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OBJECTIVE: To observe the effects of acupuncture at "antihypertensive acupoint prescription" on endothelial active factors and related autonomic neurotransmitters in spontaneous hypertension rats, and explore the vascular regulation and central regulation mechanisms of acupuncture for anti-hypertension. METHODS: Thirty SPF grade male spontaneous hypertension rats were randomly divided into a model group (15 rats) and an acupuncture group (15 rats). Besides, 15 Wistar Kyoto rats were collected as a blank control group (normal group). In the acupuncture group, acupuncture was delivered at the "antihypertensive acupoint prescription" (bilateral "Renying" [ST 9], "Quchi" [LI 11], "Zusanli" [ST 36], "Taichong" [LR 3] and "Neiguan" [PC 6]), with needles retained for 30 min, once daily. The duration of intervention was 28 days. Every week, using the the irritation scale, the sign of sympathetic irritation was evaluated dynamically. The arterial blood pressure of the rats tail was determined, using non-invasive blood pressure measurement system. ELISA was adopted to detect the levels of calcitonin gene-related peptide (CGRP), nitric oxide (NO), endothelin-1 (ET-1), neuropeptide Y (NPY) in the serum. DAB chromogenic in situ hybridization (CISH) was provided to detect the mRNA expression of endothelial nitric oxide synthase (eNOS) in the internal carotid artery and the arcuate nucleus (ARC), and that of CGRP in the paraventricular nucleus posterior (PVP) and the ventrolateral medulla (VLM). Liquid chromatography-mass spectrometry (LC-MS) was used to detect the levels of epinephrine (E) and norepinephrine (NE) in the paraventricular nucleus anterior (PVA). RESULTS: Compared with the normal group, the irritation scores, systolic blood pressure and diastolic blood pressure were increased at each time point in the model group (P<0.05). When compared with the model group, the irritation scores after the intervention for 3 and 4 weeks, and systolic and diastolic blood pressure after intervention for 2, 3 and 4 weeks were reduced in the acupuncture group (P<0.05). In comparison with the normal group, the serum CGRP and NO levels of the rats were decreased (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels in PVA were increased (P<0.05) in the model group. The levels of serum CGRP and NO were elevated (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels of PVA were reduced (P<0.05) in the acupuncture group when compared with those of the model group. In the model group, the media of internal carotid artery exhibited thickening and remodeling, while the neuron volume in ARC was small. In the acupuncture group, every layer of internal carotid artery was acceptably arranged, and the parvicellular neuron of ARC was moderate in volume. For the in situ hybridization of eNOS mRNA for the rats of each group, the smooth muscle cells were predominantly expressed in each layer of the internal carotid artery, whereas the expression of parvicellular neurons was dominated in ARC. In the model group, the large and small neurosecretory cells were distributed sparsely in the nerves of PVP; in the acupuncture group, the cells of these two species were distributed regularly; and there were few species of glial cell in the VLM of either the model group or the acupuncture group. In each group, for the in situ hybridization of CGRP mRNA, the small neurosecretory cells were expressed predominately in the PVP, while, the expression of glial cell nuclei and the cell cytoplasm was dominated in the VLM. Compared with the normal group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP mRNA in the PVP and VLM was decreased in the model group (P<0.05). In the acupuncture group, when compared with the model group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP in the PVP and VLM was increased in the acupuncture group (P<0.05). CONCLUSION: Acupuncture at "antihypertensive acupoint prescription" can upregulate the level of vascular relaxing factors, downregulate the level of contracting factors, enhance the response of relaxing factors in targeting blood vessels and regulating the center. The mechanism may be related to the modulation of the sympathetic-adrenergic autonomic neurotransmitters in the paraventricular nucleus in spontaneous hypertension rats.
