RESUMO
Acute lung injury (ALI) is a clinical syndrome characterized by a diffuse lung inflammation that commonly evolves into acute respiratory distress syndrome and respiratory failure. The lung microbiota is involved in the pathogenesis of ALI. Corisin, a proapoptotic peptide derived from the lung microbiota, plays a role in ALI and acute exacerbation of pulmonary fibrosis. Preventive therapeutic intervention with a monoclonal anticorisin antibody inhibits ALI in mice. However, whether inhibition of corisin with the antibody ameliorates established ALI is unknown. Here, the therapeutic effectiveness of the anticorisin antibody in already established ALI in mice was assessed. Lipopolysaccharide was used to induce ALI in mice. After causing ALI, the mice were treated with a neutralizing anticorisin antibody. Mice treated with the antibody showed significant improvement in lung radiological and histopathologic findings, decreased lung infiltration of inflammatory cells, reduced markers of lung tissue damage, and inflammatory cytokines in bronchoalveolar lavage fluid compared with untreated mice. In addition, the mice treated with anticorisin antibody showed significantly increased expression of antiapoptotic proteins with decreased caspase-3 activation in the lungs compared with control mice treated with an irrelevant antibody. In conclusion, these observations suggest that the inhibition of corisin is a novel and promising approach for treating established ALI.
Assuntos
Lesão Pulmonar Aguda , Pneumonia , Camundongos , Animais , Pulmão/patologia , Lesão Pulmonar Aguda/patologia , Líquido da Lavagem Broncoalveolar , Pneumonia/metabolismo , Peptídeos/farmacologia , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BLRESUMO
Tissue fibrosis is characterized by the excessive accumulation of extracellular matrix in various organs, including the lungs, liver, skin, kidneys, pancreas, and heart, ultimately leading to organ failure [...].
Assuntos
Matriz Extracelular , Fígado , Humanos , Morte Celular , Coração , FibroseRESUMO
Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.
Assuntos
Proteínas do Citoesqueleto , Doxorrubicina , Camundongos Knockout , Podócitos , Animais , Humanos , Masculino , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose , Proteínas do Citoesqueleto/metabolismo , Proteínas do Citoesqueleto/genética , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/genética , Síndrome Nefrótica/patologia , Podócitos/metabolismo , Podócitos/patologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the development of pulmonary fibrosis. Lung fibrosis was induced by bleomycin in wild-type mice and transgenic mice overexpressing human matrix metalloproteinase-2. Mice expressing human matrix metalloproteinase-2 showed significantly decreased infiltration of inflammatory cells and inflammatory and fibrotic cytokines in the lungs compared to wild-type mice after induction of lung injury and fibrosis with bleomycin. The computed tomography score, Ashcroft score of fibrosis, and lung collagen deposition were significantly reduced in human matrix metalloproteinase transgenic mice compared to wild-type mice. The expression of anti-apoptotic genes was significantly increased, while caspase-3 activity was significantly reduced in the lungs of matrix metalloproteinase-2 transgenic mice compared to wild-type mice. Active matrix metalloproteinase-2 significantly decreased bleomycin-induced apoptosis in alveolar epithelial cells. Matrix metalloproteinase-2 appears to protect against pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells.
Assuntos
Fibrose Pulmonar Idiopática , Metaloproteinase 2 da Matriz , Camundongos , Humanos , Animais , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Pulmão/patologia , Fibrose Pulmonar Idiopática/metabolismo , Bleomicina/efeitos adversos , Camundongos Transgênicos , Fibrose , Camundongos Endogâmicos C57BLRESUMO
The terminal stage of many chronic inflammatory diseases is organ fibrosis [...].
