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1.
Anticancer Res ; 39(12): 6645-6652, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810929

RESUMO

BACKGROUND/AIM: We have previously reported that chemokine (C-X-C motif) receptor 2 (CXCR2) signaling was associated with the malignant progression of gastric cancer (GC). We thus examined the clinicopathological significance of CXCR2 ligands, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8, in GC. PATIENTS AND METHODS: The expression of CXCR2 ligands in 590 GC cases was investigated by immunohistochemistry. RESULTS: The expression was as follows: CXCL1, 46.2% (257/557); CXCL2, 20.7% (122/590); CXCL3, 17.1% (101/589); CXCL5/CXCL6, 2.9% (17/589); CXCL7, 36.4% (215/590); and CXCL8 1.7% (10/585) of the cases. High invasion depth was correlated with CXCL1 expression. Lymph node metastasis and peritoneal cytology positivity were correlated with high expression of CXCL1 and CXCL7. The prognoses of the CXCL1-positive patients were significantly poorer than those of the CXCL1-negative patients (p<0.001). CONCLUSION: Among the CXCR2 ligands, CXCL7 and especially CXCL1, might play an important role in the malignant progression of GC via CXCR2 signaling.


Assuntos
Proteínas de Neoplasias/metabolismo , Receptores de Interleucina-8B/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Análise de Variância , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocina CXCL5/metabolismo , Quimiocina CXCL6/metabolismo , Quimiocinas CXC/metabolismo , Progressão da Doença , Feminino , Humanos , Interleucina-8/metabolismo , Ligantes , Metástase Linfática , Masculino , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , beta-Tromboglobulina/metabolismo
2.
Am J Physiol Gastrointest Liver Physiol ; 317(6): G773-G783, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31604030

RESUMO

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2-/- mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2-/- mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2-/- mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver-/Myeloid- mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid- and CXCR2Liver-/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid- and CXCR2Liver-/Myeloid-) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.


Assuntos
Movimento Celular/efeitos dos fármacos , Fígado , Neutrófilos/fisiologia , Compostos de Fenilureia/farmacologia , Receptores de Interleucina-8B , Animais , Inibição de Migração Celular , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Colestase/complicações , Modelos Animais de Doenças , Infarto Hepático/tratamento farmacológico , Infarto Hepático/etiologia , Infarto Hepático/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Necrose , Substâncias Protetoras/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo
3.
Integr Cancer Ther ; 18: 1534735419876341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31517546

RESUMO

Background: Inflammatory response and inflammation-induced vascular hyper-permeability were established leading to the abnormalities of the pulmonary microenvironment in pre-metastasis stage of breast cancer. Ruyiping is a commonly used compound drug for clinical treatment of breast cancer metastasis, and Platycodon grandiflorum is mainly used to treat pulmonary inflammatory diseases. Therefore, this study used ruyiping combined with Platycodon grandiflorum (abbreviated as RP) to investigate their inhibitory effect on pre-metastatic microenvironment of lung in 4T1 tumor-bearing mice. Study Design and Methods: The permeability of lung tissue was detected by Evans blue method. The localization of S100A8/A9 in lung tissue was obtained by double-labeling immunofluorescence staining. The level of fibrinogen in pre-metastatic microenvironment of lung as well as the levels of pro-inflammatory factors (interleukin [IL]-1ß and IL-6) and chemokines (CXCL2 and CXCL5) in bronchoalveolar lavage fluid was detected by ELISA (enzyme-linked immunosorbent assay). Results: From the experimental results, RP could protect the integrity of microvascular, inhibit the release of S100A8/A9, reduce the extravasation of fibrinogen, and decrease the expressions of IL-1ß, IL-6, CXCL2, and CXCL5. Conclusions: RP could inhibit the extravasation of fibrinogen by protecting pulmonary vascular integrity and then interrupted its interaction with carcinoma in situ, thereby inhibiting the formation of inflammatory pre-metastatic microenvironment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Substâncias Protetoras/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Quimiocina CXCL2/metabolismo , Quimiocina CXCL5/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos BALB C , Platycodon/química
4.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434191

