RESUMEN
Ischemia/reperfusion (I/R) injury of the small intestine caused by occlusion of the superior mesenteric artery affects the intestinal tissue as well as components of the blood circulatory system from the microvasculature to mesenteric vessels. The aim of this work was to study the correlation between the dynamics of destruction development in the intestinal tissue, microvasculature, and mesenteric vessels in I/R of the small intestine. The microvasculature was analyzed by whole-organ continuous monitoring of the intestinal mucosal blood perfusion by laser Doppler flowmetry during the entire I/R. Real-time RT-PCR was used to assess gene expression of NF-κB, caspase-3, Ki67, and TNF-α in blood vessels. At the start of reperfusion, the first targets to be disrupted are microvessels in the apical villi. Injury of the apical part of the microcirculatory bloodstream correlates with the reduction in intestinal mucosal blood perfusion, which occurred simultaneously with apical villous destruction. By the end of the reperfusion period, the low intestinal mucosal blood perfusion is mirrored by the destruction of the microvasculature and mucosal structures in the entire organ. The development of mesenteric vessel injury is characterized by a change in NO metabolism and damaged endothelial cells concomitant with an alteration in the expression of genes encoding NF-κB, caspase-3, and Ki67 by the end of the reperfusion period. In I/R injury, detrimental effects on the intestinal tissue, microvasculature, and mesenteric vessels develop and exhibit common mechanisms of function, which show strong correlations.
Asunto(s)
Intestino Delgado/irrigación sanguínea , Intestino Delgado/patología , Daño por Reperfusión/patología , Animales , Apoptosis/genética , Vasos Sanguíneos/patología , Diferenciación Celular/genética , Proliferación Celular/genética , Intestino Delgado/fisiopatología , Masculino , Microcirculación , Microscopía Fluorescente , Óxido Nítrico/metabolismo , Ratas Wistar , Flujo Sanguíneo Regional , Daño por Reperfusión/fisiopatologíaRESUMEN
Low efficacy of cationic polymer-based formulations (polyplexes) for systemic gene delivery to tumors remains the crucial concern for their clinical translation. Here we show that modulating the physiological state of a tumor using clinically approved pharmaceuticals can improve delivery of intravenously injected polyplexes to murine melanoma tumors with different characteristics. Direct comparison of drugs with different mechanisms of action has shown that application of nitroglycerin or losartan improved extravasation and tumor uptake of polyplex nanoparticles, whereas angiotensin II had almost no effect on polyplex accumulation and microdistribution in the tumor tissue. Application of nitroglycerin and losartan caused from 2- to 6-fold enhanced efficacy of polyplex-mediated gene delivery depending on the tumor model. The results obtained on polyplex behavior in tumor tissues depending on physiological state of the tumor can be relevant to optimize delivery of polyplexes and other nanomedicines with similar physicochemical properties.
Asunto(s)
Sistemas de Liberación de Medicamentos , Técnicas de Transferencia de Gen , Melanoma Experimental/terapia , Administración Intravenosa , Angiotensina II/administración & dosificación , Angiotensina II/farmacocinética , Angiotensina II/farmacología , Animales , Línea Celular Tumoral , Colágeno Tipo I/metabolismo , ADN/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Losartán/administración & dosificación , Losartán/farmacocinética , Losartán/farmacología , Luciferasas de Luciérnaga/genética , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/fisiopatología , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Nanopartículas/administración & dosificación , Nitroglicerina/administración & dosificación , Nitroglicerina/farmacocinética , Nitroglicerina/farmacología , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacocinética , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Polietileneimina/administración & dosificación , Polietileneimina/análogos & derivados , Polietileneimina/farmacocinética , Polietileneimina/farmacología , Receptor de Melanocortina Tipo 1/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Vasoconstrictores/administración & dosificación , Vasoconstrictores/farmacocinética , Vasoconstrictores/farmacología , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND/PURPOSE: The objective was to study age-related alterations in the time-amplitude characteristics of the oscillatory components of peripheral blood flow in healthy humans during postocclusive reactive hyperemia. METHODS: Forearm blood skin perfusion was studied by the method of laser Doppler flowmetry in 120 healthy volunteers, who were divided into two age groups: young (19-30 years old; n = 82) and middle-age (30-60 years old; n = 38). The forearm occlusion approach was used to reveal the reaction of the microvascular bed to transient ischemia. To estimate the age-related changes of separate oscillatory components of LDF signals during postocclusive reactive hyperemia, we applied adaptive time-amplitude wavelet analysis. RESULTS: A statistically significant increase in the skin blood perfusion after occlusion removal was revealed: 4-fold in the 1st and 3.5-fold in the 2nd group respectively. Both the amplitude of blood flow oscillations at rest and the postocclusive growth of the amplitude showed an age-related decline in the frequency intervals associated with the myogenic (0.052-0.145 Hz), sympathetic (0.021-0.052 Hz) and endothelial (0.0095-0.021 Hz) activity. CONCLUSION: The time-amplitude characteristics of the oscillatory components of peripheral blood flow depend on age, with the dependence becoming more evident after a transient ischemia.
