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1.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R390-R398, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913684

RESUMO

Local skin heating to 42°C causes cutaneous thermal hyperemia largely via nitric oxide (NO) synthase (NOS)-related mechanisms. We assessed the hypothesis that ATP-sensitive K+ (KATP) channels interact with NOS to mediate cutaneous thermal hyperemia. In 13 young adults (6 women, 7 men), cutaneous vascular conductance (CVC) was measured at four intradermal microdialysis sites that were continuously perfused with 1) lactated Ringer solution (control), 2) 5 mM glibenclamide (KATP channel blocker), 3) 20 mM NG-nitro-l-arginine methyl ester (NOS inhibitor), or 4) a combination of KATP channel blocker and NOS inhibitor. Local skin heating to 42°C was administered at all four treatment sites to elicit cutaneous thermal hyperemia. Thirty minutes after the local heating, 1.25 mM pinacidil (KATP channel opener) and subsequently 25 mM sodium nitroprusside (NO donor) were administered to three of the four sites (each 25-30 min). The local heating-induced prolonged elevation in CVC was attenuated by glibenclamide (19%), but the transient initial peak was not. However, glibenclamide had no effect on the prolonged elevation in CVC in the presence of NOS inhibition. Pinacidil caused an elevation in CVC, but this response was abolished at the glibenclamide-treated skin site, demonstrating its effectiveness as a KATP channel blocker. The pinacidil-induced increase in CVC was unaffected by NOS inhibition, whereas the increase in CVC elicited by sodium nitroprusside was partly (15%) inhibited by glibenclamide. In summary, we showed an interactive effect of KATP channels and NOS for the plateau of cutaneous thermal hyperemia. This interplay may reflect a vascular smooth muscle cell KATP channel activation by NO.


Assuntos
Hiperemia/enzimologia , Canais KATP/metabolismo , Microcirculação , Microvasos/enzimologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Pele/irrigação sanguínea , Vasodilatação , Adulto , Velocidade do Fluxo Sanguíneo , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Hiperemia/etiologia , Hiperemia/fisiopatologia , Hipotermia Induzida , Ativação do Canal Iônico , Canais KATP/antagonistas & inibidores , Masculino , Microcirculação/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Microvasos/fisiopatologia , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/administração & dosagem , Transdução de Sinais , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adulto Jovem
2.
Indian J Pharmacol ; 51(5): 296-301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31831918

RESUMO

Nicorandil is a well-known antianginal agent, which has been recommended as one of the second-line treatments for chronic stable angina as justified by the European guidelines. It shows an efficacy equivalent to that of classic antianginal agents. Nicorandil has also been applied clinically in various cardiovascular diseases such as variant or unstable angina and reperfusion-induced damage following coronary angioplasty or thrombolysis. Different mechanisms have been involved in the protective effects of nicorandil in various diseases through either opening of adenosine triphosphate-sensitive potassium (KATP) channel or donation of nitric oxide (NO). The predominance or participation of any of these proposed mechanisms depends on the dose of nicorandil used, the location of diseased conditions, and if this mechanism is still functioning or not. The protection afforded by nicorandil has been shown to be mainly attributed to KATP channel opening in experimental models of myocardial and pulmonary fibrosis as well as renal injury or glomerulonephritis, whereas NO donation predominates as a mechanism of protection in hepatic fibrosis and inflammatory bowel diseases. Therefore, in different diseased conditions, it is important to know which mechanism plays the major role in nicorandil-induced curative or protective effects. This can bring new insights into the proper use of selected medication and its recommended dose for targeting certain disease.


Assuntos
Antiarrítmicos/administração & dosagem , Nicorandil/administração & dosagem , Angina Estável/tratamento farmacológico , Animais , Antiarrítmicos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Canais KATP/efeitos dos fármacos , Canais KATP/metabolismo , Nicorandil/farmacologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/farmacologia
3.
J Pathol ; 249(3): 368-380, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31265742