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Terapia por Acupuntura , Presión Sanguínea , Péptido Relacionado con Gen de Calcitonina , Endotelina-1 , Hipertensión , Neuropéptido Y , Óxido Nítrico , Ratas Endogámicas SHR , Animales , Masculino , Ratas , Hipertensión/terapia , Hipertensión/fisiopatología , Hipertensión/metabolismo , Humanos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/genética , Endotelina-1/metabolismo , Endotelina-1/sangre , Neuropéptido Y/metabolismo , Neuropéptido Y/genética , Óxido Nítrico/metabolismo , Neurotransmisores/metabolismo , Ratas Endogámicas WKY , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico Sintasa de Tipo III/genéticaRESUMEN
The knowledge of structural evolution among thiolate-protected gold nanoclusters is not only helpful for understanding their structure-property relationship but also provides scientific evidence to rule-guided structure predictions of gold nanoclusters. In this paper, three new atomic structures of medium-sized thiolate-protected gold nanoclusters, i.e. Au44(SR)30, Au56(SR)32, and Au60(SR)34, are predicted based on the grand unified model and ring model. Two structural evolution rules, i.e., Au44(SR)28 + [Au12(SR)4] â Au56(SR)32 + [Au12(SR)4] â Au68(SR)36 and Au44(SR)30 + [Au8(SR)2] â Au52(SR)32 + [Au8(SR)2] â Au60(SR)34 + [Au8(SR)2] â Au68(SR)36, are explored. The generic growth patterns underlying both sequences of nanoclusters can be viewed as sequential addition of four and three highly stable tetrahedral Au4 units on the cores, respectively. In addition, density functional theory calculations show that these three newly predicted gold nanoclusters have very close formation energies with their adjacent structures, large highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gaps, and all-positive harmonic vibration frequencies, indicating their high stabilities.
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Warm needling, i.e. acupuncture with the needle warmed by burning moxa stick or cone, is frequently employed in the treatment of cold and dampness type disorders. During treatment, accidental skin scald may occur if the burning moxa drops on the skin due to slight changes in patient's body position. Thus, we designed and developed an anti-scald device for warm needling which is suitable for any part of the body. This device is made up of two parts, a stainless steel-grid moxa cartridge (including half cylinder, hinge shaft, lug, limit bar, clamping arm, connecting arm, torsion spring, heat insulation pad, through holes) and a clamp holder which is in an integrated structure. The grid moxa cartridge can be used to wrap the burning mugwort cone in all directions to prevent the ignited moxa-cone from falling and skin scalding, and effectively collect the burned moxa ash. At the same time, the clamp holder can be used to help fix the moxa-cone to increase the stability of warm needling operation. The device is convenient to operate and novel in design, can effectively reduce the occurrence of scald accidents in clinical treatment, save time and manpower, and has both economic and ecological benefits, being helpful to the promotion and use of warm needling.
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Terapia por Acupuntura , Moxibustión , Humanos , Calor , Piel , AgujasRESUMEN
Understanding the excited state behavior of isomeric structures of thiolate-protected gold nanoclusters is still a challenging task. In this paper, based on grand unified model and ring model for describing thiolate-protected gold nanoclusters, we have predicted four isomers of Au24(SR)16nanoclusters. Density functional theory calculations show that the total energy of one of the predicted isomers is 0.1 eV lower in energy than previously crystallized isomer. The nonradiative relaxation dynamics simulations of Au24(SH)16isomers are performed to reveal the effects of structural isomerism on relaxation process of the lowest energy states, in which that most of the low-excited states consist of core states. In addition, crystallized isomer possesses the shorter e-h recombination time, whereas the most stable isomer has the longer recombination time, which may be attributed to the synergistic effect of nonadiabatic coupling and decoherence time. Our results could provide practical guidance to predict new gold nanoclusters for future experimental synthesis, and stimulate the exploration of atomic structures of same sized gold nanoclusters for photovoltaic and optoelectronic devices.
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Structural prediction of thiolate-protected gold nanoclusters (AuNCs) with diverse charge states can enrich the understanding of this species. Untill now, the number of anion AuNCs is still deficient. In this work, a series of gold nanoclusters with negative total charge, including [Au28(SR)17]-, [Au35(SR)20]-, [Au42(SR)23]-, [Au49(SR)26]-, and [Au56(SR)29]-, are designed. Following a crystallized [Au23(SR)16]- prototype structure, the inner core of the newly predicted clusters is obtained through packing crossed Au7. Next, proper protecting thiolate ligands are arranged to fulfill the duet rule to obtain Au3(2e) and Au4(2e). Extensive analysis indicates that these clusters own high stabilities. Molecular orbital analysis shows that the orbitals for the populations of the valence electron locate at each Au3(2e) and Au4(2e), which demonstrates the reliability of the grand unified model. This work should be helpful for enriching the structural diversity of AuNCs.
