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The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.
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Anticuerpos Biespecíficos/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , SARS-CoV-2/inmunología , Animales , Anticuerpos Biespecíficos/química , Anticuerpos Biespecíficos/genética , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/genética , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/química , Anticuerpos Antivirales/genética , COVID-19/inmunología , COVID-19/patología , COVID-19/prevención & control , COVID-19/virología , Clonación Molecular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta Inmunológica , Epítopos , Humanos , Macaca mulatta , Ratones , Pruebas de Neutralización , Ingeniería de Proteínas/métodos , Relación Estructura-ActividadRESUMEN
BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by ß-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of ß-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues . METHODS: We compared the difference of ß-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of ß-catenin in the development of AF was also explored in mice and primary cells. RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of ß-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, ß-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3ß (GSK-3ß) and Adenomatous Polyposis Coli (APC), which participated in the degradation of ß-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting ß-catenin expression in the AF model mice. CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that ß-catenin was associated with atrial fibrosis and AF progression.
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Fibrilación Atrial , Fibrosis , Atrios Cardíacos , Miocitos Cardíacos , beta Catenina , Humanos , Fibrilación Atrial/patología , Fibrilación Atrial/metabolismo , beta Catenina/metabolismo , Animales , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Cadherinas/metabolismo , Uniones Comunicantes/metabolismo , Persona de Mediana Edad , Ratones , Femenino , Conexina 43/metabolismo , Ratones Endogámicos C57BL , AncianoRESUMEN
Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease and the clinical heterogeneity of which is largely unknown. Retrospective cohort analysis was conducted on hospitalized GPP patients between January 2010 and November 2022. A total of 416 patients with GPP and psoriasis vulgaris (PV) respectively were included, matched 1:1 by sex and age. The heterogeneity of GPP was stratified by PV history and age. Compared with PV, GPP was significantly associated with prolonged hospitalization (11.7 vs. 10.3 day, p < 0.001), elevated neutrophil lymphocyte ratio (NLR) (5.93 vs. 2.44, p < 0.001) and anemia (13.9% vs. 1.2%, p < 0.001). Moreover, GPP alone (without PV history) was a relatively severer subtype with higher temperature (37.6°C vs. 38.0°C, p = 0.002) and skin infections (5.2% vs. 11.4%, p = 0.019) than GPP with PV. For patients across different age, compared with juvenile patients, clinical features support a severer phenotype in middle-aged, including higher incidence of anaemia (7.5% vs. 16.0%, p = 0.023) and NLR score (3.83 vs. 6.88, p < 0.001). Interleukin-6 (r = 0.59), high density lipoprotein cholesterol (r = -0.56), albumin (r = -0.53) and C-reactive protein-to-albumin ratio (r = 0.49) were the most relevant markers of severity in GPP alone, GPP with PV, juvenile and middle-aged GPP, respectively. This retrospective cohort suggests that GPP is highly heterogeneous and GPP alone and middle-aged GPP exhibit severe disease phenotypes. More attention on the heterogeneity of this severe disease is warranted to meet the unmet needs and promote the individualized management of GPP.
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Exantema , Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Persona de Mediana Edad , Humanos , Estudios Retrospectivos , Psoriasis/genética , Enfermedad Aguda , Enfermedad Crónica , Proteína C-ReactivaRESUMEN
BACKGROUND: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. OBJECTIVES: We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms. METHODS: Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated. RESULTS: Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1ß secretion through modulation of ER stress via the PERK-eIF2α-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. CONCLUSIONS: In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.
