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1.
J Ethnopharmacol ; 247: 112275, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31589966

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is a terrible microvascular disorder causing blindness. Retinal inflammation is the early stage in DR, which is believed to play a crucial role in the development of it. Shengpuhuang-tang (ST), a traditional herbal formula, which has effective treatment of fundus bleeding disorder. ST exerts protective effects against DR in rats, but its underlying mechanism of this efficacy remains unknown. Thus, the objective of this study is to examine the mechanism and the efficacy of ST on retinal inflammation in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The administration of ST was initiated at 4 weeks after diabetes induction and continued for 12 weeks. Retinal vessel permeability was evaluated by using FITC-dextran and Evans blue. Retinal leukostasis was evaluated with FITC-coupled concanavalin A lectin (ConA). Moreover, western blotting was performed to detect TNF-α, ICAM-1 and the relative expression levels of IκBα, IKKß, and p65 in vivo. RESULTS: The results showed that the retinal inflammation in streptozotocin-induced diabetic rats was significantly decreased by ST. ST could decreased the expression levels of TNF-α, ICAM-1 and inhibited the expression of p-IKKß, p-p65 and IκBα. It could also inhibited the nuclear transfer of p65. CONCLUSIONS: In conclusion, these data suggested that ST may have potential treatment strategies against early stage of diabetic retinopathy through NF-κB pathway.


Assuntos
Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Leucostasia/tratamento farmacológico , Vasos Retinianos/efeitos dos fármacos , Administração Oral , Animais , Capilares/efeitos dos fármacos , Capilares/metabolismo , Capilares/patologia , Permeabilidade Capilar/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Leucostasia/etiologia , Masculino , NF-kappa B/imunologia , NF-kappa B/metabolismo , Ratos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Estreptozocina/toxicidade
2.
Oxid Med Cell Longev ; 2019: 1202676, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531177

RESUMO

Malaysian Tualang honey (TH) is a known therapeutic honey extracted from the honeycombs of the Tualang tree (Koompassia excelsa) and has been reported for its antioxidant, anti-inflammatory, antiproliferative, and wound healing properties. However, the possible vascular protective effect of TH against oxidative stress remains unclear. In this study, the effects of TH on hydrogen peroxide- (H2O2-) elicited vascular hyperpermeability in human umbilical vein endothelial cells (HUVECs) and Balb/c mice were evaluated. Our data showed that TH concentrations ranging from 0.01% to 1.00% showed no cytotoxic effect to HUVECs. Induction with 0.5 mM H2O2 was found to increase HUVEC permeability, but the effect was significantly reversed attenuated by TH (p < 0.05), of which the permeability with the highest inhibition peaked at 0.1%. In Balb/c mice, TH (0.5 g/kg-1.5 g/kg) significantly (p < 0.05) reduced H2O2 (0.3%)-induced albumin-bound Evans blue leak, in a dose-dependent manner. Immunofluorescence staining confirmed that TH reduced actin stress fiber formation while increasing cortical actin formation and colocalization of caveolin-1 and ß-catenin in HUVECs. Signaling studies showed that HUVECs pretreated with TH significantly (p < 0.05) decreased intracellular calcium release, while sustaining the level of cAMP when challenged with H2O2. These results suggested that TH could inhibit H2O2-induced vascular hyperpermeability in vitro and in vivo by suppression of adherence junction protein redistribution via calcium and cAMP, which could have a therapeutic potential for diseases related to the increase of both oxidant and vascular permeability.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Mel , Células Endoteliais da Veia Umbilical Humana/metabolismo , Peróxido de Hidrogênio/farmacologia , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Malásia , Fibras de Estresse/metabolismo , Fibras de Estresse/patologia
3.
Magnes Res ; 32(1): 16-24, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31503002

RESUMO

The blood-brain barrier (BBB) tightly regulates the homeostasis of the central nervous system, and its dysfunction has been described in several neurological disorders. Since magnesium exerts a protective effect in the brain, we assessed whether supraphysiological concentrations of different magnesium salts modulate the permeability and magnesium transport in in vitro models of rat and human BBB. Among various formulations tested, magnesium pidolate was the most efficient in reducing the permeability and in enhancing magnesium transport through the barrier. We then compared magnesium pidolate and magnesium sulfate, a widely used salt in experimental models and in clinical practice. Magnesium pidolate performs better than sulfate also in preventing lipopolysaccharide-induced damage to in vitro generated BBB. We conclude that magnesium pidolate emerges as an interesting alternative to sulfate to protect BBB and maintain correct intracerebral concentrations of magnesium.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Compostos de Magnésio/farmacocinética , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Técnicas de Cultura de Células , Células Cultivadas , Células Endoteliais/metabolismo , Humanos , Compostos de Magnésio/química , Compostos de Magnésio/farmacologia , Ratos
4.
Int J Mol Med ; 44(3): 1078-1090, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524227