RESUMO

Offspring of preeclampsia patients have an increased risk of developing neurological deficits and cognitive impairment. While low placental perfusion, common in preeclampsia and growth restriction, has been linked to neurological deficits, a causative link is not fully established. The goal of this study was to test the hypothesis that placental ischemia induces neuroinflammation and micro-hemorrhages in utero. Timed-pregnant Sprague Dawley rats were weight-matched for sham surgery (abdominal incision only) or induced placental ischemia (surgical reduction of utero-placental perfusion (RUPP)); n = 5/group on gestational day 14. Fetal brains (n = 1-2/dam/endpoint) were collected at embryonic day (E19). Placental ischemia resulted in fewer live fetuses, increased fetal demise, increased hematocrit, and no difference in brain water content in exposed fetuses. Additionally, increased cerebral micro-bleeds (identified with H&E staining), pro-inflammatory cytokines: IL-1ß, IL-6, and IL-18, eotaxin (CCL11), LIX (CXCL5), and MIP-2 (CXCL2) were observed in RUPP-exposed fetuses. Microglial density in the sub-ventricular zone decreased in RUPP-exposed fetuses, with no change in cortical thickness. Our findings support the hypothesis that exposure to placental ischemia contributes to microvascular dysfunction (increased micro-bleeds), fetal brain inflammation, and reduced microglial density in proliferative brain areas. Future studies will determine whether in utero abnormalities contribute to long-term behavioral deficits in preeclampsia offspring through impaired neurogenesis regulation.


Assuntos
Feto/metabolismo , Isquemia/metabolismo , Placenta/metabolismo , Animais , Pressão Sanguínea/fisiologia , Quimiocina CCL11/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocina CXCL5/metabolismo , Feminino , Inflamação/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Microglia/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
5.
Physiol Res ; 68(5): 739-745, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31424256

RESUMO

In order to reduce tissue damage caused by ischemia-reperfusion injury, this study aims to investigate the protective effect and mechanism of ?-lipoic acid on hepatic ischemia-reperfusion injury in rats. The bloodstream of rats was blocked in the left middle and left lateral liver lobes of the liver. Forty rats were randomly divided into two groups: treatment group and injury group. Rats were injected with either 25 mg/1 ml of alpha-lipoic acid (treatment group) or 1 ml of saline (injury group) into the caudal vein 15 min before hepatic ischemia-reperfusion. Rat serum alanine aminotransferase (GPT), glutathione (GSH) and superoxide dismutase (SOD) levels were examined at various time points (1, 3, 6 and 12 h) in both groups. Changes in nuclear factor kappa B P65 (NF-kappaB P65) expression in ischemia-reperfusion liver at various time points after reperfusion (1, 3, 6 and 12 h) were evaluated through immunohistochemistry assay. Changes in macrophage inflammatory protein-2 (MIP-2) mRNA and inducible nitric oxide synthase (iNOS) mRNA expression in ischemic reperfused rat livers were detected by RT-PCR. Serum GPT level was significantly higher in the injury group than in the treatment group (P<0.01). NF-kappaB P65, MIP-2 mRNA and iNOS mRNA expression in ischemic reperfused rat livers were significantly higher in the injury group than in the treatment group (P<0.01). Serum GSH and SOD levels were higher in the treatment group than in the injury group (P<0.01). Alpha-lipoic acid significantly reduced ischemia-reperfusion injury in rat livers. This may be associated to the direct scavenging of oxygen-free radicals, increased GSH production, and the activation of downstream media due to decreased NF-kappaB and GSH consumption.


