phenotype. Thus, a metabolic alteration is apparent in CBMΦ, which might be dependent on S100A8/A9 expression.


Assuntos
Citotoxicidade Imunológica , Metabolismo Energético/imunologia , Macrófagos/metabolismo , Adulto , Fatores Etários , Calgranulina A/imunologia , Calgranulina A/metabolismo , Calgranulina B/imunologia , Calgranulina B/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Sangue Fetal/citologia , Glicólise/imunologia , Voluntários Saudáveis , Humanos , Recém-Nascido , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Macrófagos/imunologia , Cultura Primária de Células , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/imunologia , Serina-Treonina Quinases TOR/metabolismo
7.
PLoS One ; 14(3): e0213344, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30865695

RESUMO

S100A8 and S100A9 proteins are highly upregulated in patients with psoriasis and have been proposed as potential biomarkers for psoriasis. The present study was designed to analyze the effect of narrowband ultraviolet B therapy on these proteins. S100A8, S100A9 gene expression and S100A8/A9 heterocomplex protein levels were analyzed in lesional and non-lesional skin before and after narrowband-UVB treatment in patients with chronic plaque type psoriasis. In addition, disease severity was measured by psoriasis area and severity index (PASI) and serum protein levels of S100A8/A9 were repeatedly analyzed. Narrowband-UVB treatment significantly reduced S100A8, S100A9 gene expression and S100A8/A9 protein levels in lesional skin while serum levels showed no significant change. No correlation between PASI and serum S100A8/A9 protein levels was found. These results implicate a role of S100A8/A9 in the anti-inflammatory effect of narrowband-UVB. Serum S100A8/A9 levels do not respond to treatment suggesting that serum S100A8/A9 does not originate from psoriasis skin keratinocytes. Serum S100A8/A9 levels do not correlate with PASI questioning serum S100A8/A9 as a biomarker for psoriasis skin activity. Trial Registration: DRKS 00014817.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Psoríase/metabolismo , Psoríase/radioterapia , Terapia Ultravioleta , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Calgranulina A/sangue , Calgranulina A/genética , Calgranulina B/sangue , Calgranulina B/genética , Regulação para Baixo/efeitos da radiação , Feminino , Expressão Gênica/efeitos da radiação , Humanos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Pele/metabolismo , Pele/efeitos da radiação , Suécia
8.
Cancer Lett ; 452: 178-190, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-30904617

RESUMO

Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Melanoma Experimental/patologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Animais , Antígeno CD146/metabolismo , Calgranulina A/genética , Calgranulina B/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas Ligadas por GPI/metabolismo , Células HEK293 , Humanos , Queratinócitos/patologia , Neoplasias Pulmonares/secundário , MAP Quinase Quinase Quinases/metabolismo , Metaloproteinases da Matriz Associadas à Membrana/metabolismo , Melanoma/terapia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Pele/patologia , Neoplasias Cutâneas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Dairy Sci ; 102(5): 4674-4681, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852007

RESUMO

This study aimed to determine the production site of antimicrobial peptide S100A8 in the goat mammary gland and changes in its concentration in milk after lipopolysaccharide (LPS) challenge. Sixteen Tokara goats were used in this study for mammary gland tissue, blood leukocyte, and milk somatic cell collection and LPS challenge. The mRNA expression and protein localization of S100A8 in the mammary gland parenchyma and teat, blood leukocytes, and milk somatic cells were examined by reverse-transcription PCR and immunohistochemistry. The S100A8 concentration in milk was measured at 0 to 144 h after intramammary challenge of LPS by enzyme immunoassay. The mRNA of S100A8 was expressed in the parenchyma and teat, leukocytes isolated from blood, and milk somatic cells. Antimicrobial peptide S100A8 was immunolocalized in the outermost layer of the teat skin of udders with and without LPS infusion, whereas in the mammary gland it was immunolocalized only in the leukocytes infiltrated in the alveoli after LPS infusion. Antimicrobial peptide S100A8 was also immunolocalized in the blood and milk leukocytes. The number of S100A8-positive cells in milk was higher than that in blood. The concentration of S100A8 in milk increased significantly at 72 h after intramammary infusion of LPS. These results suggest that S100A8 is produced in the leukocytes and that its secretion into milk is affected by LPS stimulation.


