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Herein, single-atom iron doped carbon dots (SA Fe-CDs) were successfully prepared as novel electrochemiluminescence (ECL) emitters with high ECL efficiency, and a biosensor was constructed to ultrasensitively detect microRNA-222 (miRNA-222). Importantly, compared with the conventional without single-atom doped CDs with low ECL efficiency, SA Fe-CDs exhibited strong ECL efficiency, in which single-atom iron as an advanced coreactant accelerator could significantly enhance the generation of reactive oxygen species (ROS) from the coreactant S2O82- for improving the ECL efficiency. Moreover, a neoteric amplification strategy combining the improved strand displacement amplification with Nt.BbvCI enzyme-induced target amplification (ISDA-EITA) could produce 4 output DNAs in every cycle, which greatly improved the amplification efficiency. Thus, a useful ECL biosensor was built with a detection limit of 16.60 aM in the range of 100 aM to 1 nM for detecting traces of miRNA-222. In addition, miRNA-222 in cancer cell lysate (MHCC-97L) was successfully detected by using the ECL biosensor. Therefore, this strategy provides highly efficient single-atom doped ECL emitters for the construction of sensitive ECL biosensing platforms in the biological field and clinical diagnosis.
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Técnicas Biosensibles , Carbono , Técnicas Electroquímicas , Hierro , Mediciones Luminiscentes , MicroARNs , Puntos Cuánticos , MicroARNs/análisis , Carbono/química , Hierro/química , Técnicas Electroquímicas/métodos , Puntos Cuánticos/química , Humanos , Técnicas Biosensibles/métodos , Límite de DetecciónRESUMEN
BACKGROUND: CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy. METHODS: We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging. RESULTS: Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice. CONCLUSIONS: Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging.
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Hesperidina , Envejecimiento de la Piel , Anciano , Animales , Humanos , Ratones , Queratinocitos , Mamíferos , Ratones TransgénicosRESUMEN
Donor-acceptor (D-A) conjugated polymer (CP) featuring high charge mobility and widely tunable energy bands have shown promising prospects in photocatalysis. In this work, a library of ternary D-A CPs (22 polymers) based on benzothiadiazole, bithiophene, and fluorene derivatives (i.e., fluorene [Fl], 9,9-dihexylfluorene [HF], and 9,9'-spirobifluorene [SF]) with and without alkyl side chains, and with 3D geometry are designed and synthesized via atom-economical direct C-H arylation polymerization to explore the synergetic effects of stereochemistry, D/A ratio, and alkyl chains on the properties and photocatalytic performances, which reveal that 1) the cross-shaped 3D spirobifluorene (SF) building block shows the highest hydrogen evolution rates (HER) owing to the sufficient photocatalytic active sites exposed, 2) the alkyl-free linear polymer (FlBtBT0.05 ) exhibit the highest photocatalytic pollutant degradation performance owing to its superior charge separation, and 3) the alkyl side chains are redundances that will exert detrimental effects on the aqueous photocatalysis owing to their insulating and hydrophobic property. The structure-property-performance correlation results obtained will provide a desirable guideline for the rational design of CP-based photocatalysts.
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Contaminantes Ambientales , Fluorenos , Hidrógeno , Polimerizacion , PolímerosRESUMEN
Herein, Zn2+-induced gold cluster aggregation (Zn2+-GCA) as a high-efficiency electrochemiluminescence (ECL) emitter is first employed to construct an ECL biosensor to ultrasensitively detect microRNA-21 (miRNA-21). Impressively, Zn2+ not only can induce the aggregation of monodispersed gold clusters (Au NCs) to limit the ligand vibration of Au NCs for improving ECL emission but also can be utilized as a coreaction accelerator to catalyze the dissociation of coreactant S2O82- into sulfate radicals (SO4â¢-) to improve the interaction efficiency between Zn2+-GCA and S2O82-, resulting in further intense ECL emission. Compared to Au NCs stabilized by bovine serum albumin with ECL efficiency of 0.40%, Zn2+-GCA possessed high ECL efficiency of 10.54%, regarding the [Ru(bpy)3]2+/S2O82- system as a standard. Furthermore, output DNA modified with poly adenine (polyA) obtained from enzyme-free target recycling amplification can be efficiently immobilized on the surface of gold nanoparticles (Au NPs) to reduce the defect of special design, cumbersome operation, and low stability. Thus, an ultrasensitive ECL biosensor based on the Zn2+-GCA/S2O82- ECL system and enzyme-free target recycling amplification achieved ultrasensitive detection of miRNA-21 with the detection limit of 44.7 aM. This strategy presents a new idea to design highly efficient ECL emitters, which is expected to be used in the field of bioanalysis for clinical diagnosis.
