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1.
Bratisl Lek Listy ; 120(7): 527-531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602989

RESUMO

AIM: Carbon tetrachloride (CCl4) is an organic chemical that produces different tissue­damaging effects when ingested or inhaled. Present study aims to determine whether the application of exogenous melatonin, a neurohormone with numerous biological properties, can prevent disturbances in lung tissue antioxidative capacities and arginine metabolism, tissue inflammation and oxidative damage induced by exposure to CCl4 in rats. METHODS: The effects of melatonin on the changes occurring in rat lung tissue after an acute exposure to CCl4 were studied by monitoring alterations in antioxidant capacities, inflammatory parameters, parameters of arginine metabolism, and lipid and protein oxidative damage. RESULTS: The results indicated that melatonin prevents CCl4-induced lung damage by mitigating tissue antioxidant capacity and preventing nitric oxide production through a shift from nitric oxide synthase to arginase. Also, melatonin partially prevented tissue inflammation and molecules' oxidative modification seen after exposure to CCl4. CONCLUSIONS: The protective activity of melatonin can be attributed to its ability to scavenge both free radicals, as well as to its potential to increase tissue antioxidant capacity. The modulation of inflammatory response through both decrease in tissue inflammatory parameters and influence on arginine-nitric oxide metabolism might be an additional mechanism of action (Tab. 1, Fig. 2, Ref. 33).


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Antioxidantes/metabolismo , Melatonina/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Arginina/metabolismo , Tetracloreto de Carbono , Inflamação/tratamento farmacológico , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos
2.
Eur J Med Chem ; 183: 111704, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557608

RESUMO

Curcumin is a small organic molecule with pleiotropic biological activities. However, its multiple structural-pharmacokinetic challenges prevent its development into a clinical drug. Various structural modifications have been made to improve its drug profile. In this review, we focus on the methods adopted in the synthesis of asymmetric curcumin derivatives and their biological activities and forecast the future of this exciting class of compounds in the field of medicine.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Curcumina/farmacologia , Neoplasias/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Curcumina/síntese química , Curcumina/química , Humanos , Estrutura Molecular
3.
Artigo em Chinês | MEDLINE | ID: mdl-31495108

RESUMO

Objective: To investigate the protective effect of oligomeric proanthocyanidins (OPCs) in paraquat-exposed mice. Methods: An acute lung injury model was established by a single intraperitoneal injection of paraquat (PQ) in BALB/c mice. The mice were randomized into control group, paraquat-exposed group (PQ group) , oligomeric proanthocyanidins group (OPCs group) , and paraquat and oligomeric proanthocyanidins-exposed group (PQ+OPCs group) , with 10 mice in each group. Only normal saline was intraperitoneally injected into the mice in the control group. The mice in the PQ group were divided into 8 subgroups according to the dose of poison administered, i.e., 0, 25, 50, 75, 100, 150, 200, and 300 mg/kg; the mice in each subgroup were given a single intraperitoneal injection of PQ and were observed and recorded for death at 3, 6, 12, 24, 36, 48, 60, 84, and 96 hours after PQ injection. Origin 8.0 was used to calculate the median lethal dose (LD(50)) of the mice at 24, 36, 48, and 60 hours after PQ injection, and the PQ dose (100 mg/kg, ip) was chosen based on the accumulated mortality rate. An OPCs-treated experimental model was established by an intraperitoneal injection of OPCs followed by a single PQ injection (100 mg/kg, ip) 1 hour later to observe the effects of OPCs on the apparent poisoning effect and fatality rate in PQ-induced mice. Immunohistochemistry was used to determine the effect of OPCs on PQ-induced lung tissue lesions. The peripheral blood samples of the mice were collected to determine the effects of OPCs on PQ-induced inflammatory factors such as tumor necrosis factor-α (TNF-α) , interleukine-1ß (IL-1ß) , and transforming growth factor-ß1 (TGF-ß1) using enzyme-linked immunosorbent assay. Results: The mortality rate was significantly correlated with the dose and exposure time in PQ-exposed mice; the mortality rate gradually increased with increasing dose and exposure time of the poison (P<0.05) . The LD(50) values for the mice were 216.67, 124.11, and 71.24 mg/kg at 24, 48, and 72 hours after PQ exposure, respectively. PQ could induce animal death at 12 hours after injection, and the mortality rate of the animals was 40% (4/10) at 48 hours after PQ exposure. The PQ-induced mortality rate of the mice in the PQ+OPCs group was reduced, and the mortality rate of the animals was 10% (1/10) at 48 hours after PQ exposure. Compared with treatment in the control group, OPCs exposure alone had no significant effect on the expression of TNF-α and TGF-ß1 in the peripheral blood (P>0.05) , but it significantly inhibited the expression of IL-1ß (P<0.05) . After 48 hours, the expression of TNF-α, TGF-ß1, and IL-1ß in peripheral blood significantly increased by 39%, 45%, and 38%, respectively, in the PQ group (P<0.05) , but they significantly decreased by 31%, 13%, and 22%, respectively, in the OPCs+PQ group as compared with the PQ group (P<0.05) . Conclusion: OPCs pretreatment can significantly alleviate PQ-induced poisoning effect.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Paraquat/toxicidade , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Interleucina-1beta/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Fator de Crescimento Transformador beta1/sangue , Fator de Necrose Tumoral alfa/sangue
4.
Int J Nanomedicine ; 14: 5215-5228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371957