RESUMO

The aim of the present study was to explore the possible mechanisms by which hypertonic saline (HS) effectively ameliorates cerebral oedema via the vascular endothelial growth factor receptor 2 (VEGFR2)­mediated endothelial nitric oxide synthase (eNOS) pathway of endothelial cells in rats. A middle cerebral artery occlusion (MCAO) model in Sprague­Dawley rats and an oxygen­glucose deprivation (OGD) model in cells were used in the present study. Evans blue (EB) staining and a horseradish peroxidase flux assay were performed to evaluate the protective effect of 10% HS on the blood­brain barrier (BBB). The expression levels of vascular endothelial growth factor (VEGF), VEGFR2, zonula occludens 1 (ZO1) and occludin were quantified. The results demonstrated that 10% HS effectively reduced EB extravasation in the peri­ischaemic brain tissue. At 24 h after MCAO, the protein expression levels of VEGF and VEGFR2 in the peri­ischaemic brain tissue were downregulated following treatment with 10% HS. In vitro experiments demonstrated that the permeability of a monolayer endothelial cell barrier was decreased significantly following HS treatment. In addition, VEGF and VEGFR2 protein expression levels were increased in endothelial cells under hypoxic conditions, but that effect was suppressed by HS treatment. Furthermore, HS inhibited the downregulation of ZO1 and occludin effectively, possibly through the VEGFR2/phospholipase C γ1 (PLCγ1)/eNOS signalling pathway. In conclusion, 10% HS may alleviate cerebral oedema through reducing ischaemia­induced BBB permeability, as a consequence of inhibiting VEGFR2/PLCγ1/eNOS­mediated downregulation of ZO1 and occludin.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Solução Salina Hipertônica/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Biomarcadores , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Permeabilidade , Ratos , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Am J Chin Med ; 47(6): 1237-1251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31495180

RESUMO

Inhalation of fine particulate matter (PM2.5) is associated with elevated pulmonary injury caused by the loss of vascular barrier integrity. Black ginseng (BG), steamed and dried ginseng nine times, exhibits various pharmacological activities such as antibacterial, antihyperglycemic, anti-atopic, antibacterial, and anti-inflammatory activities. In this study, we investigated the beneficial effects of black ginseng extract (BGE) against PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated ECs and mice. BGE significantly scavenged PM2.5-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase (MAPK). Concurrently, BGE activated Akt, which helped maintain endothelial integrity. Furthermore, BGE reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid in PM-induced lung tissues. These results indicated that BGE may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability.


Assuntos
Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Panax/química , Material Particulado/efeitos adversos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos BALB C , Extratos Vegetais/isolamento & purificação , Pneumonia/etiologia , Pneumonia/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Mol Carcinog ; 58(12): 2316-2326, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31553086

RESUMO

Primary tumor can induce the formation of premetastatic niche. The hyperpermeability of the vessels in the premetastatic niche is the first step in the development of metastasis. However, the cellular and molecular mechanisms of vascular hyperpermeability remain to be elucidated. In this study, 4T1 breast cells were injected into the breasts of mice to establish a tumor model. Our results showed that primary tumors induced hyperpermeability of the vessels in the premetastatic lung. Subsequent studies showed that the level of vascular endothelial growth factor (VEGF) was elevated in the tumor-bearing mice serum and the levels of tight junction (TJ) proteins occludin and ZO-1 were decreased in the premetastatic lung. In vitro studies demonstrated that VEGF increased the permeability of dextran and decreased the levels of occludin and ZO-1 in human umbilical vein endothelial cells. Moreover, the hyperpermeability of vessels and the degradation of occludin was blocked by bevacizumab. Overexpression of occludin alleviated the VEGF-induced hyperpermeability. Further investigations revealed that VEGF-induced occludin phosphorylation at Ser-490 and ubiquitination. Finally, we showed that VEGF accelerated the process of occludin degradation through the ubiquitin-proteasome system. In conclusion, primary tumor-secrete VEGF induce the occludin phosphorylation/ubiquitination and downregulation, resulting in the disruption of TJs and hyperpermeability of vessels in premetastatic lung. The occludin phosphorylation/ubiquitination pathway may be the mechanism of VEGF-induced vascular hyperpermeability in the lung premetastatic niche.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Experimentais/metabolismo , Ocludina/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Camundongos Endogâmicos BALB C , Mutação de Sentido Incorreto , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Ocludina/genética , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Ubiquitinação/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Biosci Biotechnol Biochem ; 83(12): 2280-2287, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31412751