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Técnicas Biosensibles , Nanopartículas del Metal , MicroARNs , Oro , Límite de Detección , Mediciones Luminiscentes/métodos , Técnicas Electroquímicas/métodos , Técnicas Biosensibles/métodos , MicroARNs/análisis , ZincRESUMEN
Herein, the novel alloyed silver gold sulfur quantum dots (AgAuS QDs) with highly efficient near-infrared (NIR) electrochemiluminescence (ECL) emission at 707 nm were successfully prepared to construct a biosensing platform for ultrasensitive detection of microRNA-222 (miRNA-222). Interestingly, AgAuS QDs revealed excellent ECL efficiency (34.91%) compared to that of Ag2S QDs (10.30%), versus the standard [Ru(bpy)3]2+/S2O82- system, which benefited from the advantages of abundant surface defects and narrow bandgaps by Au incorporation. Additionally, an improved localized catalytic hairpin self-assembly (L-CHA) system was developed to display an increased reaction speed by improving the local concentration of DNA strands, which addressed the obstacles of time-consuming traditional CHA systems. As a proof of concept, based on AgAuS QDs as an ECL emitter and improved localized CHA systems as a signal amplification strategy, a "signal on-off" ECL biosensor was developed to exhibit a superior reaction rate and excellent sensitivity with a detection limit of 10.5 aM for the target miRNA-222, which was further employed for the analysis of miRNA-222 from cancer cell (MHCC-97L) lysate. This work advances the exploration of highly efficient NIR ECL emitters to construct an ultrasensitive biosensor for the detection of biomolecules in disease diagnosis and NIR biological imaging.
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Técnicas Biosensibles , MicroARNs , Puntos Cuánticos , MicroARNs/análisis , Mediciones Luminiscentes/métodos , Técnicas Electroquímicas/métodos , Técnicas Biosensibles/métodos , Oro , Azufre , Límite de DetecciónRESUMEN
Understanding the evolutionary processes that shape the landscape of genetic variation and influence the response of species to future climate change is critical for biodiversity conservation. Here, we sampled 27 populations across the distribution range of a dominant forest tree, Quercus acutissima, in East Asia, and applied genome-wide analyses to track the evolutionary history and predict the fate of populations under future climate. We found two genetic groups (East and West) in Q. acutissima that diverged during Pliocene. We also found a heterogeneous landscape of genomic variation in this species, which may have been shaped by population demography and linked selections. Using genotype-environment association analyses, we identified climate-associated SNPs in a diverse set of genes and functional categories, indicating a model of polygenic adaptation in Q. acutissima. We further estimated three genetic offset metrics to quantify genomic vulnerability of this species to climate change due to the complex interplay between local adaptation and migration. We found that marginal populations are under higher risk of local extinction because of future climate change, and may not be able to track suitable habitats to maintain the gene-environment relationships observed under the current climate. We also detected higher reverse genetic offsets in northern China, indicating that genetic variation currently present in the whole range of Q. acutissima may not adapt to future climate conditions in this area. Overall, this study illustrates how evolutionary processes have shaped the landscape of genomic variation, and provides a comprehensive genome-wide view of climate maladaptation in Q. acutissima.
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Cambio Climático , Quercus , Árboles , Bosques , Estudio de Asociación del Genoma Completo , Genómica , Quercus/genética , Árboles/genéticaRESUMEN
BACKGROUND: The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. METHODS: Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. RESULTS: Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. CONCLUSIONS: Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.
