RESUMO
BACKGROUND: The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown. METHODS: Angiotensin II (490 ng·kg-1·min-1) or deoxycorticosterone acetate (DOCA) salt-induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction [PCR] analysis), vascular remodeling (studied by haematoxylin and eosin and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate [NADPH] oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2+ cells in normotensive controls and hypertension patients were analyzed by flow cytometry. RESULTS: Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45+ CXCR2+ cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2-/-) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2-/- bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2+ proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20). CONCLUSIONS: Infiltration of CXCR2+ cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.
Assuntos
Angiotensina II/farmacologia , Hipertensão/prevenção & controle , Receptores de Interleucina-8B/biossíntese , Regulação para Cima/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hipertensão/genética , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/genética , Regulação para Cima/genética , Remodelação Vascular/genéticaRESUMO
CONTEXT: Silicosis is a devastating, irreversible lung fibrosis condition exposed to crystalline silica. The mononuclear phagocyte system plays an important role in the pathogenesis of silicosis. OBJECTIVE: The present study was aimed to explore the dynamic changes of mononuclear phagocytes in circulating, pulmonary alveolar and interstitial compartments in experimental silicosis model. MATERIALS AND METHODS: A mouse model of lung fibrosis was developed with crystalline silica particles (2 mg/40 µL via oropharyngeal instillation) using male C57BL/6 mice, and were killed on days 1, 3, 7, 14, and 28. The lung inflammation and fibrosis was investigated using hematoxylin-eosin staining and bronchoalveolar lavage fluid (BALF) analysis, Masson's trichrome staining, and immunofluorescence. Circulating monocyte subsets (Ly6C(hi) and Ly6C(lo)), polarization state of BALF-derived alveolar macrophages (AMÏ) and lung interstitial macrophages (IMÏ, derived from enzymatically digested lung tissue) were analyzed by flow cytometry. RESULTS: The percentage of Ly6C(hi) monocytes significantly increased on day 1 after silica exposure, which reached the peak level from day 7 till day 28. Moreover, M2 (alternative activation) AMÏ (PI - CD64 + CD206+) was dramatically and progressively increased from day 1 to day 28. A parallel increase in IMÏ with M2 polarization (PI-CD64 + CD11b + CD206+) was also observed from day 1 to day 28. CONCLUSION: Our data demonstrate a dynamic view of mononuclear phagocyte change in three compartments after silica challenge, which highlights the remodeling of mononuclear phagocyte system as a potential therapeutic target for silicosis.
Assuntos
Líquido da Lavagem Broncoalveolar/citologia , Pulmão/patologia , Macrófagos Alveolares/patologia , Monócitos/patologia , Alvéolos Pulmonares/patologia , Silicose/patologia , Animais , Antígenos Ly/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Alvéolos Pulmonares/imunologia , Silicose/sangue , Silicose/imunologiaRESUMO
Emerging evidence suggests a potential role of neutrophil extracellular traps (NETs) in linking sterile inflammation and thrombosis. We hypothesized that NETs would be induced during myocardial ischemia-reperfusion (I/R), and NET-mediated microthrombosis may contribute to myocardial "no-reflow". Male Wistar rats were randomly divided into I/R control, DNase (DNase I, 20 µg/rat), recombinant tissue-type plasminogen activator (rt-PA, 420 µg/rat), DNase + rt-PA, and sham control groups after 45-min myocardial ischemia. In situ NET formation, the anatomic "no re-flow" area, and infarct size were evaluated immediately after 3 h of reperfusion. Long-term left ventricular (LV) functional and histological analyses were performed 45 days after operation. Compared with the I/R controls, the DNase + rt-PA group exhibited reduced NET density [8.38 ± 1.98 vs. 26.86 ± 3.07 (per 200 × field), P < 0.001] and "no-flow" area (15.22 ± 0.06 vs. 34.6 ± 0.05%, P < 0.05) in the ischemic region, as well as reduced infarct size (38.39 ± 0.05 vs. 71.00 ± 0.03%, P < 0.001). Additionally, compared with the I/R controls, DNase + rt-PA treatment significantly ameliorated I/R injury-induced LV remodeling (LV ejection fraction: 64.22 ± 3.37 vs. 33.81 ± 2.98%, P < 0.05; LV maximal slope of the LV systolic pressure increment: 3,785 ± 216 vs. 2,596 ± 299 mmHg/s, P < 0.05). The beneficial effect was not observed in rats treated with DNase I or rt-PA alone. Our study provides evidence for the existence of NETs in I/R-challenged myocardium and confirms the long-term benefit of a novel DNase-based reperfusion strategy (DNase I + rt-PA), which might be a promising option for the treatment of myocardial I/R injury and coronary no-reflow.