RESUMO

The increasing number of patients suffering from allergic diseases is a global health problem. Grifola frondosa is an edible mushroom consumed as a health food in Asia, and has recently been reported to have anti-allergic effects. We previously reported that G. frondosa extract (GFE) and its active components, ergosterol and its derivatives, inhibited the antigen-induced activation of RBL-2H3 cells. Here, we demonstrated that GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow-derived mast cells (BMMCs) and alleviated anaphylactic cutaneous responses in mice. Using an air pouch-type allergic inflammation mouse model, we confirmed that oral administration of GFE and ergosterol suppressed the degranulation of mast cells in vivo. Our findings suggest that G. frondosa, including ergosterol as its active component, reduces type I allergic reactions by suppressing mast cell degranulation in mice, and might be a novel functional food that prevents allergic diseases.


Assuntos
Degranulação Celular/efeitos dos fármacos , Ergosterol/farmacologia , Grifola/química , Hipersensibilidade/prevenção & controle , Mastócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Alimento Funcional , Liberação de Histamina/efeitos dos fármacos , Hipersensibilidade/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
8.
Invest Ophthalmol Vis Sci ; 60(10): 3547-3555, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415078

RESUMO

Purpose: Current treatments for diabetic retinopathy (DR) have considerable limitations, underpinning the need for new therapeutic options. In this article, the ability of an engineered angiopoietin-1 variant (COMP-Ang1) to ameliorate the injurious effects of hyperglycemia on barrier integrity in a human retinal microvascular endothelial cell (HRMvEC) model is comprehensively investigated. Methods: Confluent HRMvECs were treated (0-72 hours) with d-glucose (5 or 30 mM) in the absence and presence of COMP-Ang1 (10-200 ng/mL). l-glucose (30 mM) was used as osmotic control. Posttreatment, intact cell monolayers were monitored for permeability to FITC-dextran 40 kDa. Cells were also harvested for analysis of interendothelial junction targets by RT-qPCR and Western blotting. The impact of receptor tyrosine kinase Tie2 gene silencing on COMP-Ang1 efficacy was also evaluated. Results: Treatment with 30 mM d-glucose (but not l-glucose) demonstrated a time-dependent elevation in the mean rate of FITC-dextran diffusion across intact HRMvEC monolayers, in parallel with significant reductions in mRNA/protein levels of occludin, claudin-5, ZO-1, and VE-Cadherin. These effects were all attenuated by COMP-Ang1 in a concentration-dependent fashion, with 200 ng/mL recovering barrier function by ∼88%, and recovering reduced interendothelial junction protein levels by more than 50%. Finally, Tie2 knockdown by small interfering RNA silencing blocked the ability of COMP-Ang1 to mitigate against hyperglycemia-induced permeabilization of HRMvECs and depletion of junctional expression levels. Conclusions: In summary, this article presents a reproducible in vitro cell study that quantifies the concentration-dependent efficacy of COMP-Ang1 to mitigate the injurious effects of hyperglycemic challenge on HRMvEC barrier properties via Tie2-mediated signaling.


Assuntos
Barreira Hematorretiniana/fisiologia , Células Endoteliais/efeitos dos fármacos , Hiperglicemia/prevenção & controle , Proteínas Recombinantes de Fusão/farmacologia , Vasos Retinianos/efeitos dos fármacos , Antígenos CD/genética , Western Blotting , Caderinas/genética , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Claudina-5/genética , Dextranos/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Inativação Gênica/fisiologia , Glucose/farmacologia , Humanos , Hiperglicemia/metabolismo , Ocludina/genética , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor TIE-2/genética , Vasos Retinianos/metabolismo
9.
Int J Mol Med ; 44(4): 1255-1266, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432099