RESUMO

Background: Resveratrol (RSV) has attracted interest as an alternative drug for the treatment of acute lung injury (ALI) and other pulmonary diseases, but its poor oral bioavailability is a limitation. In this study, we employed drug delivery nanotechnology to improve the stability, lung localization and efficacy of orally administered resveratrol to control lung damage leading to ALI. Methods and materials: RSV-loaded lipid-core nanocapsules (RSV-LNCs), prepared by interfacial deposition of biodegradable polymers, were given orally to A/J mice prior to lipopolysaccharide (LPS) intranasal instillation. Inflammatory changes, oxidative stress and lung tissue elastance were assessed 24 h after LPS challenge. Results: RSV-LNCs (5 mg/kg), given 1, 4, 6 or 12 h but not 24 h before provocation, inhibited LPS-induced leukocyte accumulation in the bronchoalveolar fluid (BALF), whereas unloaded nanocapsules (ULNCs) or free RSV (5 mg/kg) were ineffective. RSV-LNCs (2.5-10 mg/kg) but not ULNCs or RSV improved lung function and prevented total leukocyte and neutrophil accumulation equally in both BALF and lung tissue when given 4 h before LPS challenge. Similar findings were seen concerning the generation of a range of pro-inflammatory cytokines such as IL-6, KC, MIP-1α, MIP-2, MCP-1 and RANTES in lung tissue. In addition, only RSV-LNCs inhibited MDA levels and SOD activity in parallel with blockade of the ERK and PI3K/Akt pathways following LPS provocation. Conclusion: Nanoformulation of RSV in biodegradable oil-core polymers is an effective strategy to improve the anti-ALI activity of RSV, suggesting that the modified-release formulation of this plant polyphenol may be of great value in clinical conditions associated with ALI and respiratory failure.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Nanocápsulas/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol/administração & dosagem , Resveratrol/uso terapêutico , Transdução de Sinais , Lesão Pulmonar Aguda/complicações , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Masculino , Camundongos Endogâmicos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/patologia , Resveratrol/farmacologia
5.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(7): 867-872, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31441412

RESUMO

OBJECTIVE: To investigate the preventive effect of Xuebijing injection on acute lung injury induced by cardiopulmonary bypass (CPB) and the underlying mechanism. METHODS: (1) In vivo experiment: 30 Sprague-Dawley (SD) rats were randomly divided into sham group, CPB group, Xuebijing pretreatment group (XBJ+CPB group) with 10 rats in each group. CPB model was reproduced in rats; and CPB was not performed in sham group, but only through arteriovenous puncture. In the XBJ+CPB group, 4 mL/kg Xuebijing injection was injected intraperitoneally 2 hours before CPB, sham group and CPB group were injected with equal volume of normal saline at the same time. The blood from femoral artery was analyzed 4 hours after operation, and the oxygenation index (PaO2/FiO2) was calculated. Then the rats were sacrificed to collect bronchoalveolar lavage fluid (BALF), and the lung permeability index (PPI) was calculated. The lung tissues were harvested, and the wet/dry weight ratio (W/D) of lung tissue was measured. The index of quantitative evaluation of alveolar injury (IQA) was measured. The levels of interleukins (IL-1, IL-6) and tumor necrosis factor-α (TNF-α) in lung tissue and BALF were measured by enzyme-linked immunosorbent assay (ELISA). The content of malondialdehyde (MDA) and the activities of myeloperoxidase (MPO) and superoxide dismutase (SOD) in lung tissue were detected by biochemical method. The microRNA-17-5p (miR-17-5p) expression in lung tissue was determined by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). (2) In vitro experiments: type II alveolar epithelial cells (AEC II) were cultured in vitro, and they were randomly divided into control group (the cells were treated by preoperative serum of CPB in patients with ventricular septal defect), CPB group (the cells were treated by serum after CPB in patients), and XBJ+CPB group (Xuebijing injection 10 g/L+serum after CPB in patients). After 12 hours of culture in each group, the expression of miR-17-5p was detected by RT-qPCR. AEC II cells were transfected with miR-17-5p mimic, inhibitor or corresponding control oligonucleotide (negative control), respectively, to observe the effect of miR-17-5p on Xuebijing regulating CPB-induced apoptosis rate and caspase-3 activity. RESULTS: (1) In vivo experiment: compared with the sham group, the PPI, lung W/D ratio, IQA, and IL-1, IL-6, TNF-α in lung tissue and BALF, as well as MDA content and MPO activity in lung tissue were significantly increased, PaO2/FiO2 and SOD activity in lung tissue were significantly decreased. The parameters of the XBJ+CPB group were significantly improved, suggesting that Xuebijing pretreatment could improve CPB-induced ALI in rats. The expression of miR-17-5p in lung tissue of the CPB group was significantly down-regulated as compared with sham group (2-ΔΔCt: 0.48±0.13 vs. 1.00±0.11, P < 0.05); while the expression of miR-17-5p in the XBJ group was significantly up-regulated as compared with the CPB group (2-ΔΔCt: 1.37±0.09 vs. 0.48±0.13, P < 0.05), indicating that the improvement of Xuebijing injection on lung injury after CPB might be related to miR-17-5p. (2) In vitro experiment: the changes in miR-17-5p expression in each group of AEC II cells confirmed in vivo results. After transfection of miR-17-5p mimic, the apoptotic rate and caspase-3 activity of each group were significantly lower than those transfected with negative control, and the decrease was more significant in the XBJ+CPB group [apoptotic rate: (7.37±0.95)% vs. (12.60±1.90)%, caspase-3 (A value): 0.82±0.09 vs. 1.37±0.08, both P < 0.05]. After transfection of miR-17-5p inhibitor, the apoptotic rate and caspase-3 activity of each group were significantly more than those transfected with negative control [in the XBJ+CPB group: apoptotic rate was (16.30±1.86)% vs. (12.60±1.90)%, caspase-3 (A value) was 1.78±0.13 vs. 1.37±0.08, both P < 0.05]. This indicated that the apoptosis of AEC II cells cultured in serum after CPB was significantly reduced by miR-17-5p, and further reduced by the pretreatment with Xuebijing. CONCLUSIONS: Xuebiing injection can reduce the inflammatory reaction and oxidative stress of lung tissue in rats with ALI induced by CPB, and improve oxygenation. The mechanism may be related to up-regulation of miR-17-5p expression in AEC II cells and inhibition of apoptosis of AEC II cells.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ponte Cardiopulmonar , Medicamentos de Ervas Chinesas/uso terapêutico , MicroRNAs/metabolismo , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Pulmão , Ratos , Ratos Sprague-Dawley
6.
AAPS PharmSciTech ; 20(7): 270, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363872

