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1.
Antioxidants (Basel) ; 13(3)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38539860

RESUMO

Neuroinflammation and brain oxidative stress are recognized as significant contributors to hypertension including salt sensitive hypertension. Extracellular vesicles (EVs) play an essential role in intercellular communication in various situations, including physiological and pathological ones. Based on this evidence, we hypothesized that EVs derived from the brains of hypertensive rats with salt sensitivity could trigger neuroinflammation and oxidative stress during hypertension development. To test this hypothesis, we compared the impact of EVs isolated from the brains of hypertensive Dahl Salt-Sensitive rats (DSS) and normotensive Sprague Dawley (SD) rats on inflammatory factors and mitochondrial reactive oxygen species (mtROS) production in primary neuronal cultures and brain cardiovascular relevant regions, including the hypothalamic paraventricular nucleus (PVN) and lamina terminalis (LT). We found that brain-derived DSS-EVs significantly increased the mRNA levels of proinflammatory cytokines (PICs) and chemokines, including TNFα, IL1ß, CCL2, CCL5, and CCL12, as well as the transcriptional factor NF-κB in neuronal cultures. DSS-EVs also induced oxidative stress in neuronal cultures, as evidenced by elevated NADPH oxidase subunit CYBA coding gene mRNA levels and persistent mtROS elevation. When DSS-EVs were injected into the brains of normal SD rats, the mRNA levels of PICs, chemokines, and the chronic neuronal activity marker FOSL1 were significantly increased in the PVN and LT. Furthermore, DSS-EVs caused mtROS elevation in brain PVN and LT, particularly in neurons. Our study reveals a novel role for brain-derived EVs from hypertensive rats in triggering neuroinflammation, upregulating chemokine expression, and inducing excessive ROS production. These findings provide insight into the complex interactions between EVs and hypertension-associated processes, offering potential therapeutic targets for hypertension-linked neurological complications.

2.
ACS Omega ; 9(2): 2585-2596, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38250363

RESUMO

Conducting in vivo brain imaging can be a challenging task due to the complexity of brain tissue and the strict requirements for safe and effective imaging agents. However, a new fluorescent dye called Cy5-PEG2 has been developed that selectively accumulates in mitochondria, enabling the visualization of these essential organelles in various cell lines. This dye is versatile and can be used for the real-time monitoring of mitochondrial dynamics in living cells. Moreover, it can cross the blood-brain barrier, making it a promising tool for noninvasive in vivo brain imaging. Based on the assessment of glial cell responses in the hippocampus and neocortex regions using GFAP and Iba1 biomarkers, Cy5-PEG2 seems to have minimal adverse effects on brain immune response or neuronal health. Therefore, this mitochondria-targeting fluorescent dye has the potential to advance our understanding of mitochondrial dynamics and function within the broader context of whole-brain physiology and disease progression. However, further research is needed to evaluate the safety and efficacy of Cy5-PEG2.

3.
bioRxiv ; 2023 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-37461660

RESUMO

Mitochondrial dysfunction is implicated in both brain tumors and neurodegenerative diseases, leading to various cellular abnormalities that can promote tumor growth and resistance to thera-pies, as well as impaired energy production and compromised neuronal function. Developing targeted therapies aimed at restoring mitochondrial function and improving overall cellular health could potentially be a promising approach to treating these conditions. Brain-derived exosomes (BR-EVs) have emerged as potential drug delivery vessels for neurological conditions. Herein, we report a new method for creating mitochondria-targeting exosomes and test its application in vitro and in vivo.

4.
ACS Omega ; 8(51): 48984-48993, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38162779

RESUMO

Mitochondrial dysfunction is associated with various health conditions, including cardiovascular and neurodegenerative diseases. Mitochondrial-targeting therapy aims to restore or enhance mitochondrial function to treat or alleviate these conditions. Exosomes, small vesicles that cells secrete, containing a variety of biomolecules, are critical in cell-to-cell communication and have been studied as potential therapeutic agents. Exosome-based therapy has the potential to treat both cardiovascular and neurodegenerative diseases. Combining these two approaches involves using exosomes as carriers to transport mitochondrial-targeting agents to dysfunctional or damaged mitochondria within target cells. This article presents a new technique for engineering brain-derived exosomes that target mitochondria and has demonstrated promise in initial tests with primary neuron cells and healthy rats. This promising development represents a significant step forward in treating these debilitating conditions.

