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Various assaults on mitochondria occur during the human aging process, contributing to mitochondrial dysfunction. This mitochondrial dysfunction is intricately connected with aging and diseases associated with it. In vivo, the accumulation of defective mitochondria can precipitate inflammatory and oxidative stress, thereby accelerating aging. Mitophagy, an essential selective autophagy process, plays a crucial role in managing mitochondrial quality control and homeostasis. It is a highly specialized mechanism that systematically removes damaged or impaired mitochondria from cells, ensuring their optimal functioning and survival. By engaging in mitophagy, cells are able to maintain a balanced and stable environment, free from the potentially harmful effects of dysfunctional mitochondria. An ever-growing body of research highlights the significance of mitophagy in both aging and age-related diseases. Nonetheless, the association between mitophagy and inflammation or oxidative stress induced by mitochondrial dysfunction remains ambiguous. We review the fundamental mechanisms of mitophagy in this paper, delve into its relationship with age-related stress, and propose suggestions for future research directions.
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Cardiovascular diseases have become a serious threat to human health and life worldwide and have the highest fatality rate. Therefore, the prevention and treatment of cardiovascular diseases have become a focus for public health experts. The expression of S100 proteins is cell- and tissue-specific; they are implicated in cardiovascular, neurodegenerative, and inflammatory diseases and cancer. This review article discusses the progress in the research on the role of S100 protein family members in cardiovascular diseases. Understanding the mechanisms by which these proteins exert their biological function may provide novel concepts for preventing, treating, and predicting cardiovascular diseases.
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Enfermedades Cardiovasculares , Neoplasias , Humanos , Proteínas S100/metabolismoRESUMEN
BACKGROUND: Mechanical ventilation is a supportive therapy used to maintain respiratory function in several clinical and surgical cases but is always accompanied by lung injury risk due to improper treatment. We investigated how tidal volume and oxygen delivery would contribute independently or synergistically to ventilator-induced lung injury (VILI). METHODS: Under general anesthesia and tracheal intubation, healthy female C57BL/6 N mice (9 weeks old) were randomly ventilated for 2 h by standard (7 ml/kg) or high (14 ml/kg) tidal volume at positive end-expiratory pressure (PEEP) of 2 cmH2O, with room air, 50% O2 (moderate hyperoxia), or 100% O2 (severe hyperoxia); respectively. Mice were sacrificed 4 h after mechanical ventilation, and lung tissues were collected for experimental assessments on lung injury. RESULTS: Compared with the healthy control, severe hyperoxia ventilation by either standard or high tidal volume resulted in significantly higher wet-to-dry lung weight ratio and higher levels of IL-1ß and 8-OHdG in the lungs. However, moderate hyperoxia ventilation, even by high tidal volume did not significantly increase the levels of IL-1ß and 8-OHdG in the lungs. Western blot analysis showed that the expression of RhoA, ROCK1, MLC2, and p-MLC2 was not significantly induced in the ventilated lungs, even by high tidal volume at 2 cmH2O PEEP. CONCLUSION: Severe hyperoxia ventilation causes inflammatory response and oxidative damage in mechanically ventilated lungs, while high tidal volume ventilation at a reasonable PEEP possibly does not cause VILI.