RESUMO

Currently, there is no specific treatment for acute lung injury (ALI). E-selectin-binding peptide (Esbp), a high-affinity peptide that delivers drugs targeting inflammatory vascular endothelial cells, can bind to E-selectin and act as a targeting ligand for selective drug delivery. In this study, we coupled the thiol groups of Esbp to the amino groups on the surface of bovine serum albumin (BSA) using succinimidyl iodoacetic acid to make Esbp-modified BSA nanoparticles (BSANPs) at the average ratio of 19.3 µg Esbp to 1 mg BSA. The Esbp-modified BSANPs were spherical in shape and had a particle size of 266.7 ± 2.7 nm, polydispersity index of 0.165 ± 0.02, zeta potential of - 33.64 ± 1.23 mV, encapsulation efficiency of 84.3 ± 2.3%, and drug loading of 6.7 ± 0.32%. The cumulative release rate of dexamethasone-loaded Esbp-modified BSANPs was 51.2% within 12 h, significantly lower than that of 88.2% of free drugs. Moreover, Esbp-modified BSANPs could be uptaken in vitro by activated human umbilical vein endothelial cells and in vivo by the lungs of the established ALI mouse model. These results indicated that our Esbp-modified BSANPs delivery system has characteristics of good targeting ability and biocompatibility and is able to inhibit inflammation. Overall, our Esbp-modified BSANPs delivery system has therapeutic potentials as a new targeting drug system for the treatment of ALI in the future.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Dexametasona/administração & dosagem , Selectina E/administração & dosagem , Antígenos HLA-D/administração & dosagem , Nanopartículas/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Lesão Pulmonar Aguda/metabolismo , Animais , Bovinos , Linhagem Celular Tumoral , Dexametasona/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Selectina E/metabolismo , Antígenos HLA-D/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Nanopartículas/metabolismo , Tamanho da Partícula , Soroalbumina Bovina/metabolismo , Resultado do Tratamento
7.
J Agric Food Chem ; 67(28): 7855-7868, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31274310

RESUMO

Bee pollen (BP) collected from different floras possesses various potential bioactivities, but the mechanism-related research on anti-inflammatory effects is limited. Here, three types of BP originating from Camellia sinensis L. (BP-Cs), Nelumbo nucifera Gaertn. (BP-Nn), and Brassica campestris L. (BP-Bc) were assessed using molecular and metabolomics methods to determine their anti-inflammatory effects. The differences in polyphenolic abundance of three types of BP extracts were determined by HPLC-DAD/Q-TOF-MS. In vitro anti-inflammatory effects of three BP extracts were evaluated in a lipopolysaccharide (LPS)-induced RAW 264.7 cells model. BP-Cs extract with the most abundant polyphenols was found to be the most effective in reducing inflammation by downregulating inflammatory-related genes expression and blocking the activation of MAPK and NF-κB signaling pathways. Polyphenol-rich BP-Cs was further evaluated for their in vivo anti-inflammatory effect in a LPS-induced acute lung injury mouse model. An UPLC-Q-TOF/MS-based metabolomics approach was applied to analyze metabolite changes in mouse serum. Weshowed that the pretreated BP-Cs extract alleviated inflammation and regulated glycerophospholipid metabolism significantly. Our findings provide a foundation for developing and justifying BP as a potential anti-inflammatory ingredient in functional foods or nutraceutical formulations.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Extratos Vegetais/administração & dosagem , Pólen/química , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Animais , Anti-Inflamatórios/química , Abelhas , Brassica/química , Camellia sinensis/química , Cromatografia Líquida de Alta Pressão , Humanos , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos ICR , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Nelumbo/química , Extratos Vegetais/química , Polifenóis/administração & dosagem , Polifenóis/química , Células RAW 264.7
8.
Chin J Nat Med ; 17(6): 461-468, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262458