RESUMO

Treatment with cold atmospheric plasma (CAP) has been reported to promote wound healing in animals. However, how this process is mediated remains unclear. In this study we examined the mechanisms which underlie the improved wound healing effects of CAP and the roles of associated reactive oxygen and nitrogen species (RONS), which are generated by plasma. By using in vitro models which mimicked various steps of angiogenesis, we demonstrated that CAP triggered the production of nitric oxide (NO), and enhanced cell migration and the assembly of endothelial cells into vessel-like structures. These are both hallmarks of the proliferative phase of wound healing. Using a mouse model of a third-degree burn wound, we went on to show that CAP treatment was associated with enhanced angiogenesis, characterised by accelerated in vivo wound healing and increased cellular proliferation. Here, CAP significantly increased the in vivo production of endothelial NO synthase (eNOS), an enzyme that catalyses NO synthesis in endothelial cells, and significantly increased the expression of pro-angiogenic PDGFRß and CD31 markers in mouse wounds. Mechanistically, we showed that CAP induced eNOS phosphorylation and activation, thereby increasing the levels of endogenous NO in endothelial cells. Increased NO generation facilitated by CAP further stimulated important pro-angiogenic VEGFA/VEGFR2 signalling in vitro. This proof-of-concept study may guide future efforts aimed at addressing the use of physical plasma and its therapeutic applications in a variety of pathological scenarios. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Queimaduras/terapia , Hélio/administração & dosagem , Neovascularização Fisiológica , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Gases em Plasma/administração & dosagem , Transplante de Pele , Pele/irrigação sanguínea , Pele/enzimologia , Cicatrização , Animais , Queimaduras/enzimologia , Queimaduras/patologia , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Necrose , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Fosforilação , Transdução de Sinais , Pele/lesões , Pele/patologia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Nutrients ; 11(7)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336832

RESUMO

Type 1 diabetes (T1D) is associated with a greater occurrence of cardiovascular pathologies. Vascular dysfunction has been shown at the level of the endothelial layers and failure to maintain a continuous pool of circulating nitric oxide (NO) has been implicated in the progression of poor vascular health. Biochemically, NO can be produced via two distinct yet inter-related pathways that involve an upregulation in the enzymatic activity of nitric oxide synthase (NOS). These pathways can be split into an endogenous oxygen-dependent pathway i.e., the catabolism of the amino acid L-arginine to L-citrulline concurrently yielding NO in the process, and an exogenous oxygen-independent one i.e., the conversion of exogenous inorganic nitrate to nitrite and subsequently NO in a stepwise fashion. Although a body of research has explored the vascular responses to exercise and/or compounds known to stimulate NOS and subsequently NO production, there is little research applying these findings to individuals with T1D, for whom preventative strategies that alleviate or at least temper vascular pathologies are critical foci for long-term risk mitigation. This review addresses the proposed mechanisms responsible for vascular dysfunction, before exploring the potential mechanisms by which exercise, and two supplementary NO donors may provide vascular benefits in T1D.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Diabetes Mellitus Tipo 1/terapia , Exercício Físico , Doadores de Óxido Nítrico/administração & dosagem , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia
5.
Int J Pharm ; 565: 481-487, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31102802

RESUMO

The modulation of blood flow to tumors is a prominent strategy for improving the tumor accumulation of nanomedicines, resulting from the enhanced permeability and retention (EPR) effect. We previously reported a promising EPR enhancer-a nitric oxide (NO) donor-containing liposome (NO-LP)-which showed enhanced accumulation in tumor tissue. Herein, we study NO-LP in greater detail to clarify its practical use as an EPR enhancer. NO-LP was found to have advantages as a NO donor, including the ability to maintain NO donation over long periods of time, and a constant rate of NO-release irrespective of the environmental pH. NO-LP showed rapid accumulation in tumor tissue after injection (1 h), and then accumulation was continuously enhanced until 48 h. Enhanced NO-LP accumulation was observed specifically in tumor, while the accumulation in other organs remained relatively unchanged. The results obtained show the promising features of NO-LP as an EPR enhancer.


Assuntos
Neoplasias/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico/metabolismo , Compostos Nitrosos/administração & dosagem , Animais , Linhagem Celular Tumoral , Lipossomos , Masculino , Camundongos Endogâmicos BALB C , Permeabilidade
6.
Gastroenterology ; 156(6): 1753-1760.e1, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30772342