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Hiperoxia , Lesión Pulmonar Inducida por Ventilación Mecánica , Femenino , Animales , Ratones , Ratones Endogámicos C57BL , Volumen de Ventilación Pulmonar , Hiperoxia/complicaciones , Respiración , 8-Hidroxi-2'-DesoxicoguanosinaRESUMEN
Nanoplastics (NPs) frequently cause adverse health effects by transporting organic pollutants such as dibutyl phthalate (DBP) into organisms by utilizing their large specific surface area, large surface charge, and increased hydrophobicity. However, the effects of NPs combined with DBP on the reproductive systems of mammals are still unclear. The present investigation involved the administration of polystyrene NPs (PS-NPs) to BALB/c mice via gavage, with a size of 100 nm and at doses of 5 mg/kg/day or 50 mg/kg/day, along with DBP at a dose of 0.5 mg/kg/day, or a combination of PS-NPs and DBP, for 30 days, to assess their potential for reproductive toxicity. The co-exposure of mice to PS-NPs and DBP resulted in a significant increase in reproductive toxicities compared to exposure to PS-NPs or DBP alone. This was demonstrated by a marked decrease in sperm quality, significant impairment of spermatogenesis, and increased disruption of the blood-testis barrier (BTB). Furthermore, a combination of in vivo and in vitro investigations were conducted to determine that the co-exposure of DBP and PS-NPs resulted in a noteworthy reduction in the expressions of tight junction proteins (ZO-1 and occludin). Moreover, the in vitro findings revealed that monobutyl phthalate (MBP, the active metabolite of DBP, 0.5 µg/mL) and PS-NPs (30 µg/mL or 300 µg/mL) inhibited autophagy in Sertoli cells, thereby increasing the expression of matrix metalloproteinases (MMPs). The study found that PS-NPs and DBP co-exposure caused harmful effects in male reproductive organs by disrupting BTB, which may be alleviated by reactivating autophagy. The paper's conclusions provided innovative perspectives on the collective toxicities of PS-NPs and other emerging pollutants.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Contaminantes Ambientales , Masculino , Animales , Ratones , Dibutil Ftalato/toxicidad , Barrera Hematotesticular , Microplásticos , Poliestirenos/toxicidad , Semen , Autofagia , Contaminantes Ambientales/toxicidad , Ratones Endogámicos BALB C , MamíferosRESUMEN
Intraoperatively acquired pressure injuries (IAPIs) occur frequently among patients who undergo surgical procedures that last longer than 3 h. Several studies indicated that heat shock proteins (HSPs) play an important role in the protection of stress-induced damages in skin tissues. Hence, the aim of this study was to investigate the potential preventive effect of thermal preconditioning (TPC) on IAPIs in surgical patients and rats and to identify the differentially expressed HSP genes in response to the above treatment. TPC was performed on one group of hairless rats before the model of pressure injuries was established. Subsequently, the size of skin lesions was measured and the expression levels of mRNA and protein of HSPs of the pressured skin were detected by real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemical staining. For human studies, 118 surgical patients were randomly divided into the TPC group (n = 59) and the control group (n = 59), respectively. The temperature and pressure of sacral skin, as well as the incidence of pressure injury (PI) were detected and compared. In animal studies, TPC significantly reduced both the size and incidence of PI in rats on the second, third and fourth days post treatment. In addition, the expression levels of both mRNA and protein of HSP27 were increased in the TPC group, compared with the control group. Immunohistochemical staining showed that HSP27 was distributed in various types of dermal cells and increased in basal cells. In human studies, a significant reduction (75%) of IAPIs was observed among the patients in the TPC group. TPC can reduce the incidence of PI in rats and humans, and the upregulation of HSP27 may play an important role in this biological progress. Further studies are warranted to explore the molecular mechanism of the preventive effect in PI mediated by HSP27.
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Úlcera por Presión , Ratas , Humanos , Animales , Úlcera por Presión/prevención & control , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Incidencia , ARN Mensajero/genética , Proteínas HSP70 de Choque Térmico/genéticaRESUMEN
Evodia rutaecarpa (Juss.) Benth is a traditional Chinese medicine. The active ingredient, evodiamine, is a quinolone alkaloid and is found in Evodiae fructus. We investigated the effect of evodiamine on atherosclerosis using LDLR-/- mice fed on a high-fat diet and ox-LDL-induced MOVAS cell lines to construct mouse models and cell-line models. We report a significant reduction in atherosclerotic plaque formation in mice exposed to evodiamine. Our mechanistic studies have revealled that evodiamine can regulate the proliferation, migration, and inflammatory response of and oxidative stress in vascular smooth muscle cells by inhibiting the activation of the PI3K/Akt axis, thus inhibiting the occurrence and development of atherosclerosis. In conclusion, our findings reveal a role for evodiamine in the regulation of vascular smooth muscle cells in atherosclerosis, highlighting a potential future role for the compound as an anti-atherosclerotic agent.