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Longevidad , Proteínas del Tejido Nervioso , Envejecimiento/genética , Animales , Proteínas Relacionadas con la Autofagia , Hesperidina , Humanos , Longevidad/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genéticaRESUMEN
CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction.
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Envejecimiento Prematuro/genética , Envejecimiento/fisiología , Bloqueo Atrioventricular/genética , Proteínas Relacionadas con la Autofagia/genética , Corazón/fisiopatología , Proteínas del Tejido Nervioso/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Envejecimiento Prematuro/metabolismo , Envejecimiento Prematuro/fisiopatología , Animales , Bloqueo Atrioventricular/diagnóstico por imagen , Bloqueo Atrioventricular/metabolismo , Bloqueo Atrioventricular/fisiopatología , Proteínas Relacionadas con la Autofagia/deficiencia , Calcio/metabolismo , Electrocardiografía , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Corazón/fisiología , Homeostasis/fisiología , Masculino , Ratones , Ratones Noqueados , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/fisiología , Proteínas del Tejido Nervioso/deficiencia , Sarcómeros/fisiología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , TranscriptomaRESUMEN
The aging human population with age-associated diseases has become a problem worldwide. By 2050, the global population of those who are aged 65 years and older will have tripled. In this context, delaying age-associated diseases and increasing the healthy lifespan of the aged population has become an important issue for geriatric medicine. CDGSH iron-sulfur domain 2 (CISD2), the causative gene for Wolfram syndrome 2 (WFS2; MIM 604928), plays a pivotal role in mediating lifespan and healthspan by maintaining mitochondrial function, endoplasmic reticulum integrity, intracellular Ca2+ homeostasis, and redox status. Here, we summarize the most up-to-date publications on CISD2 and discuss the crucial role that this gene plays in aging and age-associated diseases. This review mainly focuses on the following topics: (1) CISD2 is one of the few pro-longevity genes identified in mammals. Genetic evidence from loss-of-function (knockout mice) and gain-of-function (transgenic mice) studies have demonstrated that CISD2 is essential to lifespan control. (2) CISD2 alleviates age-associated disorders. A higher level of CISD2 during natural aging, when achieved by transgenic overexpression, improves Alzheimer's disease, ameliorates non-alcoholic fatty liver disease and steatohepatitis, and maintains corneal epithelial homeostasis. (3) CISD2, the expression of which otherwise decreases during natural aging, can be pharmaceutically activated at a late-life stage of aged mice. As a proof-of-concept, we have provided evidence that hesperetin is a promising CISD2 activator that is able to enhance CISD2 expression, thus slowing down aging and promoting longevity. (4) The anti-aging effect of hesperetin is mainly dependent on CISD2 because transcriptomic analysis of the skeletal muscle reveals that most of the differentially expressed genes linked to hesperetin are regulated by hesperetin in a CISD2-dependent manner. Furthermore, three major metabolic pathways that are affected by hesperetin have been identified in skeletal muscle, namely lipid metabolism, protein homeostasis, and nitrogen and amino acid metabolism. This review highlights the urgent need for CISD2-based pharmaceutical development to be used as a potential therapeutic strategy for aging and age-associated diseases.
