RESUMEN
Induction of mild mitochondrial uncoupling is protective in a variety of disorders; however, it is unclear how to recognize the mild mitochondrial uncoupling induced by chemical mitochondrial uncouplers. The aim of the present study is to identify the pharmacological properties of mitochondrial uncoupling induced by mitochondrial uncouplers in cardiomyocytes. Neonatal rat cardiomyocytes were cultured. Protein levels were measured by using western blot technique. The whole cell respiratory function was determined by using high-resolution respirometry. The typical types of chemical mitochondrial uncouplers, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), niclosamide, and BAM15, induced biphasic change of STAT3 activity in cardiomyocytes, activating STAT3 at low dose and inhibiting STAT3 at high dose, though the dose range of these drugs was distinct. Low-dose uncouplers induced STAT3 activation through the mild increase of mitochondrial ROS (mitoROS) generation and the subsequent JAK/STAT3 activation in cardiomyocytes. However, high-dose uncouplers induced inhibition of STAT3, decrease of ATP production, and cardiomyocyte death. High-dose uncouplers induced STAT3 inhibition through the excessive mitoROS generation and the decreased ATP -induced AMPK activation. Low-dose mitochondrial uncouplers attenuated doxorubicin (DOX)-induced STAT3 inhibition and cardiomyocyte death, and activated STAT3 contributed to the cardioprotection of low-dose mitochondrial uncouplers. Uncoupler-induced mild mitochondrial uncoupling in cardiomyocytes is characterized by STAT3 activation and ATP increase whereas excessive mitochondrial uncoupling is characterized by STAT3 inhibition, ATP decrease and cell injury. Development of mitochondrial uncoupler with optimal dose window of inducing mild uncoupling is a promising strategy for heart protection.
Asunto(s)
Mitocondrias/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Desacopladores/farmacología , Adenosina Trifosfato/metabolismo , Animales , Células Cultivadas , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Ratas , Factor de Transcripción STAT3/efectos de los fármacos , Factor de Transcripción STAT3/metabolismoRESUMEN
Nitric oxide (NO), carbon monoxide, and hydrogen sulfide in addition to hydrogen are well established as gaseous signal molecules throughout the body. Although the role of gasotransmitters in acute pancreatitis (AP) has been explored for many years, many details remain to be elucidated. The physiologic effect of NO in AP mainly relies on induced NO synthase, which stimulates the production of cytokines in the blood. Carbon monoxide inhibits nuclear factor-κB activation, which leads to amelioration of the inflammatory response. Hydrogen sulfide displays a dual role in the mechanism of AP according to its concentration in the system. Hydrogen is a newly discovered gaseous signaling molecule, and currently, there is little evidence that it has any function in alleviating inflammation. We discovered that hyperbaric oxygen is a novel gasotransmitter that has potential use in the treatment of AP. The correlation among hyperbaric oxygen, hypoxia inducible factor 1α, and other signaling pathways should be further studied. We also discuss some prospects and issues that remain to be resolved in this review. In summary, the discovery of gaseous signal molecules has established a new platform for deep investigation of the mechanism of AP, and our knowledge of the role of gasotransmitters in AP will increase with further research.
Asunto(s)
Oxigenoterapia Hiperbárica , Óxido Nítrico/metabolismo , Páncreas/metabolismo , Pancreatitis/metabolismo , Pancreatitis/terapia , Transducción de Señal , Enfermedad Aguda , Animales , Monóxido de Carbono/metabolismo , Gases , Humanos , Hidrógeno/metabolismo , Sulfuro de Hidrógeno/metabolismoRESUMEN
Curcumin has multiple biological and pharmacological activities, including antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and antitumor activities. However, the clinical use of curcumin is limited because of its poor oral absorption and extremely poor bioavailability. In order to overcome these limitations, we conjugate curcumin chemically into the known biocompatible and biodegradable polymer, poly(glycerol-sebacate), and prepare the unitary poly(glycerol-sebacate-curcumin) polymer. The structure, the in vitro degradation, the drug release, and antitumor activity as well as the in vivo degradation and tissue biocompatibility of poly(glycerol-sebacate-curcumin) polymer are investigated. The in vitro degradation and drug release profile of poly(glycerol-sebacate-curcumin) are in a linear manner. The in vitro antitumor assay shows that poly(glycerol-sebacate-curcumin) polymer significantly inhibits human malignant glioma cells, U87 and T98 cells. In view of the cytotoxicity against brain gliomas, local use of this polymer would be a potential method for brain tumors.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Curcumina/uso terapéutico , Decanoatos/uso terapéutico , Glioma/tratamiento farmacológico , Glicerol/análogos & derivados , Polímeros/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Curcumina/química , Curcumina/farmacología , Decanoatos/síntesis química , Decanoatos/química , Decanoatos/farmacología , Módulo de Elasticidad/efectos de los fármacos , Geles , Glioma/patología , Glicerol/síntesis química , Glicerol/química , Glicerol/farmacología , Glicerol/uso terapéutico , Humanos , Microscopía Electrónica de Rastreo , Polímeros/síntesis química , Polímeros/química , Polímeros/farmacología , Ratas , Ratas Wistar , Espectrofotometría Infrarroja , Agua/química , Difracción de Rayos XRESUMEN
The pharmacological basis of isosorbide mononitrate (ISMN), a widely used drug for cardiovascular diseases, is that it is metabolized to nitric oxide (NO). However, NO is a double-edged sword that results in either beneficial or detrimental effect. Vascular injury is the common consequence of many cardiovascular diseases, but it is not determined whether ISMN influences the restoration of injured artery in vivo. Carotid artery injury was induced by electric stimulation in mice. Vasoconstriction and endothelium-dependent and -independent relaxation were recorded by a multichannel acquisition and analysis system. ISMN (10 mg/kg, p.o.) treatment for 1 week and 1 month had no effect on reendothelialization, histology and function of carotid artery injured by electric stimulation. L-arginine (500 mg/kg, p.o.) and Nomega-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg, p.o.) treatment for 1 week did not affect the reendothelialization process, but L-NAME treatment induced neointimal hyperplasia and inhibited endothelium-dependent relaxation in electrically injured artery. These results suggest that supplement of exogenous or endogenous NO has no effect on the restoration of injured artery, but inhibition of endogenous NO induces neointimal hyperplasia in injured artery. ISMN treatment does not affect the restoration of injured artery.