RESUMO

In the present study, we investigated anti-inflammatory effect of Cardamine komarovii flower (CKF) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We determined the effect of CKF methanolic extracts on LPS-induced pro-inflammatory mediators NO and prostaglandin E2 (PGE2), production of pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6), and related protein expression levels of MyD88/TRIF signaling pathways in peritoneal macrophages (PMs). Nuclear translocation of NF-κB-p65 was analyzed by immunofluorescence. For the in vivo experiments, an ALI model was established to detect the number of inflammatory cells and inflammatory factors (IL-1ß, TNF-α, and IL-6) in bronchoalveolar lavage fluid (BALF) of mice. The pathological damage in lung tissues was evaluated through H&E staining. Our results showed that CKF can decrease the production of inflammatory mediators, such as NO and PGE2, by inhibiting their synthesis-related enzymes iNOS and COX-2 in LPS-induced PMs. In addition, CKF can downregulate the mRNA levels of IL-1ß, TNF-α, and IL-6 to inhibit the production of inflammatory factors. Mechanism studies indicated that CKF possesses a fine anti-inflammatory effect by regulating MyD88/TRIF dependent signaling pathways. Immunocytochemistry staining showed that the CKF extract attenuates the LPS-induced translocation of NF-kB p65 subunit in the nucleus from the cytoplasm. In vivo experiments revealed that the number of inflammatory cells and IL-1ß in BALF of mice decrease after CKF treatment. Histopathological observation of lung tissues showed that CKF can remarkably improve alveolar clearance and infiltration of interstitial and alveolar cells after LPS stimulation. In conclusion, our results suggest that CKF inhibits LPS-induced inflammatory response by inhibiting the MyD88/TRIF signaling pathways, thereby protecting mice from LPS-induced ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Cardamine/química , Fator 88 de Diferenciação Mieloide/metabolismo , Extratos Vegetais/administração & dosagem , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Feminino , Flores/química , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Int Immunopharmacol ; 73: 568-574, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203114

RESUMO

PIM kinase is involved in the cellular processes of growth, differentiation and apoptosis. However, the role of PIM1 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains largely unknown. A trend of PIM1 in the lung tissue of LPS-induced ALI at different time points was detected. Histology, wet/dry (W/D) ratio, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and survival rate analyses were performed when mice received the PIM1 inhibitor SMI-4a intratracheally 3 h before LPS administration. Cytokine production in vivo and in vitro was measured after SMI-4a pretreatment. NF-κB subunit p65 expression in nuclei and phosphorylation at Ser276 in lung tissues or cells were detected by Western blot analysis. The results showed that PIM1 mRNA and protein were upregulated in the lung tissue of LPS-induced ALI. The PIM1 inhibitor SMI-4a markedly improved the survival rate after lethal LPS administration, reduced the severity of lung edema, attenuated the histologic injuries of the lung tissue and reduced the counts of infiltrated inflammatory cells in the BALF. The PIM1 inhibitor SMI-4a suppressed the production of cytokines in LPS-treated RAW264.7 cell supernatants and BALF. Furthermore, LPS administration upregulated the levels of nuclear p65 and phosphorylated p65 (p-p65) at Ser276, whereas pretreatment with the PIM1 inhibitor SMI-4a reduced p65 upregulation in the nucleus and p-p65 at Ser276. Taken together, these data indicate that the PIM1 inhibitor SMI-4a may serve as a promising therapeutic strategy for LPS-induced ALI by suppressing macrophage production of cytokines via a reduction of p65 activities.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Compostos de Benzilideno/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Tiazolidinedionas/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Compostos de Benzilideno/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Tiazolidinedionas/farmacologia , Fator de Transcrição RelA/imunologia
10.
Int Immunopharmacol ; 73: 451-460, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154290