Assuntos
Depuradores de Radicais Livres/farmacologia , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Ácido Tióctico/farmacologia , Animais , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Citoproteção , Modelos Animais de Doenças , Glutationa/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Superóxido Dismutase/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
6.
Sheng Li Xue Bao ; 71(4): 575-580, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440754

RESUMO

The aim of the present study was to investigate the effect of salidroside (Sal) on inflammatory activation induced by lipopolysaccharide (LPS) in the co-culture of rat alveolar macrophages (AM) NR 8383 and type II alveolar epithelial cells (AEC II) RLE-6TN. CCK-8 colorimetric method was used to detect cell proliferation percentage. The enzyme-linked immunosorbent assay (ELISA) was used to determine the content of tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein-2 (MIP-2) and interleukin-10 (IL-10) in the supernatant. Western blot was used to examine the expression levels of phosphorylated AKT (p-AKT) and total AKT protein. The results showed that pretreatment of RLE-6TN cells or co-culture of RLE-6TN and NR 8383 cells with 32 and 128 µg/mL Sal for 1 h, followed by continuous culture for 24 h, significantly increased the cell proliferation (P < 0.05). Compared with control group, 32 and 128 µg/mL Sal pretreatment significantly increased the ratio of p-AKT/AKT in RLE-6TN cells (P < 0.05). Pretreatment of 32 µg/mL Sal not only inhibited the secretion of TNF-α and MIP-2 by NR 8383 cells induced by LPS (P < 0.05), but also enhanced the inhibitory effect of RLE-6TN and NR 8383 cells co-culture on the secretion of TNF-α and MIP-2 by NR 8383 cells induced by LPS (P < 0.05). In addition, 32 µg/mL Sal pretreatment promoted LPS-induced IL-10 secretion by NR 8383 cells (P < 0.05), and enhanced the promoting effect of co-culture of RLE-6TN and NR 8383 cells on the IL-10 secretion by LPS-induced NR 8383 cells (P < 0.05). In conclusion, Sal may directly inhibit LPS-induced inflammatory activation of AM (NR 8383), promote the proliferation of AEC II (RLE-6TN) through PI3K/AKT signaling pathway, and enhance the regulatory effect of AEC II on LPS-induced inflammatory activation of AM.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Glucosídeos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Fenóis/farmacologia , Transdução de Sinais , Células Epiteliais Alveolares/metabolismo , Animais , Linhagem Celular , Quimiocina CXCL2/metabolismo , Técnicas de Cocultura , Interleucina-10/metabolismo , Lipopolissacarídeos , Macrófagos Alveolares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
7.
Mol Immunol ; 114: 362-368, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31450181

RESUMO

Madi-Ryuk (MDR) is a traditional Korean medicine and it has been widely used in Korea to treat arthritis and we previously reported the anti-allergic inflammatory effect of MDR in vitro model. However, therapeutic evidence of MDR on in vivo model of allergic inflammatory reaction has not yet been demonstrated. The research purpose was to investigate the efficacy of MDR and its active ingredient tannic acid (TA) in ovalbumin (OVA)-induced AR mice model. OVA-challenged AR mice orally medicated MDR or its active ingredient TA daily for ten days. In mice having a AR, MDR and TA prominently diminished number of rubs and levels of histamine, IgE, thymic stromal lymphopoietin, interleukin (IL)-1ß, IL-4, IL-5, IL-13, IL-33, and tumor necrosis factor-α. In addition, protein expression levels and activities of caspase-1 were declined by oral medication of MDR and TA. Decline in levels of macrophage inflammatory protein-2 and intercellular adhesion molecules-1 and reduction in penetrations of inflammatory cells into inflamed tissue were also noted in MDR and TA groups. Taken together, identification of MDR effect in preclinical models suggests that MDR may be a therapeutic drug for the treatment and prevention of AR.


