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1.
Neural Regen Res ; 20(3): 845-857, 2025 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38886957

RESUMO

JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

2.
Chin J Integr Med ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38941044

RESUMO

Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.

3.
Neural Regen Res ; 18(5): 1040-1045, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36254990

RESUMO

Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue (cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.

4.
Front Pharmacol ; 13: 908830, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814200

RESUMO

Plant exosome-like nanoparticles (ELNs) have shown great potential in treating tumor and inflammatory diseases, but the neuroprotective effect of plant ELNs remains unknown. In the present study, we isolated and characterized novel ELNs from Momordica charantia (MC) and investigated their neuroprotective effects against cerebral ischemia-reperfusion injury. In the present study, MC-ELNs were isolated by ultracentrifugation and characterized. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) and MC-ELN injection intravenously. The integrity of the blood-brain barrier (BBB) was examined by Evans blue staining and with the expression of matrix metalloproteinase 9 (MMP-9), claudin-5, and ZO-1. Neuronal apoptosis was evaluated by TUNEL and the expression of apoptotic proteins including Bcl2, Bax, and cleaved caspase 3. The major discoveries include: 1) Dil-labeled MC-ELNs were identified in the infarct area; 2) MC-ELN treatment significantly ameliorated BBB disruption, decreased infarct sizes, and reduced neurological deficit scores; 3) MC-ELN treatment obviously downregulated the expression of MMP-9 and upregulated the expression of ZO-1 and claudin-5. Small RNA-sequencing revealed that MC-ELN-derived miRNA5266 reduced MMP-9 expression. Furthermore, MC-ELN treatment significantly upregulated the AKT/GSK3ß signaling pathway and attenuated neuronal apoptosis in HT22 cells. Taken together, these findings indicate that MC-ELNs attenuate ischemia-reperfusion-induced damage to the BBB and inhibit neuronal apoptosis probably via the upregulation of the AKT/GSK3ß signaling pathway.

5.
Chin J Nat Med ; 16(10): 756-765, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30322609

RESUMO

Liver injury remains a significant global health problem and has a variety of causes, including oxidative stress (OS), inflammation, and apoptosis of liver cells. There is currently no curative therapy for this disorder. Sanwei Ganjiang Prescription (SWGJP), derived from traditional Chinese medicine (TCM), has shown its effectiveness in long-term liver damage therapy, although the underlying molecular mechanisms are still not fully understood. To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view, in the present study, a systems pharmacology approach was developed, which involved drug target identification and multilevel data integration analysis. Using a comprehensive systems approach, we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets. We further deciphered the mechanisms of SWGJP in treating liver injury, including compound-target network analysis, target-function network analysis, and integrated pathways analysis. We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway, such as Nrf2-dependent anti-oxidative stress module. Notably, systems pharmacology provides an alternative way to investigate the complex action mode of TCM.


Assuntos
Medicamentos de Ervas Chinesas/química , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/lesões , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Farmacologia
6.
Acta Pharmacol Sin ; 39(5): 669-682, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29595191

RESUMO

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO-), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-ß-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.


Assuntos
Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/fisiopatologia , Caveolina 1/metabolismo , Caveolina 1/fisiologia , Humanos , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/fisiologia , Momordica charantia/química , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Nitrogênio/fisiologia , Acidente Vascular Cerebral/fisiopatologia
7.
BMC Med Educ ; 17(1): 221, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29157232

RESUMO

BACKGROUND: Interprofessional learning is gaining momentum in revolutionizing healthcare education. During the academic year 2015/16, seven undergraduate-entry health and social care programs from two universities in Hong Kong took part in an interprofessional education program. Based on considerations such as the large number of students involved and the need to incorporate adult learning principles, team-based learning was adopted as the pedagogy for the program, which was therefore called the interprofessional team-based learning program (IPTBL). The authors describe the development and implementation of the IPTBL program and evaluate the effectiveness of the program implementation. METHODS: Eight hundred and one students, who are predominantly Chinese, participated in the IPTBL. The quantitative design (a pretest-posttest experimental design) was utilized to examine the students' gains on their readiness to engage in interprofessional education (IPE). RESULTS: Three instructional units (IUs) were implemented, each around a clinical area which could engage students from complementary health and social care disciplines. Each IU followed a team-based learning (TBL) process: pre-class study, individual readiness assurance test, team readiness assurance test, appeal, feedback, and application exercise. An electronic platform was developed and was progressively introduced in the three IUs. The students' self-perceived attainment of the IPE learning outcomes was high. Across all four subscales of RIPLS, there was significant improvement in student's readiness to engage in interprofessional learning after the IPTBL. A number of challenges were identified: significant time involvement of the teachers, difficulty in matching students from different programs, difficulty in making IPTBL count towards a summative assessment score, difficulty in developing the LAMS platform, logistics difficulty in managing paper TBL, and inappropriateness of the venue. CONCLUSIONS: Despite some challenges in developing and implementing the IPTBL program, our experience showed that TBL is a viable pedagogy to be used in interprofessional education involving hundreds of students. The significant improvement in all four subscales of RIPLS showed the effects of the IPTBL program in preparing students for collaborative practice. Factors that contributed to the success of the use of TBL for IPE are discussed.