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Electrones , Oro , Aniones , Oro/química , Ligandos , Reproducibilidad de los ResultadosRESUMEN
The charge states of thiolate-protected gold nanoclusters (AuNCs) are vital to their stabilities through affecting the number of the valence electrons. However, the origin of the charge states of AuNCs has not been fully understood yet. Herein, through fulfilling the duet-rule derived Au3(2e) and Au4(2e) elementary blocks in the grand unified model (GUM), analysis on the substantial crystal structures indicates the charge states of AuNCs can correlate with their core structural packing, especially the number of Au3(2e) elementary blocks. In addition, aided by the Au3(2e) block's role in tailoring the population of valence electron, three new AuNCs including Au18(SCH3)14, Au30(SCH3)20, and [Au30(SCH3)21]- are predicted through controllably specifying the exact number of Au3(2e) in the core. This work shows that GUM can bridge the gap among the charge states of the cluster, the inner core structure of the cluster, and the detachment of outer ligands via the electron counting rule.
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This study presents thorough structural insights into the stability of crystallized Au22(SAdm)16 (HSAdm = 1-adamantanethiol) nanocluster. With the recently developed Ring Model for describing the interaction between inner gold cores and outer protecting ligands in thiolate-protected gold nanoclusters, the experimental spontaneous transformation from the crystallized Au22(SAdm)16 to Au21(SAdm)15 could be well understood as structurally unfavorable for the current Au22(SAdm)16 and could also be attributed to the weaker aurophilic interaction between the inner Au4 core and the surrounding rings in Au22(SAdm)16 over that in Au21(SAdm)15. Furthermore, with the Ring Model and the grand unified model, two new Au22(SCH3)16 isomers with evident lower energies, higher HOMO-LUMO gaps as well as distinct optical properties over the available crystallized isomer were obtained. This study deepens the current knowledge on the structure of the Au22(SR)16 cluster from a new structural point of view and also confirms the validity as well as practicability of the Ring Model in understanding and predicting the stable structures of thiolate-protected gold nanoclusters.
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The search of ground-state structures (GSSs) of gold (Au) clusters is a formidable challenge due to the complexity of potential energy surface (PES). In this work, we have built a high-dimensional artificial neural network (ANN) potential to describe the PES of Au20clusters. The ANN potential is trained through learning the GSS search process of Au20by the combination of density functional theory (DFT) method and genetic algorithm. The root mean square errors of energy and force are 7.72 meV atom-1and 217.02 meV Å-1, respectively. As a result, it can find the lowest-energy structure (LES) of Au20clusters that is consistent with previous results. Furthermore, the scalability test shows that it can predict the energy of smaller size Au16-19clusters with errors less than 22.85 meV atom-1, and for larger size Au21-25clusters, the errors are below 36.94 meV atom-1. Extra attention should be paid to its accuracy for Au21-25clusters. Applying the ANN to search the GSSs of Au16-25, we discover two new structures of Au16and Au21that are not reported before and several candidate LESs of Au16-18. In summary, this work proves that an ANN potential trained for specific size clusters could reproduce the GSS search process by DFT and be applied in the GSS search of smaller size clusters nearby. Therefore, we claim that building ANN potential based on DFT data is one of the most promising ways to effectively accelerate the GSS pre-screening of clusters.