RESUMO

The primary mechanism underlying sepsis­induced cardiac dysfunction is loss of endothelial barrier function. Neuregulin­1 (NRG­1) exerts its functions on multiple targets. The present study aimed to identify the protective effects of NRG­1 in myocardial cells, including endothelial, anti­inflammatory and anti­apoptotic effects. Subsequent to lipopolysaccharide (LPS)­induced sepsis, rats were administered with either a vehicle or recombinant human NRG­1 (rhNRG­1; 10 µg/kg/day) for one or two days. H9c2 cardiomyoblasts were subjected to LPS (10 µg/ml) treatment for 12 and 24 h with or without rhNRG­1 (1 µg/ml). Survival rates were recorded at 48 h following sepsis induction. The hemodynamic method was performed to evaluate cardiac function, and myocardial morphology was observed. Von Willebrand Factor levels were detected using an immunofluorescence assay. Serum levels of tumor necrosis factor α, interleukin­6, intercellular cell adhesion molecule­1 and vascular endothelial growth factor were detected using an enzyme­linked immunosorbent assay; the reductase method was performed to detect serum nitric oxide levels. Apoptosis rates were determined using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Ras homolog family member A (RhoA) and Rho­associated protein kinase 1 (ROCK1) protein levels were assessed using western blotting. Transmission electron microscopy was used to observe endothelial cells and myocardial ultrastructure changes. Results revealed that NRG­1­treated rats displayed less myocardial damage compared with sham rats. NRG­1 administration strengthened the barrier function of the vasculature, reduced the secretion of endothelial­associated biomarkers and exerted anti­inflammatory and anti­apoptotic effects. In addition, NRG­1 inhibited RhoA and ROCK1 signaling. The results revealed that NRG­1 improves cardiac function, increases the survival rate of septic rats and exerts protective effects via multiple targets throughout the body. The present results contribute to the development of a novel approach to reverse damage to myocardial and endothelial cells during sepsis.


Assuntos
Cardiotônicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Neuregulina-1/farmacologia , Sepse/complicações , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/metabolismo , Cardiopatias/tratamento farmacológico , Cardiopatias/mortalidade , Testes de Função Cardíaca , Humanos , Mediadores da Inflamação , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Ratos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia
10.
Int Immunopharmacol ; 75: 105802, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401380

RESUMO

Dihydroberberine (DHB), a hydrogenated derivative of berberine (BBR), has been firstly identified in Phellodendri Chinese Cortex (PC) by HPLC-ESI-MS/MS. Nowadays most researches on PC focus on its main components like BBR, however, the role of its naturally-occurring derivatives remains poorly defined heretofore. The present work aimed to comparatively evaluate the in vivo anti-inflammatory properties and mechanisms of DHB and BBR in three typical inflammatory murine models. The results showed that DHB effectively mitigated acetic acid-induced vascular permeability, xylene-elicited ear edema and carrageenan-caused paw edema. Meanwhile, DHB markedly attenuated the inflammatory cell infiltration in pathological sections of ears and paws. DHB was also observed to significantly decrease the production and mRNA expression levels of IL-6, IL-1ß, TNF-α, NO (iNOS) and PGE2 (COX-2), increase the release of IL-10, and inhibit the activation of NF-κB and MAPK signaling pathways. The anti-inflammatory effect of DHB was weaker than that of BBR. The results might further contribute to unraveling the pharmacodynamic basis of PC and support its ethnomedical use in the treatment of inflammatory diseases. DHB possesses good potential to be further developed into a promising anti-inflammatory alternative, and can serve as a lead template for novel anti-inflammatory candidate.


Assuntos
Anti-Inflamatórios/farmacologia , Berberina/análogos & derivados , Edema/metabolismo , Ácido Acético , Animais , Anti-Inflamatórios/uso terapêutico , Berberina/farmacologia , Berberina/uso terapêutico , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Citocinas/genética , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/imunologia , Feminino , Pé/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , NF-kappa B/metabolismo , Phellodendron , Casca de Planta , Xilenos
11.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443389

RESUMO

Alcohol exerts significant immunomodulatory effects on innate and adaptive immune responses, impairing host defense against infections. Gut-mucosa-derived dendritic cells (DCs) traffic to mesenteric lymph nodes (MLNs) through mesenteric lymphatic vessels (MLVs), contributing to intestinal antigen homeostasis. Previously, we demonstrated that acute alcohol administration to male rats induces MLV hyperpermeability resulting in perilymphatic adipose tissue (PLAT) inflammation and insulin signaling dysregulation. We hypothesized that alcohol-induced MLV hyperpermeability can lead to DC leakage to PLAT. DCs promote adipose tissue regulatory T cell (Treg) expansion, and this has been proposed as a mechanism underlying age-associated insulin resistance (IR). The aim of this study was to determine whether chronic alcohol consumption promotes DC leakage to PLAT and results in metabolic dysregulation. Male rats received a Lieber-DeCarli liquid diet containing 36% of calories from alcohol for 10 weeks. Time-matched control animals were pair-fed. PLAT, MLNs, and peripheral blood leukocytes (PBLs) were isolated for flow cytometry analyses. PLAT explants were used for determinations of insulin-induced glucose uptake. Chronic alcohol consumption decreased MLN CD4/CD8 ratio and Treg frequency in PBLs. Alcohol increased the frequency of DCs, CD4 T cells, and Tregs in PLAT. Lastly, alcohol decreased insulin-stimulated glucose uptake in PLAT. Collectively, these findings suggest that alcohol-induced immune cell deviation from the gut-MLN pathway is associated with PLAT immunometabolic dysregulation. Whether this immune cell deviation impacts induction of mucosal immunity warrants further investigation.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Etanol/farmacologia , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/metabolismo , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Consumo de Bebidas Alcoólicas , Animais , Relação CD4-CD8 , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Ratos , Circulação Esplâncnica , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
12.
Inflammation ; 42(5): 1901-1912, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31273573