Assuntos
Ocupações em Saúde/educação , Relações Interprofissionais , Estudantes de Ciências da Saúde , Disciplinas das Ciências Biológicas/educação , Comportamento Cooperativo , Feminino , Hong Kong , Humanos , Masculino , Medicina Tradicional Chinesa , Serviço Social/educação , Universidades , Adulto Jovem
8.
Curr Neuropharmacol ; 15(1): 134-156, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27334020

RESUMO

Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke treatment, but its clinical use is limited due to the narrow therapeutic time window and severe adverse effects, including hemorrhagic transformation (HT) and neurotoxicity. One of the potential resolutions is to use adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window. However, therapies modulating single target seem not to be satisfied, and a multitarget strategy is warranted to resolve such complex disease. Recently, large amount of efforts have been made to explore the active compounds from herbal supplements to treat ischemic stroke. Some natural compounds revealed both neuro- and bloodbrain- barrier (BBB)-protective effects by concurrently targeting multiple cellular signaling pathways in cerebral ischemia-reperfusion injury. Thus, those compounds are potential to be one-drug-multi-target agents as combined therapy with t-PA for ischemic stroke. In this review article, we summarize current progress about molecular targets involving in t-PA-mediated HT and neurotoxicity in ischemic brain injury. Based on these targets, we select 23 promising compounds from currently available literature with the bioactivities simultaneously targeting several important molecular targets. We propose that those compounds merit further investigation as combined therapy with t-PA. Finally, we discuss the potential drawbacks of the natural compounds' studies and raise several important issues to be addressed in the future for the development of natural compound as an adjunct therapy.


Assuntos
Produtos Biológicos/uso terapêutico , Acidente Vascular Cerebral/terapia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Animais , Ácido Ascórbico , Isquemia Encefálica/complicações , Quimioterapia Combinada , Flavonoides , Humanos , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
9.
CNS Neurosci Ther ; 21(7): 585-90, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25996167

RESUMO

AIM: Hemorrhagic transformation (HT) is a major complication of delayed tissue plasminogen activator (t-PA) treatment in ischemic stroke. We aimed to explore whether peroxynitrite decomposition catalyst (PDC) could prevent such complication. METHODS: Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) with t-PA (10 mg/kg) or t-PA plus FeTMPyP (3 mg/kg, a representative PDC) at MCAO for 2 or 5 h and reperfusion for 22 or 19 h, respectively. HT was assessed with hemoglobin assay. Neurological deficit was evaluated with Modified Neurological Severity Score (mNSS). Peroxynitrite formation was examined by detecting 3-nitrotyrosine (3-NT) formation. The expression and activity of MMP-9/MMP-2 were assessed by Western blotting and gelatin zymography. RESULTS: t-PA treatment at 2 h of MCAO did not induce HT but attenuated neurological deficit, whereas treatment at 5 h significantly induced HT and worsened the neurological outcome. Such complications were prevented by FeTMPyP cotreatment. Early t-PA treatment inhibited 3-NT and MMP-9/MMP-2 expression, whereas delayed treatment induced 3-NT and MMP-9/MMP-2 expression and activity. FeTMPyP cotreatment downregulated 3-NT and inhibited MMP-9/MMP-2 in both time points. CONCLUSION: Peroxynitrite decomposition catalyst could prevent hemorrhagic transformation and improve neurological outcome ischemic rat brains with delayed t-PA treatment via inhibiting peroxynitrite-mediated MMP activation.


