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1.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575918

RESUMO

Dehydrocostus lactone (DHL), a natural sesquiterpene lactone isolated from the traditional Chinese herbs Saussurea lappa and Inula helenium L., has important anti-inflammatory properties used for treating colitis, fibrosis, and Gram-negative bacteria-induced acute lung injury (ALI). However, the effects of DHL on Gram-positive bacteria-induced macrophage activation and ALI remains unclear. In this study, we found that DHL inhibited the phosphorylation of p38 MAPK, the degradation of IκBα, and the activation and nuclear translocation of NF-κB p65, but enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Nrf2 and HO-1 in lipoteichoic acid (LTA)-stimulated RAW264.7 cells and primary bone-marrow-derived macrophages (BMDMs). Given the critical role of the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways in the balance of M1/M2 macrophage polarization and inflammation, we speculated that DHL would also have an effect on macrophage polarization. Further studies verified that DHL promoted M2 macrophage polarization and reduced M1 polarization, then resulted in a decreased inflammatory response. An in vivo study also revealed that DHL exhibited anti-inflammatory effects and ameliorated methicillin-resistant Staphylococcus aureus (MRSA)-induced ALI. In addition, DHL treatment significantly inhibited the p38 MAPK/NF-κB pathway and activated AMPK/Nrf2 signaling, leading to accelerated switching of macrophages from M1 to M2 in the MRSA-induced murine ALI model. Collectively, these data demonstrated that DHL can promote macrophage polarization to an anti-inflammatory M2 phenotype via interfering in p38 MAPK/NF-κB signaling, as well as activating the AMPK/Nrf2 pathway in vitro and in vivo. Our results suggested that DHL might be a novel candidate for treating inflammatory diseases caused by Gram-positive bacteria.


Assuntos
Anti-Inflamatórios/farmacologia , Lactonas/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pneumonia Estafilocócica/etiologia , Sesquiterpenos/farmacologia , Doença Aguda , Animais , Plasticidade Celular/efeitos dos fármacos , Plasticidade Celular/imunologia , Modelos Animais de Doenças , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Fosforilação , Pneumonia Estafilocócica/tratamento farmacológico , Pneumonia Estafilocócica/metabolismo , Pneumonia Estafilocócica/patologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
2.
Acta Pharmacol Sin ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417573

RESUMO

Ethyl ferulate (EF) is abundant in Rhizoma Chuanxiong and grains (e.g., rice and maize) and possesses antioxidative, antiapoptotic, antirheumatic, and anti-inflammatory properties. However, its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is still unknown. In the present study, we found that EF significantly alleviated LPS-induced pathological damage and neutrophil infiltration and inhibited the gene expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) in murine lung tissues. Moreover, EF reduced the gene expression of TNF-α, IL-1ß, IL-6, and iNOS and decreased the production of NO in LPS-stimulated RAW264.7 cells and BMDMs. Mechanistic experiments revealed that EF prominently activated the AMPK/Nrf2 pathway and promoted Nrf2 nuclear translocation. AMPK inhibition (Compound C) and Nrf2 inhibition (ML385) abolished the beneficial effect of EF on the inflammatory response. Furthermore, the protective effect of EF on LPS-induced ALI was not observed in Nrf2 knockout mice. Taken together, the results of our study suggest that EF ameliorates LPS-induced ALI in an AMPK/Nrf2-dependent manner. These findings provide a foundation for developing EF as a new anti-inflammatory agent for LPS-induced ALI/ARDS therapy.