RESUMO

Acute respiratory distress syndrome (ARDS) is a severe acute disease that threatens human health, and few drugs that can effectively treat this disease are available. Fraxin, one of the main active ingredients of Cortex Fraxini, a Chinese herbal medicine, has presented various pharmacological and biological activities. However, the effects of fraxin on ARDS have yet to be reported. In the present study, the protective effect of fraxin in lipopolysaccharide (LPS)-induced ARDS in a mouse model was analyzed. Results from the hematoxylin and eosin staining showed that fraxin might alleviate pathological changes in the lung tissues of mice with ARDS. ELISA and Western blot results revealed that fraxin might inhibit the production of inflammatory factors, namely, IL-6, TNF-α, and IL-1ß, and the activation of NF-κB and MAPK signaling pathways in the lungs. Thus, the inflammatory responses were reduced. Fraxin might inhibit the increase in reactive oxygen species (ROS) and malondialdehyde (MDA), a product of lipid peroxidation in lung tissues. Fraxin might increase the superoxide dismutase (SOD) activity to avoid oxidative damage. Vascular permeability was also assessed through Evans blue dye tissue extravasation and fluorescein isothiocyanate-labeled albumin (FITC-albumin) leakage. Fraxin might inhibit the increase in pulmonary vascular permeability and relieve pulmonary edema. Fraxin was also related to the inhibition of the increase in matrix metalloproteinase-9, which is a glycocalyx-degrading enzyme, and the relief of damages to the endothelial glycocalyx. Thus, fraxin elicited protective effects on mice with LPS-induced ARDS and might be used as a drug to cure ARDS induced by Gram-negative bacterial infection.


Assuntos
Cumarínicos/farmacologia , Síndrome do Desconforto Respiratório do Adulto/prevenção & controle , Animais , Permeabilidade Capilar/efeitos dos fármacos , Cumarínicos/uso terapêutico , Regulação para Baixo , Glicocálix/metabolismo , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico
13.
Int Rev Neurobiol ; 146: 103-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349925

RESUMO

Bradykinin is a mediator of vasogenic brain edema formation. Recent reports suggest that bradykinin interacts with nitric oxide synthase (NOS) system in the central nervous system (CNS). However, role of bradykinin in spinal cord injury (SCI) induced alterations in the blood-spinal cord barrier (BSCB), spinal cord blood flow (SCBF), edema formation and cell changes are still not well known. Our previous reports showed that SCI induces marked upregulation of neuronal NOS (nNOS) in the cord associated with BSCB disruption, edema formation and cell injury. Thus, a possibility exists that bradykinin participates in SCI induced nNOS upregulation and cord pathology. To explore this idea a potent bradykinin B2 receptor antagonist HOE-140 was used in our rat model of SCI and cord pathology. SCI was inflicted in Equithesin anesthetized rats by making a longitudinal incision (2mm deep and 5mm long) into the right dorsal horn of the T10-11 segment. The animals were allowed to survive 5h after injury. A focal SCI significantly disrupted BSCB to Evans blue and [131]I-sodium in the traumatized and adjacent segments. Interestingly, far remote spinal cord segments C4 and T5 segments also affected within 5h. These spinal cord segments also exhibited pronounced reductions in the SCBF (mean-30%), increased edematous swelling and profound neuronal damages. Upregulation of nNOS expression is seen in both the dorsal and ventral horns of the spinal cord exhibiting cord pathology. At the ultrastructural level, exudation of lanthanum is seen within the endothelial cell cytoplasm and occasionally in the basal lamina. Pretreatment with low doses of HOE-140 (0. 1mg to 1mg/kg, i.v.) 30min prior to SCI significantly enhanced the SCBF and reduced the BSCB disruption, edema formation, nNOS upregulation and cell injury. However, HOE-140 in doses ranging from 2mg to 5mg/kg, i.v. did not induce significant neuroprotection. These observations are the first to suggest that bradykinin B2 receptors play an important role in BSCB permeability, SCBF, edema formation, nNOS upregulation and cell injury following acute SCI, not reported earlier.