Assuntos
Neoplasias , Progressão da Doença , Fibrose , Humanos , Cirrose HepáticaRESUMO
Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorß1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorß1 is associated with insulin resistance and the rapid progression of transforming growth factorß1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorß1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorß1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorß1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorß1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Resistência à Insulina , Humanos , Camundongos , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/tratamento farmacológico , Fibrose , Rim/metabolismo , Camundongos Transgênicos , Glucose/metabolismo , Diabetes Mellitus/patologiaRESUMO
Two compounds 1 and 2 were isolated from the culture broth of Lepista luscina. This is the first time that compound 1 was isolated from a natural source. The structure of compound 1 was identified via 1D and 2D NMR and HRESIMS data. Compounds 1 and 2 along with 8-nitrotryptanthrin (4) were evaluated for their biological activities using the A549 lung cancer cell line. As a result, 1 and 2 inhibited the expression of Axl and immune checkpoint molecules. In addition, compounds 1, 2 and 4 were tested for HIF inhibitory activity. Compound 2 demonstrated statistically significant HIF inhibitory effects on NIH3T3 cells and 1 and 2 against ARPE19 cells.
Assuntos
Proteínas de Checkpoint Imunológico , Neoplasias Pulmonares , Animais , Camundongos , Humanos , Células NIH 3T3 , Neoplasias Pulmonares/metabolismo , Células A549 , Subunidade alfa do Fator 1 Induzível por Hipóxia , Linhagem Celular TumoralRESUMO
Chk1 (encoded by CHEK1 in mammals) is an evolutionarily conserved protein kinase that transduces checkpoint signals from ATR to Cdc25A during the DNA damage response (DDR). In mammals, Chk1 also controls cellular proliferation even in the absence of exogenous DNA damage. However, little is known about how Chk1 regulates unperturbed cell cycle progression, and how this effect under physiological conditions differs from its regulatory role in DDR. Here, we have established near-diploid HCT116 cell lines containing endogenous Chk1 protein tagged with a minimum auxin-inducible degron (mAID) through CRISPR/Cas9-based gene editing. Establishment of these cells enabled us to induce specific and rapid depletion of the endogenous Chk1 protein, which resulted in aberrant accumulation of DNA damage factors that induced cell cycle arrest at S or G2 phase. Cdc25A was stabilized upon Chk1 depletion before the accumulation of DNA damage factors. Simultaneous depletion of Chk1 and Cdc25A partially suppressed the defects caused by Chk1 single depletion. These results indicate that, similar to its function in DDR, Chk1 controls normal cell cycle progression mainly by inducing Cdc25A degradation.
Assuntos
Quinase 1 do Ponto de Checagem/metabolismo , Dano ao DNA , Pontos de Checagem da Fase G2 do Ciclo Celular , Proteólise , Pontos de Checagem da Fase S do Ciclo Celular , Fosfatases cdc25/metabolismo , Sistemas CRISPR-Cas , Quinase 1 do Ponto de Checagem/genética , Edição de Genes , Células HCT116 , Humanos , Fosfatases cdc25/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Activation of the blood coagulation system is a common observation in inflammatory diseases. The role of coagulation in COPD is underexplored. METHODS: The study included 413 COPD patients and 49 controls from the 3-year Bergen COPD Cohort Study (BCCS). One hundred and forty-eight COPD patients were also examined during AECOPD. The plasma markers of coagulation activation, TAT complex, APC-PCI complex and D-dimer, were measured at baseline and during exacerbations by enzyme immunoassays. Differences in levels of the markers between stable COPD patients and controls, and between stable COPD and AECOPD were examined. The associations between coagulation markers and later AECOPD and mortality were examined by negative binomial and Cox regression analyses. RESULTS: TAT was significantly lower in stable COPD (1.03 ng/mL (0.76-1.44)) than in controls (1.28 (1.04-1.49), P = 0.002). During AECOPD, all markers were higher than in the stable state: TAT 2.56 versus 1.43 ng/mL, APC-PCI 489.3 versus 416.4 ng/mL and D-dimer 763.5 versus 479.7 ng/mL (P < 0.001 for all). Higher D-dimer in stable COPD predicted a higher mortality (HR: 1.60 (1.24-2.05), P < 0.001). Higher TAT was associated with both an increased risk of later exacerbations, with a yearly incidence rate ratio of 1.19 (1.04-1.37), and a faster time to the first exacerbation (HR: 1.25 (1.10-1.42), P = 0.001, all after adjustment). CONCLUSION: Activation of the coagulation system is increased during COPD exacerbations. Coagulation markers are potential predictors of later COPD exacerbations and mortality.