Assuntos
Anti-Inflamatórios/farmacologia , Rinite Alérgica/tratamento farmacológico , Taninos/farmacologia , Animais , Caspase 1/metabolismo , Quimiocina CXCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Histamina/metabolismo , Imunoglobulina E/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Medicina Tradicional Coreana/métodos , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Ovalbumina/farmacologia , Rinite Alérgica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Shanghai Kou Qiang Yi Xue ; 28(2): 128-132, 2019.
Artigo em Chinês | MEDLINE | ID: mdl-31384895

RESUMO

PURPOSE: To investigate the effect of lipopolysaccharides(LPS) extracted from Porphyromonas endodontalis(P.e) on the expression of macrophage inflammatory protein-2 (MIP-2) mRNA and protein levels in MC3T3-E1 cells and the influence of resveratrol on the expression of MIP-2 protein in P.e-LPS induced cells. METHODS: MC3T3-E1 cells were treated with different concentrations of P.e-LPS(0-50 mg/L) and 20 mg/L P.e-LPS for different time (0-48 h). The expression of MIP-2 mRNA and protein was detected by real-time RT-PCR and enzyme linked immunosorbent assay (ELISA). MC3T3-E1 cells were pretreated with resveratrol for 1 h in the presence of 20 mg/L P.e-LPS for 24 h,which was detected by ELISA. Statistical analysis was performed using one-way ANOVA and Dunnett t test with SPSS 13.0 software package. RESULTS: Treatment of MC3T3-El cells with different concentrations of P.e-LPS(0-50 mg/L) caused a significantly increase in MIP-2 mRNA and protein expression in dose-dependent manners.The expression of MIP-2 protein increased from (41.86±2.49) ng/L to (3126.74±158.30) ng/L, and the difference was significant(P<0.05). In the observation time (0-48 h), the impact of 20 mg/L P.e-LPS on induction of MIP-2 in MC3T3-El cells exhibited a time-dependent manner. At 48 h, the maximal induction of MIP-2 protein expression was (2102.55±123.27) ng/L(P<0.01). Incubation of cells with 10 µmol/L resveratrol for 1h significantly decreased the expression of MIP-2 protein from (1805.33±67.54) ng/L to(813.82±47.21) ng/L, and the difference was significant(P<0.05). CONCLUSIONS: The results suggest that P.e-LPS may mediate MIP-2 expression in MC3T3-E1 cells, and resveratrol has a significant inhibitory effect on this process.


Assuntos
Quimiocina CXCL2 , Lipopolissacarídeos , Osteoblastos , Resveratrol , Animais , Quimiocina CXCL2/efeitos dos fármacos , Quimiocina CXCL2/metabolismo , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Porphyromonas endodontalis , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Resveratrol/farmacologia
9.
Future Microbiol ; 14: 705-716, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31161794

RESUMO

Aim: Aspergillus fumigatus is one of the most common opportunistic fungi that can cause invasive infection. To profile the kinetic variation of immune cells and cytokines after exposure to A. fumigatus thoroughly, we established a pulmonary A. fumigatus infection model in temporarily immunosuppressed mice. Materials & methods: Systematic and kinetic studies of different immune cells and cytokines were performed. Results: We observed that the granulocytes and macrophages recruited to the site of infection played an important role in the infectious phase. There was a significant increase in the cytokines IFN-γ, IL-6, TNF-α as well as the chemokines CXCL1, MIP-1α, MIP-2 and CCL5 after infection. IL-10 was found to participate in balancing the anti-inflammatory response in the recovery phases. The immune response mediated by T cells was mainly presented by the Th1-type on day 7 after exposure with a high proportion of IFN-γ+ CD4+ T cells and CD4+CD44highCD62Llow effector T cells. Conclusion: These kinetic parameters of the immune response might provide diagnostic clues for A. fumigatus infection.


Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/patogenicidade , Quimiocinas/metabolismo , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Animais , Linfócitos T CD4-Positivos , Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocinas/sangue , Citocinas/sangue , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Cinética , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/microbiologia , Linfonodos/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Linfócitos T/imunologia , Células Th1/imunologia , Fator de Necrose Tumoral alfa/metabolismo
10.
Int J Biol Sci ; 15(5): 1020-1029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182922

RESUMO

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.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/patologia , Animais , Linhagem Celular Tumoral , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Feminino , Imunofluorescência , Humanos , Immunoblotting , Imuno-Histoquímica , Interleucina-8/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína Sequestossoma-1/metabolismo
11.
Microb Pathog ; 134: 103563, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175974