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Dermatitis , Proteínas Filagrina , Animales , Humanos , Ratones , Acetona/metabolismo , Acetona/farmacología , Dermatitis/metabolismo , Epidermis/metabolismo , Inflamasomas/metabolismo , Inflamación , Queratinocitos/metabolismo , Proteínas NLR/metabolismoRESUMEN
Fibroblasts are critical pro-inflammatory regulators in chronic inflammatory and fibrotic skin diseases. However, fibroblast heterogeneity and the absence of a unified cross-disease taxonomy have hindered our understanding of the shared/distinct pathways in non-communicable skin inflammation. By integrating 10× single-cell data from 75 skin samples, we constructed a single-cell atlas across inflammatory and fibrotic skin diseases and identified 9 distinct subsets of skin fibroblasts. We found a shared subset of CCL19+ fibroblasts across these diseases, potentially attracting and educating immune cells. Moreover, COL6A5+ fibroblasts were a distinct subset implicated in the initiation and relapse of psoriasis, which tended to differentiate into CXCL1+ fibroblasts, inducing neutrophil chemotaxis and infiltration; while CXCL1+ fibroblasts exhibited a more heterogeneous response to certain inflammatory conditions. Differentiation trajectory and regulatory factors of these fibroblast subsets were also revealed. Therefore, our study presents a comprehensive atlas of skin fibroblasts and highlights pathogenic fibroblast subsets in skin disorders.
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AIMS: The aim of this study was to investigate the dynamics of bacterial communities and natural fermentation quality in three steppe types [meadow steppe (MS); typical steppe (TS); and desert steppe (DS)] on the Mongolian Plateau. METHODS AND RESULTS: PacBio single molecule with real-time sequencing technology was applied to provide insights into the dynamics of the physicochemical characteristics and the complex microbiome of native grass after 1, 7, 15, and 30 days of fermentation process. The dry matter, crude protein, and water soluble carbohydrate (WSC) contents of the three groups slowly decreased after 1 day of fermentation process, and the lowest WSC concentration after 30 days of ensiling was detected in the DS group compared to that in the MS and TS groups. There was no significant effect of steppe types on lactic acid and butyric acid content (P > 0.05). The pH was higher in the early stages of fermentation. After 30 days of fermentation, the pH of MS and DS dropped to â¼5.60, while TS was as high as 5.94. At different ensiling days, the pH of TS was significantly higher than that of MS (P < 0.05). The ammonia nitrogen content of MS was significantly higher than TS and DS (P < 0.05). During the whole fermentation process, Leuconostoc mesenteroides and Pseudocitrobacter faecalis were the main species of DS, while Enterobacter roggenkampii and Faecalibacterium prausnitzii dominated the fermentation process in MS and TS, respectively. CONCLUSIONS: The fermentation quality of native grass silage of different steppe types was less satisfactory, with the silage quality ranging from DS, MS, and TS in descending order. The epiphytic bacteria dominating the fermentation process differed between steppe types of silage. Leuconostoc mesenteroides as the main strain of DS had a modulating effect on pH and LA content, while the main strains of MS and TS (Enterobacter roggenkampii and Faecalibacterium prausnitzii) dominated the silage without significant effect on improving fermentation characteristics and nutritional quality.
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Pradera , Poaceae , Poaceae/microbiología , Enterobacter , Carbohidratos , Ensilaje/microbiología , FermentaciónRESUMEN
BACKGROUND: Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown. METHODS: We showed that vitamin C deficiency leads to acute tubular necrosis (ATN) using a vitamin C-deficient mouse model (Gulo knock-out). DNA/RNA epigenetic modifications and injured S3 proximal tubule cells were identified in the vitamin C-deficient kidneys using whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing. RESULTS: Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C-deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C-induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN. CONCLUSIONS: Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.
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Deficiencia de Ácido Ascórbico , Necrosis Tubular Aguda , Animales , Ácido Ascórbico/farmacología , Modelos Animales de Enfermedad , Células Endoteliales , Epigénesis Genética , Femenino , Humanos , Necrosis Tubular Aguda/etiología , Masculino , Ratones , Necrosis , ARNRESUMEN
In this study, the triterpenoids in the leaves of Lactuca indica L.cv. Mengzao (LIM) were extracted via microwave-assisted ethanol extraction, and the optimum extraction conditions for triterpenoids were determined through single-factor experiments and the Box-Behnken method. The effects of three factors (solid-liquid ratio, microwave power and extraction time) on the total triterpenoids content (TTC) were evaluated. The TTC of different parts (roots, stems, leaves and flowers) of LIM in different growth stages was studied, and the scavenging effects of the highest TTC parts on DPPH, ABTS and hydroxyl free radicals were investigated. The results showed that the optimum extraction conditions for microwave-assisted extraction of total triterpenoids from LIM leaves were as follows: solid-liquid ratio of 1:20 g/mL; microwave power of 400 W; and extraction time of 60 min. Under these conditions, the TTC was 29.17 mg/g. Compared with the fresh raw materials, the TTC of the materials increased after freeze drying. The leaves of LIM had the highest TTC, and the flowering stage was the best time. The triterpenoids from the leaves had a strong ability to eliminate DPPH and ABTS free radicals, and the elimination effect of dried leaves was better than that of fresh leaves, while the elimination effect of hydroxyl free radicals was not obvious. The tested method was used to extract total triterpenoids from LIM using a simple process at low cost, which provides a reference for developing intensive processing methods for L. indica.