Assuntos
Intervenção Coronária Percutânea , Doença Pulmonar Obstrutiva Crônica , Coagulação Sanguínea , Estudos de Coortes , Progressão da Doença , HumanosRESUMO
Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-ß1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-ß1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-ß1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.
Assuntos
Insuficiência Renal Crônica , Fator de Crescimento Transformador beta1 , Fibrose , Proteínas de Ligação ao GTP , Humanos , Rim/patologia , Proteínas Proto-Oncogênicas c-akt , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Trombomodulina/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Bronchial asthma is a chronic disease characterized by inflammation, obstruction, and hyperresponsiveness of the airways. There is currently no curative therapy for asthma. Type 2 helper T cell response plays a critical role in the pathogenesis of the disease. Protein S is a glycoprotein endowed with anticoagulant, anti-inflammatory, and anti-apoptotic properties. Whether protein S can suppress bronchial asthma and be useful for its therapy is unknown. METHODS: To address this question here we compared the development of allergen-associated bronchial asthma between wild type and protein S-overexpressing transgenic mice. Mice were sensitized and challenged with ovalbumin. We also evaluated the circulating levels of total and active protein S in patients with bronchial asthma and healthy controls. RESULTS: The circulating level of total protein S and of its active form was significantly decreased in patients with bronchial asthma compared to controls. Allergic protein S transgenic mice showed a significant reduction of airway hyperresponsiveness, lung tissue inflammatory cell infiltration, lung levels of Th2 cytokines and IgE compared to their wild-type counterparts. Administration of exogenous human protein S also decreased airway hyperresponsiveness and Th2-mediated lung inflammation in allergic wild-type mice compared with their untreated mouse counterparts. Human protein S significantly shifted the Th1/Th2 balance to Th1 and promoted the secretion of Th1 cytokines (IL-12, tumor necrosis factor-α) from dendritic cells. CONCLUSIONS: These observations suggest the strong protective activity of protein S against the development of allergic bronchial asthma implicating its potential usefulness for the disease treatment.
Assuntos
Asma , Hiper-Reatividade Brônquica , Animais , Asma/prevenção & controle , Citocinas , Modelos Animais de Doenças , Humanos , Imunoglobulina E , Pulmão , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Proteína S , Células Th2RESUMO
A novel compound, (R)-4-ethoxy-2-hydroxy-4-oxobutanoic acid (1), and six known compounds (2-7) were isolated from the fruiting bodies of the wild edible mushroom Leucopaxillus giganteus. The planar structure of 1 was determined by the interpretation of spectroscopic data analysis. The absolute configuration of 1 was determined by comparing specific rotation of the synthetic compounds. In the plant regulatory assay, the isolated compounds (1-7) and the chemically prepared compounds (8-10) were evaluated their biological activity against the lettuce (Lactuca sativa) growth. Compounds 1 and 3-10 showed the significant regulatory activity of lettuce growth. 1 showed the strongest inhibition activity among the all the compounds tested. In the lung cancer assay, all the compounds were assessed the mRNA expression of Axl and immune checkpoints (PD-L1, PD-L2) in the human A549 alveolar epithelial cell line by RT-PCR. Compounds 1-10 showed significant inhibition activity against Axl and/or immune checkpoint.