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Envejecimiento Prematuro , Rejuvenecimiento , Humanos , Animales , Ratones , Anciano , Longevidad/genética , Envejecimiento/genética , MamíferosRESUMEN
Baicalin is reported as an effective drug for ulcerative colitis (UC). However, its effect on gut microbiota and short-chain fatty acids (SCFAs) remains unknown. In this study, we investigated the role of baicalin on Th17/Treg balance, gut microbiota community, and SCFAs levels in trinitrobenzene sulphonic acid (TNBS)-induced UC rat model. We found the DAI scores were significantly increased in the TNBS-treated rats, while reduced in the baicalin-treated group in a dose-dependent manner, accompanied with the alleviation of mucosal injury, the reduction of ZO-1, Occludin, and MUC2 expression. At the meanwhile, baicalin repressed the increased levels of reactive oxygen species (ROS) and MDA, while deceased the GSH and SOD levels in colon tissue of rats treated with TNBS. On the other hand, administration of baicalin attenuated the TNBS-induced upregulations of Th17/Treg ratio, indicating a strong amelioration in the colorectal inflammation. More importantly, pyrosequencing of the V4 regions of 16S rRNA genes in rat feces revealed a deviation of the gut microbiota in response to baicalin treatment. In particular, the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels indicated that baicalin reversed TNBS-induced gut dysbiosis OTUs. In addition, we further investigated the fecal levels of major SCFAs in rats and found that baicalin significantly resorted the fecal butyrate levels in rats treated with TNBS. The increased butyrate levels were in consistent with the higher abundance of butyrate-producing species such as Butyricimonas spp., Roseburia spp., Subdoligranulum spp., and Eubacteriu spp. in baicalin-treated group. In conclusion, our findings suggest that baicalin possibly protected rats against ulcerative colitis by regulation of Th17/Treg balance, and modulation of both gut microbiota and SCFAs. Baicalin may be used as a prebiotic agent to treat ulcerative colitis-associated inflammation and gut dysbiosis.
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Colitis Ulcerosa/prevención & control , Ácidos Grasos Volátiles/análisis , Flavonoides/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Butiratos/análisis , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Modelos Animales de Enfermedad , Disbiosis/tratamiento farmacológico , Disbiosis/prevención & control , Flavonoides/uso terapéutico , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Prebióticos/administración & dosificación , Ratas , Ácido Trinitrobencenosulfónico/administración & dosificaciónRESUMEN
The taxonomic status and phylogenetic affinities of Mymaridae and Scelionidae are controversial, based on similarities between these families in the characteristics of adults, larvae, and eggs. In this study, we sequenced the mitochondrial (mt) genomes of representatives from these two families and found that the derived secondary structure of tRNA-Arg was the same in each family due to the absence of the D-stem. The segment of "cox1 trnL2cox2 trnK trnD atp8 atp6 cox3" in Gonatocerus sp. (Mymaridae) is conserved and distinct from those of four other species of Chalcidoidea but similar to that in Proctotrupoidea and Platygastroidea. However, phylogenetic analysis indicated that Gonatocerus sp. was sister group to other species of Chalcidoidea. Comparisons based on complete gene orders may be more useful in a phylogenetic and systematic context, as different branches may exhibit partially homoplastic gene orders.
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Genes de Insecto , Genoma Mitocondrial , Himenópteros/genética , Filogenia , Animales , Orden Génico , Himenópteros/clasificación , ARN de Transferencia/química , ARN de Transferencia/genética , Homología de SecuenciaRESUMEN
This article is aimed to reevaluate the systematic reviews(Meta-analysis) of traditional Chinese medicine in the treatment of ulcerative colitis, and provide reference for evidence-based decision-making of traditional Chinese medicine(TCM). According to the preferred reporting items for overviews(preferred reporting items for overview of systematic reviews, PRIO-harms), the main Chinese and English electronic literature databases(PubMed, Cochrane Library, EMbase, CNKI, CBM, etc.) were retrieved, supplemented by manual retrieval. Systematic reviews for the treatment of ulcerative colitis with Chinese medicine up to February 2019 were included. Two researchers independently performed literature screening and data extraction. The methodology quality, reporting quality and evidence quality of the literature were evaluated by AMSTAR 2 tool, PRISMA scale and GRADE system respectively. Subgroup analysis was performed by using RevMan 5.3 software. A total of 21 systematic reviews were included, and the interventions mainly included TCM internal and external treatment, with 53 outcome indicators. The AMSTAR 2 results showed that 5 articles were of high quality, 9 of medium quality, 4 of low quality, and 3 of extremely low quality. The most problematic items were as follows: the list of excluded documents was not provided; the sources of funding for each study were not reported; and the research methods were not determined before implementation. PRISMA scale had an average score of(20.38±1.43) points, less than 22 points for 15 articles, with certain reporting defects. The GRADE system suggested that the quality of the evidence for the 30 outcome indicators was low or very low. The most important factors leading to degrading was the limitation, followed by publication bias and inconsistency. The results showed that as compared with conventional Western medicine, TCM oral or enema treatment for mild to moderate ulcerative colitis had better clinical efficacy and safety. Due to the quality limitations of the included studies, it is necessary to further strengthen the top-level design and follow the scientific research paradigm to provide a higher level of evidence for the clinical evidence-based decision-making of TCM.