Assuntos
Bradicinina/análogos & derivados , Permeabilidade Capilar/efeitos dos fármacos , Edema/fisiopatologia , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Traumatismos da Medula Espinal/prevenção & controle , Animais , Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Azul Evans/metabolismo , Masculino , Ratos , Iodeto de Sódio/metabolismo , Medula Espinal/irrigação sanguínea , Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Regulação para Cima/efeitos dos fármacos
14.
Int Rev Neurobiol ; 146: 153-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349926

RESUMO

Spinal cord injury (SCI) is a devastating disease inflicting lifetime disability to the victims. Military personnel are quite often victims of SCI for which no suitable therapeutic strategies have been developed so far. The main reason for SCI induced disability is loss of neural connections below and above the lesion site causing motor paralysis and somatosensory disturbances Loss of neuronal connections thwart spinal cord conduction resulting in motor function disability. To enhance spinal cord conduction grafting of peripheral nerves, implant of hydrogels filled with neuroprotective drugs is used but so far, no satisfactory results re achieved. In this regards implants of microelectrode for enhancing tissue connectivity is suggested that is still under experimental state. We have used titanium implant with or without TiO2 nanowires in a focal spinal cord injury and studies spinal cord pathology and motor function. In addition, we also combined with nanowired delivery of a potential neuroprotective drug DL-3-n-butylphthalide (DL-NBP) to the spinal cord in a rat model. Our observations show that a combination of titanium implant with nanowired delivery of DL-NBP induces superior neuroprotection and enhance motor functions after SCI. This treatment also restored blood-spinal cord barrier (BSCB) function and reduces edema formation and cell injury after SCI, not reports earlier.


Assuntos
Benzofuranos/farmacologia , Permeabilidade Capilar/fisiologia , Edema/fisiopatologia , Locomoção/fisiologia , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal/prevenção & controle , Titânio/farmacologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Implantes de Medicamento/farmacologia , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Masculino , Nanoestruturas/química , Nanofios/química , Ratos , Traumatismos da Medula Espinal/fisiopatologia , Titânio/química
15.
Aquat Toxicol ; 214: 105224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255847

RESUMO

Polybrominated diphenyl ethers (PBDEs) are distributed throughout the environment. Despite a moratorium on their use, concentrations of PBDEs in the atmosphere and in residential environments remain high due to their persistence. The environmental health risks remain concerning and one of the major adverse effects is neurodevelopmental toxicity. However, the early response and effects of PBDEs exposure on the developing brain remain unknown. In the present study, we investigated the impacts of 2,2',4,4',5-pentabrominated diphenyl ether (BDE-99) on vascular growth and vascular barrier function with an emphasis on cerebral blood vessels, in the early life stages, using a zebrafish model. No general toxicity was observed in exposing zebrafish larvae to 0-0.5 µM BDE-99 at 72 hpf. BDE-99 exposure resulted in neither general toxicity nor pronounced developmental impairment in somatic blood vessels, including intersegmental vessels (ISV) and common cardinal veins (CCV). Meanwhile, both 0.05 µM and 0.5 µM of BDE-99 reduced cerebrovascular density as well as down-regulation of VEGFA and VEGFR2 in the head. In addition, BDE-99 exposure increased vascular leakage, both in cerebral and truncal vasculature at 72 hpf. The accentuated vascular permeability was observed in the head. The mRNA levels of genes encoding tight junction molecules decreased in the BDE-99-exposed larvae, and more robust reductions in Cldn5, Zo1 and Jam were detected in the head than in the trunk. Moreover, proinflammatory factors including TNF-α, IL-1ß and ICAM-1 were induced, and the expression of neurodevelopment-related genes was suppressed in the head following BDE-99 exposure. Taken together, these results reveal that developmental exposure to BDE-99 impedes cerebrovascular growth and disturbs vascular barrier formation. The cerebral vasculature in developing zebrafish, a more sensitive target for BDE-99, may be a promising tool for the assessment of the early neurodevelopmental effects due to PBDEs exposure.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Exposição Ambiental , Éteres Difenil Halogenados/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Encéfalo/irrigação sanguínea , Encéfalo/crescimento & desenvolvimento , Permeabilidade Capilar/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inflamação/genética , Inflamação/patologia , Larva/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética
16.
Physiol Res ; 68(4): 675-679, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31177801