RESUMO

In the present study, the anomalin was investigated to determine the protective effects and underlying mechanism against LPS-induced acute lung injury in mice. Anomalin administration 30 min after the LPS injection, significantly attenuated the mechanical allodynia, decrease body temperature, and improved the histological changes and inhibited the infiltration of leukocytes. The anomalin treatment markedly inhibited the production of pro-inflammatory mediators such as cytokines (IL-1ß, IL-6 and TNF-α) and NO in contrast to the LPS treated groups. Similarly, the anomalin also enhanced the level of anti-oxidant enzymes such as GST, GSH, Catalase and inhibited oxidative stress marker such as MDA. In order to explore the molecular mechanism the effect of anomalin was evaluated for mitogen activated protein kinases (MAPK) in LPS-stimulated RAW264.7 cells. The anomalin treatment significantly attenuated the MAPK proteins such as ERK1/2, JNK and p38 (which is downstream signaling proteins to the MAPKKKs and MAPKKs protein) in the RAW264.7 macrophages using western blot analysis. Furthermore, the western blot analysis showed that anomalin treatment significantly inhibited the activation of the Akt proteins in the RAW264.7 macrophages. The AP-1 served as downstream target for the MAPK pathways and the blocking MAPK pathways is responsible for the inhibition of the AP-1 protein. The AP-1/DNA binding was assessed in the RAW264.7 cells using EMSA. The anomalin treatment significantly restricted the AP-1/DNA binding activity and the decrease in the AP-1/DNA binding activity might be contributed due to the upstream inhibition of the MAPKs signaling.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Cumarínicos/farmacologia , Fator de Transcrição AP-1/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Cumarínicos/uso terapêutico , Citocinas/metabolismo , DNA/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo
11.
Life Sci ; 230: 208-217, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152815

RESUMO

Mushroom Phellinus linteus ("Sanghuang" in Chinese) is a popular medicinal polypore used to treat several disorders through its various biological functions. Inonotus sanghuang is claimed to produce general immune-potentiating and strengthening, anti-inflammatory, anti-tumor and anti-microbial properties, but its effect on acute lung inflammation and oxidative stress are not clearly understood. To determine the effect and mechanism of the polyphenols-rich ethyl acetate fraction from wild I. sanghuang extract (ISE) on acute lung injury (ALI) induced by bleomycin (BLM), female C57BL/6 mice were fed ISE (0%, 0.15% or 0.6% in diet) for 4 weeks prior to challenge with BLM. Bronchoalveolar lavage fluid (BALF) from lung, spleen and lung tissues were collected on day 3 after BLM challenge for histological, oxidative stress, molecular and biochemical analysis. ISE supplementation improved pathological features in lung injury scores and reduced lung wet-to-dry ratios. Moreover, ISE reduced inflammatory cell infiltration and the pro-inflammatory cytokines including IL-1ß, IL-6 and TNF-α in BALF, decreased the MPO activity and the MDA level and increased the SOD, CAT and GSH-Px activities in lung tissue homogenates. Further mechanism analysis demonstrated that dietary ISE inhibited NF-κB signal. Finally, peripheral immune function analysis showed that ISE had less effect on immune response including splenocyte producing inflammatory cytokines and T cell proliferation except for IL-1ß and IL-2. Our findings indicate the possibility that dietary ISE attenuates ALI induced by BLM through correcting the inflammation and oxidation balance at least in part via inhibiting NF-κB signal in vivo, suggesting that ISE might be a valuable medicinal food effective in improving lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Extratos Vegetais/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Agaricales/isolamento & purificação , Agaricales/metabolismo , Animais , Antioxidantes/farmacologia , Bleomicina/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Feminino , Inflamação/patologia , Interleucina-1beta/farmacologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/isolamento & purificação , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
12.
Int J Mol Med ; 44(2): 479-490, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173183

RESUMO

Acute lung injury (ALI) is a critical syndrome that is associated with a high morbidity and mortality in patients. Sevoflurane has a lung protective effect in ALI as it reportedly has anti­inflammatory and apoptotic­regulating activity. However, the mechanism is still not entirely understood. The aim of the present study was to explore the effects of sevoflurane on lipopolysaccharide (LPS)­induced ALI in mice and the possible mechanisms involved. The results revealed that sevoflurane treatment improved LPS­induced lung injury, as evidenced by the reduction in mortality, lung permeability, lung wet/dry ratio and lung histopathological changes in mice. Total cell counts and the production of pro­inflammatory cytokines [tumor necrosis factor­α, interleukin (IL)­1ß and IL­6] in bronchoalveolar fluid were also decreased following treatment with sevoflurane. Additionally, LPS­triggered apoptosis in lung tissues, which was eliminated by sevoflurane. Furthermore, a miRCURY™ LNA array was employed to screen for differentially expressed microRNAs (miRs/miRNAs). Among these miRNAs, 6 were differentially expressed and were involved in the inflammatory response, but only miR­27a­3p (miR­27a) was regulated by sevoflurane. Subsequently, the present study investigated whether sevoflurane exerts its function through the modulation of miR­27a. The results demonstrated that the overexpression of miR­27a via an injection with agomiR­27a produced similar protections as sevoflurane, while the inhibition of miR­27a suppressed the lung protective effects of sevoflurane in ALI mice. In addition, the present study identified that miR­27a inhibited Toll­like receptor 4 (TLR4) by binding to its 3'­untranslated region. Western blot analysis demonstrated that sevoflurane may ameliorate the inflammatory response by blocking the miR­27a/TLR4/MyD88/NF­κB signaling pathway. The present results indicate that sevoflurane may be a viable therapeutic option in the treatment of patients with ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , MicroRNAs/imunologia , NF-kappa B/imunologia , Sevoflurano/uso terapêutico , Receptor 4 Toll-Like/imunologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Lipopolissacarídeos/imunologia , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Fator 88 de Diferenciação Mieloide/imunologia , Sevoflurano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
13.
Respir Res ; 20(1): 131, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242908