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We present a [Au7(SR)7] ring as a new type of protection ligand in a new atomic structure of Au15(SR)13 nanocluster for the first time based on the ring model developed to understand how interfacial interaction dictates the structures of protection motifs and gold cores in thiolate-protected gold nanoclusters. This new Au15(SR)13 model shows a tetrahedral Au4 core protected by one [Au7(SR)7] ring and two [Au2(SR)3] "staple" motifs. Density functional theory (DFT) calculations show that the newly predicted Au15(SR)13 (R = CH3/Ph) has a lower energy of 0.24/0.68 eV than previously proposed isomers. By comparing calculated optical absorption spectra (UV), circular dichroism (CD) spectra, and powder X-ray diffraction (XRD) patterns with related experimental spectra, the calculated CD spectra of the newly predicted Au15(SR)13 (R = CH3/Ph) cannot reproduce the experimental results, indicating that the newly predicted Au15(SR)13 is a new structure that needs to be confirmed by experiment. In addition, DFT calculations also show that the newly predicted Au15(SR)13 (R = CH3/Ph) exhibits a large HOMO-LUMO gap, suggesting its high chemical stability. The proposition of the [Au7(SR)7] ring as a protection ligand in the newly predicted Au15(SR)13 not only enriches the types of protection ligands in thiolate-protected gold nanoclusters but also further confirms the effectiveness and rationality of the ring model for understanding the interfacial interaction between the protection motifs and gold cores in thiolate-protected gold nanoclusters.
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The atomic structures of 10-electron (10e) thiolate-protected gold nanoclusters have not received extensive attention both experimentally and theoretically. In this paper, five new atomic structures of 10e thiolate-protected gold nanoclusters, including three Au32(SR)22 isomers, one Au28(SR)18, and one Au33(SR)23, are theoretically predicted. Based on grand unified model (GUM), four Au17 cores with different morphologies can be obtained via three different packing modes of five tetrahedral Au4 units. Then, five complete structures of three Au32(SR)22 isomers, one Au28(SR)18, and one Au33(SR)23 isomers can be formed by adding the thiolate ligands to three Au17 cores based on the interfacial interaction between thiolate ligands and gold core in known gold nanoclusters. Density functional theory calculations show that the relative energies of three newly predicted Au32(SR)22 isomers are quite close to two previously reported isomers. In addition, five new 10e gold nanoclusters have large highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gaps and all-positive harmonic vibration frequencies, indicating their high stabilities.
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Understanding the effect of interfacial interactions between the protection motifs and gold cores on the stabilities of thiolate-protected gold nanoclusters is still a challenging task. Based on analyses of 95 experimentally crystallized and theoretically predicted thiolate-protected gold nanoclusters, we present a ring model to offer a deeper insight into the interfacial interactions for this class of nanoclusters. In the ring model, all the gold nanoclusters can be generically viewed as a fusion or interlocking of several [Aum(SR)n] (m = 4-8, 10, and 12 and 0 ≤ n ≤ m) rings. Guided by the ring model and the grand unified model, a new Au42(SR)26 isomer is predicted, whose total energy is lower than those of two previously crystallized isomers. The ring model offers a mechanistic understanding of the interactions between the protection ligands and gold cores and practical guidance on predicting new gold nanoclusters for future experimental synthesis and confirmation.
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In this paper, six new atomic structures of thiolate-protected gold nanoclusters, i.e. Au32(SR)20, Au40(SR)26, Au48(SR)30, two Au56(SR)34, and Au60(SR)36, are predicted. Considering these six newly predicted structures and six previously predicted or crystallized Au28(SR)20, Au36(SR)24, Au44(SR)28, Au52(SR)32, and Au60(SR)36 altogether, the two-dimensional (2D) growth mode of Au28+4n(SR)20+2n (n = 0-8) nanoclusters is completely presented to compare with their one-dimensional (1D) growth mode. In Au28+4n(SR)20+2n (n = 0-8) nanoclusters with both 1D and 2D growth modes, the same number of gold-core atoms with different morphologies can be seen. Furthermore, the growth of the gold cores occurs via sequential fusion of one tetrahedral Au4 unit by sharing one gold atom. In addition, density functional theory calculations show that these six newly predicted gold nanoclusters following the 2D growth mode have relative energies very close to those of their isomeric structures following the 1D growth mode, large highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gaps, and all-positive harmonic vibration frequencies, indicating their high stabilities. Therefore, the complete presentation of the 2D growth mode of Au28+4n(SR)20+2n (n = 0-8) is beneficial not only for a better understanding of the structural growth of gold nanoclusters, but also for a theoretical guidance on the prediction of new stable structures for experimental confirmation.