Assuntos
Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Ácido Peroxinitroso/uso terapêutico , Ativador de Plasminogênio Tecidual/efeitos adversos , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Doenças do Sistema Nervoso/etiologia , Ratos , Ratos Sprague-Dawley , Reperfusão , Índice de Gravidade de Doença
10.
Environ Toxicol Pharmacol ; 38(1): 279-87, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24998504

RESUMO

Our previous study has demonstrated that naringin attenuates EGF-induced MUC5AC hypersecretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways. However, the volume of airway mucus is determined by two factors including the number of mucous cells and capacity of mucus secretion. The aim of the present study is to explore the mucoactive effects of naringin in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and beagle dogs. The results demonstrated that naringin of 12.4 mg/kg treatment significantly decreased LPS-induced enhancement of sputum volume and pulmonary inflammation, remarkably increased the subglottic sputum volume and solids content in sputum of lower trachea, while partially, but not fully, significantly increased the elasticity and viscosity of sputum in lower trachea of beagle dogs. Moreover, the MUC5AC content in BALF and goblet-cells in large airways of LPS-induced ALI mice were significantly attenuated by dexamethasone (5 mg/kg), ambroxol (25 mg/kg), and naringin (15, 60 mg/kg). However, the goblet-cells hyperplasia in small airways induced by LPS was only significantly inhibited by dexamethasone and naringin (60 mg/kg). In conclusion, naringin exhibits mucoactive effects through multiple targets which including reduction of goblet cells hyperplasia and mucus hypersecretion, as well as promotion of sputum excretion.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Flavanonas/farmacologia , Muco/metabolismo , Pneumonia/metabolismo , Escarro/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Cães , Elasticidade , Feminino , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Hiperplasia/induzido quimicamente , Hiperplasia/imunologia , Hiperplasia/metabolismo , Interleucina-8/imunologia , Contagem de Leucócitos , Lipopolissacarídeos , Masculino , Camundongos , Mucina-5AC/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Escarro/química , Fator de Necrose Tumoral alfa/imunologia , Viscosidade
11.
Oncol Lett ; 8(1): 17-24, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24959213

RESUMO

Our previous study demonstrated that inhibition of erythropoietin-producing hepatoma cell line-B2 (EphB2) expression resulted in the promotion of cancer growth, with EphB2 acting as a tumor suppressor in pancreatic cancer. Qingyihuaji formula (QYHJ), a traditional Chinese medicine, acts as an independent protective factor for pancreatic cancer patient survival and different patients have shown various responses to QYHJ treatment. In the current study, the different effects on tumor growth inhibition following QYHJ treatment in cells with different levels of EphB2 expression were investigated to reveal the mechanism. A subcutaneously transplanted tumor model using cancer cells with different levels of EphB2 expression were established in vivo and received a four-week QYHJ intervention. Tumor weight inhibitory rate and tumor volume deflation were evaluated. The cell cycle and apoptosis were analyzed by flow cytometry, and reverse transcription polymerase chain reaction and western blot analysis were used to assess mRNA and protein levels. The results showed that the tumor weight inhibitory rate was 31.40, 31.33 and 18.36% in CFPAC-1, CFPAC-1 control RNAi and CFPAC-1 EphB2 RNAi cells following QYHJ treatment, respectively. A statistically significant difference was identified in CFPAC-1 (P<0.05) and CFPAC-1 control RNAi (P<0.01) cells. In addition, a statistically significant increase was identified in the G0/G1 phase population (P<0.05) and a statistically significant decrease was identified in the S phase population (P<0.05) in CFPAC-1 and CFPAC-1 control RNAi cells; however, no significant difference was identified in the CFPAC-1 EphB2 RNAi cells following QYHJ treatment. QYHJ upregulated the mRNA and protein level of Eph receptor-interacting B1 (EphrinB1) in the cells that were expressing different levels of EphB2, however, QYHJ did not regulate EphB2 expression. In CFPAC-1 and CFPAC-1 control RNAi cells, the QYHJ treatment resulted in a statistically significant decrease in cyclin-dependent kinase 6 (CDK6) mRNA (P<0.05) and protein (P<0.05) levels. The high expression of EphB2 predicted the superior response rate to the QYHJ treatment through a mechanism of inhibiting the cell cycle by an EphrinB1-EphB2-induced CDK6 decrease in CFPAC-1 cells. Therefore, EphB2 acts as a predictive factor for QYHJ treatment in pancreatic cancer CFPAC-1 cells.