RESUMO

BACKGROUND: Patients with acute lung injury (ALI) have increased levels of pro-inflammatory mediators, which impair endothelial progenitor cell (EPC) function. Increasing the number of EPC and alleviating EPC dysfunction induced by pro-inflammatory mediators play important roles in suppressing ALI development. Because the high density lipoprotein reverse-D-4F (Rev-D4F) improves EPC function, we hypothesized that it might repair lipopolysaccharide (LPS)-induced lung damage by improving EPC numbers and function in an LPS-induced ALI mouse model. METHODS: LPS was used to induce ALI in mice, and then the mice received intraperitoneal injections of Rev-D4F. Immunohistochemical staining, flow cytometry, MTT, transwell, and western blotting were used to assess the effect of Rev-D4F on repairment of lung impairment, and improvement of EPC numbers and function, as well as the signaling pathways involved. RESULTS: Rev-D4F inhibits LPS-induced pulmonary edema and decreases plasma levels of the pro-inflammatory mediators TNF-α and ET-1 in ALI mice. Rev-D4F inhibited infiltration of red and white blood cells into the interstitial space, reduced lung injury-induced inflammation, and restored injured pulmonary capillary endothelial cells. In addition, Rev-D4F increased numbers of circulating EPC, stimulated EPC differentiation, and improved EPC function impaired by LPS. Rev-D4F also acted via a PI3-kinase-dependent mechanism to restore levels of phospho-AKT, eNOS, and phospho-eNOS suppressed by LPS. CONCLUSIONS: These findings indicate that Rev-D4F has an important vasculoprotective role in ALI by improving the EPC numbers and functions, and Rev-D4F reverses LPS-induced EPC dysfuncion partially through PI3K/AKT/eNOS signaling pathway.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Peptídeos/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Animais , Relação Dose-Resposta a Droga , Células Progenitoras Endoteliais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia
14.
Mol Med Rep ; 20(1): 455-462, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180535

RESUMO

Acute lung injury (ALI) is a major cause of morbidity and mortality globally, and is characterized by widespread inflammation in the lungs. Increased production of reactive oxygen species is hypothesized to be associated with ALI. Matrine and lycopene are active products present in traditional Chinese medicine. Matrine is an effective inhibitor of inflammation, whereas lycopene decreases lipid peroxidation. Therefore, it was hypothesized that combinatorial treatment with matrine and lycopene may provide synergistic protection against ALI. In the present study, mice were treated with dexamethasone (DEX; 5 mg/kg), matrine (25 mg/kg), lycopene (100 mg/kg), and matrine (25 mg/kg) + lycopene (100 mg/kg) for 7 days prior to injury induction using lipopolysaccharide (LPS; 5 mg/kg) for 6 h. Lung tissues were collected following the sacrifice of the mice and hematoxylin and eosin staining was used for histological analysis. Malondialdehyde (MDA), glutathione (GSH) and myeloperoxidas (MPO) levels were examined by respective kits. The expressions of interleukin­6 (IL­6) and tumor necrosis factor­α (TNF­α) were evaluated by ELISA. The expressions of IκBα and NF­κB p65 were examined by reverse transcription­quantitative polymerase chain reaction, western blotting and immunohistochemistry. The results indicated that the combined treatment exhibited a similar effect to DEX, both of which attenuated lung structural injuries, downregulated the expressions of IL­6, TNF­α, MPO and MDA, and upregulated that of GSH. Furthermore, the combined treatment and DEX inhibited NF­κB p65 activation. The present study revealed that combined treatment with matrine and lycopene exhibited protective effects on an LPS­induced mouse model of ALI, suggesting that they may serve as a potential alternative to glucocorticoid therapy for ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Alcaloides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Licopeno/uso terapêutico , Quinolizinas/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Sinergismo Farmacológico , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
15.
BMC Complement Altern Med ; 19(1): 124, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182097