RESUMO

BACKGROUND & AIMS: Acute pancreatitis is a major adverse event of endoscopic retrograde cholangiopancreatography (ERCP). Rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of post-ERCP pancreatitis (PEP). Little is known about the combined effects of sublingual nitrate and NSAIDs. We performed a randomized trial to assess whether the combination of NSAIDs and sublingual nitrate is more effective than NSAIDs alone in preventing PEP. METHODS: In a prospective superiority trial, eligible patients underwent ERCP at 12 endoscopic units in Japan, from March 2015 through May 2018. Patients were randomly assigned to groups given diclofenac suppositories (50 mg) within 15 minutes after the endoscopic procedure alone (diclofenac-alone group, n = 442) or in combination with sublingual isosorbide dinitrate (5 mg) 5 minutes before the endoscopic procedure (combination group, n = 444). The primary endpoint was the occurrence of PEP. RESULTS: PEP developed in 25 patients in the combination group (5.6%), and in 42 patients in the diclofenac-alone group (9.5%) (relative risk 0.59; 95% confidence interval 0.37-0.95; P = .03). Moderate to severe pancreatitis developed in 4 patients (0.9%) in the combination group, and 10 patients (2.3%) in the diclofenac-alone group (relative risk 0.12; 95% confidence interval 0.13-1.26; P = .12). There was no serious adverse event related to the additional administration of sublingual nitrate. CONCLUSIONS: In a randomized controlled trial, we found that prophylaxis with rectal diclofenac and sublingual nitrate significantly reduces the overall incidence of PEP compared with diclofenac suppository alone. ClinicalTrials.gov, no: UMIN 000016274.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Diclofenaco/uso terapêutico , Dinitrato de Isossorbida/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Pancreatite/prevenção & controle , Administração Sublingual , Idoso , Quimioterapia Combinada , Feminino , Humanos , Dinitrato de Isossorbida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Doadores de Óxido Nítrico/administração & dosagem , Pancreatite/etiologia , Estudos Prospectivos
7.
Nano Lett ; 19(2): 997-1008, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30676760

RESUMO

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor ( S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Colágeno/metabolismo , Doxorrubicina/administração & dosagem , Neoplasias Mamárias Animais/tratamento farmacológico , Doadores de Óxido Nítrico/administração & dosagem , S-Nitrosotióis/administração & dosagem , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/ultraestrutura , Doadores de Óxido Nítrico/farmacologia , Proteólise/efeitos dos fármacos , S-Nitrosotióis/farmacologia , Dióxido de Silício/química , Microambiente Tumoral/efeitos dos fármacos
8.
Bioconjug Chem ; 30(3): 583-591, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30678457

RESUMO

Nitric oxide (NO) exerts multiple functions in many life processes and was of great significance in a variety of biomedical scenarios. However, the mismatches between releasing locations and NO active sites seriously limited the available NO at areas of interest and greatly dampen the overall efficiency of delivery systems. Therefore, in the present study, a NO donor was developed to achieve intracellular delivery and release of NO to overcome the aforementioned challenges. Enhanced uptake and effective intracellular release of NO were realized via ß-cyclodextrin (ß-CD) mediated endocytosis and high level glutathione (GSH) inside cells, respectively. We demonstrated that intracellularly delivered NO would exert stronger bioeffects than premature release of NO outside targeted cells. Besides, ß-CD assisted cellular uptake proved indispensable in maximizing the influence of NO in modulating cellular behavior. These results demonstrated the significance of intracellular delivery and release of NO in improving its bioutilization. The carrier could efficiently inhibit proliferation of SMCs, while promoting the growth of ECs. Such cell-type-differed physiological effects were advantageous in re-endothelialization and might hold great potential in cardiovascular applications.


Assuntos
Preparações de Ação Retardada/metabolismo , Glutationa/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , beta-Ciclodextrinas/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , GMP Cíclico/metabolismo , Endocitose , Humanos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacocinética , Doadores de Óxido Nítrico/farmacologia , Coelhos
9.
Biomaterials ; 194: 117-129, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30590241