Assuntos
Adenocarcinoma Bronquioloalveolar/metabolismo , Agaricales/química , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Células A549 , Adenocarcinoma Bronquioloalveolar/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carpóforos/química , Humanos , Lactuca/efeitos dos fármacos , Lactuca/crescimento & desenvolvimento , Neoplasias Pulmonares/patologia , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tirosina Quinase AxlRESUMO
Protein S is a vitamin K-dependent glycoprotein produced mainly in the liver with anticoagulant, anti-inflammatory, immune-modulatory, and antiapoptotic properties. Protein S exacerbates acute liver injury by prolonging the survival of liver immune cells. However, the effect of protein S on chronic liver injury and fibrosis is unknown. Here, we investigated whether human protein S can affect chronic liver injury and fibrosis. Liver injury/fibrosis was induced by carbon tetrachloride injection in mice overexpressing human protein S and in wild-type mice. Human protein S transgenic mice receiving carbon tetrachloride showed significantly higher circulating levels of liver transaminases, increased liver expression of inflammatory cytokines, significantly more extended liver fibrosis, and areas with DNA breakage after chronic injury compared with wild-type mice. Wild-type mice infused with exogenous human protein S exhibited exacerbated liver injury and increased number of hepatic stellate cells compared with untreated mice. Human protein S inhibited apoptosis and increased Akt pathway activation in hepatic stellate cells. The antiapoptotic activity of protein S may play a role in chronic liver injury and subsequent liver fibrosis.
Assuntos
Doença Hepática Terminal/metabolismo , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Proteína S/metabolismo , Animais , Apoptose/fisiologia , Tetracloreto de Carbono , Doença Hepática Terminal/induzido quimicamente , Doença Hepática Terminal/patologia , Fibrose/metabolismo , Fibrose/patologia , Células Estreladas do Fígado/patologia , Fígado/patologia , Camundongos , Camundongos Transgênicos , Proteína S/genética , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: The diagnostic yield of peripheral pulmonary lesions has significantly increased with the use of radial endobronchial ultrasound with guide sheath within the lesion. Here, we retrospectively evaluated factors leading to misdiagnosis of pulmonary malignant tumors using endobronchial ultrasound with the guide sheath within the lesion. METHODS: We assessed the final histopathological diagnosis of biopsy samples taken from 130 patients with lung malignant tumors that underwent endobronchial ultrasound with guide sheath within the lesion. RESULTS: Among 130 patients, 8 (6%) showed no definite malignant findings in biopsy samples but the presence of malignant cells (primary lung cancer 7, diffuse large B cell lymphoma 1) was subsequently confirmed by histopathological study of specimens taken by computed tomography-guided needle biopsy or surgery. Of the eight cases with diagnostic failure, the size of the biopsy sample was insufficient in five due to technical difficulties during the diagnostic procedure, and the diagnosis of malignant tumor was difficult in five cases because of extensive scarring tissue or central necrosis. CONCLUSIONS: The results of this study showed that technical difficulties and/or pathological heterogeneity of the tumor might lead to failure to diagnose lung malignant tumor in cases using endobronchial ultrasound with guide sheath within the lesion.
Assuntos
Broncoscopia/métodos , Endossonografia/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Diagnóstico Ausente , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncoscopia/normas , Endossonografia/normas , Feminino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ultrassonografia de Intervenção/normasAssuntos
Epoprostenol , Hipertensão Arterial Pulmonar , Humanos , Epoprostenol/uso terapêutico , Epoprostenol/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Linfócitos T Reguladores , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Resultado do TratamentoRESUMO
Fibrosis is the end-stage of chronic inflammatory diseases and tissue damage resulting from a dysregulated wound-healing response [...].
Assuntos
Fibrose/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Inflamação/metabolismo , Transdução de Sinais/fisiologia , Cicatrização/fisiologiaRESUMO
Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study was to evaluate whether human protein S inhibits cell apoptosis in acute lung injury. Acute lung injury in human protein S transgenic and wild-type mice was induced by intratracheal instillation of lipopolysaccharide. The effect of human protein S on apoptosis of lung tissue cells was evaluated by Western blotting. Inflammatory cell infiltration, alveolar wall thickening, myeloperoxidase activity, and the expression of inflammatory cytokines were reduced in human protein S transgenic mice compared to the wild-type mice after lipopolysaccharide instillation. Apoptotic cells and caspase-3 activity were reduced while phosphorylation of extracellular signal-regulated kinase was enhanced in the lung tissue from human protein S transgenic mice compared to wild-type mice after lipopolysaccharide instillation. The results of this study suggest that human protein S is protective in lipopolysaccharide-induced acute lung injury by inhibiting apoptosis of lung cells.