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In order to meet the higher accuracy and system reliability requirements, the information fusion for multi-sensor systems is an increasing concern. Dempster-Shafer evidence theory (D-S theory) has been investigated for many applications in multi-sensor information fusion due to its flexibility in uncertainty modeling. However, classical evidence theory assumes that the evidence is independent of each other, which is often unrealistic. Ignoring the relationship between the evidence may lead to unreasonable fusion results, and even lead to wrong decisions. This assumption severely prevents D-S evidence theory from practical application and further development. In this paper, an innovative evidence fusion model to deal with dependent evidence based on rank correlation coefficient is proposed. The model first uses rank correlation coefficient to measure the dependence degree between different evidence. Then, total discount coefficient is obtained based on the dependence degree, which also considers the impact of the reliability of evidence. Finally, the discount evidence fusion model is presented. An example is illustrated to show the use and effectiveness of the proposed method.
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Magnetic flux leakage (MFL) inspection is one of the most important and sensitive nondestructive testing approaches. For online MFL inspection of a long-range railway track or oil pipeline, a fast and effective defect profile estimating method based on a multi-power affine projection algorithm (MAPA) is proposed, where the depth of a sampling point is related with not only the MFL signals before it, but also the ones after it, and all of the sampling points related to one point appear as serials or multi-power. Defect profile estimation has two steps: regulating a weight vector in an MAPA filter and estimating a defect profile with the MAPA filter. Both simulation and experimental data are used to test the performance of the proposed method. The results demonstrate that the proposed method exhibits high speed while maintaining the estimated profiles clearly close to the desired ones in a noisy environment, thereby meeting the demand of accurate online inspection.
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In this paper, efficient managing particle swarm optimization (EMPSO) for high dimension problem is proposed to estimate defect profile from magnetic flux leakage (MFL) signal. In the proposed EMPSO, in order to strengthen exchange of information among particles, particle pair model was built. For more efficient searching when facing different landscapes of problems, velocity updating scheme including three velocity updating models was also proposed. In addition, for more chances to search optimum solution out, automatic particle selection for re-initialization was implemented. The optimization results of six benchmark functions show EMPSO performs well when optimizing 100-D problems. The defect simulation results demonstrate that the inversing technique based on EMPSO outperforms the one based on self-learning particle swarm optimizer (SLPSO), and the estimated profiles are still close to the desired profiles with the presence of low noise in MFL signal. The results estimated from real MFL signal by EMPSO-based inversing technique also indicate that the algorithm is capable of providing an accurate solution of the defect profile with real signal. Both the simulation results and experiment results show the computing time of the EMPSO-based inversing technique is reduced by 20%-30% than that of the SLPSO-based inversing technique.
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BACKGROUND: The inducible cyclic adenosine monophosphate (cAMP) early repressor (ICER) is highly expressed in the central nervous system and functions as a repressor of cAMP response element-binding protein (CREB) transcription. The present study sought to clarify the role of ICER in the effects of methamphetamine (METH). METHODS AND FINDINGS: We tested METH-induced locomotor sensitization in wildtype mice, ICER knockout mice, and ICER I-overexpressing mice. Both ICER wildtype mice and knockout mice displayed increased locomotor activity after continuous injections of METH. However, ICER knockout mice displayed a tendency toward higher locomotor activity compared with wildtype mice, although no significant difference was observed between the two genotypes. Moreover, compared with wildtype mice, ICER I-overexpressing mice displayed a significant decrease in METH-induced locomotor sensitization. Furthermore, Western blot analysis and quantitative real-time reverse transcription polymerase chain reaction demonstrated that ICER overexpression abolished the METH-induced increase in CREB expression and repressed cocaine- and amphetamine-regulated transcript (CART) and prodynorphin (Pdyn) expression in mice. The decreased CART and Pdyn mRNA expression levels in vivo may underlie the inhibitory role of ICER in METH-induced locomotor sensitization. CONCLUSIONS: Our data suggest that ICER plays an inhibitory role in METH-induced locomotor sensitization.
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Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , Locomoción/efectos de los fármacos , Metanfetamina/farmacología , Animales , Western Blotting , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Encefalinas/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Precursores de Proteínas/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaAsunto(s)
Modulador del Elemento de Respuesta al AMP Cíclico/genética , Modulador del Elemento de Respuesta al AMP Cíclico/fisiología , Expresión Génica , Locomoción/efectos de los fármacos , Metanfetamina/efectos adversos , Animales , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/etiologíaRESUMEN
Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex)) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.