Assuntos
Anti-Infecciosos/metabolismo , Calgranulina A/metabolismo , Cabras/fisiologia , Mastite/veterinária , Leite/química , Peptídeos/metabolismo , Animais , Calgranulina A/genética , Feminino , Cabras/genética , Infusões Parenterais/veterinária , Lipopolissacarídeos/administração & dosagem , Glândulas Mamárias Animais/metabolismo , Mastite/induzido quimicamente , Mastite/tratamento farmacológico , Mastite/microbiologia , Peptídeos/genética , Peptídeos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866458

RESUMO

H. pylori is classified as a group I carcinogen by WHO because of its involvement in gastric cancer development. Several reports have suggested anti-bacterial effects of menadione, although the effect of menadione on major virulence factors of H. pylori and H. pylori-induced inflammation is yet to be elucidated. In this study, therefore, we demonstrated that menadione has anti-H. pylori and anti-inflammatory effects. Menadione inhibited growth of H. pylori reference strains and clinical isolates. Menadione reduced expression of vacA in H. pylori, and translocation of VacA protein into AGS (gastric adenocarcinoma cell) was also decreased by menadione treatment. This result was concordant with decreased apoptosis in AGS cells infected with H. pylori. Moreover, cytotoxin-associated protein A (CagA) translocation into H. pylori-infected AGS cells was also decreased by menadione. Menadione inhibited expression of several type IV secretion system (T4SS) components, including virB2, virB7, virB8, and virB10, that are responsible for translocation of CagA into host cells. In particular, menadione inhibited nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation and thereby reduced expression of the proinflammatory cytokines such as IL-1ß, IL-6, IL-8, and TNF-α in AGS as well as in THP-1 (monocytic leukemia cell) cell lines. Collectively, these results suggest the anti-bacterial and anti-inflammatory effects of menadione against H. pylori.


Assuntos
Infecções por Helicobacter/imunologia , Helicobacter pylori/efeitos dos fármacos , NF-kappa B/metabolismo , Vitamina K 3/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Transporte Proteico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
11.
Mol Carcinog ; 58(6): 980-995, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30720226

RESUMO

Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-ß (NPTNß), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNß showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNß as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNß has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNß mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNß axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/metabolismo , Regulação para Cima , Células A549 , Animais , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Fatores de Transcrição NFI/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Transdução de Sinais
12.
Methods Mol Biol ; 1929: 739-754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30710308

RESUMO

S100A8/A9 represents a novel biomarker and therapeutic target in sterile inflammatory diseases. Among the various S100 proteins, S100A8 and S100A9 have been shown to be the most important of all the damage-associated molecular pattern (DAMP) proteins in sterile inflammatory conditions such as diabetes, cardiovascular disease, autoimmune disorders, etc. We present here methods to quantify S100A8/A9 expression in various tissues in mouse models of myocardial infarction (MI) using flow cytometry (FC), immunofluorescence, quantitative real-time polymerase chain reaction (q-RT-PCR), and enzyme-linked immunosorbent assays (ELISA).


Assuntos
Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Infarto do Miocárdio/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Sangue/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Humanos , Camundongos , Monócitos/metabolismo , Infarto do Miocárdio/genética , Miocárdio/metabolismo , Neutrófilos/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
13.
Methods Mol Biol ; 1929: 763-771, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30710310

RESUMO

Oncologic relevant members of S100 proteins are described as promising biomarkers in molecular pathology for risk estimation in oral neoplasia exhibiting different stages of malignancy: gingiva as healthy tissue, irritation fibroma as benign, leukoplakia as precancerous, and oral squamous cell carcinoma as malignant entity. Gene expression levels of S100A4 (metastasin), S100A7 (psoriasin), S100A8 (calgranulin A), and S100A9 (calgranulin B) were analyzed using quantitative RT-PCR. In addition, immunohistochemistry-based microscopy was used to examine cellular localization and distribution of these biomarkers in tissue sections. The results indicate that S100 proteins represent promising biomarkers for early-stage diagnosis in oral lesions. The inclusion of expression profiles and ratios for each entity even improves their diagnostic validity.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Bucais/diagnóstico , Proteínas S100/genética , Proteínas S100/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Transformação Celular Neoplásica/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína A7 Ligante de Cálcio S100/genética , Proteína A7 Ligante de Cálcio S100/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/genética , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Distribuição Tecidual
14.
Cancer ; 125(10): 1717-1725, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30633331

