RESUMEN
Molecular hydrogen is an emerging broad-spectrum antioxidant molecule that can be used to treat myocardial infarction (MI). However, with hydrogen inhalation, the concentration that can be reached within target organs is low and the duration of action is short, which makes it difficult to achieve high dose targeted delivery of hydrogen to the heart, seriously limiting the therapeutic potential of hydrogen for MI. As a result of reactions with the internal environment of the body, subcutaneous implantation of magnesium slices leads to continuous endogenous hydrogen production, leading to a higher hydrogen concentration and a longer duration of action in target organs. In this study, we propose magnesium implant-based hydrogen therapy for MI. After subcutaneous implantation of magnesium slices in the dorsum of rats, we measured hydrogen production and efficiency, and evaluated the safety of this approach. Compared with hydrogen inhalation, it significantly improved cardiac function in rats with MI. Magnesium implantation also cleared free radicals that were released as a result of mitochondrial dysfunction, as well as suppressing cardiomyocyte apoptosis.
Asunto(s)
Hidrógeno , Magnesio , Infarto del Miocardio , Animales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Magnesio/metabolismo , Ratas , Masculino , Ratas Sprague-Dawley , Apoptosis/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Recently, radiotherapy (RT) has entered a new realm of precision cancer therapy with the introduction of magnetic resonance (MR) imaging guided radiotherapy systems into the clinic. Nonetheless, identifying an optimized radiotherapy time window (ORTW) is still critical for the best therapeutic efficacy of RT. Here we describe pH and O2 dual-sensitive, perfluorooctylbromide (PFOB)-based and glycerol-weighted chemical exchange saturation transfer (CEST) nano-molecular imaging probes (Gly-PFOBs) with dual fluorine and hydrogen proton based CEST MR imaging properties (19F/1H-CEST). Oxygenated Gly-PFOBs ameliorate tumor hypoxia and improve O2-dependent radiotherapy. Moreover, the pH and O2 dual-sensitive properties of Gly-PFOBs could be quantitatively, spatially, and temporally monitored by 19F/1H-CEST imaging to optimize ORTW. In this study, we describe the CEST signal characteristics exhibited by the glycerol components of Gly-PFOBs. The pH and O2 dual-sensitive Gly-PFOBs with19F/1H-CEST MR dual-modality imaging properties, with superior therapeutic efficacy and biosafety, are employed for sensitive imaging-guided lung cancer RT, illustrating the potential of multi-functional imaging to noninvasively monitor and enhance RT-integrated effectiveness.
Asunto(s)
Neoplasias , Protones , Humanos , Glicerol , Concentración de Iones de Hidrógeno , Fantasmas de Imagen , Imagen por Resonancia Magnética/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapiaRESUMEN
Hydrogen gas is recently proven to have anti-oxidative and anti-inflammation effects on ischemia-reperfusion injury. However, the efficacy of hydrogen therapy is limited by the efficiency of hydrogen storage, targeted delivery, and controlled release. In this study, H2 -PFOB nanoemulsions (NEs) is developed with high hydrogen loading capacity for targeted ischemic myocardium precision therapy. The hydrogen-carrying capacity of H2 -PFOB NEs is determined by gas chromatography and microelectrode methods. Positive uptake of H2 -PFOB NEs in ischemia-reperfusion myocardium and the influence of hydrogen on 19 F-MR signal are quantitatively visualized using a 9.4T MR imaging system. The biological therapeutic effects of H2 -PFOB NEs are examined on a myocardial ischemia-reperfusion injury mouse model. The results illustrated that the developed H2 -PFOB NEs can efficaciously achieve specific infiltration into ischemic myocardium and exhibit excellent antioxidant and anti-inflammatory properties on myocardial ischemia-reperfusion injury, which can be dynamically visualized by 19 F-MR imaging system. Moreover, hydrogen burst release induced by low-intensity focused ultrasound (LIFU) irradiation further promotes the therapeutic effect of H2 -PFOB NEs with a favorable biosafety profile. In this study, the potential therapeutic effects of H2 -PFOB NEs is fully unfolded, which may hold great potential for future hydrogen-based precision therapeutic applications tailored to ischemia-reperfusion injury.