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Aterosclerosis , Evodia , Placa Aterosclerótica , Ratones , Animales , Músculo Liso Vascular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Placa Aterosclerótica/metabolismo , Proliferación Celular , Miocitos del Músculo Liso/metabolismoRESUMEN
A complex pathophysiological mechanism is involved in brain injury following cerebral infarction. The neurovascular unit (NVU) is a complex multi-cellular structure consisting of neurons, endothelial cells, pericyte, astrocyte, microglia and extracellular matrix, etc. The dyshomeostasis of NVU directly participates in the regulation of inflammatory immune process. The components of NVU promote inflammatory overreaction and synergize with the overactivation of autonomic nervous system to initiate stroke-induced immunodepression (SIID). SIID can alleviate the damage caused by inflammation, however, it also makes stroke patients more susceptible to infection, leading to systemic damage. This article reviews the mechanism of SIID and the roles of NVU in SIID, to provide a perspective for reperfusion, prognosis and immunomodulatory therapy of cerebral infarction.
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Células Endoteliales , Accidente Cerebrovascular , Humanos , Neuronas/fisiología , Terapia de Inmunosupresión/efectos adversos , Infarto CerebralRESUMEN
Voltage-dependent K+ (Kv) channels are widely expressed on vascular smooth muscle cells and regulate vascular tone. Here, we explored the inhibitory effect of encainide, a class Ic anti-arrhythmic agent, on Kv channels of vascular smooth muscle from rabbit coronary arteries. Encainide inhibited Kv channels in a concentration-dependent manner with an IC50 value of 8.91 ± 1.75 µM and Hill coefficient of 0.72 ± 0.06. The application of encainide shifted the activation curve toward a more positive potential without modifying the inactivation curve, suggesting that encainide inhibited Kv channels by altering the gating property of channel activation. The inhibition by encainide was not significantly affected by train pulses (1 and 2 Hz), indicating that the inhibition is not use (state)-dependent. The inhibitory effect of encainide was reduced by pretreatment with the Kv1.5 subtype inhibitor. However, pretreatment with the Kv2.1 subtype inhibitor did not alter the inhibitory effects of encainide on Kv currents. Based on these results, encainide inhibits vascular Kv channels in a concentration-dependent and use (state)-independent manner by altering the voltage sensor of the channels. Furthermore, Kv1.5 is the main Kv subtype involved in the effect of encainide.
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Desmodus rotundus plasminogen activator alpha 1(DSPAα1) is a thrombolytic protein with advantages, such as a long half-life, high accuracy and specificity for thrombolysis, wide therapeutic window, and no neurotoxicity. To date, DSPAα1 has only been expressed in the Chinese hamster ovary, insect cells, transgenic tobacco plants, and Pichia pastoris. To the best of our knowledge, we are the first to report the expression of DSPAα1 in transgenic rabbit mammary glands, extract the product, and analyze its pharmacology activity. An efficient mammary gland-specific expression vector pCL25/DSPAα1 was transferred to prokaryotic zygotes in rabbits by microinjection to generate six DSPAα1 transgenic rabbits. The recombinant DSPAα1 (rDSPAα1) expression in transgenic rabbit milk was 1.19 ± 0.26 mg/mL. The rDSPAα1 purification protocol included pretreatment, ammonium sulfate precipitation, benzamidine affinity chromatography, cation exchange chromatography, and Cibacron blue affinity chromatography; approximately 98% purity was achieved using gel electrophoresis. According to sequencing results, the primary structure of rDSPAα1 was consistent with the theoretical design sequence, and its molecular weight was consistent with that of the natural protein. N-terminal sequencing results indicated rDSPAα1 to be a mature protein, as the goat signal peptide sequence of the expression vector was no longer detected. The fibrinolytic activity of rDSPAα1 was estimated to be 773,333 IU/mg. Fibrin-agarose plate assay and in vitro rat blood clot degradation assay showed that rDSPAα1 had strong thrombolytic activity. In conclusion, we report recombinant DSPAα1 with high thrombolytic activity expressed in transgenic rabbit mammary glands.