3.
J Inflamm Res ; 14: 803-816, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732006

RESUMO

Background: Alveolar arrest and the impaired angiogenesis caused by chronic inflammation and oxidative stress are two main factors in bronchopulmonary dysplasia (BPD). Short-chain fatty acids (SCFAs), especially propionate, possess anti-oxidant and anti-inflammatory effects. The present study was designed to examine the roles of sodium propionate (SP) on lipopolysaccharide (LPS)-challenged BPD and its potential mechanisms. Methods: WT, Nrf2-/- mice and pulmonary microvascular endothelial cells (HPMECs) were used in this study. LPS was performed to mimic BPD model both in vivo and vitro. Lung histopathology, inflammation and oxidative stress-related mRNA expressions in lungs involved in BPD pathogenesis were investigated. In addition, cell viability and angiogenesis were also tested. Results: The increased nuclear factor erythroid 2-related factor (Nrf2) and decreased Kelch-like ECH-associated protein-1 (Keap-1) expressions were observed after SP treatment in the LPS-induced neonatal mouse model of BPD. In LPS-induced wild-type but not Nrf2-/- neonatal mice, SP reduced pulmonary inflammation and oxidative stress and exhibited obvious pathological alterations of the alveoli. Moreover, in LPS-evoked HPMECs, SP accelerated Nrf2 nuclear translocation presented and exhibited cytoprotective and pro-angiogenesis effects. In addition, SP diminished the LPS-induced inflammatory response by blocking the activation of nuclear factor-kappa B pathway. Moreover, pretreatment with ML385, an Nrf2 specific inhibitor, offsets the beneficial effects of SP on inflammation, oxidative stress and angiogenesis in LPS-evoked HPMECs. Conclusion: SP protects against LPS-induced lung alveolar simplification and abnormal angiogenesis in neonatal mice and HPMECs in an Nrf2-dependent manner.

4.
Int Immunopharmacol ; 90: 107187, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33249045

RESUMO

Sophoricoside (SOP), an isoflavone glycoside isolated from seed of Sophora japonica L., has been reported to have various pharmacological activities, including anti-cancer, anti-allergy and anti-inflammation. However, the effect of SOP on lipopolysaccharides (LPS)-acute lung injury (ALI) is completely unclear. Here, we found that SOP pretreatment significantly ameliorated LPS-induced pathological damage, tissue permeability, neutrophil infiltration and the production of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) in a murine model of ALI. Besides, SOP reduced the production of pro-inflammatory mediators such as iNOS, NO and inflammatory cytokines including TNF-α, IL-1ß and IL-6 in LPS-stimulated RAW264.7 cells and bone marrow derived macrophages. Interestingly, treatment with SOP exhibited no effect on the activation of NF-κB and MAPKs in macrophages but prominently accelerated the expression and nuclear translocation of Nrf2. By using ML385, a specific Nrf2 inhibitor, we found that inhibition of Nrf2 abolished the inhibitory effect of SOP on LPS-induced iNOS expression, NO production as well as pro-inflammatory cytokine generation. SOP also activated AMPK, an upstream protein of Nrf2, under LPS stimuli. Furthermore, we demonstrated that the accelerated expression of Nrf2 induced by SOP was reversed by interference with the AMPK inhibitor Compound C. Taken together, our results suggested that SOP attenuated LPS-induced ALI in AMPK/Nrf2 dependent manner and indicated that SOP might be a potential therapeutic candidate for treating ALI/ARDS.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia/prevenção & controle , Proteínas Quinases Ativadas por AMP/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Macrófagos/enzimologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/enzimologia , Pneumonia/patologia , Células RAW 264.7 , Transdução de Sinais
5.
Int Immunopharmacol ; 90: 107221, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33293260

RESUMO

Salvinorin A (SA), a neoclerodane diterpene, is isolated from the dried leaves ofSalvia divinorum. SA has traditionally been used treatments for chronic pain diseases. Recent research has demonstrated that SA possesses the anti-inflammatory property. The present study aim to explore the effects and potentialmechanisms ofSA in protection against Methicillin Resistant Staphylococcus aureus (MRSA)-induced acute lung injury (ALI). Here, we firstly found that verylowdosesof SA (50 µg/kg) could markedly decrease the infiltration of pulmonary neutrophils, mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) and then attenuated ALI cause by MRSA infection in mice. In vitro findings revealed that SA attenuated lipoteichoicacid-induced apoptosis, inflammation and oxidative stress in RAW264.7 cells. Mechanism research revealed that SA increased both mRNA levels and protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and up-regulated mRNA expression of its downstream genes (HO-1, Gclm, Trx-1, SOD1 and SOD2). Additionally, Nrf2 knockout mice abolished the inhibitory effect of SA on neutrophil accumulation and oxidative stress in MRSA-induced ALI. In conclusion, SA attenuates MRSA-induced ALI via Nrf2 signaling pathways.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Diterpenos Clerodânicos/farmacologia , Pulmão/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Estafilocócica/prevenção & controle , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Estafilocócica/metabolismo , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/patologia , Células RAW 264.7 , Transdução de Sinais
6.
Respir Res ; 21(1): 232, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907551