RESUMO

Nitric oxide (NO) is a highly potent, yet short-lived bioactive molecule with a broad spectrum of physiological functions. Continuous and controllable in situ generation of NO from vascular stent surface can effectively prevent restenosis and thrombosis after its implantation. In this study, inspired by the adhesion and protein cross-linking in the mussel byssus, through immersing the stents into an aqueous solution with dopamine (DA) and copper ions (CuII), we developed a one-step metal-catecholamine assembled strategy to prepare a durable in situ NO-generating biomimetic coating (DA-CuII). Due to the high NO catalytic efficacy and robust chelation of CuII into the DA-CuII network, the coated stents exhibited excellent hemocompatibility. The coating also catalytically decomposed endogenous S-nitrosothiols (RSNOs) from fresh blood, and locally generated NO for over 30 days with a flux comparable to its physiological range (0.5-4 × 10-10 mol × cm-2 × min-1). Moreover, the optimized biomimetic coatings displayed specific cell selectivity to significantly enhance endothelial cell (EC) growth while substantially inhibit smooth muscle cell (SMC) growth and migration. This feature impressively promoted regeneration of a new endothelial cell layer after stent implantation, hence improved the anti-thrombogenic and anti-restenosis qualities of vascular stents in vivo. We envision that our long-term in situ NO-generating coatings could serve as biosurfaces for long-term prevention of stent thrombosis and restenosis.


Assuntos
Materiais Revestidos Biocompatíveis/química , Cobre/química , Dopamina/química , Doadores de Óxido Nítrico/administração & dosagem , Stents , Trombose/prevenção & controle , Animais , Materiais Biomiméticos/química , Catálise , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/uso terapêutico , Coelhos , Stents/efeitos adversos , Trombose/etiologia
10.
High Blood Press Cardiovasc Prev ; 25(4): 401-405, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30471072

RESUMO

INTRODUCTION: Beyond the well-known effects on blood pressure (BP) of the dietary approaches to stop hypertension (DASH) and the Mediterranean diets associated to a correct lifestyle, often a lifestyle change is not simple and can show only long-time results: in this sense, a possible support might be derived from the use of some anti-hypertensive supplements or nutraceuticals, which may provide a significant reduction in blood pressure. AIM: We conducted a randomized, double-blind, placebo-controlled clinical trial in a group of 36 pre-hypertensive and first-degree hypertensive patients. METHODS: The treatment period with a mix of bioactive substances (BPLN®, containing a donor of nitric oxide, magnesium, and vitamins) or placebo was 16-week long and was preceded by 4 weeks of diet stabilization. RESULTS: At the end of the intervention, patients treated with the nutraceutical product showed a significant reduction of all morning pressure parameters and of evening systolic blood pressure, both versus the baseline and versus the group treated with placebo. These effects were maintained even after the first 16 weeks of treatment, confirming that the preliminary results were not due to simple changes in volume and do not lead to adaptation/tachyphylaxis. No patient complained of any side effects while taking the active treatment and placebo. CONCLUSIONS: The tested nutraceutical composite reduces systolic and diastolic blood pressure in the medium term, leading to a significant reduction in the estimated cardiovascular risk in a sample of patients with pre-hypertension or first-degree hypertension.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Dieta Saudável , Abordagens Dietéticas para Conter a Hipertensão , Suplementos Nutricionais , Hipertensão/terapia , Terapia Combinada , Dieta Mediterrânea , Dieta Hipossódica , Método Duplo-Cego , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Itália , Magnésio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Doadores de Óxido Nítrico/administração & dosagem , Projetos Piloto , Fatores de Tempo , Resultado do Tratamento , Vitaminas/administração & dosagem
11.
J Am Chem Soc ; 140(37): 11686-11697, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30198716

RESUMO

Photoacoustic (PA) tomography is a noninvasive technology that utilizes near-infrared (NIR) excitation and ultrasonic detection to image biological tissue at centimeter depths. While several activatable small-molecule PA sensors have been developed for various analytes, the use of PA molecules for deep-tissue analyte delivery and monitoring remains an underexplored area of research. Herein, we describe the synthesis, characterization, and in vivo validation of photoNOD-1 and photoNOD-2, the first organic, NIR-photocontrolled nitric oxide (NO) donors that incorporate a PA readout of analyte release. These molecules consist of an aza-BODIPY dye appended with an aryl N-nitrosamine NO-donating moiety. The photoNODs exhibit chemostability to various biological stimuli, including redox-active metals and CYP450 enzymes, and demonstrate negligible cytotoxicity in the absence of irradiation. Upon single-photon NIR irradiation, photoNOD-1 and photoNOD-2 release NO as well as rNOD-1 or rNOD-2, PA-active products that enable ratiometric monitoring of NO release. Our in vitro studies show that, upon irradiation, photoNOD-1 and photoNOD-2 exhibit 46.6-fold and 21.5-fold ratiometric turn-ons, respectively. Moreover, unlike existing NIR NO donors, the photoNODs do not require encapsulation or multiphoton activation for use in live animals. In this study, we use PA tomography to monitor the local, irradiation-dependent release of NO from photoNOD-1 and photoNOD-2 in mice after subcutaneous treatment. In addition, we use a murine model for breast cancer to show that photoNOD-1 can selectively affect tumor growth rates in the presence of NIR light stimulation following systemic administration.