RESUMO

Chemokine (C-X-C motif) receptor 4 (CXCR4) agonists have been shown to protect lung endothelial barrier function in vitro. In vivo effects of CXCR4 modulation on lung endothelial permeability are unknown. Here we tested the effects of the CXCR4 agonist ubiquitin and the antagonist AMD3100 on lung vascular permeability and cytokine concentrations in a rat hemorrhage model. Animals were hemorrhaged (mean arterial blood pressure 30 mmHg for 30 min), treated with vehicle, ubiquitin (0.7 and 3.5 µmol/kg) or AMD3100 (3.5 µmol/kg), and resuscitated with crystalloids. Evans blue extravasation was employed to quantify lung vascular permeability. Ubiquitin dose-dependently reduced Evans blue extravasation into the lung. AMD3100 increased Evans blue extravasation. With AMD3100, TNFalpha levels in lung homogenates were increased; while TNFalpha levels were lower with ubiquitin, these differences did not reach statistical significance. Our findings suggest that CXCR4 regulates lung vascular permeability and further point towards CXCR4 as a drug target to confer lung protection during resuscitation from traumatic-hemorrhagic shock.


Assuntos
Permeabilidade Capilar/fisiologia , Receptores CXCR4/fisiologia , Mucosa Respiratória/metabolismo , Ressuscitação , Choque Hemorrágico/metabolismo , Choque Hemorrágico/terapia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores CXCR4/agonistas , Receptores CXCR4/antagonistas & inibidores , Mucosa Respiratória/efeitos dos fármacos , Ressuscitação/tendências , Ubiquitina/farmacologia
17.
Exp Eye Res ; 186: 107695, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31201804

RESUMO

Activated protein C (APC) exerts diverse cell signaling pathways which results in multiple distinct cytoprotective actions. These include anti-apoptotic and anti-inflammatory activities and stabilization of endothelial and epithelial barriers. We studied the ability of APC to inhibit the leakage and the growth of newly formed as well as pre-existing choroidal neovascularization (CNV) and examined the ability of APC to stabilize the Retinal Pigmented Epithelium (RPE). We explored the contribution of Tie2 receptor to the protective effects of APC. CNV was induced by laser photocoagulation in C57BL/6J mice. APC was injected intravitreally immediately or 7 days after CNV induction. Neovascularization was evaluated on RPE-choroidal flatmounts using FITC-dextran perfusion and CD31 immunofluorescence. CNV leakage was measured by fluorescein angiography (FA). The ability of APC to stabilize the RPE barrier was evaluated in-vitro by dextran permeability and zonula occludens 1 (ZO1) immunostaining. Tie2 blocking was induced in-vivo by intraperitoneal injection of Tie2 kinase inhibitor and in-vitro by incubation with anti Tie2 antibodies. APC treatment dramatically inhibited the generation of newly formed CNV leakage sites and reversed leakage in 85% of the pre-existing CNV leaking sites. In RPE cell culture, APC induced translocation of ZO1 to the cell membrane, accompanied by reduction in permeability of the monolayer. Inhibition of Tie2 significantly decreased APC protective activities in both the mouse model and the RPE cell culture. Our results show that APC treatment significantly inhibits the leakage and growth of newly formed, as well as pre-existing CNV, and its protective activities are partially mediated via the Tie2 receptor. The data suggest that APC should be further investigated as a possible effective treatment for CNV.


Assuntos
Anti-Infecciosos/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Modelos Animais de Doenças , Proteína C/uso terapêutico , Animais , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade da Membrana Celular , Corioide/irrigação sanguínea , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/fisiopatologia , Relação Dose-Resposta a Droga , Angiofluoresceinografia , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/uso terapêutico , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
18.
BMC Res Notes ; 12(1): 307, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146784

RESUMO

OBJECTIVE: The microenvironment of outer retina is largely regulated by retinal pigment epithelium (RPE) and choroid. Damage to either of these layers lead to the development of age related macular degeneration (AMD). A simplified cell culture model that mimics the RPE/Bruch's membrane (BM) and choroidal layers of the eye is a prerequisite for elucidating the molecular mechanism of disease progression. RESULTS: We have isolated primary retinal pigment epithelial cells (hRPE) and human primary choroidal endothelial cells (hCEC) from donor eyes to construct a bilayer of hCEC/hRPE on transwell inserts. Secretion of VEGF in the insert grown bilayer was significantly higher (22 pg/ml) than hCEC monolayer (3 pg/ml). To mimic the disease condition the model was treated with 100 ng/ml of VEGF, which increased the permeability of bilayer for 20 kDa FITC dextran while addition of bevacizumab, a humanized anti-VEGF drug, reversed the effect. To conclude the transwell insert based human primary hCEC/hRPE bilayer model would be an ideal system for studying the disease mechanisms and the crosstalk between RPE and choroid. This model will also be useful in screening small molecules and performing drug permeability kinetics.