RESUMO

BACKGROUND: Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. METHODS: we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. RESULTS: Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. CONCLUSIONS: These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Afogamento/metabolismo , Ferroptose/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Água do Mar/efeitos adversos , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Linhagem Celular , Afogamento/etiologia , Afogamento/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Respiratória/metabolismo
8.
J Agric Food Chem ; 68(24): 6554-6563, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32452677

RESUMO

Short-chain fatty acids (SCFAs), especially propionate, originate from the fermentation of dietary fiber in the gut and play a key role in inhibiting pulmonary inflammation. Chronic inflammation may induce an epithelial-mesenchymal transition (EMT) in alveolar epithelial cells and result in fibrotic disorders. This study was designed to investigate the beneficial effect of sodium propionate (SP) on lipopolysaccharide (LPS)-induced EMT. In cultured BEAS-2B cells, the protein expression levels of E-cadherin, α-smooth muscle actin (SMA), and vimentin were 0.66 ± 0.20, 1.44 ± 0.23, and 1.32 ± 0.21 in the LPS group vs 1.11 ± 0.36 (P < 0.05), 1.04 ± 0.30 (P < 0.05), and 0.96 ± 0.13 (P < 0.01) in the LPS + SP group (mean ± standard deviation), respectively. Meanwhile, LPS-triggered inflammatory cytokines and extracellular proteins were also reduced by SP administration in BEAS-2B cells. Moreover, SP treatment attenuated inflammation, EMT, extracellular matrix (ECM) deposition, and even fibrosis in a mouse EMT model. In terms of mechanism, LPS-treated BEAS-2B cells exhibited a higher level of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was interrupted by SP treatment. It is worth noting that the blockade of the PI3K/Akt/mTOR signaling cascade reduced the LPS-evoked EMT process in BEAS-2B cells. These results suggest that SP can block LPS-induced EMT via inhibition of the PI3K/Akt/mTOR signaling cascade, which provides a basis for possible clinical use of SP in airway and lung diseases.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Pneumopatias/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Propionatos/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Humanos , Pneumopatias/genética , Pneumopatias/metabolismo , Pneumopatias/fisiopatologia , Masculino , Camundongos , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Vimentina/genética , Vimentina/metabolismo
9.
Phytomedicine ; 67: 153138, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31881478

RESUMO

BACKGROUND: Hypoxia is commonly existed in tumors and lead to cancer cell chemo/radio-resistance. It is well-recognized that tumor hypoxia is a major challenge for the treatment of various solid tumors. Hyperoside (quercetin-3-O-galactoside, Hy) possesses antioxidant effects and has been reported to protect against hypoxia/reoxygenation induced injury in cardiomyocytes. Therefore, Hy may be attractive compound applicable to hypoxia-related diseases. PURPOSE: This study was designed to determine the role of Hy in hypoxia-induced proliferation of non-small cell lung cancer cells and the underlying mechanism. STUDY DESIGN AND METHODS: A549, a human non-small cell lung cancer (NSCLC) cell line, was used in the present study. 1% O2 was used to mimic the in vivo hypoxic condition of NSCLC. The potential mechanisms of Hy on hypoxia-induced A549 survival and proliferation, as well as the involvement of AMPK/HO-1 pathway were studied via CCK-8 assay, EdU staining, flow cytometry, qRT-PCR and western blot. RESULTS: We showed that pretreatment with Hy suppressed hypoxia-induced A549 survival and proliferation in dose-dependent manner. In terms of mechanism, hypoxia-treated A549 showed the lower AMPK phosphorylation and the reduced HO-1 expression, which were reversed by Hy pretreatment. Both AMPK inhibitor (Compound C) and HO-1 activity inhibitor (Zinc protoporphyrin IX) abolished Hy-evoked A549 cell death under hypoxia stimuli. Of note, Ferrous iron contributed to Hy-induced A549 cell death under hypoxia, while Hy had no effect on lipid peroxidation under hypoxia. CONCLUSION: Taken together, our results highlighted the beneficial role of Hy against hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Heme Oxigenase-1/metabolismo , Quercetina/análogos & derivados , Hipóxia Tumoral/efeitos dos fármacos , Células A549 , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Heme Oxigenase-1/antagonistas & inibidores , Humanos , Ferro/metabolismo , Fosforilação/efeitos dos fármacos , Protoporfirinas/farmacologia , Quercetina/administração & dosagem , Quercetina/farmacologia
11.
Onco Targets Ther ; 12: 8379-8386, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632085