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Triterpenos , Triterpenos/farmacología , Etanol/química , Hojas de la Planta/química , Flores , Radicales Libres/análisisRESUMEN
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tickborne bandavirus mainly transmitted by Haemaphysalis longicornis ticks in East Asia, mostly in rural areas. As of April 2022, the amplifying host involved in the natural transmission of SFTSV remained unidentified. Our epidemiologic field survey conducted in endemic areas in China showed that hedgehogs were widely distributed, had heavy tick infestations, and had high SFTSV seroprevalence and RNA prevalence. After experimental infection of Erinaceus amurensis and Atelerix albiventris hedgehogs with SFTSV, we detected robust but transitory viremias that lasted for 9-11 days. We completed the SFTSV transmission cycle between hedgehogs and nymph and adult H. longicornis ticks under laboratory conditions with 100% efficiency. Furthermore, naive H. longicornis ticks could be infected by SFTSV-positive ticks co-feeding on naive hedgehogs; we confirmed transstadial transmission of SFTSV. Our study suggests that the hedgehogs are a notable wildlife amplifying host of SFTSV in China.
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Phlebovirus , Síndrome de Trombocitopenia Febril Grave , Garrapatas , Animales , Erizos , Estudios Seroepidemiológicos , Filogenia , Phlebovirus/genética , China/epidemiologíaRESUMEN
This study aimed to investigate the inhibitory effect of miR-129-5p on colon cancer by targeting RSF1. For this purpose, real-time quantitative PCR was used to analyze whether the expression of miR-129-5p in colon cancer and adjacent normal tissues had an impact on the proliferation and apoptosis of cancer cells (CC). We evaluated the role of miR-129-5p by targeting RSF1 in colon cancer tissue in the experimental group. But in the control group, only miR-129-5p was considered as a protective factor. Finally, we retrospectively analyzed data of 56 cases of colon cancer patients admitted to our clinical department between January 2019 and December 2019. Twenty-eight cases were investigated through just miR-129-5p protective factors for cancer (group A). The other 28 cases were studied by miR-129-5p anti-cancer agent and a completed RSF1 carcinoma factors for cancer (group B). We evaluated the comparative analysis of the patient's age and gender, clinical indicators (including for the first time of hospitalization and postoperative hospital stay, three times of anal exhaust), and complications (including chills, vomiting, hypertension, diabetes). The results showed that miR-129-5p had a more substantial effect on the proliferation and apoptosis of CC by targeting RSF1.
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Neoplasias del Colon , MicroARNs , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estudios Retrospectivos , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
L. indica L. cv. Mengzao, a medicinal plant of the Ixeris genus, is rich in flavonoids. In order to thoroughly analyze the the distribution and dynamic change of major flavonoids in its various parts from different growth periods, the flavonoids extracted from L. indica L. cv. Mengzao were identified and quantitatively analyzed by ultra-high-performance liquid chromatography mass spectrometer (LC-MS/MS). Results indicated that 15 flavonoids were identified from L. indica L. cv. Mengzao, and rutin, luteolin, luteolin-7-O-glucoside, kaempferol, quercetin, and apigenin are the major flavonoids in L. indica L. cv. Mengzao. In general, the total flavonoids' content in different parts of L. indica L. cv. Mengzao followed the order flowers > leaves > stems > roots. Flowers and leaves are the main harvesting parts of L. indica L. cv. Mengzao, and the flowering period is the most suitable harvesting period. This study provides valuable information for the development and utilization of L. indica L. cv. Mengzao and determined the best part to harvest and the optimal time for harvesting.