Assuntos
Lâmina Basilar da Corioide/metabolismo , Técnicas de Cultura de Células/métodos , Células Endoteliais/metabolismo , Células Epiteliais/metabolismo , Adulto , Inibidores da Angiogênese/farmacologia , Bevacizumab/farmacologia , Lâmina Basilar da Corioide/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Corioide/citologia , Células Endoteliais/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Modelos Biológicos , Epitélio Pigmentado da Retina/citologia , Doadores de Tecidos , Fator A de Crescimento do Endotélio Vascular/farmacologia
19.
Inflammation ; 42(4): 1504-1510, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102123

RESUMO

In the present study, we aimed to investigate the effects of puerarin on the hyperpermeability of vascular endothelial cells induced by lipopolysaccharide (LPS) and its underlying mechanisms. Human umbilical vein endothelial cells (HUVECs) were pre-incubated with puerarin (25, 50, and 100 µM) for 1 h, and then exposed to LPS (1 µg/mL). The monolayer permeability of endothelial cells was assessed by measuring the paracellular flux of FITC-dextran 40,000 (FD40). The expression of vascular endothelial cadherin (VE-cadherin) in HUVECs was examined by Western blotting analysis. A total of 18 mice were randomly assigned into three groups as follows: control group, LPS group, and puerarin group. The pulmonary W/D ratio (wet-to-dry weight ratios) was calculated, and the lung morphology was examined. The levels of TNF-α and IL-1ß in cell supernatant and mouse serum were determined by ELISA. Compared with the control group, LPS obviously increased the flux of FD40 and the monolayer permeability, raised the levels of TNF-α and IL-1ß in cell supernatant, and reduced the VE-cadherin expression in HUVECs. However, puerarin (25, 50, and 100 µM) was able to relieve such LPS-induced increase in flux of FD40 and then reduce the hyperpermeability. Puerarin decreased the levels of TNF-α and IL-1ß in cell supernatant and increased the VE-cadherin expression in HUVECs (P < 0.05). Moreover, LPS obviously increased the levels of TNF-α and IL-1ß in mouse serum and elevated the pulmonary W/D ratios, resulting in lung injury. However, all of above-mentioned LPS-induced changes were improved by puerarin pre-treatment. Puerarin could alleviate LPS-induced hyperpermeability in endothelial cells via preventing downregulation of endothelial cadherin.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Isoflavonas/farmacologia , Animais , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-1beta/análise , Interleucina-1beta/metabolismo , Isoflavonas/uso terapêutico , Lipopolissacarídeos/farmacologia , Camundongos , Substâncias Protetoras , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Vasodilatadores
20.
Cell Mol Neurobiol ; 39(6): 883-898, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31140018

RESUMO

Increasing evidences have shown that resveratrol could protect the brain from ischemic injury; the mechanisms underlying its neuroprotective effects are multifactorial and not fully understood. It remains unclear whether resveratrol could exert neuroprotection through modulating gut-brain axis, which plays important roles in stroke pathology. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 3 days. Resveratrol, when applied immediately after MCAO onset for 3 days, promoted Th1/Th2 balance towards Th2 polarization and skewed Treg/Th17 balance towards Treg in the small intestinal lamina propria (SI-LP), and decreased small intestinal pro-inflammatory cytokines expression through modulating intestinal flora at 3 days post-ischemia (dpi). Resveratrol attenuated cerebral ischemia-induced increase in the epithelial and vascular permeability of small intestine as evidenced by reduced evans blue extravasasion and decreased protein leakage by feces/plasma albumin ratio at 3 dpi. The blood levels of pro-inflammatory cytokines at 3 dpi were also attenuated by resveratrol due to inhibiting intestinal pro-inflammatory immunity and decreasing epithelial and vascular permeability. Resveratrol robustly protected against post-stroke inflammation-induced blood-brain barrier disruption not only in the cortex but also in the striatum at 3 dpi. Furthermore, resveratrol mediated smaller cerebral infarcts and less neurological deficits via decreasing the levels of pro-inflammatory cytokines in the peri-infarct area at 3 dpi. Our results for the first time demonstrated that resveratrol may inhibit systemic post-stroke inflammation and neuroinflammation via modulating intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift in SI-LP, which may be one of the mechanisms underlying the neuroprotective effects of resveratrol.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/patologia , Trato Gastrointestinal/patologia , Neuroproteção , Traumatismo por Reperfusão/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/imunologia , Isquemia Encefálica/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/sangue , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Inflamação/imunologia , Inflamação/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neuroproteção/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/fisiopatologia , Resveratrol/farmacologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
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