RESUMO

Tuberculosis (TB) is one of the most prevalent pulmonary diseases caused by Mycobacterium tuberculosis (Mtb). MiRNAs (miRNAs) participate in TB progression by modulating the host-pathogen interaction. Bioinformatics advancements provide basis for exploring novel immunoregulatory miRNAs and their performance as diagnostic biomarkers. Gene and miRNA expression datasets, GSE29190 and GSE54992, were downloaded from Gene Expression Omnibus (GEO) database. Based on fold changes and statistical significance, a total of 7463 differentially expressed mRNAs (DE-mRNAs) and 38 differentially expressed miRNAs (DE-miRNAs) were screened. Function annotation and protein-protein interaction (PPI) network were constructed to reveal underlying mechanisms of TB pathogenesis. Functional annotation identified the MAPK signalling pathway and leukocyte migration as the top enriched processes. The PPI and MGIP networks indicated that chemokine ligands like CXCL1/CXCL2 and receptors, like CCR7 were important down-regulated genes, implying that a protective mechanism against overdue inflammation induced cell death. MiRNA-gene-immune processes (MGIP) network enriched 7 deregulated miRNAs, and their expression was further examined with quantitative real-time PCR (qRT-PCR), in PBMC samples of 20 active TB patients and 20 healthy donors. The diagnostic performance was evaluated with ROC curves. MiR-892b; miR-199b-5p and miR-582-5p were significantly deregulated in TB patients, compared with healthy participants. The best overall performance was from miR-892b, with an area under curve (AUC) of 0.77, 55% sensitivity and 90% specificity. AUC of miR-199b-5p and miR-582-5p were 0.71 and 0.70, respectively. MiR-892b, miR-199b-5p and miR-582-5p could be considered promising novel diagnostic biomarkers for active tuberculosis.


Assuntos
Biomarcadores/sangue , Biologia Computacional/métodos , Fatores Imunológicos , MicroRNAs/imunologia , Tuberculose/diagnóstico , Tuberculose/imunologia , Morte Celular , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , China , Regulação para Baixo , Expressão Gênica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos Mononucleares/microbiologia , MicroRNAs/genética , Mycobacterium tuberculosis/genética , Receptores CCR7/metabolismo , Sensibilidade e Especificidade
12.
BMC Med Genomics ; 12(Suppl 2): 38, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871526

RESUMO

BACKGROUND: Anlotinib has been demonstrated its anti-tumor efficacy on non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, anlotinib resistance occurs during its administration, and the underlying mechanism is still unclear. METHODS: Anlotinib resistant lung cancer cell line NCI-H1975 was established in vitro. Toxicologic effects undergoing anlotinib stress were observed upon NCI-H1975 cells and anlotinib resistant NCI-H1975 cells, respectively. Transcriptome profiling was performed to screen anlotinib resistance-associated genes between NCI-H1975 cells and anlotinib resistant NCI-H1975 cells. Functional assays were performed to examine the correlations between CXCL2 gene expression and anlotinib resistance. RESULTS: We found anlotinib inhibits cell proliferation and cell viability in NCI-1975 cells, whereas it attenuates these activities in anlotinib resistant NCI-H1975 cells. Transcriptome profiling analysis identified 769 anlotinib-responsive genes enriched in the biological processes of microtubule-based process, cytoskeleton organization, and wound healing. Furthermore, we found 127 genes are associated with anlotinib resistance. In particular, we demonstrated that CXCL2 contributes to anlotinib resistance in NCI-H1975 cells. CONCLUSIONS: This study suggested that CXCL2 is involved in anlotinib resistance in NCI-H1975 cells and provided an insight for understanding the resistant mechanism of anlotinib.