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Colitis Ulcerosa/tratamiento farmacológico , Medicina Tradicional China , Humanos , Proyectos de Investigación , Resultado del TratamientoRESUMEN
Hepatocellular carcinoma (HCC) is one of the most fatal cancers with common features of invasion and metastasis. Recent evidence indicate that the long noncoding RNA NORAD is a potential oncogene and is significantly upregulated in several cancers. However, the general biological role and clinical value of NORAD in HCC remains unknown. Here, NORAD expression was measured in 29 paired tumor and paratumor tissues via quantitative real-time polymerase chain reaction (qPCR). The effects of NORAD on HCC cell malignant potential were investigated via NORAD overexpression and knockdown both in vitro and in vivo. The mechanism of competitive endogenous RNAs (ceRNAs) was acquired and identified by bioinformatics analyses and luciferase assays. Moreover, the impact of NORAD level on the transforming growth factor ß (TGF-ß) pathway was further determined by qPCR. We found that HCC tissues had a high level of NORAD compared with the paratumor tissues, and NORAD upregulation was associated with the shorter overall survival of patients with HCC. Furthermore, NORAD overexpression was demonstrated to promote HCC cell migration and invasion. Mechanically, NORAD might function as a ceRNA to regulate miR-202-5p, which served as a tumor-suppressing microRNA via the TGF-ß pathway. We address that NORAD has a tumor-promoting effect in HCC and describes a novel mechanism whereby NORAD regulates the TGF-ß pathway as a ceRNA of Homo sapiens (hsa)-miR-202-5p.
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Carcinoma Hepatocelular/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Adulto , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Chronic kidney disease (CKD) is a traumatic disease with significant psychic consequences to the patient's overall physical condition. microRNA-206 (miR-206) has been reported to play an essential role in the development of various diseases. The purpose of the present study is to investigate the effect of miR-206 through the JAK/STAT signaling pathway on epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells and glomerulosclerosis in rats with CKD. The targeting relationship between miR-206 and ANXA1 was verified. To explore the role of miR-206 in CKD, the model of CKD rats was established to detect glomerular sclerosis index (GSI), contents of interleukin-6 (IL-6) and transforming growth factor-beta1 (TGF-ß1), and expression of type IV collagen. Moreover, to further determine the roles of both miR-206 and the JAK/STAT signaling pathway in CKD, the gain- and loss-of function approaches were performed with the expression of ANXA1, α-SMA, E-cadherin, vimentin, N-cadherin, and the JAK/STAT signaling pathway-related genes detected. miR-206 negatively targeted ANXA1. Overexpressed miR-206 inhibited the degeneration and interstitial fibrosis of renal tubular epithelial cells, decreased GSI of rats, and the expression of type IV collagen, TGF-ß1 and IL-6. Overexpressed miR-206 inhibited the degeneration of renal tubular epithelial cells, the expression of ANXA1, α-SMA, TGF-ß1, p-STAT3, STAT3, p-STAT1, STAT1, p-JAK2, and JAK2, while promoted the expression of E-cadherin. Taken together the results, miR-206 inhibits EMT of renal tubular epithelial cells and glomerulosclerosis by inactivating the JAK/STAT signaling pathway via ANXA1 in CKD.