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Glándulas Mamarias Animales , Activadores Plasminogénicos , Señales de Clasificación de Proteína , Animales , Células CHO , Cricetinae , Cricetulus , Glándulas Mamarias Animales/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Activadores Plasminogénicos/genética , Activadores Plasminogénicos/metabolismo , Conejos , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Cardiovascular disease is one of the leading causes of human mortality worldwide, mainly due to atherosclerosis (AS), and the phenotypic transition of vascular smooth muscle cells (VSMCs) is a key event in the development of AS. Exosomes contain a variety of specific nucleic acids and proteins that mediate intercellular communication. The role of exosomes in AS has attracted attention. This review uses the VSMC phenotypic transition in AS as the entry point, introduces the effect of exosomes on AS from different perspectives, and discusses the status quo, deficiencies, and potential future directions in this field to provide new ideas for clinical research and treatment of AS. Video Abstract.
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Aterosclerosis , Exosomas , Ácidos Nucleicos , Aterosclerosis/metabolismo , Células Cultivadas , Exosomas/metabolismo , Humanos , Músculo Liso Vascular , Miocitos del Músculo Liso/metabolismo , Ácidos Nucleicos/metabolismo , FenotipoRESUMEN
Pressure injury (PI) prevention is a huge industry and involves various interventions. Temperature and moisture are important factors for wound healing; however, the active mechanism by which "moist heat" affects PI prevention has not yet been clarified. Thus, we explored the protective and therapeutic effects of hydrotherapy on PI based on the preconditioning (PC) principle, which might be useful for clinical practice. This study aimed to investigate the preventive mechanisms of heat shock preconditioning on PIs in rat models. The experiment was performed in the basic medical laboratory of Nagano College of Nursing in Japan. Ten rats were divided into two groups, with five rats in each group. Rats in the control group were not bathed. Rats in the preconditioning group (PC group) were bathed with hot tap-water. Bathing was conducted thrice a week. After bathing for 4 weeks, the PI model was constructed on the rats' dorsal skin. The skin temperature, skin moisture, and area of ulcers were compared between the two groups. In vitro, we investigated the expression of heat shock protein 27 (Hsp27) in 6, 12, and 24 h after the PI model was constructed through Western blot analysis. Ulcers occurred in the control group 24 h after the PI model constructed, wheras the PC group exhibited ulcers after 36 h. The ulcer area was larger in the control group than that in the PC group after 24 h (all p < 0.05). The temperatures of PI wounds in the control group decreased and were lower than those in the PC group after 1, 6, 12, 36, and 48 h (all p < 0.05). However, the skin moisture levels of PI wounds increased in the control group and were higher than those in the PC group at the same time (all p < 0.05). Using Western blot analysis, hydrotherapy preconditioning showed the potential to increase Hsp27 expression after pressure was released (p < 0.05). We determine that heat shock preconditioning had a preventive effect on PIs in rat models, a result that may be associated with their actions in the upregulation of Hsp27.
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Proteínas de Choque Térmico HSP27 , Proteínas HSP70 de Choque Térmico , Úlcera por Presión , Animales , Ratas , Respuesta al Choque Térmico , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Úlcera , Regulación hacia ArribaRESUMEN
Ischemic stroke is characterized by cute onset and high mortality. The suppression of neuroinflammation is crucial in the treatment of ischemic stroke. Exosomes derived from mesenchymal stem cell (MSC) have attracted extensive research attention due to their wide origin, small size, and containing large number of active components. Recent studies have shown that MSC-derived exosomes can inhibit the proinflammatory activity of microglia and astrocytes and stimulate their neuroprotective activity; also can inhibit neuroinflammation by regulating immune cells and inflammatory mediators. This article reviews the roles and related mechanism of MSC-derived exosomes in neuroinflammation after ischemic stroke, hoping to provide ideas and references for the development of a novel approach for the treatment of ischemic stroke diseases.