RESUMO

BACKGROUND: Women with breast cancer (BCa) experience heightened distress, which is related to greater inflammation and poorer outcomes. The s100 protein family facilitates the inflammatory response by regulating myeloid cell function through the binding of Toll-like receptor 4 and the receptor for advanced glycation end products (RAGE). The heterodimer s100A8/A9 RAGE ligand is associated with hastened tumor development and metastasis. Previously, a 10-week stress-management intervention using cognitive behavioral therapy (CBT) and relaxation training (RT) was associated with less leukocyte inflammatory gene expression in patients with BCa; however, its impact on s100A8/A9 was not examined. Because a 10-week intervention may be impractical during primary treatment for BCa, the authors developed briefer forms of CBT and RT and demonstrated their efficacy in reducing distress over 12 months of primary treatment. Here, the effects of these briefer interventions were tested effects on s100A8/A9 levels over the initial 12 months of BCa treatment. METHODS: Postsurgical patients with BCa (stage 0-IIIB) were randomized to a 5-week, group-based condition: CBT, RT, or health education control (HE). At baseline and at 12 months, women provided sera from which s100A8/A9 levels were determined using any enzyme-linked immunosorbent assay. RESULTS: Participants (mean age ± standard deviation, 54.81 ± 9.63 years) who were assigned to either CBT (n = 41) or RT (n = 38) had significant s100A8/A9 decreases over 12 months compared with those who were assigned to HE (n = 44; F[1,114]  = 4.500; P = .036) controlling for age, stage, time since surgery, and receipt of chemotherapy or radiation. Greater increases in stress-management skills from preintervention to postintervention predicted greater reductions in s100A8/A9 levels over 12 months (ß = -0.379; t[101]  = -4.056; P < .001). CONCLUSIONS: Brief, postsurgical, group-based stress management reduces RAGE-associated s100A8/A9 ligand levels during primary treatment for BCa.


Assuntos
Neoplasias da Mama/genética , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Terapia Cognitivo-Comportamental/métodos , Terapia de Relaxamento/métodos , Estresse Psicológico/terapia , Idoso , Análise de Variância , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/psicologia , Neoplasias da Mama/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Mediadores da Inflamação/metabolismo , Pessoa de Meia-Idade , Valores de Referência , Estresse Psicológico/diagnóstico , Resultado do Tratamento
15.
Leukemia ; 33(7): 1759-1772, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30651631

RESUMO

RPS14, CSNK1A1, and miR-145 are universally co-deleted in the 5q- syndrome, but mouse models of each gene deficiency recapitulate only a subset of the composite clinical features. We analyzed the combinatorial effect of haploinsufficiency for Rps14, Csnk1a1, and miRNA-145, using mice with genetically engineered, conditional heterozygous inactivation of Rps14 and Csnk1a1 and stable knockdown of miR-145/miR-146a. Combined Rps14/Csnk1a1/miR-145/146a deficiency recapitulated the cardinal features of the 5q- syndrome, including (1) more severe anemia with faster kinetics than Rps14 haploinsufficiency alone and (2) pathognomonic megakaryocyte morphology. Macrophages, regulatory cells of erythropoiesis and the innate immune response, were significantly increased in Rps14/Csnk1a1/miR-145/146a deficient mice as well as in 5q- syndrome patient bone marrows and showed activation of the innate immune response, reflected by increased expression of S100A8, and decreased phagocytic function. We demonstrate that Rps14/Csnk1a1/miR-145 and miR-146a deficient macrophages alter the microenvironment and induce S100A8 expression in the mesenchymal stem cell niche. The increased S100A8 expression in the mesenchymal niche was confirmed in 5q- syndrome patients. These data indicate that intrinsic defects of the 5q- syndrome hematopoietic stem cell directly alter the surrounding microenvironment, which in turn affects hematopoiesis as an extrinsic mechanism.