Assuntos
Neoplasias Mamárias Animais/tratamento farmacológico , Doadores de Óxido Nítrico/farmacologia , Técnicas Fotoacústicas , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Raios Infravermelhos , Injeções Subcutâneas , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Óxido Nítrico/análise , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/química , Distribuição Tecidual
12.
Mol Pharm ; 15(11): 5277-5290, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30234992

RESUMO

Vascular endothelial dysfunction and platelet activation play a key role in tumor metastasis, and therefore, both of these processes are considered important therapeutic targets in cancer. The aim of our studies was to analyze antimetastatic activity of combination therapy using nitric oxide donor DETA/NO and antiplatelet drug clopidogrel. Nitric oxide acts as a vasoprotective mediator, while clopidogrel inhibits ADP-mediated platelet aggregation. 4T1-luc2-tdTomato cell line transplanted intravenously (i.v.) and 4T1 cell line transplanted orthotopically were used as metastatic mammary gland cancer models. Moreover, antiaggregation action of compounds was tested ex vivo on the blood samples taken from breast cancer patients. We have shown that in selected dosage regimes, DETA/NO combined with clopidogrel significantly reduced lung metastatic foci formation in an i.v. model, and such inhibition was transiently observed also in an orthotopic model. The antimetastatic effect was correlated with a significant increase of prostacyclin (PGI2) metabolite and reduction of endothelin-1, sE-selectin, sI-CAM, and TGF-ß plasma levels as well as decreased V-CAM expression on the endothelium. Combination therapy decreased fibrinogen binding to the resting platelets at the early stage of tumor progression (day 14). However, at the later stages (days 21 and 28), the markers of platelet activation were detected (increased JON/A antibody bound, P-selectin level, binding of fibrinogen, and vWf). Decreased aggregation as well as a lower release of TGF-ß were detected in platelets incubated ex vivo with compounds tested from metastatic breast cancer patients. Although combination therapy increases E-cadherin, the increase of N-cadherin and α-SMA in tumor tissue was also observed. The results showed that at the early stages of tumor progression, combined therapy with DETA/NO and clopidogrel improves vasoprotective and antiplatelet activity. However, in advanced tumors, some adverse effects toward platelet activation can be observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Doadores de Óxido Nítrico/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Animais , Neoplasias da Mama/sangue , Linhagem Celular Tumoral/transplante , Clopidogrel/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , Humanos , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Ativação Plaquetária/efeitos dos fármacos , Plasma Rico em Plaquetas/efeitos dos fármacos , Triazenos/administração & dosagem
13.
Eur J Pharm Biopharm ; 132: 94-102, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30223029

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds have become a significant clinical issue worldwide. Recently, nitric oxide (NO) has emerged as a potent antibacterial agent against MRSA infections and a wound-healing enhancer. Nevertheless, clinical applications of NO have been largely restricted by its gaseous state and short half-life. In this study, our aim was to develop S-nitrosoglutathione (GSNO, an endogenous NO donor)-loaded poly(lactic-co-glycolic acid) [PLGA] microparticles (GSNO-MPs) that release NO over a prolonged period, to accelerate the healing of MRSA-infected wounds with less frequent dosing. GSNO was successfully encapsulated into PLGA microparticles by a solid-in-oil-in-water emulsion solvent evaporation method. Scanning electron microscopy and X-ray diffraction analyses confirmed the successful fabrication of GSNO-MPs. The latter released NO in a prolonged manner over 7 days and exerted a remarkable antibacterial activity against MRSA in a concentration- and time-dependent manner. Moreover, GSNO-MPs had good antibacterial efficacy and were found to accelerate wound healing in a mouse model of MRSA-infected wounds. Therefore, NO-releasing MPs devised in this study may be a promising option for the treatment of cutaneous wounds infected by drug-resistant bacteria such as MRSA.