RESUMO

Objective: To evaluate the impact of systematic nutrition management (SNM) on nutritional status, treatment-related toxicity, quality of life (QoL), response rates, and survival in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) treated by radiotherapy (RT). Methods: In this retrospective study, 56 patients with LA-NPC were selected as nutrition management group (NG) for SNM during RT till 1 month later. Another 56 patients with LA-NPC receiving RT without SNM as control group (CG) were identified from the hospital database and matched pairs with NG patients according to age, gender, stage, and body mass index (BMI) prior to RT. Results: At 1 month after RT, the percentage of malnourished patients with BMI <18.5 kg/m2 was statistically significant reduced in NG as compared to the CG group (35.7% vs 58.9%, P=0.014). Nutritional indexes of body weight, hemoglobin, prealbumin, and lymphocyte in the NG were statistically significant higher than those in the CG group (P<0.05). NG patients had statistically significant less grade 3-4 oral mucositis during RT compared with the CG group (32.1% vs 51.8%, P=0.035). Furthermore, at 1 month after RT, an improved QoL was observed in NG patients with respect to physical, role and social functions, symptom scales of fatigue and pain, and the global health status as compared to the CG group (P<0.05). With a median follow-up of 24.8 months, there were no statistical differences between NG and CG (P>0.05) for the 2-year progression-free survival and overall survival (84.2% versus 79.5% and 94.7% versus 92.3%, respectively.). Conclusion: SNM for LA-NPC patients treated by RT resulted in better nutritional status, reduced treatment-related toxicity and improved QoL.

12.
Int Immunopharmacol ; 74: 105634, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254959

RESUMO

OBJECTIVE: Heme oxygenase-1 (HO-1) plays a critical protective role in various insults-induced acute lung injury (ALI) through its strong anti-inflammatory, anti-oxidant, and anti-apoptotic properties, but its protective role and mechanism on seawater aspiration-induced acute lung injury remains unclear. This study aimed to explore the therapeutic potential and mechanism of HO-1 to attenuate seawater aspiration-induced ALI in vivo and in vitro. METHODS: The viability and invasion of A549 cell were analyzed through cell counting kit-8 and lactate dehydrogenase release assay; the transcriptional level of inflammatory cytokines (TNF-α, IL-6, IL-8 and MCP-1) and cell proliferation-related cytokines (FoxM1, Ccnb1 and Cdc25C) in seawater-treated A549 cell were tested by qPCR; apoptotic cells were analyzed by flow cytometryd; HO-1mRNA and protein were determined by qPCR and western blotting; the fluorescent indicators (DCFH-DA, dihydroethidium, MitoSox Red and Fluo-4) were used to monitor generation of ROS and mitochondrial function. The lung wet/dry weight radio and lactate dehydrogenase activity, Sirius red staining, TUNEL assay and immunohistochemical staining with anti-pan Cytokeratin antibody were analyzed in seawater-drowning mice. The role of HO-1 on seawater-drowning pulmonary injury was explored via HO-1 activity inhibitors (Zinc protoporphyrin) in vitro and in vivo. RESULTS: Seawater exposure decreased the cellular viability, increased the production of pro-inflammatory cytokines (IL-6, IL-8 and TNF-α), induced cellular apoptosis and inhibited the expression of cell proliferation-related cytokines (FoxM1, Ccnb1 and Cdc25C). Moreover, seawater exposure led to mitochondrial dysfunction in A549 cells. Supplement of HO-1 sepcific inducer (heme) or its catalytic product (biliverdin) significantly attenuated seawater-induced A549 damage and promoted cell proliferation. However, Zinc protoporphyrin abolished the beneficial effects of HO-1 on seawater drowning-induced pulmonary tissue injury. CONCLUSION: HO-1 attenuates seawater drowning-induced lung injury by its anti-inflammatory, anti-oxidative, and anti-apoptosis function.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Afogamento/metabolismo , Heme Oxigenase-1/metabolismo , Células A549 , Animais , Biliverdina/metabolismo , Proliferação de Células , Citocinas/genética , Humanos , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Água do Mar
13.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(5): 468-472, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31894682