Assuntos
Anemia Macrocítica/imunologia , Anemia/imunologia , Caseína Quinase Ialfa/fisiologia , Haploinsuficiência , MicroRNAs/fisiologia , Proteínas Ribossômicas/fisiologia , Microambiente Tumoral/imunologia , Anemia/metabolismo , Anemia/patologia , Anemia Macrocítica/metabolismo , Anemia Macrocítica/patologia , Animais , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Calgranulina A/genética , Calgranulina A/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 5/imunologia , Cromossomos Humanos Par 5/metabolismo , Eritropoese , Feminino , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Megacariócitos/imunologia , Megacariócitos/metabolismo , Megacariócitos/patologia , Camundongos , Camundongos Knockout , Fenótipo , Células Tumorais Cultivadas
16.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 56-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343141

RESUMO

Translocator protein (TSPO) is a high-affinity cholesterol- and drug-binding mitochondrial protein. Nuclear receptor subfamily 5 group A member 1 or steroidogenic factor 1 (Nr5a1)-Cre mice were previously used to generate steroidogenic cell-specific Tspo gene conditional knockout (cKO) mice. TSPO-depleted homozygotes showed no response to adrenocorticotropic hormone (ACTH) in stimulating adrenal cortex corticosterone production but showed increased epinephrine synthesis in the medulla. No other phenotype was observed under normal growth conditions. During these studies, we noted that pairing two cKO mice resulted in the generation of small pups. These pups showed low growth rate at weaning, which has been linked to the development of type 2 diabetes (T2D) in adulthood. Experimental verification of T2D symptoms via blood testing of the adult mice, including glycated hemoglobin and insulin C-peptide measurements, showed that these Tspo cKO mice exhibited sustained hyperglycemia, a sign of prediabetes, likely due to the augmentation of hepatic glucose production mediated by the increased epinephrine. We also observed increased expression of the S100a8 gene, which is upregulated after chronic glucose stimulation. Taken together, the observed prediabetes phenotype and lack of response to ACTH indicate that Tspo cKO mice (Nr5a1-Cre+/-, Tspofl/fl) could provide a useful model to study the link between diabetes and stress.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Integrases/metabolismo , Estado Pré-Diabético/metabolismo , Receptores de GABA/metabolismo , Fator Esteroidogênico 1/metabolismo , Estresse Fisiológico , Animais , Glicemia , Calgranulina A/genética , Calgranulina A/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Hiperglicemia , Fígado/metabolismo , Masculino , Camundongos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais , Receptores de GABA/genética
17.
Int J Cancer ; 144(12): 3138-3145, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30365872

RESUMO

Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNß, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Melanoma Experimental/prevenção & controle , Melanoma Experimental/secundário , Proteínas Recombinantes de Fusão/farmacologia , Animais , Basigina/química , Basigina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/farmacologia , Humanos , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/farmacologia , Imunoglobulina G/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Domínios Proteicos , Receptor para Produtos Finais de Glicação Avançada/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo
18.
Am J Respir Cell Mol Biol ; 60(3): 299-307, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30277795

RESUMO

Pulmonary emphysema is characterized by alveolar wall destruction, and cigarette smoking is the main risk factor in this disease development. S100A8 is a member of the S100 protein family, with an oxidative stress-related and antiinflammatory role. The mechanisms of human alveolar type II (ATII) cell injury contributing to emphysema pathophysiology are not completely understood. We wanted to determine whether S100A8 can protect ATII cells against injury induced by cigarette smoke and this disease development. We used freshly isolated ATII cells from nonsmoking and smoking organ donors, as well as patients with emphysema to determine S100A8 function. S100A8 protein and mRNA levels were low in individuals with this disease and correlated with its severity as determined by using lung tissue from areas with mild and severe emphysema obtained from the same patient. Its expression negatively correlated with high oxidative stress as observed by 4-hydroxynonenal levels. We also detected decreased serine phosphorylation within S100A8 by PKAα in this disease. This correlated with increased S100A8 ubiquitination by SYVN1. Moreover, we cultured ATII cells isolated from nonsmokers followed by treatment with cigarette smoke extract. We found that this exposure upregulated S100A8 expression. We also confirmed the cytoprotective role of S100A8 against cell injury using gain- and loss-of-function approaches in vitro. S100A8 knockdown sensitized cells to apoptosis induced by cigarette smoke. In contrast, S100A8 overexpression rescued cell injury. Our results suggest that S100A8 protects ATII cells against injury and cigarette smoke-induced emphysema. Targeting S100A8 may provide a potential therapeutic strategy for this disease.