5.
ACS Omega ; 6(47): 31447-31456, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34869971

RESUMO

Many organelles, such as lysosomes and mitochondria, maintain a pH that is different from the cytoplasmic pH. These pH differences have important functional ramifications for those organelles. Many cellular events depend upon a well-compartmentalized distribution of H+ ions spanning the membrane for the optimal function. Cells have developed a variety of mechanisms that enable the regulation of organelle pH. However, the measurement of organellar acidity/alkalinity in living cells has remained a challenge. Currently, most existing probes for the estimation of intracellular pH show a single -organelle targeting capacity. Such probes provide data that fails to comprehensively reveal the pathological and physiological roles and connections between mitochondria and lysosomes in different species. Mitochondrial and lysosomal functions are closely related and important for regulating cellular homeostasis. Accordingly, the design of a single fluorescent probe that can simultaneously target mitochondria and lysosomes is highly desirable, enabling a better understanding of the crosstalk between these organelles. We report the development of a novel fluorescent sensor, rhodamine-coumarin pH probe (RCPP), for detection of organellar acidity/alkalinity. RCPP simultaneously moves between mitochondrion and lysosome subcellular locations, facilitating the simultaneous monitoring of pH alterations in mitochondria and lysosomes.

6.
ACS Omega ; 3(11): 15850-15864, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30533582

RESUMO

Clinically approved therapeutics that mitigate chemotherapy-induced cardiotoxicity, a serious adverse effect of chemotherapy, are lacking. The aim of this study was to determine the putative protective capacity of a novel indole alkaloid derivative B (IADB) against 5-fluorouracil (5-FU)-induced cardiotoxicity. To assess the free-radical scavenging activities of IADB, the acetylcholine-induced relaxation assay in rat thoracic aorta was used. Further, IADB was tested in normal and cancer cell lines with assays gauging autophagy induction. We further examined whether IADB could attenuate cardiotoxicity in 5-FU-treated male ICR mice. We found that IADB could serve as a novel bifunctional agent (displaying both antioxidant and autophagy-modulating activities). Further, we demonstrated that IADB induced production of cytosolic autophagy-associated structures in both cancer and normal cell lines. We observed that IADB cytotoxicity was much lower in normal versus cancer cell lines, suggesting an enhanced potency toward cancer cells. The cardiotoxicity induced by 5-FU was significantly relieved in animals pretreated with IADB. Taken together, IADB treatment, in combination with chemotherapy, may lead to reduced cardiotoxicity, as well as the reduction of anticancer drug dosages that may further improve chemotherapeutic efficacy with decreased off-target effects. Our data suggest that the use of IADB may be therapeutically beneficial in minimizing cardiotoxicity associated with high-dose chemotherapy. On the basis of the redox status difference between normal and tumor cells, IADB selectively induces autophagic cell death, mediated by reactive oxygen species overproduction, in cancer cells. This novel mechanism could reveal novel therapeutic targets in chemotherapy-induced cardiotoxicity.

7.
Bioorg Med Chem ; 25(9): 2545-2568, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28359673

RESUMO

Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Óxidos N-Cíclicos/uso terapêutico , Indóis/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Antioxidantes/administração & dosagem , Antioxidantes/química , Aspirina/farmacologia , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/síntese química , Citocromos c/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Indóis/administração & dosagem , Indóis/síntese química , Indóis/farmacologia , Intestino Delgado/irrigação sanguínea , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Simulação de Dinâmica Molecular , Infiltração de Neutrófilos/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Bioorg Med Chem Lett ; 26(16): 4042-51, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27390069