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Metanfetamina/farmacología , Fenciclidina/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Locomoción , Metanfetamina/farmacocinética , Ratones , Ratones Noqueados , Fenciclidina/farmacocinética , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
The liver is the major site of pigment epithelium-derived factor (PEDF) synthesis. Recent evidence suggests a protective role of PEDF in liver cirrhosis. In the present study, immunohistochemical analyses revealed lower PEDF levels in liver tissues of patients with cirrhosis and in animals with chemically induced liver fibrosis. Delivery of the PEDF gene into liver cells produced local PEDF synthesis and ameliorated liver fibrosis in animals treated with either carbon tetrachloride or thioacetamide. In addition, suppression of peroxisome proliferator-activated receptor gamma expression, as well as nuclear translocation of nuclear factor-kappa B was found in hepatic stellate cells (HSCs) from fibrotic livers, and both changes were reversed by PEDF gene delivery. In culture-activated HSCs, PEDF, through the induction of peroxisome proliferator-activated receptor gamma, reduced the activity of nuclear factor-kappa B and prevented the nuclear localization of JunD. In conclusion, our observations that PEDF levels are reduced during liver cirrhosis and that PEDF gene delivery ameliorates cirrhosis suggest that PEDF is an intrinsic protector against liver cirrhosis. Direct inactivation of HSCs and the induction of apoptosis of activated HSCs may be two of the mechanisms by which PEDF suppresses liver cirrhosis.
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Proteínas del Ojo/metabolismo , Células Estrelladas Hepáticas/metabolismo , Factor Intrinseco/metabolismo , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Serpinas/metabolismo , Animales , Apoptosis , Western Blotting , Tetracloruro de Carbono/toxicidad , Proliferación Celular , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Proteínas del Ojo/genética , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas para Inmunoenzimas , Inmunoprecipitación , Factor Intrinseco/genética , Hígado/citología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/genética , FN-kappa B/metabolismo , Factores de Crecimiento Nervioso/genética , PPAR gamma/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serpinas/genética , Transducción de Señal , Tioacetamida/toxicidadRESUMEN
PURPOSE: To investigate the protective effects of cobalt protoporphyrin (CoPP), a potent heme oxygenase (HO)-1 inducer, in a rat model of ischemia-reperfusion injury and to document the possible antiapoptotic and anti-inflammatory mechanisms underlying the protection. METHODS: Rats pretreated with intraperitoneal injection of CoPP (5 mg/kg) were subjected to retinal ischemia by increases in intraocular pressure to 130 mm Hg for 60 minutes. The protective effects of CoPP were evaluated by determining the morphology of the retina, counting the survival of retinal ganglion cells (RGCs), and measuring apoptosis in retinal layers. In addition, expressions of HO-1, caspase-3, p53, Bcl-xL, monocyte chemoattractant protein (MCP)-1, and inducible nitric oxide synthase (iNOS) were documented by Western blot analysis. Detection of HO-1, NF-kappaB, and CD68 protein in the retina was performed by immunohistochemistry or immunofluorescence. RESULTS: Pharmacologic induction of HO-1 by CoPP led to HO-1 expression in the full retinal layer. HO-1 overexpression alleviated apoptosis in the retina, preserved RGCs, and attenuated the reduction of inner retinal thickness after ischemia-reperfusion injury. Concurrently, overexpression of HO-1 was associated with inhibition of caspase-3, p53, NF-kappaB, and iNOS and with increased expression of Bcl-xL. Meanwhile, the anti-inflammatory effect of HO-1 was related to reduction in the recruitment of macrophage infiltration in the retina through the suppression of MCP-1. These beneficial effects of HO-1 induced by CoPP were diminished by the HO-1 inhibitor ZnPP. CONCLUSIONS: Overexpression of HO-1 by pharmacologic induction protected the retina from subsequent cellular damage caused by ischemia-reperfusion injury through antiapoptotic and anti-inflammatory effects.