Assuntos
Desoxirribonucleases/farmacologia , Armadilhas Extracelulares/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Reperfusão Miocárdica/métodos , Neutrófilos/efeitos dos fármacos , Fenômeno de não Refluxo/tratamento farmacológico , Animais , Desoxirribonucleases/uso terapêutico , Masculino , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Fenômeno de não Refluxo/diagnóstico por imagem , Ativadores de Plasminogênio/farmacologia , Ativadores de Plasminogênio/uso terapêutico , Ratos , Ratos Wistar , UltrassonografiaRESUMO
OBJECTIVE: This study was aimed to investigate the toxic effects of 3 nanomaterials, i.e. multi-walled carbon nanotubes (MWCNTs), graphene oxide (GO), and reduced graphene oxide (RGO), on zebrafish embryos. METHODS: The 2-h post-fertilization (hpf) zebrafish embryos were exposed to MWCNTs, GO, and RGO at different concentrations (1, 5, 10, 50, 100 mg/L) for 96 h. Afterwards, the effects of the 3 nanomateria on spontaneous movement, heart rate, hatching rate, length of larvae, mortality, and malformations ls were evaluated. RESULTS: Statistical analysis indicated that RGO significantly inhibited the hatching of zebrafish embryos. Furthermore, RGO and MWCNTs decreased the length of the hatched larvae at 96 hpf. No obvious morphological malformation or mortality was observed in the zebrafish embryos after exposure to the three nanomaterials. CONCLUSION: MWCNTs, GO, and RGO were all toxic to zebrafish embryos to influence embryos hatching and larvae length. Although no obvious morphological malformation and mortality were observed in exposed zebrafish embryos, further studies on the toxicity of the three nanomaterials are still needed.
Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Grafite/toxicidade , Nanotubos de Carbono/toxicidade , Óxidos/toxicidade , Animais , Embrião não Mamífero , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Movimento/efeitos dos fármacos , Testes de Toxicidade , Peixe-ZebraRESUMO
The dissipation of metaldehyde on cabbage and in soil was studied and half-life (DT(50)) was estimated in a field study carried out at three different locations. Metaldehyde was sprayed on cabbage at 937.5 and 1406.25 ga.i.ha(-1) for residue study and 1,875 ga.i.ha(-1) for dissipation study in cabbage and soil. Samples of cabbage and soil for dissipation experiment were collected at 0, 1, 2, 3, 5, 7, 14 and 21 days after treatment. For residue studies, cabbage and soil samples were sampled at 5, 7 and 10 days after treatment. Quantification of residues was done by LC-MS/MS. The DT(50) of metaldehyde in cabbage and soil were 0.48-1.61 days and 0.75-1.02 days, respectively, when applied at 2 times of the recommended high dosage. Residues of metaldehyde in cabbage were all below the maximum residue levels of 1.0 mg kg(-1) at both recommended high dosage and 1.5 times the recommended high dosage.
Assuntos
Acetaldeído/análogos & derivados , Brassica/química , Moluscocidas/análise , Resíduos de Praguicidas/análise , Poluentes do Solo/análise , Acetaldeído/análise , Acetaldeído/química , Meia-Vida , Moluscocidas/química , Resíduos de Praguicidas/química , Solo/química , Poluentes do Solo/química , Espectrometria de Massas em TandemRESUMO
Transglutaminase (TGase) was cross-linked with glutaraldehyde, and cross-linked crystalline transglutaminase was immobilized on a polypropylene microporous membrane by UV-induced grafting. Immobilized enzyme activity were calculated to be 0.128 U/cm² polypropylene microporous membrane. The microstructure and enzyme characteristics of free, cross-linked and immobilized transglutaminase were compared. The optimum temperature of free transglutaminase was determined to be approximately 40 °C, while cross-linking and immobilization resulted in an increase to approximately 45 °C and 50 °C. At 60 °C, immobilized, cross-linked and free transglutaminase retained 91.7 ± 1.20%, 63.2 ± 1.05% and 37.9 ± 0.98% maximum activity, respectively. The optimum pH was unaffected by the state of transglutaminase. However, the thermal and pH stabilities of cross-linked and immobilized transglutaminase were shown to increase.