RESUMO

We describe several novel curcumin analogues that possess both anti-inflammatory antioxidant properties and thrombolytic activities. The therapeutic efficacy of these curcumin analogues was verified in a mouse ear edema model, a rat arterial thrombosis assay, a free radical scavenging assay performed in PC12 cells, and in both in vitro and in vivo ischemia/reperfusion models. Our findings suggest that their protective effects partially reside in maintenance of optimal mitochondrial function.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/análogos & derivados , Sequestradores de Radicais Livres/farmacologia , Mitocôndrias/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Citocromos c/metabolismo , Modelos Animais de Doenças , Edema/prevenção & controle , Ensaio de Imunoadsorção Enzimática , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Interleucina-6/sangue , Camundongos , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Teoria Quântica , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Fator de Necrose Tumoral alfa/sangue
9.
Bioorg Med Chem Lett ; 26(8): 2005-13, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26961795

RESUMO

Mitochondrial oxidative damage contributes to a wide range of pathologies, including ischemia/reperfusion (I/R) injury, cardiovascular disorders and neurodegenerative diseases. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel kyotorphin-nitroxide hybrid molecules, and examined their free radical scavenging activities, in addition to their anti-inflammatory and analgesic activities. We have further characterized these compounds in a simulated I/R cellular model. Our findings suggest that the protective effects of kyotorphin-nitroxides partially reside in maintaining optimal mitochondrial function.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Endorfinas/farmacologia , Óxidos de Nitrogênio/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Endorfinas/química , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Óxidos de Nitrogênio/química , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Relação Estrutura-Atividade , Xilenos
10.
Bioorg Med Chem Lett ; 25(17): 3476-80, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26189896

RESUMO

Mitochondrial oxidative stress has been implicated in aging, neurodegenerative diseases, diabetes, stroke, ischemia/reperfusion injury, age-related macular degeneration (AMD) and cancer. Recently, we developed two new mitochondria-targeting fluorescent probes, MitoProbes I/II, which specifically localize in mitochondria and employed both in vivo and in vitro for detection of mitochondrial oxidative stress. Here, we report the design and synthesis of these agents, as well as their utility for real-time imaging of mitochondrial oxidative stress in cells.


Assuntos
Corantes Fluorescentes/metabolismo , Microscopia Confocal/métodos , Mitocôndrias/metabolismo , Células HeLa , Humanos , Modelos Moleculares , Estresse Oxidativo
11.
Sci Rep ; 5: 9004, 2015 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-25758662

RESUMO

Intracellular pH plays an important role in the response to cancer invasion. We have designed and synthesized a series of new fluorescent probes (Superior LysoProbes) with the capacity to label acidic organelles and monitor lysosomal pH. Unlike commercially available fluorescent dyes, Superior LysoProbes are lysosome-specific and are highly stable. The use of Superior LysoProbes facilitates the direct visualization of the lysosomal response to lobaplatin elicited in human chloangiocarcinoma (CCA) RBE cells, using confocal laser scanning microscopy. Additionally, we have characterized the role of lysosomes in autophagy, the correlation between lysosome function and microtubule strength, and the alteration of lysosomal morphology during apoptosis. Our findings indicate that Superior LysoProbes offer numerous advantages over previous reagents to examine the intracellular activities of lysosomes.


Assuntos
Apoptose , Corantes Fluorescentes , Lisossomos/metabolismo , Imagem Molecular , Coloração e Rotulagem , Apoptose/efeitos dos fármacos , Transporte Biológico , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Cloroquina/farmacologia , Ciclobutanos/farmacologia , Citoesqueleto/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Espaço Intracelular/metabolismo , Microscopia Confocal , Compostos Organoplatínicos/farmacologia
12.
Sci Rep ; 5: 8576, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25715948

RESUMO

We report the design, synthesis and application of several new fluorescent probes (LysoProbes I-VI) that facilitate lysosomal pH monitoring and characterization of lysosome-dependent apoptosis. LysoProbes are superior to commercially available lysosome markers since the fluorescent signals are both stable and highly selective, and they will aid in characterization of lysosome morphology and trafficking. We predict that labeling of cancer cells and solid tumor tissues with LysoProbes will provide an important new tool for monitoring the role of lysosome trafficking in cancer invasion and metastasis.