Assuntos
S-Nitrosoglutationa/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Preparações de Ação Retardada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Varredura , Microesferas , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , S-Nitrosoglutationa/farmacologia , Infecções Estafilocócicas/microbiologia , Fatores de Tempo , Difração de Raios X
14.
Biomaterials ; 185: 51-62, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30218836

RESUMO

This study reports a tumor-specific ROS-responsive nanoplatform capable of the combination of nitric oxide (NO)-based gas therapy and sensitized photodynamic therapy (PDT). The nanoplatform is constructed on porous coordination network (PCN), which contains NO donor L-Arg and is concurrently coated with cancer cell membrane (L-Arg@PCN@Mem). Under near infrared light (NIR) irradiation, L-Arg@PCN@Mem produces plenty of reactive oxygen species (ROS) directly for PDT therapy, while a part of ROS take the role of oxidative to converse L-Arg into NO for combined gas therapy. The results indicate that the transformation of ROS to NO can enhance PDT efficacy in hypoxic tumors owing to the ability of NO in freely diffusing into deep hypoxic tumor site. Moreover, homologous targeting function originated from the coating of cancer cells membrane further improves the tumor treatment effect owing to the biotargeting toward homologous tumors. This L-Arg@PCN@Mem nanoplatform provides a new therapy paradigm of overcoming the hypoxia barrier of tumor therapy, and holds great potential for the treatment of tumor and NO-related diseases.


Assuntos
Nanoestruturas/administração & dosagem , Neoplasias/tratamento farmacológico , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico/metabolismo , Fármacos Fotossensibilizantes/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Doadores de Óxido Nítrico/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Porosidade , Hipóxia Tumoral/efeitos dos fármacos
15.
J Psychopharmacol ; 32(6): 711-722, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29737230

RESUMO

BACKGROUND: An excitatory imbalance in the hypothalamus of rodents caused by local chemical stimulation elicits fear-related defensive reactions such as escape and freezing. In addition, these panic attack-like defensive reactions induced by hypothalamic neurons may cause antinociception. However, there is a shortage of studies showing the participation of the anterior hypothalamic nucleus in these adaptive defensive mechanisms. Nitric oxide (NO) donors have been shown to evoke fear-related defensive responses when microinjected into paralimbic and limbic structures, and this excitatory neuromodulation can recruit the glutamatergic system. AIMS: The aim of this work was to investigate the influence of the glutamatergic system in the nitrergic effects on fear-related defensive responses organised by anterior hypothalamic neurons. METHODS: The present study evaluates the effects of the molsidomine active metabolite SIN-1 NO donor administered into the anterior hypothalamus (AH) of mice at different concentrations (75, 150 and 300 nmol/0.1 µL). Then, we investigated the effects of pre-treatment of the AH with AP-7 (an N-methyl-d-aspartate (NMDA) receptor-selective antagonist; 0.02, 0.2 and 2 nmol/0.1 µL) on the behavioural and antinociceptive effects provoked by AH chemical stimulation with SIN-1 microinjections. RESULTS: The 300 nmol dose of SIN-1 was the most effective at causing panic-like defensive behaviours followed by a significant antinociceptive response. In addition, both of these effects were attenuated or inhibited by AH pre-treatment with AP-7. CONCLUSIONS: These findings suggest that the panicogenic and antinociceptive effects evoked by intra-AH microinjections of SIN-1 depend on NMDA receptor activation.


Assuntos
Medo/efeitos dos fármacos , Molsidomina/análogos & derivados , Doadores de Óxido Nítrico/administração & dosagem , Pânico/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipotálamo Anterior/efeitos dos fármacos , Hipotálamo Anterior/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Molsidomina/administração & dosagem , Molsidomina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo
16.
J Neurophysiol ; 120(2): 720-728, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29742029