Asunto(s)
Adaptación Fisiológica/fisiología , Envejecimiento/fisiología , Hiperemia/fisiopatología , Isquemia/fisiopatología , Flujo Sanguíneo Regional/fisiología , Piel/irrigación sanguínea , Adulto , Femenino , Antebrazo/irrigación sanguínea , Humanos , Flujometría por Láser-Doppler , Masculino , Microcirculación/fisiología , Persona de Mediana Edad , Periodicidad , Adulto JovenRESUMEN
The effects of low-intensity extremely high-frequency electromagnetic radiation (EHF EMR; 42.2 GHz, 0.1 mW/cm(2) , exposure duration 20 min) on the fatty acid (FA) composition of thymic cells and blood plasma in normal mice and in mice with peritoneal inflammation were studied. It was found that the exposure of normal mice to EHF EMR increased the content of polyunsaturated FAs (PUFAs) (eicosapentaenoic and docosapentaenoic) in thymic cells. Using a model of zymosan-induced peritoneal inflammation, it was shown that the exposure of mice to EHF EMR significantly increased the content of PUFAs (dihomo-γ-linolenic, arachidonic, eicosapentaenoic, docosapentaenoic, and docosahexaenoic) and reduced the content of monounsaturated FAs (MUFAs) (palmitoleic and oleic) in thymic cells. Changes in the FA composition in the blood plasma were less pronounced and manifested themselves as an increase in the level of saturated FAs during the inflammation. The data obtained support the notion that MUFAs are replaced by PUFAs that can enter into the thymic cells from the external media. Taking into account the fact that the metabolites of PUFAs are lipid messengers actively involved in inflammatory and immune reactions, we assume that the increase in the content of n-3 and n-6 PUFAs in phospholipids of cellular membranes facilitates the realization of anti-inflammatory effects of EHF EMR.
Asunto(s)
Ácidos Grasos Monoinsaturados/metabolismo , Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos/metabolismo , Inflamación/metabolismo , Animales , Línea Celular/efectos de la radiación , Ácidos Grasos/efectos de la radiación , Ácidos Grasos Monoinsaturados/efectos de la radiación , Ácidos Grasos Insaturados/efectos de la radiación , Inflamación/inducido químicamente , Ratones , Radiación , Dosis de Radiación , Timo/efectos de la radiación , ZimosanRESUMEN
The perfusion of forearm skin with blood was studied by the method of laser Doppler flowmetry (LDF) in 94 healthy volunteers. We studied the reaction of the microvascular bed to the transient ischemia, which was initiated by the forearm occlusion. After occlusion, we registered, on average, a 4-fold increase of skin blood perfusion as compared to the level of this parameter at rest. In the study, we also analyzed changes of the oscillatory components of LDF signals during post-occlusive reactive hyperemia; these components were revealed with the adaptive time-amplitude wavelet analysis. It was found that the time needed for oscillations to reach their maximal amplitude is different for each of the frequency intervals examined. After occlusion, a statistically significant rise of the amplitude of blood flow oscillations was revealed-for the frequency intervals corresponding to the cardiac (0.6-2 Hz), respiratory (0.145-0.6 Hz), myogenic (0.052-0.145 Hz), sympathetic (0.021-0.052 Hz), and endothelial (0.0095-0.021 Hz) activity (a more than 11-, 8-, 6-, 3-, and 6-fold increase, respectively, as compared to the state of rest). The method applied here for the analysis of oscillatory components of LDF signals can, therefore, be used to study the dynamics of oscillations of peripheral blood flow under various functional tests.
Asunto(s)
Hiperemia/fisiopatología , Flujo Sanguíneo Regional/fisiología , Reperfusión , Piel/irrigación sanguínea , Adulto , Femenino , Antebrazo/irrigación sanguínea , Humanos , Isquemia/fisiopatología , Flujometría por Láser-Doppler , MasculinoRESUMEN
The paper describes an original method for analysis of the peripheral blood flow oscillations measured with the laser Doppler flowmetry (LDF) technique. The method is based on the continuous wavelet transform and adaptive wavelet theory and applies an adaptive wavelet filtering to the LDF data. The method developed allows one to examine the dynamics of amplitude oscillations in a wide frequency range (from 0.007 to 2 Hz) and to process both stationary and non-stationary short (6 min) signals. The capabilities of the method have been demonstrated by analyzing LDF signals registered in the state of rest and upon humeral occlusion. The paper shows the main advantage of the method proposed, which is the significant reduction of 'border effects', as compared to the traditional wavelet analysis. It was found that the low-frequency amplitudes obtained by adaptive wavelets are significantly higher than those obtained by non-adaptive ones. The method suggested would be useful for the analysis of low-frequency components of the short-living transitional processes under the conditions of functional tests. The method of adaptive wavelet filtering can be used to process stationary and non-stationary biomedical signals (cardiograms, encephalograms, myograms, etc), as well as signals studied in the other fields of science and engineering.
Asunto(s)
Flujometría por Láser-Doppler/métodos , Flujo Sanguíneo Regional , Procesamiento de Señales Asistido por Computador , Factores de TiempoRESUMEN
Using a model of acute zymosan-induced paw edema in NMRI mice, we test the hypothesis that anti-inflammatory effects of extremely high-frequency electromagnetic radiation (EHF EMR) can be essentially modified by application of pulse modulation with certain frequencies. It has been revealed that a single exposure of animals to continuous EHF EMR for 20 min reduced the exudative edema of inflamed paw on average by 19% at intensities of 0.1-0.7 mW/cm(2) and frequencies from the range of 42.2-42.6 GHz. At fixed effective carrier frequency of 42.2 GHz, the anti-inflammatory effect of EHF EMR did not depend on modulation frequencies, that is, application of different modulation frequencies from the range of 0.03-100 Hz did not lead to considerable changes in the effect level. On the contrary, at "ineffective" carrier frequencies of 43.0 and 61.22 GHz, the use of modulation frequencies of 0.07-0.1 and 20-30 Hz has allowed us to restore the effect up to a maximal level. The results obtained show the critical dependence of anti-inflammatory action of low-intensity EHF EMR on carrier and modulation frequencies. Within the framework of this study, the possibility of changing the level of expected biological effect of modulated EMR by a special selection of combination of carrier and modulation frequencies is confirmed.