Assuntos
Reagentes de Ligações Cruzadas/metabolismo , Enzimas Imobilizadas/metabolismo , Enzimas Imobilizadas/ultraestrutura , Membranas Artificiais , Polipropilenos/química , Transglutaminases/metabolismo , Transglutaminases/ultraestrutura , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Porosidade , TemperaturaRESUMO
The title compound, C(29)H(28)O(9), was isolated from the reaction of 4,6-dimeth-oxy-2-(4-methoxy-phen-yl)-3-benzofuran and α-methoxy-carbonyl-cinnaminate. The two aromatic rings form a dihedral angle of 22.7â (1)°. One methoxy-carbonyl group is disordered between two orientations in a 0.612â (4):0.388â (4) ratio. The crystal structure exhibits no significantly short inter-molecular contacts.
RESUMO
The title compound, C(19)H(12)F(3)NO(4), was synthesized by the reaction of 5-(4-fluoro-phen-yl)-2-furan-methanol and 2,6-difluoro-benzoyl-isocyanate. The seven atoms of the fluorophenyl group are disordered over two positions with site occupancy factors ca 0.6 and 0.4. The dihedral angle between the furan and fluorophenyl rings is 1.58°. In the crystal structure, the mol-ecules are linked via inter-molecular N-Hâ¯O hydrogen bonds to form chains.
RESUMO
AIMS/OBJECTIVE: Atherosclerosis is a progressive disease of large arteries characterized with chronic inflammation and aberrant immune response. Pseudolaric acid B (PB) has been found to exert multiple effects by inhibiting inflammatory response. However, there is no comprehensive assessment of the effects of PB on atherosclerosis using relevant in vivo and in vitro models. MATERIAL AND METHODS: Male ApoE-/- mice were treated with PB orally with a high fat diet (HFD) to clarify its anti-atherosclerotic activities. RAW264.7 macrophage line, a well-accepted cell model of atherosclerosis, was used to investigate anti-inflammatory effects and molecular mechanisms of PB. RESULTS: PB significantly attenuated atherosclerotic lesions by modulating plasma lipid profiles as well as inhibiting inflammatory responses in macrophages of atherosclerotic mice. Meanwhile, PB markedly suppressed the expression of pro-inflammatory cytokines, and regulated cholesterol efflux related genes in oxidative low density lipoprotein (ox-LDL)-loaded macrophages. The cellular uptake of Dil-labeled ox-LDL was significantly inhibited by PB either. Moreover, the ability of PB to suppress nuclear factor kappa B (NF-κB) and activate peroxisome proliferator-activated receptor gamma (PPARγ) was confirmed using luciferase reporter assays. Conversely, the selective PPARγ antagonist GW9662 reversed the influence of PB in macrophages. CONCLUSION: Together, these findings indicate that PB exerts its protective effects on atherosclerosis by inhibiting macrophage-mediated inflammatory response and cellular ox-LDL uptake, and promoting cholesterol efflux by suppressing NF-κB activation PPARγ-dependently. Therefore, PB may be a promising agent for inflammatory and atherosclerotic diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/sangue , Aterosclerose/metabolismo , Dieta Hiperlipídica , Progressão da Doença , Interleucina-1beta/sangue , Interleucina-1beta/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , PPAR gama/metabolismo , Células RAW 264.7 , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genéticaRESUMO
To investigate potential clinical characteristics associated with discordance between platelet vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) flow cytometry (FCM) assay and light transmission aggregometry (LTA) in defining high on-clopidogrel platelet reactivity (HPR) after ST-segment elevation myocardial infarction (STEMI). In this study, platelet responsiveness was measured by the above 2 methods simultaneously on day 1 and on day 6 of STEMI onset in 90 consecutive patients who underwent primary percutaneous coronary intervention. The FCM-derived platelet reactivity index and LTA-derived platelet aggregation rate were both significantly reduced after dual antiplatelet therapy on day 6. Multiple variable-adjusted logistic regression analysis revealed that smoking (odds ratio [OR]: 4.507, 95% confidence interval [CI]: 1.123-18.09, P = .034) and onset-to-admission time (per 1 hour increase, OR: 1.196, 95% CI: 1.023-1.398, P = .025) both were independent predictors for the discordance between the 2 methods. Additionally, improved correlation and concordance was observed in nonsmokers compared with smokers. Our data show that smoking and prolonged onset-to-admission time are associated with discordance between platelet VASP-P and LTA in defining HPR after STEMI, which should be considered when planning personalized antiplatelet therapy.