RESUMO

OBJECTIVE: To investigate the protective effects of curcumin on bile duct ligation(BDL)-induced liver cholestasis in mice, so as to provide a new treatment strategy for liver fibrosis. METHODS: Forty-two healthy adult male BALB/c mice were randomly divided into sham group (n =6), sham+curcumin group (n=6), BDL treatment group (n=10), BDL+curcumin group(n=10), BDL+curcumin+ZnPP group (n=10). Seven days after BDL operation, the sham operation + curcumin group and the BDL+ curcumin group were treated with curcumin at the dose of 30 mg/kg by intraperitoneal injection once a day for 7 days.The mice in BDL+ curcumin +ZnPP group were treated with curcumin (30 mg/kg) and ZnPP (50 µmol/kg) by intraperitoneal injection once a day for 7 days. For the sham group and the BDL group, mice were treated with equal-volume saline daily by intraperitoneal injection. After 14 days of BDL, the plasma and liver tissues were collected, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. The pathological changes of liver tissue and liver fibrosis were observed, and the protein expression of HO-1 in liver tissue was detected. RESULTS: Compared with the sham group, mice in the BDL group had enlarged liver gallbladder and the serum levels of ALT and AST were increased significantly (P<0.05). Meanwhile, the results of Sirius red staining and qRT-PCR of pro-fibrosis related genes showed collagen deposition in the liver, and immunohistochemistry of macrophages and neutrophils showed inflammatory cell infiltration in the liver. Compared with the BDL group, the serum levels of ALT and AST in the curcumin treatment group were decreased significantly (P<0.05), collagen deposition and inflammatory cell infiltration were improved, and HO-1 expression was increased (P<0.05) after curcumin treatement. In the curcumin treatment group, the protective effect of curcumin on liver injury could be reversed by HO-1 active inhibitor ZnPP. CONCLUSION: Curcumin can improve liver inflammation and fibrosis caused by BDL, and this protective effect is related to the regulation of HO-1 activity by curcumin.


Assuntos
Colestase , Curcumina , Cirrose Hepática , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Resultado do Tratamento
14.
Int Immunopharmacol ; 63: 137-144, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30092496

RESUMO

OBJECTIVE: Resident alveolar macrophages (AMs) are activated and release proinflammatory mediators and chemokines during acute lung injury. We have previous reported that caveolin-1 (Cav-1) scaffolding domain (CSD) peptide inhibited the proinflammatory cytokines expression by up-regulating heme oxygenase-1 (HO-1) activity. In this study, we aimed to investigate the effect of residue R101 in CSD peptide on the activity of HO-1 in AMs. METHODS: The binding mode between HO-1 and CSD peptides (WT CSD and Δ101 CSD truncation peptides) was analyzed and the free energy was calculated. The inflammatory genes and M1/M2macrophage polarization-associated genes expression were measured by real-time PCR. The activities of HO-1 were determined by the spectrophotometical method. Western blot analyzed the content of Cav-1, HO-1, IκB and MAPK signals (phosphorylated ERK, JNK and p38 MAPK). RESULTS: Δ101CSD peptide could bind to HO-1 protein and to disrupt the interaction of HO-1 and Cav-1. However, Δ101CSD peptide had lower activity of HO-1 in LPS-treated AMs compared with WT CSD. The expression of IL-1ß and MCP-1 and NO content were decreased by WT CSD peptide in LPS treated AMs. However, only MCP-1 expression and NO content were downregulated byΔ101CSD peptide. Meanwhile, compared with those in LPS + hemin + WT CSD group, the mRNA expression of TNF-α, Cd86, IL-12b and NOS2 significantly increased while expression of IL10, Arg1 and CD163 significantly decreased in LPS + hemin + Δ101CSD group. The effect of WT CSD peptide on the inhibition of MAPK signaling pathway were stronger than Δ101 CSD peptide evidenced by the level of phosphorylated ERK, JNK and p38 MAPK. CONCLUSION: Deletion of residue R101 impairs the ability of CSD peptide to increase HO-1 activity and to dampen inflammatory response in LPS-challenged rat AMs.