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Exosomas , Accidente Cerebrovascular Isquémico , Células Madre Mesenquimatosas , Humanos , Enfermedades Neuroinflamatorias , MicroglíaRESUMEN
OBJECTIVE: To screen for prognosis related genes in bladder cancer, and to establish prognosis model of bladder cancer. METHODS: The clinical information and bladder tissue RNA sequencing data of 406 bladder cancer patients, and the bladder tissue RNA sequencing data of 28 healthy individuals were downloaded from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database through the UCSC Xena platform. The weighted gene co-expression network analysis (WGCNA), univariate Cox regression, LASSO regression analysis and multivariate Cox regression analysis were used to screen the prognosis-related genes of bladder cancer and the prognostic model was established. The prognostic model was evaluated with receiver operator characteristic curve (ROC curve). RESULTS: A total of 2308 differentially expressed genes related to bladder cancer were obtained from the analysis. Six gene modules were obtained by WGCNA, and 829 genes with significant effect on bladder cancer prognosis were screened out. Univariate Cox regression and LASSO regression analysis showed that 24 genes were related to the prognosis of bladder cancer patients. Multivariate Cox regression analysis revealed 9 genes as independent predictors in training set, namely ADCY9, MAFG_DT, EMP1, CAST, PCOLCE2, LTBP1, CSPG4, NXPH4, SLC1A6, which were used to establish the prognosis model of bladder cancer patients. The 3-year survival rates of the high-risk group and the low-risk group in the training set were 31.814% and 59.821%, respectively. The 3-year survival rates of the high-risk group and the low-risk group in the test set were 32.745% and 68.932%, respectively. The areas under the ROC curve of the model for predicting the prognosis of bladder cancer patients in both the training set and the test set were above 0.7. CONCLUSION: The established model in this study has good predictive ability for the survival of bladder cancer patients.
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Neoplasias de la Vejiga Urinaria , Biomarcadores de Tumor/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Humanos , Pronóstico , Transcriptoma , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
OBJECTIVE: Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of ß-VLDLs-the major atherogenic lipoproteins. ß-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than ß-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. CONCLUSIONS: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.
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Enfermedades de la Aorta/prevención & control , Apolipoproteína C-III/deficiencia , Aterosclerosis/prevención & control , Enfermedad de la Arteria Coronaria/prevención & control , Triglicéridos/sangre , Animales , Animales Modificados Genéticamente , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Apolipoproteína C-III/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Biomarcadores/sangre , HDL-Colesterol/sangre , VLDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Modelos Animales de Enfermedad , Femenino , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Lipoproteínas IDL/sangre , Hígado/metabolismo , Masculino , Oxidación-Reducción , Placa Aterosclerótica , ConejosRESUMEN
BACKGROUND: High levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3-knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis. METHODS: An sgRNA anchored to exon 2 of APOC3 was designed to edit embryo genomes using the CRISPR/Cas9 system. The founder rabbits were sequenced, and their lipid profile, inflammatory cytokines, and atherosclerotic plaques were analyzed. RESULTS: When given a normal chow (NC) diet, all APOC3-KO rabbits had 50% lower triglyceride (TG) levels than those of the matched age control group. Additionally, their plasma lipoprotein lipase increased. When fed a high-fat diet, APOC3 deficiency was observed to be more conducive to the maintenance of plasma TG, total cholesterol, and low-density lipoprotein cholesterol levels, and the inhibition of the inflammatory response and the protection against atherosclerosis in rabbits. CONCLUSION: APOC3 deficiency can delay the formation of atherosclerosis-induced HFD in rabbits, indicating this is a novel therapeutic target to treat atherosclerosis.