Assuntos
Plaquetas/metabolismo , Fosfoproteínas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Fumar/sangue , Ticlopidina/análogos & derivados , Idoso , Plaquetas/patologia , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Fumar/efeitos adversos , Ticlopidina/administração & dosagem , Fatores de TempoRESUMO
A water-soluble polysaccharide (SCP-80-I) was isolated from sweet corncob using microwave-assisted compound-enzyme extraction and column chromatography. SCP-80-I is composed mainly of arabinose, mannose, glucose, and galactose in a molar ratio of 0.369:0.824:10.759:0.333, and has a molecular mass of 18350 Da and ß-glycosides linkages in its molecular structure. The preliminary hypoglycemic and hypolipidemic activity in streptozotocin-induced diabetic rats was investigated. Rats were administered daily with 100, 200, and 400 mg/kg SCP-80-I for 21 d. The SCP-80-I increased the rat body mass significantly and reduced the blood glucose level in a dose-dependent manner. The SCP-80-I reduced liver swelling; kidney and pancreas hypertrophy; and total cholesterol, triglyceride, and low-density lipoprotein-C levels significantly; and increased the level of high-density lipoproteins in streptozotocin-induced diabetic rats. These results indicate that SCP-80-I exerts a potential hypoglycemic effect in streptozotocin-induced diabetic rats.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Zea mays/química , Animais , Glicemia/efeitos dos fármacos , Colesterol/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Galactose/análise , Hipoglicemiantes/isolamento & purificação , Rim/efeitos dos fármacos , Rim/patologia , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Manose/análise , Pâncreas/patologia , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Estruturas Vegetais/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/metabolismo , Ratos Wistar , Estreptozocina , Triglicerídeos/sangueRESUMO
BACKGROUND: Measuring human monocyte subsets (CD14++CD16-, CD14++CD16+, and CD14 + CD16++) and subset-specific monocyte-platelet aggregates (MPA) is vulnerable to analytical bias due to unavailability of a standardized methodology. We aimed to address this issue by focusing on the impacts of time-delayed sample processing and measurement between two commonly used anticoagulants. METHODS: Ethylenediaminetetraacetic acid (EDTA)- and sodium citrate (SC)-anticoagulated blood samples from 12 healthy donors were subject to either delayed (2-h delay, kept at 4°C) or immediate processing (without fixation) before four-color flow cytometry (FCM) analysis. RESULTS: In SC-anticoagulated samples, a 2-h delay in sample processing contributed to a significant decrease in CD14++CD16- monocyte percent and a reciprocal increase in CD14++CD16+ monocytes, as well as increases in all three subset-specific MPA. Similar slight, but non-significant changes were observed in EDTA-treated samples. In samples processed immediately and stored at 4°C, delayed measurement at 0, 1, 3, and 5 h after processing led to a time-dependent decrease in CD14++CD16- monocyte percent and a reciprocal increase in CD14++CD16+ subset in SC-treated, but not in EDTA-treated, samples. Moreover, a time-dependent increase in all three subset-specific MPA was observed in SC-treated samples, which, to a lesser extent, was only observed in CD14++CD16+ MPA in EDTA-treated samples after storage at 4°C for 3-5 h after processing. CONCLUSIONS: We recommend EDTA for anticoagulation. Additionally, sample should be stored at 4°C and processing and measuring should be performed within 2 h after harvest and 3 h after processing, respectively. © 2016 International Clinical Cytometry Society.