Assuntos
Caveolina 1/farmacologia , Heme Oxigenase-1/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Animais , Citocinas/metabolismo , Heme Oxigenase-1/genética , Macrófagos Alveolares/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley
15.
Biochem Pharmacol ; 148: 265-277, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29309766

RESUMO

Although methylene blue (MB) has showed strong antioxidant effect, its effect related with heme oxygenase-1 (HO-1) is still unclear. Thus, we investigated the effects of MB on HO-1 protein content and enzyme activity, and its protective effect against hydrogen peroxide (H2O2)-induced oxidative damage in RAW264.7 macrophage. The cell viability and the release of lactate dehydrogenase of RAW264.7 were determined. The mitochondrial functions were valuated through these indexes: content of adenosine triphosphate, superoxide dismutase, concentration of reactive oxygen species and mitochondrial membrane potential. Meanwhile, high content screening tested generation of ROS, MMP and intracellular concentration of calcium ion. qRT-PCR valuated macrophage phenotype markers expression. Lastly, flow cytometry and caspase-3 detection analyzed RAW264.7 apoptosis. Our data showed that (1) Both pretreatment and posttreatment of MB increased HO-1 protein content and enzyme activity; (2) MB rescued cells from H2O2-induced mitochondrial dysfunction; (3) High content screening revealed that MB alleviated the changes including generation of reactive oxygen species, mitochondrial membrane potential and intracellular concentration of calcium ion in H2O2 exposed RAW264.7; (4) MB attenuated H2O2-induced apoptosis; (5) MB pretreatment decreased the expression of M1 macrophage markers (Tnf and Nos2) while increasing the expression of M2 macrophage markers (Mrc1 and Il10); (6) The beneficial effect of MB was abolished by zinc protoporphyrin IX (HO-1 activity inhibitor) or HO-1 siRNA. In summary, MB protects RAW264.7 cells from H2O2-induced injury through up-regulation HO-1.


Assuntos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/toxicidade , Macrófagos/efeitos dos fármacos , Animais , Heme Oxigenase-1/genética , Macrófagos/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Células RAW 264.7
16.
Respir Physiol Neurobiol ; 247: 12-19, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28870868

RESUMO

The aim of the present study was to investigate whether heme oxygenase-1(HO-1) participated in the resolution of seawater drowning-induced acute respiratory distress syndrome (ARDS). In this study, gross and microscopic morphology of pulmonary tissue, computed tomography images and biochemical indexes were continuously observed from 15min to 15day after seawater drowning. The content and activity of HO-1 were determined by western-blot and spectrophotometric method, respectively. The morphological and biochemical indexes indicated that the seawater drowning could lead to the serious pulmonary hemorrhage and edema. However, 6h after drowning, these morphological and biochemical indexes gradually returned to basal level. Meanwhile, seawater drowning increased the HO-1 expression and activity while Zinc protoporphyrin (a HO-1 specific activity inhibitor) decreased the content of transforming growth factor beta-1 in lung tissue and hampered the repair process of seawater drowning-induced ARDS. Thus, HO-1 participates in the resolution of seawater drowning-induced ARDS.