RESUMO

The nitric oxide (NO)/cyclic GMP signaling pathway has been suggested to be important in the formation of olfactory memory in insects. However, the molecular targets of the NO signaling cascade in the central neurons associated with olfactory learning and memory have not been fully analyzed. In this study, we investigated the effects of NO donors on single voltage-dependent Na+ channels in intrinsic neurons, called Kenyon cells, in the mushroom bodies in the brain of the cricket. Step depolarization on cell-attached patch membranes induces single-channel currents with fast-activating and -inactivating brief openings at the beginning of the voltage steps followed by more persistently recurring brief openings all along the 150-ms pulses. Application of the NO donor S-nitrosoglutathione (GSNO) increased the number of channel openings of both types of single Na+ channels. This excitatory effect of GSNO on the activity of these Na+ channels was diminished by KT5823, an inhibitor of protein kinase G (PKG), indicating an involvement of PKG in the downstream pathway of NO. Application of KT5823 alone decreased the activity of the persistent Na+ channels without significant effects on the fast-inactivating Na+ channels. The membrane-permeable cGMP analog 8Br-cGMP increased the number of channel openings of both types of single Na+ channels, similar to the action of NO. Taken together, these results indicate that NO acts as a critical modulator of both fast-inactivating and persistent Na+ channels and that persistent Na+ channels are constantly upregulated by the endogenous cGMP/PKG signaling cascade. NEW & NOTEWORTHY This study clarified that nitric oxide (NO) increases the activity of both fast-inactivating and persistent Na+ channels via the cGMP/PKG signaling cascade in cricket Kenyon cells. The persistent Na+ channels are also found to be upregulated constantly by endogenous cGMP/PKG signaling. On the basis of the present results and the results of previous studies, we propose a hypothetical model explaining NO production and NO-dependent memory formation in cricket large Kenyon cells.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/fisiologia , GMP Cíclico/fisiologia , Gryllidae/fisiologia , Corpos Pedunculados/fisiologia , Neurônios/fisiologia , Óxido Nítrico/fisiologia , Canais de Sódio Disparados por Voltagem/fisiologia , Animais , Masculino , Potenciais da Membrana , Modelos Neurológicos , Doadores de Óxido Nítrico/administração & dosagem , S-Nitrosoglutationa/administração & dosagem , Transdução de Sinais
17.
J Control Release ; 278: 127-139, 2018 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-29630985

RESUMO

The size of nanoparticles plays a key role in utilizing enhanced permeability and retention (EPR) effect of tumor, where large-sized nanoparticles possess good retention but poor penetration, while small-sized nanoparticles are on the contrary. Although size-reducible nanoparticles have been designed to partially overcome this dilemma, the initial size and complicated tumor microenvironment remain restricting the tumor distribution of nanoparticles. Herein, we employed tumor-specific CD44 targeted, hyaluronidase-degradable hyaluronic acid (HA) and small-sized, renal-clearable, red emission, cationic bovine serum albumin-protected gold nanocluster (AuNC@CBSA) to successfully construct size-reducible nanoplatform (AuNC@CBSA@HA). By changing the ratio of HA and AuNC@CBSA, different initial sizes of AuNC@CBSA@HA were prepared and their tumor targeting efficiencies, pharmacokinetic profiles were evaluated. Then 200 nm of AuNC@CBSA@HA with optimal EPR effect was screened out to further load paclitaxel (PTX) and indocyanine green (ICG) for chemo- photothermal therapy and nitric oxide (NO) for modulating tumor microenvironment and enhancing drug delivery. The AuNC@CBSA-PTX-ICG@HA-NO3 showed size-reducible ability under triggering by hyaluronidase and high accumulation in breast cancer with homogenous intra-tumor distribution, suppressed 95.3% of in-situ tumor growth and inhibited 88.4% of lung metastasis growth. In conclusion, we provide a strategy that fully satisfied the concerns in drug delivery to tumor for improved antitumor effect.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Sistemas de Liberação de Medicamentos , Feminino , Ouro/química , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Verde de Indocianina/administração & dosagem , Verde de Indocianina/química , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , Paclitaxel/farmacologia , Tamanho da Partícula , Soroalbumina Bovina/química , Nanomedicina Teranóstica/métodos , Microambiente Tumoral
18.
Basic Res Cardiol ; 113(3): 20, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29666943

RESUMO

There remains a significant un-met need to reduce the extent of myocardial injury caused by ischaemia and reperfusion injury in patients experiencing an ST-elevation MI. Although nitric oxide is central to many cardioprotective strategies currently undergoing investigation, cardioprotection from the delivery of nitrates/nitrites has been inconsistently observed. The route of administration appears to be a critical variable. The glyceryl trinitrate (GTN) patch is commonly used as a simple and practical means of delivering nitric oxide to patients with ischaemic heart disease, but whether acute cardioprotection can be achieved by application of a GTN patch has not been investigated before. Here, we use a mouse model to demonstrate that a GTN patch is highly cardioprotective when applied immediately prior to 40 min occlusion of the left anterior coronary artery followed by 2 h reperfusion, reducing infarct size from 54 ± 4% in control mice, to 28 ± 4% (P < 0.001, N = 7). The degree of protection was similar to that achieved with a standard remote ischaemic preconditioning protocol. Furthermore, and of greater potential clinical relevance, a GTN patch was also protective when applied well after the initiation of ischaemia and 15 min prior to reperfusion (28 ± 4 vs 59 ± 4%; P < 0.01, N = 5). Confirmatory experiments verified the expected effect increase in plasma nitrite levels and decrease in blood pressure. The simplicity and rapidity of GTN patch application (easily applied in an ambulance or cardiac catheterization laboratory), and low cost (potentially relevant to low-income countries), make it attractive for further investigation.