Assuntos
Corantes Fluorescentes/química , Lisossomos/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Lactose/química , Lisossomos/fisiologia , Espectrometria de Fluorescência , Coloração e Rotulagem
13.
J Med Chem ; 55(9): 4501-5, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22439897

RESUMO

We have recently developed new Tempo-PEG-RGDs conjugates and have quantitatively examined their antithrombotic and antioxidant capabilities. These compounds were therapeutically beneficial when characterized in both in vitro platelet aggregation assays and a rat model of arterial thrombosis. Moreover, these compounds demonstrated significant protection from organ damage in a rat model of ischemia/reperfusion. Our data indicate that Tempo-PEG-RGDs represent a new class of adjuvants with therapeutic efficacy in acute and transient ischemic damage.


Assuntos
Óxidos N-Cíclicos/farmacologia , Sequestradores de Radicais Livres/síntese química , Oligopeptídeos/síntese química , Estresse Oxidativo/fisiologia , Polietilenoglicóis/síntese química , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Sequestradores de Radicais Livres/farmacologia , Membro Posterior/irrigação sanguínea , Histocitoquímica , Malondialdeído/sangue , Músculo Esquelético/fisiopatologia , Oligopeptídeos/farmacologia , Agregação Plaquetária/fisiologia , Polietilenoglicóis/farmacologia , Ratos , Traumatismo por Reperfusão/sangue , Superóxido Dismutase/sangue
14.
Bioorg Med Chem Lett ; 22(7): 2440-3, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22386664

RESUMO

We synthesized and evaluated a series of acidic fluorescent pH probes exhibiting robust pH dependence, high sensitivity and photostability, and excellent cell membrane permeability. Titration analyses indicated that probe 3 could increase its fluorescence intensity 800-fold between pH 8.0 and 4.1. Additionally, its pK(a) value is optimal for intracellular probing of acidic organelles. Fluorescent imaging of HepG2 and Hela cells further revealed that probe 3 demonstrates outstanding capacity for monitoring of intracellular [H(+)] levels. The easily accessible terminal alkyne/azido function groups of these probes offer the possibility of rapidly constructing sensor molecule libraries using 'click' chemistry.


Assuntos
Técnicas Biossensoriais , Corantes Fluorescentes/síntese química , Lactamas/síntese química , Rodaminas/síntese química , Ácidos , Permeabilidade da Membrana Celular , Citoplasma/química , Corantes Fluorescentes/química , Células HeLa , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Lactamas/química , Organelas/química , Prótons , Rodaminas/química , Espectrometria de Fluorescência
15.
Org Lett ; 14(1): 50-3, 2012 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-22176578

RESUMO

The synthesis, characteristics, and biological applications of a series of new rhodamine nitroxide fluorescent probes that enable imaging of hydroxyl radicals (•OH) in living cells are described. These probes are highly selective for •OH in aqueous solution, avoiding interference from other reactive oxygen species (ROS), and they facilitate •OH imaging in biologically active samples. The robust nature of these probes (high specificity and selectivity, and facile synthesis) offer distinct advantages over previous methods for •OH detection.


Assuntos
Corantes Fluorescentes/análise , Radical Hidroxila/análise , Espaço Intracelular/química , Óxidos de Nitrogênio/análise , Rodaminas/química , Linhagem Celular , Sobrevivência Celular , Corantes Fluorescentes/síntese química , Humanos , Radical Hidroxila/química , Estrutura Molecular , Óxidos de Nitrogênio/química , Estresse Oxidativo
16.
Eur J Med Chem ; 46(6): 2441-52, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21474215

RESUMO

We have synthesized a series of new ß-carboline-tripeptide conjugates, and examined their anti-inflammatory properties in a mouse model of xylene-induced ear edema. The analgesic capacity of these compounds was further evaluated in a rodent tail flick assay. Our results indicate that ß-carboline conjugate 4a manifests potent anti-inflammatory and analgesic activity while exerting a protective effect against mesenteric ischemia/reperfusion (I/R) injury in the rat.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Carbolinas/química , Artérias Mesentéricas/efeitos dos fármacos , Oligopeptídeos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/prevenção & controle , Masculino , Artérias Mesentéricas/patologia , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Estereoisomerismo , Xilenos/antagonistas & inibidores
17.
Eur J Med Chem ; 46(5): 1453-62, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21396750

RESUMO

We describe a novel class of ß-carboline alkaloid-peptide conjugates that possess both free radical scavenging and thrombolytic activity. These conjugates demonstrate therapeutic efficacy in a rat arterial thrombosis assay, as well as free radical scavenging capacity as evaluated in a PC12 cell survival assay. Our results indicate that ß-carboline alkaloid-peptide conjugate 26a exerts a significant protective effect against local and remote organ injury induced by limb I/R injury in the rat.