Assuntos
Afogamento/enzimologia , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Síndrome do Desconforto Respiratório/enzimologia , Síndrome do Desconforto Respiratório/etiologia , Água do Mar , Animais , Modelos Animais de Doenças , Progressão da Doença , Afogamento/diagnóstico por imagem , Afogamento/patologia , Edema/diagnóstico por imagem , Edema/enzimologia , Edema/etiologia , Edema/patologia , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Hemorragia/diagnóstico por imagem , Hemorragia/enzimologia , Hemorragia/etiologia , Hemorragia/patologia , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Proteínas de Membrana/antagonistas & inibidores , Camundongos Endogâmicos ICR , Protoporfirinas/farmacologia , Distribuição Aleatória , Recuperação de Função Fisiológica/fisiologia , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Síndrome do Desconforto Respiratório/patologia
17.
Lung ; 196(1): 73-82, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29204685

RESUMO

INTRODUCTION: Impaired mitochondrial function is a key factor attributing to the lung ischemia reperfusion injury (LIRI). Methylene blue (MB) has been reported to attenuate brain and renal ischemia-reperfusion injury. We hypothesized that MB also could have a protective effect against LIRI by preventing mitochondrial oxidative damage. METHODS: Isolated rat lungs were assigned to the following four groups (n = 6): a sham group: perfusion for 105 min without ischemia; I/R group: shutoff of perfusion and ventilation for 45 min followed by reperfusion for 60 min; and I/R + MB group and I/R + glutathione (GSH) group: 2 mg/kg MB or 4 µM glutathione were intraperitoneally administered for 2 h, and followed by 45 min of ischemia and 60 min of reperfusion. RESULTS: MB lessened pulmonary dysfunction and severe histological injury induced by ischemia-reperfusion injury. MB reduced the production of reactive oxygen species and malondialdehyde and enhanced the activity of superoxide dismutase. MB also suppressed the opening of the mitochondrial permeability transition pore and partly preserved mitochondrial membrane potential. Moreover, MB inhibited the release of cytochrome c from the mitochondria into the cytosol and decreased apoptosis. Additionally, MB downregulated the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-18). CONCLUSION: MB protects the isolated rat lungs against ischemia-reperfusion injury by attenuating mitochondrial damage.


Assuntos
Inibidores Enzimáticos/farmacologia , Azul de Metileno/farmacologia , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Citocromos c/metabolismo , Citocinas/genética , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Superóxido Dismutase , Transcrição Genética/efeitos dos fármacos
18.
Oncotarget ; 8(25): 40104-40114, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28402952

RESUMO

Caveolin-1(Cav-1) scaffolding domain (CSD) peptides compete with the plasma membrane Cav-1, inhibit the interaction of the proteins and Cav-1, and re-store the functions of Cav-1 binding proteins. Heme oxygenase-1 (HO-1) binds to Cav-1 and its enzymatic activity was inhibited. In this study, we investigated the effect of CSD peptides on interaction between HO-1 and Cav-1, and on the HO-1 activity in vitro and in vivo. Our data showed that CSD peptides decreased the compartmentalization of HO-1 and Cav-1, and increased the HO-1 activity both in LPS-treated alveolar macrophages and in mice. Meanwhile, CSD peptides obviously ameliorated the pathology changes in mice and lowered the following injury indexes: the wet/dry ratio of lung tissues, total cell numbers in bronchoalveolar lavage fluid and lactate dehydrogenase activity in the serum. Mechanistically, it was firstly found that CSD peptides promoted alveolar macrophages polarization to M2 phenotype and inhibited the IκB degeneration. Furthermore, CSD peptides down-regulated the expression of IL-1ß, IL-6, TNF-α, MCP-1, and iNOS in alveolar macrophages and in lung tissue. However, the protective role of CSD peptides on LPS-induced acute lung injury in mice could be abolished by zinc protoporphyrin IX (ZnPP, a HO-1 activity inhibitor). In summary, CSD peptides have beneficial anti-inflammatory effects by restoring the HO-1 activity suppressed by Cav-1 on plasma membrane.