Assuntos
Anticoagulantes/farmacologia , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Citometria de Fluxo/métodos , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Receptores de IgG/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Neonicotinoids, among the most important pesticides in recent decades, have played pivotal roles in controlling agricultural pests. However, the toxicity to some environmentally beneficial insects is a cause of concern. The development of novel insecticides safer to these insects is increasingly urgent. RESULTS: A novel series of hydrocarbylidene nitrohydrazinecarboximidamides were designed and synthesised, starting from S-methylisothiourea sulphate. Preliminary bioassays showed that the target molecules exhibited good activities against Lipaphis erysimi (turnip aphid) and Myzus persicae. As shown by initial insecticidal activity data, most of the target compounds had moderate to excellent activities at a concentration of 600 mg L-1 against L. erysimi, and the lethal rate of most compounds exceeded 90%. They were also highly effective against M. persicae. Some of them have shown excellent insecticidal activities, for example, the LC50 values of compounds Ie-02 to Ie-07 were found to be 3.8, 3.0, 2.5, 3.1, 4.1 and 4.0 mg L-1 respectively. CONCLUSION: Structure-activity relationship analysis indicated that a suitable flexible alkyl chain at the imine point and a Cl-substituted pyridine ring are the most crucial factors affecting the activity. © 2017 Society of Chemical Industry.
Assuntos
Amidas/química , Amidas/síntese química , Afídeos , Inseticidas/química , Inseticidas/síntese química , Animais , Bioensaio , Técnicas de Química Sintética , Desenho de FármacosRESUMO
The functions of T helper 17 (Th17) and regulatory T (Treg) cells are tightly orchestrated through independent differentiation pathways that are involved in the secretion of pro- and anti-inflammatory cytokines induced by high-salt dietary. However, the role of imbalanced Th17/Treg ratio implicated in inflammation and target organ damage remains elusive. Here, by flow cytometry analysis, we demonstrated that switching to a high-salt diet resulted in decreased Th17 cells and reciprocally increased Treg cells, leading to a decreased Th17/Treg ratio. Meanwhile, Th17-related pathway was down-regulated after one day of high salt loading, with the increase in high salt loading as shown by microarray and RT-PCR. Subsequently, blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) observed hypoxia in the renal medulla (increased R2(*) signal) during high-salt loading, which was regressed to its baseline level in a step-down fashion during low-salt feeding. The flow-mediated vasodilatation (FMD) of the branchial artery was significantly higher on the first day of high salt loading. Collectively, these observations indicate that a short-term increase in dietary salt intake could induce reciprocal switches in Th17/Treg ratio and related cytokines, which might be the underlying cellular mechanism of high-salt dietary induced end organ inflammation and potential atherosclerotic risk.
Assuntos
Inflamação/etiologia , Cloreto de Sódio na Dieta/efeitos adversos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Imunidade Adaptativa , Aterosclerose/etiologia , Aterosclerose/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Pressão Sanguínea/efeitos dos fármacos , Artéria Braquial/efeitos dos fármacos , Artéria Braquial/fisiologia , Hipóxia Celular/efeitos dos fármacos , Citocinas/metabolismo , Diurese/efeitos dos fármacos , Ontologia Genética , Humanos , Inflamação/genética , Inflamação/imunologia , Medula Renal/irrigação sanguínea , Medula Renal/imunologia , Medula Renal/patologia , Imageamento por Ressonância Magnética , Masculino , Especificidade de Órgãos , Cloreto de Sódio na Dieta/farmacologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Transcriptoma , Vasodilatação/efeitos dos fármacosRESUMO
AIM: To examine the therapeutic/preventive potential of liposome-encapsulated spironolactone (SP; Lipo-SP) for acute lung injury (ALI) and fibrosis. MATERIALS & METHODS: Lipo-SP was prepared by the film-ultrasonic method, and physicochemical and pharmacokinetic characterized for oral administration (10 and 20 mg/kg for SP-loaded liposome; 20 mg/kg for free SP) in a mouse model bleomycin-induced ALI. RESULTS: Lipo-SP enhanced bioavailability of SP with significant amelioration in lung pathology. Mechanistically, SP-mediated mineralocorticoid receptor antagonism contributes to inflammatory monocyte/macrophage modulation via an inhibitory effect on Ly6C(hi) monocytosis-directed M2 polarization of alveolar macrophages. Moreover, Lipo-SP at lower dose (10 mg/kg) exhibited more improvement in body weight gain. CONCLUSION: Our data highlight Lipo-SP as a promising approach with therapeutic/preventive potential for ALI and fibrosis.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Monócitos/efeitos dos fármacos , Espironolactona/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Bleomicina , Polaridade Celular , Humanos , Lipossomos , Macrófagos Alveolares/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/química , Monócitos/metabolismo , Tamanho da Partícula , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Espironolactona/administração & dosagem , Espironolactona/químicaRESUMO
In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes), as well as the subset-specific monocyte-platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up.Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14++CD16+ monocytes and CD14++CD16+ MPA were observed, with peak levels on day 2. During a median follow-up of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14++CD16+ monocytosis (day 1 [HR: 3.428; 95% CI: 1.597-7.358; Pâ=â0.002], day 2 [HR: 4.835; 95% CI: 1.106-21.13; Pâ=â0.04], day 3 [HR: 2.734; 95% CI: 1.138-6.564; Pâ=â0.02], and day 7 [HR: 2.647; 95% CI: 1.196-5.861; Pâ=â0.02]), as well as increased levels of CD14++CD16+ MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events.In conclusion, our data show the expansion of the CD14++CD16+ monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies after STEMI.