Assuntos
Células Epiteliais Alveolares/metabolismo , Calgranulina A/metabolismo , Alvéolos Pulmonares/metabolismo , Enfisema Pulmonar/metabolismo , Células A549 , Idoso , Aldeídos/farmacologia , Células Epiteliais Alveolares/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Fumar Cigarros/efeitos adversos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , RNA Mensageiro/metabolismo , Tabaco/efeitos adversos , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
19.
Br J Neurosurg ; 33(3): 258-260, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28494622

RESUMO

We demonstrate the presence of S100A8 and S100A9 proteins in the wall and thrombosed lumen of an enlarged intracranial aneurysm after flow diverter treatment. These proteins have shown to play an important role in vascular inflammation and may serve as a biomarker and potential therapeutic target for intracranial aneurysms.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Aneurisma Intracraniano/metabolismo , Aneurisma Intracraniano/cirurgia , Angiografia Digital , Prótese Vascular , Implante de Prótese Vascular , Calgranulina A/análise , Calgranulina B/análise , Embolização Terapêutica , Procedimentos Endovasculares , Feminino , Humanos , Imuno-Histoquímica , Aneurisma Intracraniano/diagnóstico por imagem , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Resultado do Tratamento , Transtornos da Visão/etiologia
20.
Circulation ; 139(2): 226-242, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30586702

RESUMO

BACKGROUND: Atherosclerotic occlusions decrease blood flow to the lower limbs, causing ischemia and tissue loss in patients with peripheral artery disease (PAD). No effective medical therapies are currently available to induce angiogenesis and promote perfusion recovery in patients with severe PAD. Clinical trials aimed at inducing vascular endothelial growth factor (VEGF)-A levels, a potent proangiogenic growth factor to induce angiogenesis, and perfusion recovery were not successful. Alternate splicing in the exon-8 of VEGF-A results in the formation of VEGFxxxa (VEGF165a) and VEGFxxxb (VEGF165b) isoforms with existing literature focusing on VEGF165b's role in inhibiting vascular endothelial growth factor receptor 2-dependent angiogenesis. However, we have recently shown that VEGF165b blocks VEGF-A-induced endothelial vascular endothelial growth factor receptor 1 (VEGFR1) activation in ischemic muscle to impair perfusion recovery. Because macrophage-secreted VEGF165b has been shown to decrease angiogenesis in peripheral artery disease, and macrophages were well known to play important roles in regulating ischemic muscle vascular remodeling, we examined the role of VEGF165b in regulating macrophage function in PAD. METHODS: Femoral artery ligation and resection were used as an in vivo preclinical PAD model, and hypoxia serum starvation was used as an in vitro model for PAD. Experiments including laser-Doppler perfusion imaging, adoptive cell transfer to ischemic muscle, immunoblot analysis, ELISAs, immunostainings, flow cytometry, quantitative polymerase chain reaction analysis, and RNA sequencing were performed to determine a role of VEGF165b in regulating macrophage phenotype and function in PAD. RESULTS: First, we found increased VEGF165b expression with increased M1-like macrophages in PAD versus non-PAD (controls) muscle biopsies. Next, using in vitro hypoxia serum starvation, in vivo pre clinical PAD models, and adoptive transfer of VEGF165b-expressing bone marrow-derived macrophages or VEGFR1+/- bone marrow-derived macrophages (M1-like phenotype), we demonstrate that VEGF165b inhibits VEGFR1 activation to induce an M1-like phenotype that impairs ischemic muscle neovascularization. Subsequently, we found S100A8/S100A9 as VEGFR1 downstream regulators of macrophage polarization by RNA-Seq analysis of hypoxia serum starvation-VEGFR1+/+ versus hypoxia serum starvation-VEGFR1+/- bone marrow-derived macrophages. CONCLUSIONS: In our current study, we demonstrate that increased VEGF165b expression in macrophages induces an antiangiogenic M1-like phenotype that directly impairs angiogenesis. VEGFR1 inhibition by VEGF165b results in S100A8/S100A9-mediated calcium influx to induce an M1-like phenotype that impairs ischemic muscle revascularization and perfusion recovery.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Células Endoteliais/metabolismo , Isquemia/metabolismo , Macrófagos/metabolismo , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Doença Arterial Periférica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Sinalização do Cálcio , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Humanos , Isquemia/patologia , Isquemia/fisiopatologia , Macrófagos/patologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Comunicação Parácrina , Doença Arterial Periférica/patologia , Doença Arterial Periférica/fisiopatologia , Fenótipo , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
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