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Anexina A1/genética , Anexina A1/metabolismo , MicroARNs/genética , Insuficiencia Renal Crónica/patología , Transducción de Señal , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Regulación de la Expresión Génica , Quinasas Janus/metabolismo , Masculino , Ratas , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Factores de Transcripción STAT/metabolismo , EsclerosisRESUMEN
Neuroinflammation is considered a challenging clinical problem. Chronic inflammatory responses play important roles in the onset and progression of various neurodegenerative diseases, including multiple sclerosis (MS). Previous studies have shown that astrocytes express small heat shock protein αB-crystallin (CRYAB) which is capable of inhibiting inflammatory responses in astrocytes per se. However, the underlying mechanisms of CRYAB-induced modulation of neuroinflammation are still not fully understood. In the present study, we investigated the role of extracellular CRYAB in the interaction between microglia and astrocytes in the context of MS-associated neuroinflammation. We found that the expression of CRYAB was profoundly increased in EAE mice. CRYAB was preferentially expressed in astrocytes and could be secreted via exosomes. Levels of exosomal CRYAB secreted from astrocytes were markedly increased under stress conditions. Furthermore, incubation of immortalized astrocytes or microglia cell lines with CRYAB remarkably suppressed astrocytes and microglia-mediated inflammatory responses in both autocrine and paracrine manners. Our results reveal a novel function for extracellular CRYAB in the regulation of neuroinflammation. Targeting extracellular CRYAB-modulated neuroinflammation is a potential therapeutic intervention for MS.
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Inflamación/metabolismo , Cadena B de alfa-Cristalina/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Inflamación/inducido químicamente , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismoRESUMEN
OBJECTIVE: To study the association of cytoplasmic phospholipase A2 (PLA2G4) rs932476 polymorphism with the development of bronchial asthma and the response to montelukast, a leukotriene receptor antagonist, in children. METHODS: A total of 128 children with bronchial asthma were enrolled as case group, and 100 healthy children were enrolled as control group. The genotype and allele frequencies of PLA2G4 rs932476 were compared between the two groups. The children in the case group were administered with montelukast except routine treatment for 2 months, and the changes in serum levels of leukotriene B4 (LTB4), interleukin-4 (IL-4), immunoglobulin E (IgE), and interferon gamma (IFN-γ), pulmonary function and fractional exhaled nitric oxide (FeNO) after treatment were observed. RESULTS: There were no significant differences in the genotype and allele frequencies of PLA2G4 rs932476 between the case and control groups, as well as between the groups with different severities of asthma (P>0.05). After treatment, the children with AA genotype had a significantly higher overall response rate than those with GG genotype. After treatment, the case group had significant reductions in the serum levels of IgE and IL-4 and a significant increase in the level of IFN-γ (P<0.05). After treatment, the children with GG genotype had a higher serum level of IL-4 and a lower level of IFN-γ than those with AA genotype. After treatment, the case group had significant increases in pulmonary function parameters, and the children with AA genotype had significantly higher parameters than those with GG genotype. The case group had a significant reduction in the level of FeNO, and the children with AA genotype had a significantly lower level than those with GG genotype after treatment. The case group had a significantly higher serum level of LTB4 than the control group before treatment (P<0.05). After treatment the case group had a significant reduction in the serum level of LTB4 (P<0.05). The children with GG genotype had a significantly higher level of LTB4 than those with AA genotype after treatment (P<0.05). CONCLUSIONS: PLA2G4 rs932476 polymorphism is not associated with the susceptibility and severity of bronchial asthma in children, but it may has certain influence on children's response to the leukotriene receptor antagonist montelukast, possibly by affecting the level of LTB4.