Assuntos
Antígenos CD/análise , Plaquetas/metabolismo , Monócitos , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Idoso , Agregação Celular , China , Angiografia Coronária/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/classificação , Monócitos/metabolismo , Readmissão do Paciente/estatística & dados numéricos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Período Pós-Operatório , Valor Preditivo dos Testes , Recidiva , Reoperação/estatística & dados numéricos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapiaRESUMO
To investigate the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) in evaluating human subcutaneous and visceral adipose tissue (AT) oxygenation status, as well as their responses to dietary salt loading/depletion, we enrolled 16 healthy subjects [mean body mass index (BMI): 24.8 ± 2.7 kg/m(2)] to conduct a dietary intervention study, beginning with a 3-day run-in period for usual diet, followed by a 7-day high-salt diet (≥ 15 g NaCl/day) and a 7-day low-salt diet (≤ 5 g NaCl/day). Abdominal BOLD-MRI scan was performed to evaluate oxygenation in waist subcutaneous and perirenal (visceral) AT. Two subjects with lower BMI were excluded because of the difficulty to identify subcutaneous AT. High salt diet led to a consistent increase in R2* signal (a parameter for increased hypoxia) both in subcutaneous and visceral AT (all P < 0.0001), which was completely regressed to baseline levels by low salt diet. In addition, subcutaneous AT R2* values at any time points, were all higher than that of visceral AT (all P < 0.0001). Pearson correlation analysis revealed that the visceral AT R2* levels were negatively associated obesity indicators (waist circumference, waist-to-hip ratio and BMI). On the contrary, although a trend towards negative associations between the subcutaneous AT R2* and obesity indicators was observed, none of the associations reached statistical significances. Thus, our data demonstrate the possibility of simultaneous detection of human subcutaneous and visceral AT oxygenation status using BOLD-MRI. In addition, there is a more close relationship visceral AT oxygenation status and the development of obesity.
RESUMO
Platelets are anuclear cells and are devoid of genomic DNA, but they are capable of de novo protein synthesis from mRNA derived from their progenitor cells, megakaryocytes. There is mounting evidence that microRNA (miRNA) plays an important role in regulating gene expression in platelets. miR-223 is the most abundant miRNAs in megakaryocytes and platelets. One of the miR-223-regulated genes is ADP P2Y12, a key target for current antiplatelet drug therapy. Recent studies showed that a blunted response to P2Y12 antagonist, that is, high on-treatment platelet reactivity (HTPR), is a strong predictor of major cardiovascular events (MACEs) in coronary heart disease (CHD) patients receiving antiplatelet treatment. Recent clinical cohort study showed that the level of circulating miR-223 is inversely associated with MACE in CHD patients. In addition, our recent data demonstrated that the level of both intraplatelet and circulating miR-223 is an independent predictor for HTPR, thus providing a link between miR-223 and MACE. These lines of evidence indicate that miR-223 may serve as a potential regulatory target for HTPR, as well as a diagnostic tool for identification of HTPR in clinical settings.