Asunto(s)
Fluorocarburos , Daño por Reperfusión Miocárdica , Ratones , Animales , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Hidrógeno/uso terapéutico , Preparaciones de Acción Retardada/uso terapéutico , Fluorocarburos/farmacología , Fluorocarburos/uso terapéutico , Miocardio , Isquemia , Reperfusión , Imagen por Resonancia MagnéticaRESUMEN
Hydrogen is a novel medical gas with several properties, including anti-oxidative, anti-inflammatory, anti-apoptotic, anti-allergic, and energy metabolism stimulating properties. Hydrogen therapy has been proven effective in the treatment of myocardial ischemia, myocardial infarction, and ischemia-reperfusion injury. Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication of long-term chronic diabetes that is linked to increased heart failure and arrhythmia morbidity. The effect of hydrogen on the pathogenesis of DCM is yet to be determined. Metformin is a well-known pharmacological agent for the treatment of diabetes; however, the application of large doses of the drug is limited by its side effects. Therefore, this highlights the importance of developing novel therapies against DCM. In this regard, we investigated the effect of hydrogen on DCM and the mechanisms that underlie it. Furthermore, we also assessed the efficacy of co-administration of metformin and hydrogen. In this study, we found that hydrogen improved cardiac dysfunction and abnormal morphological structure in streptozotocin-induced diabetic mice. As a mechanism, it was confirmed that hydrogen mediated its action by reducing pyroptosis via inhibition of the AMPK/mTOR/NLRP3 signaling pathway and ameliorating fibrosis via inhibition of the TGF-ß1/Smad signaling pathway. Furthermore, our findings suggested that co-administration of hydrogen and metformin shows potent protective effects, as evidenced by increased survival rates, reduced fasting blood glucose, and decreased cell injury when compared to a single application of metformin. In conclusion, our study demonstrated that hydrogen inhalation attenuates DCM by reducing pyroptosis and fibrosis and that hydrogen can be combined with metformin to exhibit a more potent cardioprotective effect in DCM.
Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Metformina , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Fibrosis , Hidrógeno/farmacología , Metformina/farmacología , Metformina/uso terapéutico , Ratones , Miocardio/metabolismo , PiroptosisRESUMEN
ABSTRACT: The energy used by the heart is generated mainly by the metabolism of fatty acids and glucose. Trimetazidine (TMZ) inhibits fatty acid metabolism and is used for the treatment of heart diseases such as heart failure. 3-Bromopyruvate (3-BrPA) can suppress glucose metabolism, and it is considered a promising candidate agent for tumor therapy. Because TMZ and 3-BrPA can separately inhibit the 2 main cardiac energy sources, it is necessary to investigate the effects of 3-BrPA combined with TMZ on the heart. Forty male Wistar rats were randomly divided into 4 groups: a control group, a TMZ group, a 3-BrPA group, and a 3-BrPA + TMZ group. Weight was recorded every day, and echocardiography was performed 14 days later. Heart function, the levels of adenosine triphosphate, oxidative stress-related factors (ROS, glutathione, oxidized glutathione, malondialdehyde, superoxide dismutase and total antioxidant capacity), and apoptosis in heart tissues were assessed to evaluate the effects of 3-BrPA and TMZ on the heart. In our study, no obvious changes occurred in the 3-BrPA group or the TMZ group compared with the control group. The combination of 3-BrPA and TMZ worsened heart function, decreased adenosine triphosphate levels, and increased oxidative stress and myocardial apoptosis. In conclusion, 3-BrPA and TMZ are not recommended for concurrent use.
Asunto(s)
Apoptosis/efectos de los fármacos , Fármacos Cardiovasculares/toxicidad , Inhibidores Enzimáticos/toxicidad , Cardiopatías/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Piruvatos/toxicidad , Trimetazidina/toxicidad , Adenosina Trifosfato/metabolismo , Animales , Cardiotoxicidad , Metabolismo Energético/efectos de los fármacos , Cardiopatías/metabolismo , Cardiopatías/patología , Cardiopatías/fisiopatología , Masculino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Transducción de Señal , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Purpose: Hydrogen (H2) is an antioxidant with anti-inflammatory and apoptosis functions.This study aimed to estimate the effects of H2 on acute myocardial infarction (AMI) in rats and its association with the inhibition of oxidative stress and cardiomyocyte pyroptosis. Methods: Sixty-four rats were randomly divided into three groups (Sham, AMI, and H2). The left anterior descending coronary artery (LAD) of rats in the AMI and H2 groups was ligated, while rats in the Sham group were threaded without ligation. In addition, 2% H2 was administered by inhalation for 24 h after ligation in the H2 group. Transthoracic echocardiography was performed after H2 inhalation, followed by collection of the serum and cardiac tissue of all rats. Results: H2 inhalation ameliorated the cardiac dysfunction, infarct size and inflammatory cell infiltration caused by AMI. Meanwhile, H2 inhalation reduced the concentration of serum Troponin I (TnI), brain natriuretic peptide (BNP), reactive oxygen species (ROS), cardiac malondialdehyde (MDA), and 8-OHdG. In addition, H2 inhalation inhibited cardiac inflammation and pyroptosis relative proteins expression. Conclusion: H2 effectively promoted heart functions in AMI rats by regulating oxidative stress and pyroptosis.