Assuntos
Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Doadores de Óxido Nítrico/administração & dosagem , Nitroglicerina/administração & dosagem , Adesivo Transdérmico , Vasodilatadores/administração & dosagem , Administração Cutânea , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nitritos/sangue , Fatores de Tempo
19.
Arch Soc Esp Oftalmol ; 93(6): 290-299, 2018 Jun.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29580758

RESUMO

INTRODUCTION: An elevated intraocular pressure (IOP) remains the main risk factor for progression of glaucoma upon which we can efficiently act. Pharmacological strategies to reduce IOP are directed towards the reduction of aqueous humour (AH) production and/or the increase in AH drainage through the uveoscleral pathway. However, there are no drugs currently available as first-line treatment to increase AH outflow primarily via the conventional route. Ocular nitric oxide (NO) production takes place in AH outflow pathways and in the ciliary muscle, modulating the cellular response to elevated IOP. METHODS: This review describes the mechanism of action of endogenous NO and NO-donating compounds that are under research. It includes information regarding pre-clinical and clinical studies previously conducted with these compounds, discussing their role and therapeutic potential in the pharmacological treatment of ocular hypertension in glaucoma. RESULTS: The topical ocular administration of NO-donating compounds significantly lowered IOP and maintained it in animal models of glaucoma and subjects with ocular hypertension. CONCLUSIONS: The mechanism of action of these compounds is novel and scientific evidence that shows promising results. However, there is a need for more comprehensive studies to assess long-term safety and tolerability in order to properly evaluate their use in chronic therapies.


Assuntos
Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Doadores de Óxido Nítrico/uso terapêutico , Administração Oftálmica , Animais , Humor Aquoso/fisiologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Olho/enzimologia , Glaucoma/fisiopatologia , Humanos , Óxido Nítrico/fisiologia , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico Sintase/metabolismo , Soluções Oftálmicas , Prostaglandinas F Sintéticas/efeitos adversos , Prostaglandinas F Sintéticas/uso terapêutico , Reologia
20.
Biomaterials ; 167: 143-152, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29571050

RESUMO

Nitric oxide (NO) possesses various functions in cardiovascular diseases; however, due to an extremely short half-life and low bioavailability, its therapeutic application is limited. In inflamed tissues, overproduced reactive oxygen species (ROS) rapidly react with the endogenous NO, reducing its bioavailability. Here, we developed a controllable NO-releasing redox injectable hydrogel (NO-RIG) formed by the electrostatic crosslinking between the polyion complex flower-type micelles composing of functional polymers to scavenge overproduced ROS and regulate the local NO expression level simultaneously. After the intracardiac injection to mice, NO-RIG converted to gel via physiological temperature-responsive character, distributed homogeneously, and retained in the myocardial tissue for more than 10 d. Treatment with NO-RIG remarkably decreased the infarction size and improved the heart function after myocardial infarction when compared to control injectable hydrogels, such as a simple NO-releasing or ROS-scavenging injectable gels. We found that NO-RIG treatment significantly enhanced the angiogenesis and new blood vessels formation in mice through the regulation of the NO sustained release and redox equilibrium. NO-RIG presents high potential in preventing and treating cardiovascular diseases.


Assuntos
Indutores da Angiogênese/administração & dosagem , Preparações de Ação Retardada/química , Hidrogéis/química , Infarto do Miocárdio/tratamento farmacológico , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico/metabolismo , Indutores da Angiogênese/uso terapêutico , Animais , Injeções , Masculino , Camundongos , Camundongos Endogâmicos ICR , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Doadores de Óxido Nítrico/uso terapêutico , Oxirredução , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
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