Assuntos
Quimiocina CXCL2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL2/metabolismo , Quimiocina CXCL2/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Indóis/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Quinolinas/farmacologia
13.
Neurosci Lett ; 703: 132-138, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30904573

RESUMO

Many trigeminal neuropathic pain patients suffer severe chronic pain. The neuropathic pain might be related with cross-excitation of the neighboring neurons and satellite glial cells (SGCs) in the sensory ganglia and increasing the pain signals from the peripheral tissue to the central nervous system. We induced trigeminal neuropathic pain by infraorbital nerve constriction injury (IONC) in Sprague-Dawley rats. We tested cytokine (CXCL2 and IL-10) levels in trigeminal ganglia (TGs) after trigeminal neuropathic pain induction, and the effect of direct injection of the anti-CXCL2 and recombinant IL-10 into TG. We found that IONC induced pain behavior. Additionally, IONC induced satellite glial cell activation in TG and cytokine levels of TGs were changed after IONC. CXCL2 levels increased on day 1 of neuropathic pain induction and decreased gradually, with IL-10 levels showing the opposite trend. Recombinant IL-10 or anti-CXCL2 injection into TG decreased pain behavior. Our results show that IL-10 or anti-CXCL2 are therapy options for neuropathic pain.


Assuntos
Quimiocina CXCL2/metabolismo , Interleucina-10/metabolismo , Neuralgia/metabolismo , Gânglio Trigeminal/metabolismo , Animais , Anticorpos/farmacologia , Quimiocina CXCL2/imunologia , Constrição Patológica , Interleucina-10/farmacologia , Masculino , Neuralgia/fisiopatologia , Medição da Dor , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia
14.
Neurol Res ; 41(5): 399-412, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30707086

RESUMO

OBJECTIVE: Ischaemic brain lesions and brain abscesses are frequent in both human and animal cases of septic embolic stroke. However, existing models of brain infection do not reflect central aspects of septic embolic stroke. Our aim was to compare septic and non-septic embolic stroke in order to identify gene expressions, inflammatory mediators and brain damage in a rat model. METHODS: We created precisely located focal brain infarcts in a rat model of Staphylococcus aureus infected embolic stroke. To cause septic embolic stroke we used a fibrin-rich embolus with bacteria, while every rat in the control group received a non-infected embolus. 64 rats were randomized to receive sham-surgery, sterile embolic stroke or septic embolic stroke. All groups were compared for brain pathology, mortality, gene expressions and inflammatory mediators using histology and reverse transcription quantitative real-time PCR. RESULTS: Although infarct volumes did not differ, septic embolic stroke caused higher mortality than sterile embolic stroke (p=  0.002). Brain abscesses were observed only in the septic group. Approximately 400-500 fold increases were observed for Orm1 and Cxcl2 respectively (1.00E-08 < p < 1.92E-07) in the septic group compared to the sterile group, and these were the most dramatically regulated genes in septic embolic stroke compared to sterile embolic stroke. CONCLUSIONS: Septic embolic stroke caused brain abscesses, increased mortality and upregulated Orm1 and Cxcl2 gene expressions compared to non-infected embolic stroke. The dramatic Orm1 increase observed in the septic group is unprecedented and suggests a significant biological role of Orm1 during septic neuroinflammation.


Assuntos
Quimiocina CXCL2/metabolismo , Embolia Intracraniana/metabolismo , Orosomucoide/metabolismo , Sepse/metabolismo , Infecções Estafilocócicas/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Abscesso Encefálico/metabolismo , Abscesso Encefálico/patologia , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/patologia , Embolia Intracraniana/patologia , Masculino , Distribuição Aleatória , Ratos Sprague-Dawley , Sepse/patologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus , Acidente Vascular Cerebral/patologia , Regulação para Cima
15.
Immunity ; 50(2): 390-402.e10, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709741

RESUMO

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.