12.
Asian Pac J Cancer Prev ; 14(10): 5761-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24289575

RESUMO

The potential correlation of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism with hepatocellular carcinoma (HCC) susceptibility is ambiguous. Taking account of inconsistent results of previous meta-analyses and new emerging literatures, we conducted a meta-analysis covering 15 case-control datasets to evaluate the relationship. Relevant studies from Medline, Embase and CNKI were retrieved. A fixed- effect model or a random-effect model, depending on between-study heterogeneity, were applied to estimate the association between XRCC1 polymorphism Arg399Gln and HCC risk with the results presented as odds ratios (ORs) and 95% confidence intervals (95% CIs). In accordance with Hardy-Weinberg equilibrium, 15 studies with data for 6,556 individuals were enrolled in this systematic review. For overall HCC,thr XRCC1 polymorphism Arg399Gln was significantly associated with HCC susceptibility in a homozygote model as well as in a dominant model (G/G vs. A/A, OR=1.253, p=0.028; G/G+A/G vs. A/A, OR= 1.281, p=0.047, respectively), but not in a heterozygote model (A/G vs. A/A, OR=1.271, p=0.066) or a recessive model (G/G vs. A/G + A/A, OR= 1.049, p=0.542). Similar results were also observed on stratification analysis by ethnicity (A/G vs. A/A, OR=1.357, p=0.025; G/G vs. A/A, OR=1.310, p=0.011; G/G+A/G vs. A/A, OR= 1.371, p=0.013). However, no potential contribution of XRCC1 Arg399Gln polymorphism to HCC susceptibility in HBV/HCV subgroups was identified. No publication bias was found in this study. In conclusion, the XRCC1 Arg399Gln polymorphism contributes to HCC susceptibility. Due to the lack of studies in Western countries, further large-sample and rigorous studies are needed to validate the findings.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Humanos , Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
14.
Food Chem Toxicol ; 58: 133-40, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23603004

RESUMO

The present study evaluates protective effects of naringin against paraquat (PQ)-induced acute lung injury (ALI) and pulmonary fibrosis in mice. Survival probability against PQ intoxication was tested by a single intraperitoneal injection of PQ. Results showed that survival rates of mice exposed to PQ only (50 mg/kg within 7 days) were much lower than that in mice daily treatment with NAC or naringin. Moreover, protection against PQ-induced ALI was tested by daily pretreatment mice with saline, NAC or naringin for 3 days before PQ (30 mg/kg, i.p.). Results showed that increase in leukocytes infiltration and overexpressions of TNF-α and TGF-ß1 caused by 8h of PQ exposure were dose-dependently ameliorated by naringin. Furthermore, protection against PQ-induced pulmonary fibrosis was tested by pretreatment mice with PQ (20 mg/kg, i.p.), and then daily administration with saline, NAC or naringin for prolonged 21 days. Results showed that naringin of 60 and 120 mg/kg significantly reduced PQ-induced upregulations of TNF-α, TGF-ß1, MMP-9 and TIMP-1, levels of pulmonary malonaldehyde and hydroxyproline, as well as pulmonary fibrosis deposition, while increased activities of SOD, GSH-Px and HO-1. These results indicated that naringin had effective protection against PQ-induced ALI and pulmonary fibrosis.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Flavanonas/farmacologia , Herbicidas/toxicidade , Paraquat/toxicidade , Fibrose Pulmonar/prevenção & controle , Lesão Pulmonar Aguda/prevenção & controle , Animais , Antioxidantes/metabolismo , Sequência de Bases , Citocinas/metabolismo , Primers do DNA , Relação Dose-Resposta a Droga , Feminino , Heme Oxigenase-1/metabolismo , Masculino , Camundongos , Estresse Oxidativo , Reação em Cadeia da Polimerase em Tempo Real
15.
Acta Pharmacol Sin ; 34(1): 67-77, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22842734

RESUMO

Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOO(-)) in ischemic brain, which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage. There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage. Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury. Herein, we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONOO(-) to treat ischemic stroke. We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemia-reperfusion injury.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Descoberta de Drogas/métodos , Terapia de Alvo Molecular/métodos , Espécies Reativas de Nitrogênio/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Humanos
16.
J Med Food ; 15(10): 894-900, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22985397