Assuntos
Alcaloides/farmacologia , Carbolinas/farmacologia , Extremidades/irrigação sanguínea , Isquemia/tratamento farmacológico , Peptídeos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Doença Aguda , Alcaloides/síntese química , Alcaloides/química , Animais , Carbolinas/síntese química , Carbolinas/química , Sobrevivência Celular/efeitos dos fármacos , Extremidades/patologia , Sequestradores de Radicais Livres/metabolismo , Isquemia/patologia , Simulação de Dinâmica Molecular , Estrutura Molecular , Células PC12 , Peptídeos/síntese química , Peptídeos/química , Ratos , Traumatismo por Reperfusão/patologia , Estereoisomerismo , Relação Estrutura-Atividade
18.
Chem Commun (Camb) ; 47(4): 1345-7, 2011 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-21082113

RESUMO

Synthetic oligodeoxynucleotide is purified by capping failure sequences with an acrylated phosphoramidite followed by polymerization and product extraction. The method is suitable for large scale oligonucleotide drug purification.


Assuntos
Oligodesoxirribonucleotídeos/síntese química , Sequência de Bases , Cromatografia Líquida de Alta Pressão , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/isolamento & purificação , Compostos Organofosforados/química , Polimerização
19.
J Med Chem ; 53(18): 6763-7, 2010 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-20731361

RESUMO

To develop more potent therapeutic agents with therapeutic efficacy for ischemia/reperfusion (I/R) injury, we linked an antiinflammatory moiety (1,3-dioxane derivative) to the key pharmacophoric moiety of melatonin. We hypothesized that the resulting new indole derivatives might induce a synergistic protection against oxidative damage associated with I/R injury. Our results indicate that one of these indole derivatives (7) manifests potent antiinflammatory antioxidant effects and exerts a protective effect against skeletal muscle injury and associated lung injury following limb I/R in rats.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Antioxidantes/síntese química , Indóis/síntese química , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Permeabilidade Capilar , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Membro Posterior/irrigação sanguínea , Indóis/química , Indóis/farmacologia , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Camundongos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Células PC12 , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Relação Estrutura-Atividade
20.
Eur J Pharmacol ; 616(1-3): 256-64, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19555683

RESUMO

Renal ischemia/reperfusion is a common cause of acute renal failure. Glycine is an effective anti-inflammatory, cytoprotective agent and is reported to have a beneficial effect against ischemia/reperfusion injury in various organs. Previous research notes that free radicals and inflammatory leukocytes both play important roles in the pathogenesis of renal ischemia/reperfusion injury. To develop new therapeutic agents against renal ischemia/reperfusion injury, we sought to link an antioxidant moiety (nitronyl nitroxide) to glycine in the hope that the resulting glycine-nitronyl nitroxide conjugate (GNN) would provide a synergetic protection against renal ischemia/reperfusion injury. In this manuscript, we report the synthesis and biological evaluation of the GNN conjugate. The biological activity of the GNN conjugate was evaluated in an in vivo rat model of renal ischemia/reperfusion induced injury and oxidative change. Since the GNN conjugate markedly reduced elevated levels of tissue lipid peroxidation and attenuated renal dysfunction in rats subjected to renal ischemia/reperfusion, it might be possible to develop the GNN conjugate into a potential therapeutic agent against renal ischemia/reperfusion injury.


Assuntos
Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Acetilcolina/farmacologia , Animais , Anti-Inflamatórios/química , Nitrogênio da Ureia Sanguínea , Sequestradores de Radicais Livres/síntese química , Glutationa/metabolismo , Glicina/síntese química , Glicina/uso terapêutico , Técnicas In Vitro , Rim/irrigação sanguínea , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Óxidos de Nitrogênio/química , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Peroxidase/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Vasodilatação/efeitos dos fármacos
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