RESUMO

BACKGROUND: Troxerutin (TRX), a naturally occurring flavonoid in various fruits, has been reported to exhibit numerous pharmacological and biological activities in vitro and in vivo. However, the molecular mechanisms underlying TRX as a treatment for disease are poorly understood. METHODS: Using pharmacophore mapping and inverse docking, a set of potential TRX target proteins that have been associated with multiple forms of diseases was obtained. Bioinformatic analyses were performed using the Enrichr and STRING servers to analyse the related biological processes and protein-protein networks. Furthermore, we investigated the potential protective effect of TRX against lipopolysaccharide-induced acute lung injury (ALI) using a mouse model. Morphological changes in the lungs were assessed using haematoxylin and eosin staining. Inflammatory cytokines, tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6 and IL-10 were investigated using ELISA. Activation of MAPK and NF-κB was detected using western blotting. RESULTS: Our network pharmacology analysis revealed the existence of multiple TRX-related chemical-target interactions and the related biological processes. We found that pretreatment with TRX protected against histological changes and obviously regulated the inflammatory cell counts and inflammatory cytokine levels in bronchoalveolar lavage fluid. Based on bioinformatic and western blot analyses, TRX may exert a protective effect against ALI by inhibiting MAPK and NF-κB signalling. CONCLUSIONS: TRX can ameliorate pulmonary injury by inhibiting the MAPK and NF-κB signalling pathways and has a potential protective effect against ALI. This study may be helpful for understanding the mechanisms underlying TRX action and for discovering new drugs from plants for the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Hidroxietilrutosídeo/análogos & derivados , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Simulação por Computador , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ontologia Genética , Hidroxietilrutosídeo/farmacologia , Hidroxietilrutosídeo/uso terapêutico , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , NF-kappa B/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Edema Pulmonar/prevenção & controle
16.
Oxid Med Cell Longev ; 2019: 7283104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182998

RESUMO

Oxidative stress is an important mechanism in acute lung injury (ALI) induced by paraquat (PQ), one of the most widely used herbicides in developing countries. In clinical prophylaxis and treatment, licorice is a widely used herbal medicine in China due to its strong alexipharmic characteristics. However, the corresponding biochemical mechanism of antioxidation and detoxification enzymes induced by licorice's ingredients is still not fully demonstrated. In this study, the detoxification effect of licorice was evaluated in vivo and in vitro. The detoxification and antioxidation effect of its active ingredients involved in the treatment was screened systematically according to Absorption, Distribution, Metabolism, and Excretion (ADME): predictions and evidence-based literature mining methods in silico approach. Data shows that licorice alleviate pulmonary edema and fibrosis, decrease Malondialdehyde (MDA) contents and increase Superoxide Dismutase (SOD) activity in PQ-induced ALI mice, protect the morphologic appearance of lung tissues, induce cytochrome 3A4 (CYA3A4) and Nuclear factor erythroid 2-related factor 2 (Nrf2) expression to active detoxification pathways, reduce the accumulation of PQ in vivo, protect or improve the liver and renal function of mice, and increase the survival rate. The 104 genes of PPI network contained all targets of licorice ingredients and PQ, which displayed the two redox regulatory enzymatic group modules cytochrome P450 (CYP450) and Nrf2 via a score-related graphic theoretic clustering algorithm in silico. According to ADME properties, glycyrol, isolicoflavonol, licochalcone A, 18beta-glycyrrhetinic acid, and licoisoflavone A were employed due to their oral bioavailability (OB) ≥ 30%, drug-likeness (DL) ≥ 0.1, and being highly associated with CYP450 and Nrf2 pathways, as potential activators to halt PQ-induced cells death in vitro. Both 3A4 inhibitor and silenced Nrf2 gene decreased the alexipharmic effects of those ingredients significantly. All these disclosed the detoxification and antioxidation effects of licorice on acute lung injury induced by PQ, and glycyrol, isolicoflavonol, licochalcone A, 18beta-glycyrrhetinic acid, and licoisoflavone A upregulated CYP450 and Nrf2 pathways underlying the alexipharmic mechanisms of licorice.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Glycyrrhiza/química , Paraquat/toxicidade , Lesão Pulmonar Aguda/metabolismo , Animais , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Sistema Enzimático do Citocromo P-450 , Flavonoides/uso terapêutico , Camundongos , Fator 2 Relacionado a NF-E2
17.
Int Immunopharmacol ; 74: 105658, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177016

RESUMO

The acute respiratory distress syndrome (ARDS), a devastating clinical syndrome, is one of the most severe complications of acute lung injury (ALI). Despite of decades of clinical trials and supportive ventilation strategies, the incidence and mortality of ALI/ARDS remain high. DL-3-n-butylphthalide (NBP) is a synthesized raceme of L-3-n-butylphthalide which has been approved to possess various activities. In the current study, we aimed to investigate the effect of NBP on ALI in lipopolysaccharide (LPS)-treated mice. We found that 10 mg/kg and 50 mg/kg NBP significantly prevented LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. Sirtuin 1 (SIRT1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was increased by NBP in lung of LPS-treated mice. Knockout of SIRT1 significantly aggravated LPS-induced ALI. Moreover, the absence of SIRT1 notably inhibited NBP-induced protective effects against LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. However, knockout of SIRT1 did not completely inhibit NBP-induced upregulation of Nrf2 and attenuation of ALI. The results demonstrated that NBP could activate Nrf2 antioxidant signaling in a SIRT1-dependent and SIRT1-independent manner, resulting in the amelioration of oxidative stress, inflammation and pulmonary edema. The data highlights the importance of SIRT1/Nrf2 signaling in the protective effects of NBP.