Assuntos
Vasos Sanguíneos/imunologia , Ritmo Circadiano/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Animais , Vasos Sanguíneos/metabolismo , Candida albicans/imunologia , Candida albicans/fisiologia , Células Cultivadas , Senescência Celular/imunologia , Quimiocina CXCL2/imunologia , Quimiocina CXCL2/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Receptores CXCR4/imunologia , Receptores CXCR4/metabolismo , Fatores de Tempo
16.
Blood ; 133(12): 1335-1345, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30723078

RESUMO

Neutrophil migration to the site of bacterial infection is a critical step in host defense. Exclusively produced in the bone marrow, neutrophil release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx during bacterial infections, its role in regulating neutrophil recruitment, granulopoiesis, and neutrophil mobilization in response to lung infection-induced sepsis is unclear. Here, we used a murine model of intrapulmonary Streptococcus pneumoniae infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx to control bacterial growth in the lungs, as well as bacterial dissemination, resulting in improved host survival. This was shown in Cxcl1 -/- mice, which exhibited defective amplification of early neutrophil precursors in granulocytic compartments, and CD62L- and CD49d-dependent neutrophil release from the marrow. Administration of recombinant CXCL2 and CXCL5 after infection rescues the impairments in neutrophil-dependent host defense in Cxcl1 -/- mice. Taken together, these findings identify CXCL1 as a central player in host defense, granulopoiesis, and mobilization of neutrophils during Gram-positive bacterial pneumonia-induced sepsis.


Assuntos
Quimiocina CXCL1/fisiologia , Homeostase , Pulmão/imunologia , Infiltração de Neutrófilos/imunologia , Infecções Pneumocócicas/complicações , Pneumonia Bacteriana/complicações , Sepse/imunologia , Animais , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Feminino , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/patologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Sepse/metabolismo , Sepse/microbiologia , Sorogrupo , Streptococcus pneumoniae/fisiologia
17.
Int Immunopharmacol ; 69: 225-234, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30738992

RESUMO

Heme oxygenase-1 (HO-1) has an anti-inflammatory action in acute pancreatitis (AP). However, its mechanism of action and natural compounds/drugs to induce HO-1 in pancreas are not well understood. In this study, we investigated the regulatory mechanisms of HO-1 during AP using desoxo-narchinol-A (DN), the natural compound inducing HO-1 in the pancreas. Female C57/BL6 Mice were intraperitoneally injected with supramaximal concentrations of cerulein (50 µg/kg) hourly for 6 h to induce AP. DMSO or DN was administered intraperitoneally, then mice were sacrificed 6 h after the final cerulein injection. Administration of DN increased pancreatic HO-1 expression through activation of activating protein-1, mediated by mitogen-activated protein kinases. Furthermore, DN treatment reduced the pancreatic weight-to-body weight ratio as well as production of digestive enzymes and pro-inflammatory cytokines. Inhibition of HO-1 by tin protoporphyrin IX abolished the protective effects of DN on pancreatic damage. Additionally, DN treatment inhibited neutrophil infiltration into the pancreas via regulation of chemokine (C-X-C motif) ligand 2 (CXCL2) by HO-1. Our results suggest that DN is an effective inducer of HO-1 in the pancreas, and that HO-1 regulates neutrophil infiltration in AP via CXCL2 inhibition.


Assuntos
Quimiocina CXCL2/metabolismo , Heme Oxigenase-1/metabolismo , Neutrófilos/fisiologia , Pâncreas/metabolismo , Pancreatite/metabolismo , Doença Aguda , Amilases/sangue , Animais , Ceruletídeo/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Naftóis/metabolismo , Infiltração de Neutrófilos , Pâncreas/patologia , Pancreatite/patologia
18.
Mucosal Immunol ; 12(2): 545-554, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30617300

RESUMO

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.


Assuntos
Envelhecimento/fisiologia , Células Epiteliais/fisiologia , Influenza Humana/imunologia , Pulmão/patologia , Neutrófilos/imunologia , Animais , Contagem de Células , Senescência Celular , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiotaxia , Células Epiteliais/virologia , Humanos , Influenza Humana/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Mortalidade , Neutrófilos/virologia , Análise de Sobrevida
19.
Am J Physiol Renal Physiol ; 316(4): F617-F623, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30648906