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Apolipoproteína C-III/metabolismo , Aterosclerosis/etiología , Lípidos/sangre , Animales , Proteína 9 Asociada a CRISPR , Sistemas CRISPR-Cas , Citocinas/sangre , Femenino , Técnicas de Silenciamiento del Gen , Intestino Delgado/metabolismo , Hígado/metabolismo , Masculino , Placa Aterosclerótica/etiología , ConejosRESUMEN
Background: In recent years, the increasing number of empty-nest elderly has become a significant global social problem, and the rapid development of medical technology and information technology has improved the feasibility of telenursing. However, few studies have been conducted on needs of telenursing among the empty-nest elderly. The aim of this study is to explore the needs of telenursing for community-dwelling empty-nest elderly who are completely independent in activities of daily living (ADL), or who are mildly disabled, and to provide a reference for improving the remote care quality. Methods: A questionnaire survey aiming to explore telenursing needs of the elderly was conducted among 268 community-dwelling empty-nest elderly who were selected using random sampling and then data were analyzed based on the Kano Model. Results: Chi-square goodness-of-fit test showed that there were significant differences between actual and expected counts for each item of telenursing needs (p < 0.01 for all), indicating that the sample had specific individual preference for the Kano category. The desired degree of telenursing service ranged from 48.37% to 80.86%, the better values (satisfaction) were between 57.09% and 67.56%, and the worse values (dissatisfaction) were between 11.92% and 37.93%. The items, remote one-button emergency caller and remote emergency assistance arrangement, were considered to be one-dimensional qualities by empty nesters and the rest were attractive qualities. In the quadrant analysis diagram, all the remote care services were categorized as attractive qualities. Discussion: The community-dwelling empty-nest elderly with ADL independence or mild impairment have positive attitudes toward telenursing services, especially the needs of remote first aid nursing. Medical policy makers and nursing managers can provide targeted telenursing services according to empty nesters' requirements, thus improving nursing care quality and satisfaction of the elderly.
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Actividades Cotidianas , Teleenfermería , Anciano , China , Humanos , Vida Independiente , Nigeria , Encuestas y CuestionariosRESUMEN
Atherosclerosis is a common pathological change in cardiovascular disease. Vascular smooth muscle cell is the main source of plaque cell and extracellular matrix, and nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating the function of vascular smooth muscle cell. In the process of atherosclerosis, Nrf2 signaling pathway has the following regulatory effects on vascular smooth muscle cell: regulating the phenotype of vascular smooth muscle cell to change to the direction conducive to the alleviation of disease progression; inhibiting the proliferation and migration of vascular smooth muscle cell; mitigating the level of blood lipid; alleviating vascular smooth muscle cell calcification, aging and apoptosis process. This article reviews the specific mechanisms of Nrf2 regulating atherosclerosis, such as phenotypic transformation, proliferation and migration, lipid metabolism, calcification, aging and apoptosis in atherosclerosis, in order to provide a basis for understanding the molecular mechanism of atherosclerosis development and finding therapeutic targets.
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Aterosclerosis , Factor 2 Relacionado con NF-E2 , Movimiento Celular , Proliferación Celular , Células Cultivadas , Humanos , Músculo Liso Vascular , Miocitos del Músculo Liso , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de SeñalRESUMEN
To establish a rabbit model of proprotein convertase subtilisin/kexin type9 () point mutation with CRISPR/Cas9 gene editing technique. According to the PubMed gene protein data, the PCSK9 protein functional regions of human and rabbit were analyzed by Blast. The 386S (Ser) amino acid functional region of human gene was homologous to the 485S of rabbit gene. Three small guide RNAs and one single-stranded donor oligonucleotide were designed according to the 485S base substitution position and sequence analysis of rabbit gene. The synthetic small guide RNAs, Cas9 mRNA and single-stranded donor oligonucleotide were co-injected into the cytoplasm of rabbit fertilized eggs and the embryos were transferred into the pregnant rabbits. PCR, TA cloning and off-target analysis were performed on the F0 rabbits to identify whether the PCSK9 mutation was successful. Fifteen F0 rabbits were obtained. The sequencing results showed that one of them was PCSK9 point mutation homozygote and two of them were PCSK9 point mutation heterozygotes, and the mutation could be stably inherited. The rabbit model of PCSK9 point mutation was successfully constructed by CRISPR/Cas9 technique, which provides an animal model for exploring the molecular mechanism of impaired PCSK9 function and developing reliable and effective diagnosis and treatment measures.