Assuntos
Lesão Pulmonar Aguda/imunologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Fator 2 Relacionado a NF-E2/imunologia , Sirtuína 1/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Benzofuranos/uso terapêutico , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/imunologia , Edema Pulmonar/patologia , Sirtuína 1/genética
18.
Drug Des Devel Ther ; 13: 1763-1772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213766

RESUMO

Background and aim: A potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor SU5416, has been developed for the treatment of solid human tumors. The binding of VEGF to VEGFR plays a crucial role in the pathophysiology of respiratory disorders. However, the impact of SU5416 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Thus, this study aimed to illuminate the biofunction of SU5416 in the mouse model of ALI. Methods: Wild-type (WT) and toll-like receptor 4 (TLR4)-deficient (TLR4-/-) C57BL/6 mice were used to establish LPS-induced ALI model. The primary pulmonary microvascular endothelial cell (PMVEC) was extracted for detection of endothelial barrier function. Results: LPS significantly increased the number of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In addition, LPS increased alveolar epithelial cells injury, inflammation infiltration and vascular permeability of PMVEC in WT and TLR4-/- mice. Western blotting experiment indicated VEGF/VEGFR and TLR4/NF-κB pathways were involved in the progression of LPS-stimulated ALI. Consistent with previous research, dexamethasone treatment appeared to be an effective therapeutic for mice with ALI. Moreover, treatment with SU5416 dramatically attenuated LPS-induced immune responses in mice lung tissues via inhibiting VEGF/VEGFR and TLR4/NF-κB pathways. Finally, SU5416 also decreased vascular permeability of PMVEC in vitro. Conclusion: SU5416 ameliorated alveolar epithelial cells injury and histopathological changes in mice lung via inhibiting VEGF/VEGFR and TLR4/NF-κB signaling pathways. We also confirmed that SU5416 could restrain vascular permeability in PMVEC through improving the integrity of endothelial cell. These findings suggested that SU5416 may serve as a potential agent for the treatment of patients with ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Indóis/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Pirróis/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/metabolismo
19.
Mar Drugs ; 17(6)2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31213027

RESUMO

Activated human monocytes/macrophages, which increase the levels of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines, are the essential mechanisms for the progression of sepsis. In the present study, we determined the functions and mechanisms of hirsutanolA (HA), which is isolated from the red alga-derived marine fungus Chondrostereum sp. NTOU4196, on the production of pro-inflammatory mediators produced from lipopolysaccharide (LPS)-treated THP-1 cells. Our results showed that HA suppressed LPS-triggered MMP-9-mediated gelatinolysis and expression of protein and mRNA in a concentration-dependent manner without effects on TIMP-1 activity. Also, HA significantly attenuated the levels of TNF-α, IL-6, and IL-1ß from LPS-treated THP-1 cells. Moreover, HA significantly inhibited LPS-mediated STAT3 (Tyr705) phosphorylation, IκBα degradation and ERK1/2 activation in THP-1 cells. In an LPS-induced endotoxemia mouse model, studies indicated that HA pretreatment improved endotoxemia-induced acute sickness behavior, including acute motor deficits and anxiety-like behavior. HA also attenuated LPS-induced phospho-STAT3 and pro-MMP-9 activity in the hippocampus. Notably, HA reduced pathologic lung injury features, including interstitial tissue edema, infiltration of inflammatory cells and alveolar collapse. Likewise, HA suppressed the induction of phospho-STAT3 and pro-MMP-9 in lung tissues. In conclusion, our results provide pharmacological evidence that HA could be a useful agent for treating inflammatory diseases, including sepsis.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Citocinas/metabolismo , Comportamento de Doença/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Sesquiterpenos/farmacologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Linhagem Celular Tumoral , Endotoxemia/complicações , Endotoxemia/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo
20.
Biomed Res Int ; 2019: 2193706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205936

RESUMO

The regulation of intracellular mitochondria degradation is mediated by mitophagy. While studies have shown that mitophagy can lead to mitochondrial dysfunction and cell damage, the role of Mdivi-1 and mitophagy remains unclear in acute lung injury (ALI) pathogenesis. In this study, we demonstrated that Mdivi-1, which is widely used as an inhibitor of mitophagy, ameliorated acute lung injury assessed by HE staining, pulmonary microvascular permeability assay, measurement of wet/dry weight (W/D) ratio, and oxygenation index (PaO2/FiO2) analysis. Then, the mitophagy related proteins were evaluated by western blot. The results indicated that LPS-induced activation of mitophagy was inhibited by Mdivi-1 treatment. In addition, we found that Mdivi-1 protected A549 cells against LPS-induced mitochondrial dysfunction. We also found that Mdivi-1 reduced pulmonary cell apoptosis in the LPS-challenged rats and protected pulmonary tissues from oxidative stress (represented by the content of superoxide dismutase, malondialdehyde and lipid peroxides in lung). Moreover, Mdivi-1 treatment ameliorated LPS-induced lung inflammatory response and cells recruitment. These findings indicate that Mdivi-1 mitigates LPS-induced apoptosis, oxidative stress, and inflammation in ALI, which may be associated with mitophagy inhibition. Thus, the inhibition of mitophagy may represent a potential therapy for treating ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Mitocôndrias/metabolismo , Quinazolinonas/farmacologia , Células A549 , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/toxicidade , Masculino , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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