Assuntos
Caveolina 1/metabolismo , Heme Oxigenase-1/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/prevenção & controle , Animais , Caveolina 1/farmacologia , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Substâncias Protetoras/farmacologia , Ligação Proteica/efeitos dos fármacos
19.
Chin Med J (Engl) ; 130(7): 859-865, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28345551

RESUMO

BACKGROUND: Biliverdin (BV) has a protective role against ischemia-reperfusion injury (IRI). However, the protective role and potential mechanisms of BV on lung IRI (LIRI) remain to be elucidated. Thus, we aimed to investigate the protective role and potential mechanisms of BV on LIRI. METHODS: Lungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model. After an initial 15 min stabilization period, the isolated lungs were subjected to ischemia for 60 min, followed by 90 min of reperfusion with or without BV treatment. RESULTS: Lungs in the I/R group exhibited significant decrease in tidal volume (1.44 ± 0.23 ml/min in I/R group vs. 2.41 ± 0.31 ml/min in sham group; P< 0.001), lung compliance (0.27 ± 0.06 ml/cmH2O in I/R group vs. 0.44 ± 0.09 ml/cmH2O in sham group; P< 0.001; 1 cmH2O=0.098 kPa), and oxygen partial pressure (PaO2) levels (64.12 ± 12 mmHg in I/R group vs. 114 ± 8.0 mmHg in sham group; P< 0.001; 1 mmHg = 0.133 kPa). In contrast, these parameters in the BV group (2.27 ± 0.37 ml/min of tidal volume, 0.41 ± 0.10 ml/cmH2O of compliance, and 98.7 ± 9.7 mmHg of PaO2) were significantly higher compared with the I/R group (P = 0.004, P< 0.001, and P< 0.001, respectively). Compared to the I/R group, the contents of superoxide dismutase were significantly higher (47.07 ± 7.91 U/mg protein vs. 33.84 ± 10.15 U/mg protein; P = 0.005) while the wet/dry weight ratio (P < 0.01), methane dicarboxylic aldehyde (1.92 ± 0.25 nmol/mg protein vs. 2.67 ± 0.46 nmol/mg protein; P< 0.001), and adenosine triphosphate contents (297.05 ± 47.45 nmol/mg protein vs. 208.09 ± 29.11 nmol/mg protein; P = 0.005) were markedly lower in BV-treated lungs. Histological analysis revealed that BV alleviated LIRI. Furthermore, the expression of inflammatory cytokines (interleukin-1ß, interleukin-6, and tumor necrosis factor-ß) was downregulated and the expression of cyclooxygenase-2, inducible nitric oxide synthase, and Jun N-terminal kinase was significantly reduced in BV group (all P< 0.01 compared to I/R group). Finally, the apoptosis index in the BV group was significantly decreased (P < 0.01 compared to I/R group). CONCLUSION: BV protects lung IRI through its antioxidative, anti-inflammatory, and anti-apoptotic effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Biliverdina/uso terapêutico , Pulmão/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo-Oxigenase 2/metabolismo , Marcação In Situ das Extremidades Cortadas , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/patologia , Linfotoxina-alfa/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Superóxido Dismutase/metabolismo
20.
Int Heart J ; 57(4): 477-82, 2016 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-27357440

RESUMO

Sirt1 is a highly conserved nicotinamide adenine dinucleotide (NAD(+)) dependent histone deacetylase which plays an important role in heart diseases. Studies performed with Sirt1 activators indicated that it protects cells from ischemia/ reperfusion (I/R) injury. The protective effects of H2S against I/R injury also have been recognized. Hence, the present study was designed to explore whether Sirt1/PGC-1α participates in the protection of exogenous H2S postconditioning against I/R injury in isolated rat hearts. Isolated rat hearts were subjected to 30 minutes of global ischemia followed by 60 minutes of reperfusion after 20 minutes of equilibrium. During this procedure, the hearts were exposed to NaHS (10 µmol/L) treatment in the absence or presence of the selective Sirt1 inhibitor EX-527 (10 µmol/L). NaHS exerted a protective effect on isolated rat hearts subjected to I/R, as shown by the improved expression of Sirt1/PGC-1α associated with restoration of Sirt1 nuclear localization, cardiac function, decreased myocardial infarct size, decreased myocardial enzyme release, and several biochemical parameters, including up-regulation of the ATP and SOD levels, and down-regulation of the MDA level. However, treatment with EX-527 could partially prevent the above effects of NaHS postconditioning. These results indicate that H2S confers protective effects against I/R injury through the activation of Sirt1/PGC1α.


Assuntos
Coração/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Sirtuína 1/genética , Trifosfato de Adenosina , Animais , Carbazóis , Circulação Coronária/efeitos dos fármacos , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase-1
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