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Asma , Acetatos , Niño , Ciclopropanos , Humanos , Antagonistas de Leucotrieno , Quinolinas , SulfurosRESUMEN
OBJECTIVE: To study the significance of plasma neutrophil extracellular trap (NET) and its markers in the diagnosis of community-acquired pneumonia (CAP) in children. METHODS: A total of 160 children with CAP were enrolled as the CAP group, and 50 healthy children were enrolled the control group. According to disease severity, the CAP group was further divided into a mild CAP subgroup with 137 children and a severe CAP subgroup with 23 children. According to the pathogen, the CAP group was further divided into a bacterial pneumonia subgroup with 78 children, a Mycoplasma pneumonia subgroup with 35 children, and a viral pneumonia subgroup with 47 children. The levels of plasma NET and its markers [antibacterial peptide (LL-37), extracellular free DNA (cfDNA), and deoxyribonuclease I (DNase I)] were measured. Receiver operating characteristic (ROC) curve was used to analyze the value of each index in diagnosing CAP and assessing its severity. RESULTS: Compared with the control group, the CAP group had significant increases in the levels of NET, LL-37, and cfDNA and a significant reduction in the activity of DNase I (P<0.05). Compared with the mild CAP subgroup, the severe CAP subgroup had significantly higher levels of NET, LL-37 and cfDNA and a significantly lower activity of DNase I (P<0.05). There were no significant differences in the levels of NET, LL-37, and cfDNA and the activity of DNase I among the bacterial pneumonia, Mycoplasma pneumonia, and viral pneumonia subgroups (P>0.05). In the CAP group, plasma NET levels were positively correlated with white blood cell count (WBC), percentage of neutrophils, and serum levels of C-reactive protein (CRP), procalcitonin and tumor necrosis factor-α (r=0.166, 0.168, 0.275, 0.181 and 0.173 respectively, P<0.05); LL-37 and cfDNA levels were positively correlated with WBC (r=0.186 and 0.338 respectively, P<0.05) and CRP levels (r=0.309 and 0.274 respectively, P<0.05); the activity of DNase I was negatively correlated with CRP levels (r=-0.482, P<0.05). The ROC curve analysis showed that NET, LL-37, cfDNA, and DNase I had an area under the ROC curve (AUC) of 0.844, 0.648, 0.727, and 0.913 respectively in the diagnosis of CAP, with optimal cut-off values of 182.89, 46.26â ng/mL, 233.13â ng/mL, and 0.39â U/mL respectively, sensitivities of 88.12%, 35.63%, 54.37%, and 91.25% respectively, and specificities of 74.00%, 92.00%, 86.00%, and 76.00% respectively. In the assessment of the severity of CAP, NET, LL-37, cfDNA, and DNase I had an AUC of 0.873, 0.924, 0.820, and 0.778 respectively, with optimal cut-off values of 257.7, 49.11â ng/mL, 252.54â ng/mL, and 0.29â U/mL respectively, sensitivities of 83.21%, 86.96%, 78.26%, and 95.65% respectively, and specificities of 78.26%, 83.94%, 76.64%, and 56.93% respectively. CONCLUSIONS: Plasma NET and its related markers have a certain value in diagnosing CAP and assessing its severity in children.
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Infecciones Comunitarias Adquiridas , Trampas Extracelulares , Neumonía , Biomarcadores , Proteína C-Reactiva , Niño , Infecciones Comunitarias Adquiridas/diagnóstico , Diagnóstico Precoz , Humanos , Curva ROCRESUMEN
BACKGROUND: The multidrug resistance of leukemia cells is closely related to the microenvironment. The present leukemia microenvironment models focus on two-dimensional co-culture system in vitro which does not mimic the in vivo cell growth, while the 3D polystyrene (PS) scaffolds have the advantage. Stromal cell derived factor-1 may be involved in the shielding of endosteal niche from leukemia cells by binding to its receptor CXCR4, but the relationship between SDF-1/CXCR4 axis and leukemia cells is unclear. DESIGN AND METHODS: The experiments were built on the 3D PS scaffolds coated with osteoblasts. Stromal cells and MV4-11 cells were plated on the scaffolds. Then G-CSF, AMD3100 and cytarabine were added. Adhesive rate, SDF-1 level, migration state, apoptosis rate, and cell cycle of leukemia cells were observed after incubation at 24h and 48h. RESULTS: G-CSF decreased the level of SDF-1 and inhibited the expression of CXCR4 and promoted stationary phase leukemia cells to enter the mitotic phase and enhanced the killing effect of chemotherapeutic drugs. AMD3100 disrupted the interaction between tumors and matrix, mobilized the leukemia cells to keep away from the protective microenvironment and strengthened the cytotoxic effect of Ara-C. The combination of G-CSF and AMD3100 had stronger effects on killing the leukemia cells induced by Ara-C. CONCLUSION: It demonstrates that AMD3100 and G-CSF may inhibit adhesion and migration abilities of leukemia cells with the bone marrow niche. Both of them inhibit the role of SDF-1/CXCR4 directly or indirectly. Thus inhibiting SDF-1/CXCR4 axis may be helpful to the treatment of refractory AML.