RESUMO

The open probability of calcium-activated voltage-gated potassium channel (BK channel) on bladder umbrella urothelial cells is increased by lipopolysaccharide (LPS). It is hypothesized that this channel's activity is important in the urothelial innate immune response during urinary tract infection (UTI). We performed in vivo studies using female C57BL/6 mice whose bladders were inoculated with LPS (150 µl of 1 mg/ml) or uropathogenic Escherichia coli (UPEC, UTI89), without and with intravesical BK inhibitor iberiotoxin (IBTX, 1 µM). Inflammatory biomarkers (chemokines and cytokines) were measured in urine specimens collected 2 h after inoculation using a 32-multiplex ELISA. Of these 32 biomarkers, 19 and 15 were significantly elevated 2 h after LPS and UPEC exposure, respectively. IBTX significantly abrogated the elevations of 15 out of 19 biomarkers after LPS inoculation and 12 out of 15 biomarkers after UPEC inoculation. In a separate experiment, qPCR for IL-6, interferon-γ-induced protein 10 (CXCL10), and macrophage inflammatory protein 2 (CXCL2) in urothelium paralleled the changes measured in urine of these same biomarkers, supporting that urinary changes in biomarker levels reflected urothelial expression changes. These in vivo data demonstrated that BK channel activity is crucial in the urothelial host innate immune response, as measured by changes in urinary biomarkers, in UTI pathogenesis.


Assuntos
Imunidade Inata , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Bexiga Urinária/metabolismo , Infecções Urinárias/imunologia , Infecções Urinárias/metabolismo , Urotélio/metabolismo , Animais , Quimiocina CXCL10/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Infecções por Escherichia coli/imunologia , Feminino , Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia
20.
J Transl Med ; 17(1): 22, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635008

RESUMO

BACKGROUND: Vascular shear stress promotes endothelial cell sprouting in vitro. The impact of hemodynamic forces on microRNA (miRNA) and gene expression within growing vascular networks in vivo, however, remain poorly investigated. Arteriovenous (AV) shunts are an established model for induction of neoangiogenesis in vivo and can serve as a tool for analysis of hemodynamic effects on miRNA and gene expression profiles over time. METHODS: AV shunts were microsurgically created in rats and explanted on postoperative days 5, 10 and 15. Neoangiogenesis was confirmed by histologic analysis and micro-computed tomography. MiRNA and gene expression profiles were determined in tissue specimens from AV shunts by microarray analysis and quantitative real-time polymerase chain reaction and compared with sham-operated veins by bioinformatics analysis. Changes in protein expression within AV shunt endothelial cells were determined by immunohistochemistry. RESULTS: Samples from AV shunts exhibited a strong overexpression of proangiogenic cytokines, oxygenation-associated genes (HIF1A, HMOX1), and angiopoetic growth factors. Significant inverse correlations of the expressions of miR-223-3p, miR-130b-3p, miR-19b-3p, miR-449a-5p, and miR-511-3p which were up-regulated in AV shunts, and miR-27b-3p, miR-10b-5p, let-7b-5p, and let-7c-5p, which were down-regulated in AV shunts, with their predicted interacting targets C-X-C chemokine receptor 2 (CXCR2), interleukin-1 alpha (IL1A), ephrin receptor kinase 2 (EPHA2), synaptojanin-2 binding protein (SYNJ2BP), forkhead box C1 (FOXC1) were present. CXCL2 and IL1A overexpression in AV shunt endothelium was confirmed at the protein level by immunohistochemistry. CONCLUSIONS: Our data indicate that flow-stimulated angiogenesis is determined by an upregulation of cytokines, oxygenation associated genes and miRNA-dependent regulation of FOXC1, EPHA2 and SYNJ2BP.


Assuntos
Hemorreologia/genética , MicroRNAs/metabolismo , Neovascularização Fisiológica/genética , Transdução de Sinais/genética , Remodelação Vascular/genética , Animais , Derivação Arteriovenosa Cirúrgica , Quimiocina CXCL2/metabolismo , Feminino , Regulação da Expressão Gênica , Interleucina-1/metabolismo , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Microtomografia por Raio-X
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