RESUMO

Naringin, a well-known flavanone glycoside of grapefruit and citrus fruits, was found to be as an effective anti-inflammatory compound in our previous lipopolysaccharide-induced acute lung injury mouse model via blockading activity of nuclear factor κB. The current study sought to explore the anti-inflammatory effects of naringin on chronic pulmonary neutrophilic inflammation in cigarette smoke (CS)-induced rats. Seventy Sprague-Dawley rats were randomly divided into seven groups to study the effects of CS with or without various concentrations of naringin or saline for 8 weeks. The results revealed that naringin supplementation at 20, 40, and 80 mg/kg significantly increased body weight of CS-induced rats as compared to that in the CS group. Moreover, naringin of 20, 40, and 80 mg/kg prevented CS-induced infiltration of neutrophils and activation of myeloperoxidase and matrix metalloproteinase-9, in parallel with suppression of the release of cytokines, such as tumor necrosis factor-α and interleukin-8 (IL-8). IL-10 in bronchoalveolar lavage fluid was significantly suppressed after CS exposure, but dose dependently elevated by naringin. The results from hematoxylin and eosin staining revealed that naringin dose dependently reduced CS-induced infiltration of inflammatory cells, thickening of the bronchial wall, and expansion of average alveolar airspace. In conclusion, our data suggest that naringin is an effective anti-inflammatory compound for attenuating chronic pulmonary neutrophilic inflammation in CS-induced rats.


Assuntos
Anti-Inflamatórios/farmacologia , Flavanonas/farmacologia , Neutrófilos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Fumar/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar/química , Feminino , Interleucina-10/antagonistas & inibidores , Interleucina-10/metabolismo , Interleucina-8/antagonistas & inibidores , Interleucina-8/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Neutrófilos/patologia , Peroxidase/genética , Peroxidase/metabolismo , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
17.
Eur J Pharmacol ; 690(1-3): 207-13, 2012 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-22766066

RESUMO

Naringenin, the aglycone of naringin, has been reported to attenuate MUC5AC secretion by inhibiting activity of nuclear factor kappa B (NF-κB) via EGFR-PI3K-Akt/ERK MAPKinase signaling pathways. However, previous studies demonstrated that the MUC5AC promoter was located in two different regions: an activator protein-1 (AP-1) binding site and a NF-κB binding site. The current study comprehensively determined the involvement of MAPKs/AP-1 and IKKs/IκB/NF-κB in epidermal growth factor (EGF)-induced A549 cells, and sought to ascertain the signaling pathways of naringin imparted in suppression of EGF-induced MUC5AC secretion. The results showed that naringin of 100 µM not only significantly decreased EGF-induced overexpressions of both MUC5AC mucin and mRNA in A549 cells, but also suppressed the phosphorylation of EGF receptor, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK), as well as nucleus NF-κB p65 and AP-1. Moreover, any of three MAPKs inhibitors (PD98059, SB203580, and SP600125) significantly inhibited EGF-induced MUC5AC secretion. And as compared to MG132, the inhibitor κB (IκB) phosphorylation inhibitor of SN50 was more effective in reducing EGF-induced MUC5AC secretion because of suppression of nucleus AP-1. Meanwhile, as compared to naringin, both SP600125 and azithromycin were less effective in suppressing EGF-induced secretion of MUC5AC because of the unchanged nucleus NF-κB p65. These results indicated that naringin attenuates EGF-induced MUC5AC secretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways.


Assuntos
Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/farmacologia , Flavanonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mucina-5AC/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Quinase I-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Pulm Pharmacol Ther ; 25(5): 349-56, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22732689

RESUMO

There is a need of in vivo COPD models for mucus hypersecretion study. The current study compared three rat models induced by cigarette smoke (CS) exposure alone or combined with pre- or post-treatment with lipopolysaccharide (LPS). Forty rats were randomly divided into the four following groups: control group, LPS + CS group (CS exposure for 4-wk combined with LPS pretreatment), CS group (CS exposure for 6-wk), CS + LPS group (CS exposure for 6-wk combined with LPS post-treatment). The results showed that both CS and CS + LPS groups had more severe pro-inflammatory cytokines secretion, inflammatory cells infiltration, and emphysema as compared to that in LPS + CS group animals. From the PAS staining sections, we found a remarkable hyperplasia of goblet-cell in epitheliums of trachea, bronchi, and bronchiole of all of three modeling groups, especially in CS and CS + LPS groups. From the western-blotting results, there were significant increase in the activities of NF-κB, AP-1, EGFR, TLR4, and MAPKs in all of three modeling groups, while HDAC2 activity was remarkably repressed in CS group only. Moreover, the expression and secretion of MUC5AC were exhibited significant increase in all of three modeling groups, which correlated well with the total transcription activity integration of NF-κB, AP-1, and HDAC2 (r = 0.946, p < 0.01). These results indicated that MUC5AC hypersecretion is consistent with activation of EGFR-AP-1/NF-κB and TLR4-AP-1/NF-κB signaling pathways, as well as repression of HDAC2 activity. Based on these results, we speculated that the 6-wk CS exposure rat model is a reliable COPD rat model, while the 6-wk CS exposure combined with LPS post-treatment rat model is a suitable COPD exacerbation model for mucus hypersecretion study.