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Materiales Biomiméticos , Factor Estimulante de Colonias de Granulocitos/farmacología , Compuestos Heterocíclicos/farmacología , Leucemia/patología , Receptor Cross-Talk/efectos de los fármacos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bencilaminas , Adhesión Celular , Movimiento Celular , Células Cultivadas , Quimiocina CXCL12/metabolismo , Ciclamas , Citarabina/farmacología , Humanos , Leucemia Mieloide Aguda/patología , Poliestirenos , Receptores CXCR4/metabolismo , Células del Estroma/citologíaRESUMEN
In plants, the copy number of the mitochondrial DNA (mtDNA) can be much lower than the number of mitochondria. The biological significance and regulatory mechanisms of this phenomenon remain poorly understood. Here, using the pollen vegetative cell, we examined the role of the Arabidopsis (Arabidopsis thaliana) mtDNA-binding protein WHIRLY2 (AtWHY2). AtWHY2 decreases during pollen development, in parallel with the rapid degradation of mtDNA; to examine the importance of this decrease, we used the pollen vegetative cell-specific promoter Lat52 to express AtWHY2. The transgenic plants (LWHY2) had very high mtDNA levels in pollen, more than 10 times more than in the wild type (ecotype Columbia-0). LWHY2 plants were fertile, morphologically normal, and set seeds; however, reciprocal crosses with heterozygous plants showed reduced transmission of LWHY2-1 through the male and slower growth of LWHY2-1 pollen tubes. We found that LWHY2-1 pollen had significantly more reactive oxygen species and less ATP compared with the wild type, indicating an effect on mitochondrial respiration. These findings reveal that AtWHY2 affects mtDNA copy number in pollen and suggest that low mtDNA copy numbers might be the normal means by which plant cells maintain mitochondrial genetic information.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/crecimiento & desarrollo , Arabidopsis/genética , ADN Mitocondrial/genética , Proteínas de Unión al ADN/metabolismo , Dosificación de Gen , Tubo Polínico/citología , Tubo Polínico/crecimiento & desarrollo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Proteínas de Arabidopsis/química , Respiración de la Célula , Segregación Cromosómica , Cruzamientos Genéticos , ADN de Plantas/metabolismo , Proteínas de Unión al ADN/química , Mitocondrias/metabolismo , Datos de Secuencia Molecular , Fenotipo , Plantas Modificadas Genéticamente , Unión Proteica , Transporte de Proteínas , Especies Reactivas de Oxígeno/metabolismo , Semillas/metabolismoRESUMEN
PURPOSE: Our purpose was to investigate the effect of posterior scleral reinforcement (PSR) combined with patching therapy for pre-school children with unilateral high myopia. METHODS: A total of 32 pre-school children with unilateral high myopia were recruited. They were randomly divided into the PSR and control group, each of which had 16 patients. The patients in the PSR group underwent the simplified PSR surgery followed by rigid gas permeable contact lens wear and traditional patching therapy, while the patients in the control group were only prescribed contact lens wear and patching. Patients were reviewed and the axial length, refraction, best-corrected visual acuity, and stereoscopic vision were respectively examined postoperatively at yearly intervals for three years. RESULTS: The best-corrected visual acuity was significantly higher in the PSR group than that in the control group at any study visit. A statistically significant difference in axial length was found between the PSR group (27.38 ± 1.30 mm) and the control group (28.29 ± 0.74 mm) at the postoperative three-year (p = 0.03) time point. There was a statistical difference in refractive error between the PSR group (-13.13 ± 2.55 D) and the control group (-15.42 ± 1.83 D) at 3-year follow-up. No significant difference was found between the two groups with respect to the stereoscopic vision by the end of follow-up at 3 years (p =0.103). CONCLUSIONS: PSR combined with the patching therapy has the potential to arrest the progression of high myopia and to help the treatment for amblyopia.