Asunto(s)
Antioxidantes/administración & dosificación , Hidrógeno/administración & dosificación , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Administración por Inhalación , Animales , Modelos Animales de Enfermedad , Ecocardiografía , Humanos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/metabolismo , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/inmunología , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/inmunología , Miocitos Cardíacos/patología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Piroptosis/efectos de los fármacos , Piroptosis/inmunología , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
It is noteworthy that prolonged cardiac structural changes and excessive fibrosis caused by myocardial infarction (MI) seriously interfere with the treatment of heart failure in clinical practice. Currently, there are no effective and practical means of either prevention or treatment. Thus, novel therapeutic approaches are critical for the long-term quality of life of individuals with myocardial ischaemia. Herein, we aimed to explore the protective effect of H2 , a novel gas signal molecule with anti-oxidative stress and anti-inflammatory effects, on cardiac remodelling and fibrosis in MI rats, and to explore its possible mechanism. First, we successfully established MI model rats, which were then exposed to H2 inhalation with 2% concentration for 28 days (3 hours/day). The results showed that hydrogen gas can significantly improve cardiac function and reduce the area of cardiac fibrosis. In vitro experiments further proved that H2 can reduce the hypoxia-induced damage to cardiomyocytes and alleviate angiotensin II-induced migration and activation of cardiac fibroblasts. In conclusion, herein, we illustrated for the first time that inhalation of H2 ameliorates myocardial infarction-induced cardiac remodelling and fibrosis in MI rats and exert its protective effect mainly through inhibiting NLRP3-mediated pyroptosis.
Asunto(s)
Fibrosis/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Hidrógeno , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Remodelación Ventricular/efectos de los fármacos , Animales , Hidrógeno/farmacología , Hidrógeno/uso terapéutico , Masculino , Miocitos Cardíacos , Cultivo Primario de Células , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Reperfusion therapy is the most common and effective treatment against ischemic heart disease (IHD), but the process inflicts massive ischemia/reperfusion (I/R) injury for which no treatment exists. Notably, reperfusion after ischemia causes ischemia/reperfusion injury (IR injury) and the "no-reflow" phenomenon seriously affecting the therapeutic effects in clinical practice. The principle purpose of this study is to validate the effect of hydrogen gas on IHD and further explore the mechanism of hydrogen gas in alleviating myocardial I/R injury and no-reflow phenomenon. MATERIALS AND METHODS: The rat model of myocardial ischemia-reperfusion was well established. Myocardial infarct size was evaluated by TTC & Evans blue staining. The no-reflow area and the cardiac function were assessed by thioflavin-S staining and echocardiography respectively. Microstructure and mitochondria of myocardial tissue were assessed by transmission electron microscope. Western blot and immunohistochemistry were used to evaluate the expression of NLRP3 mediated pyroptosis related proteins. The 8-OHdG, MDA and serum total ROS were used to evaluate the degree of oxidative stress. KEY FINDINGS: The myocardial infarct size, no-reflow area, cardiac function, microstructure and mitochondrial morphology of I/R model rats were significantly improved after hydrogen inhalation. In addition, the expression of 8-OHdG, MDA, ROS and NLRP3 mediated pyroptosis related proteins were significantly decreased. SIGNIFICANCE: We found that oxidative stress and NLRP3 mediated pyroptosis are the important mechanisms for hydrogen to alleviate myocardial I/R injury, and we also confirmed that hydrogen can significantly improve no reflow phenomenon caused by ischemia-reperfusion.
Asunto(s)
Hidrógeno/farmacología , Isquemia Miocárdica/tratamiento farmacológico , Administración por Inhalación , Animales , Supervivencia Celular/efectos de los fármacos , Hidrógeno/administración & dosificación , Inflamasomas/metabolismo , Masculino , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Piroptosis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & controlRESUMEN
The aerodynamic plasma actuator distinguishes itself from others by a set of highly asymmetric electrodes arranged on dielectric. So the plasma produced by the aerodynamic plasma actuator has special characteristics along chord-wise direction. In the present paper the characteristic of the stagger electrodes dielectric barrier discharge plasmas in chord-wise direction was investigated experimentally through spectrometer, infrared imager and laser induced fluorescence system. The mechanisms behind plasma flow control were discussed briefly based on these experimental results. It was found in the experiments that the distributions of light intensity and temperature in chord-wise direction accord with Gaussian distribution. Light intensity and temperature were enhanced by increasing supplied voltage. NO produced by DBD discharge was detected directly by the LIF system. Through numerical simulations, the distributions of electric potential and electric field near the electrodes were determined and the phenomena observed in experiments were explained. Based on these experimental results, the mechanisms behind plasma flow control were ascertained to be the consequence of collisions, temperature increasing and chemical reactions.