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Sistemas CRISPR-Cas , Proproteína Convertasa 9 , Animales , Humanos , Mutación Puntual , Proproteína Convertasa 9/genética , ConejosRESUMEN
Matrix metalloproteinase-9 (MMP-9), or gelatinase B, has been hypothesized to be involved in the progression of atherosclerosis. In the arterial wall, accumulated macrophages secrete considerable amounts of MMP-9 but its pathophysiological functions in atherosclerosis have not been fully elucidated. To examine the hypothesis that macrophage-derived MMP-9 may affect atherosclerosis, we created MMP-9 transgenic (Tg) rabbits to overexpress the rabbit MMP-9 gene under the control of the scavenger receptor A enhancer/promoter and examined their susceptibility to cholesterol diet-induced atherosclerosis. Tg rabbits along with non-Tg rabbits were fed a cholesterol diet for 16 and 28 weeks, and their aortic and coronary atherosclerosis was compared. Gross aortic lesion areas were significantly increased in female Tg rabbits at 28 weeks; however, pathological examination revealed that all the lesions of Tg rabbits fed a cholesterol diet for either 16 or 28 weeks were characterized by increased monocyte/macrophage accumulation and prominent lipid core formation compared with those of non-Tg rabbits. Macrophages isolated from Tg rabbits exhibited higher infiltrative activity towards a chemoattractant, MCP-1 in vitro and augmented capability of hydrolysing extracellular matrix in granulomatous tissue. Surprisingly, the lesions of Tg rabbits showed more advanced lesions with remarkable calcification in both aortas and coronary arteries. In conclusion, macrophage-derived MMP-9 facilitates the infiltration of monocyte/macrophages into the lesions thereby enhancing the progression of atherosclerosis. Increased accumulation of lesional macrophages may promote vascular calcification.
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Enfermedad de la Arteria Coronaria/genética , Metaloproteinasa 9 de la Matriz/genética , Calcificación Vascular/genética , Animales , Animales Modificados Genéticamente/genética , Aorta/efectos de los fármacos , Aorta/crecimiento & desarrollo , Aorta/patología , Colesterol en la Dieta/efectos adversos , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Conejos , Calcificación Vascular/patologíaRESUMEN
Brain injury has been proposed as the major cause of the poor outcomes associated with intracerebral hemorrhage (ICH). Emerging evidence indicates that the nuclear receptor, peroxisome proliferator-activated receptor ß/δ (PPAR-ß/δ), plays a crucial role in the pathological process of central nervous impairment. The present study was undertaken to evaluate the protective effects of PPAR-ß/δ activation using a selective PPAR-ß/δ agonist, GW0742, against brain injury after ICH in a mouse model. ICH was induced by intravenous injection of collagenase into the right caudate putamen. To examine the protective effect of PPAR-ß/δ activation against ICH-induced brain injury, mice were either intraperitoneally injected with GW0742 (3 mg/kg, body weight) or saline (control group) 30 min before inducing ICH. Behavioral dysfunction was evaluated 24 and 72 h after injury. Then, all mice were killed to assess hematoma volume, brain water content, and blood-brain barrier (BBB) permeability. TUNEL and Nissl staining were performed to quantify the brain injury. The expression of PPAR-ß/δ, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, Bcl-2-related X-protein (Bax), and B-cell lymphoma 2 (Bcl-2) in the perihematomal area was examined by immunohistochemistry and western blotting analysis. Mice treated with GW0742 showed significantly less severe behavioral deficits compared to the control group, accompanied by increased expression of PPAR-ß/δ and Bcl-2, and increased expression of IL-1ß, TNF-α, and Bax decreased simultaneously in the GW0742-treated group. Furthermore, the GW0742-pretreated group showed significantly less brain edema and BBB leakage. Neuronal loss was attenuated, and the number of apoptotic neuronal cells in perihematomal tissues reduced, in the GW0742-pretreated group compared to the control group. However, the hematoma volume did not decrease significantly on day 3 after ICH. These results suggest that the activation of PPAR-ß/δ exerts a neuroprotective effect on ICH-induced brain injury, possibly through anti-inflammatory and anti-apoptotic pathways.