Assuntos
Brônquios/metabolismo , Lipopolissacarídeos/toxicidade , Muco/metabolismo , Nicotiana/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumaça/efeitos adversos , Animais , Modelos Animais de Doenças , Receptores ErbB/fisiologia , Histona Desacetilase 2/fisiologia , Masculino , Mucina-5AC/genética , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/fisiologia , Fator de Transcrição RelA/metabolismo
19.
Int Immunopharmacol ; 13(3): 301-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22575871

RESUMO

Naringin is a flavanone with various bioactivities including expectorant effect, antitussive effect and inhibitory effects on asthma and acute lung injury. In present study we examined the effects of naringin on enhanced cough, airway hyperresponsiveness (AHR) and airway inflammation in chronic cigarette smoke (CS) exposure-induced chronic bronchitis in guinea pigs. To achieve this, guinea pigs were exposed to CS for 8weeks (10cigarettes/day, 6days/week). Oral administration of naringin (9.2, 18.4 and 36.8mg/kg) significantly attenuated the enhanced cough and AHR in smoke-exposed guinea pigs, reduced the concentrations of interleukin-8 (IL-8), leukotriene B4 (LTB4) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF) and decreased the myeloperoxidase (MPO) activity in both BALF and lung tissue, but did not significantly decrease the leukocytes in BALF. Naringin also improved superoxidase dismutase (SOD) activity in lung tissue and increased the content of lipoxin A4 (LXA4) in BALF in this guinea pig model of chronic bronchitis. These results suggested that naringin exhibited antitussive, anti-AHR and anti-inflammation effects on chronic CS exposure-induced chronic bronchitis in guinea pigs, and may possess novel therapeutic potential in the treatment of chronic bronchitis.


Assuntos
Bronquite Crônica/tratamento farmacológico , Flavanonas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antitussígenos/farmacologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/fisiopatologia , Bronquite Crônica/etiologia , Bronquite Crônica/fisiopatologia , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocinas/metabolismo , Tosse/tratamento farmacológico , Tosse/etiologia , Tosse/fisiopatologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Cobaias , Humanos , Masculino , Peroxidase/metabolismo , Fumaça/efeitos adversos , Fumar/efeitos adversos , Superóxido Dismutase/metabolismo , Nicotiana
20.
Breast Cancer Res Treat ; 134(3): 943-55, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22350787

RESUMO

Anti-angiogenesis targeting VEGFR-2 has been considered as an important strategy for cancer therapy. Ellagic acid is a naturally existing polyphenol widely found in fruits and vegetables. It was reported that ellagic acid interfered with some angiogenesis-dependent pathologies. Yet the mechanisms involved were not fully understood. Thus, we analyzed its anti-angiogenesis effects and mechanisms on human breast cancer utilizing in-vitro and in-vivo methodologies. The in-silico analysis was also carried out to further analyze the structure-based interaction between ellagic acid and VEGFR-2. We found that ellagic acid significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR-2 tyrosine kinase activity and its downstream signaling pathways including MAPK and PI3K/Akt in endothelial cells. Ellagic acid also obviously inhibited neo-vessel formation in chick chorioallantoic membrane and sprouts formation of chicken aorta. Breast cancer xenografts study also revealed that ellagic acid significantly inhibited MDA-MB-231 cancer growth and P-VEGFR2 expression. Molecular docking simulation indicated that ellagic acid could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR-2 kinase unit. Taken together, ellagic acid could exert anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias da Mama/metabolismo , Ácido Elágico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Trifosfato de Adenosina/química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Sítios de Ligação , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácido Elágico/química , Ativação Enzimática/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Carga Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Ensaios Antitumorais Modelo de Xenoenxerto
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