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Flavonoides/análisis , Lactuca , Componentes Aéreos de las Plantas , Raíces de Plantas , Plantas Medicinales , Lactuca/química , Lactuca/crecimiento & desarrollo , Componentes Aéreos de las Plantas/química , Componentes Aéreos de las Plantas/crecimiento & desarrollo , Raíces de Plantas/química , Raíces de Plantas/crecimiento & desarrollo , Plantas Medicinales/química , Plantas Medicinales/crecimiento & desarrolloAsunto(s)
Psoriasis , Humanos , Psoriasis/patología , Psoriasis/diagnóstico , Pronóstico , Femenino , Masculino , Persona de Mediana Edad , Adulto , Índice de Severidad de la EnfermedadRESUMEN
This study investigated a magnetically recycled modified polishing powder (CMIO@PP) as an adsorbent of phosphate; the CMIO@PP was synthesized by combining the modified La/Ce-containing waste polishing powder with CaO2-modified Fe3O4 (CMIO). Results indicate that the CMIO@PP nanocomposite presents a crystal structure comprising La (OH)3, Ce (OH)3, and Fe3O4, and that CMIO is uniformly dispersed in the modified polishing powder. The CMIO@PP (1:3) is a suitable choice considering its magnetism and adsorption capacity. The magnetic adsorbent exhibits a high adsorption capacity of 53.72 mg/g, a short equilibrium time of 60 min, and superior selectivity for phosphate. Moreover, the adsorbent strongly depends on the pH during the adsorption process and maintains a large adsorption capacity when the pH level is between 2 and 6. The adsorption of phosphate by the CMIO@PP (1:3) accords with the Langmuir isotherm model, and the adsorption process follows the pseudo-second order model. Meanwhile, adsorption-desorption experiments show that the adsorbent could be recycled a few times and that a high removal efficiency of phosphate from civil wastewater was achieved. Finally, mechanisms show that the adsorption of phosphate by the CMIO@PP (1:3) is mainly caused by electrostatic attraction and ligand exchange.
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Fosfatos , Aguas Residuales , Adsorción , Cinética , ReciclajeRESUMEN
Angiostasis mediated by interferon (IFN)-γ is a key mechanism of anti-tumour immunity; however, the effect of IFN-γ on host vascular endothelial growth factor A (VEGFA)-expressing cells during tumour progression is still elusive. Here, we developed transgenic mice with IFN-γ receptor (IFNγR) expression under control of the Vegfa promoter (V-γR). In these mice, the IFN-γ responsiveness of VEGFA-expressing cells led to dramatic growth suppression of transplanted lung carcinoma cells. Surprisingly, increased mortality and tumour metastasis were observed in the tumour-bearing V-γR mice, in comparison with the control wild-type and IFNγR-deficient mice. Further study showed that perivascular cells were VEGFA-expressing cells and potential IFN-γ targets. In vivo, tumour vascular perfusion and pericyte association with blood vessels were massively disrupted in V-γR mice. In vitro, IFN-γ inhibited transforming growth factor-ß signalling by upregulating SMAD7, and therefore downregulated N-cadherin expression in pericytes. Importantly, IFN-γ neutralization in vivo with a monoclonal antibody reduced tumour metastasis. Together, the results suggest that IFNγR-mediated dissociation of perivascular cells from blood vessels contributes to the acceleration of tumour metastasis. Thus, the inhibition of tumour growth via IFN-γ-induced angiostasis might also accelerate tumour metastasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Neoplasias Pulmonares/fisiopatología , Receptores de Interferón/fisiología , Animales , Cadherinas/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo , Fibroblastos/metabolismo , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Metástasis de la Neoplasia , Trasplante de Neoplasias , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Pericitos/metabolismo , Receptores de Interferón/deficiencia , Receptores de Interferón/metabolismo , Proteína smad7/fisiología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Regulación hacia Arriba/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor de Interferón gammaRESUMEN
BACKGROUND/AIMS: Renal tubular epithelial-mesenchymal transition (EMT) is regarded as an important factor leading to renal interstitial fibrosis. Erythropoietin (EPO) has been reported to attenuate renal fibrosis. The mechanism underlying this protective effect of EPO remains unclear. In this study, we aim to identify possible mechanisms of the EPO renoprotective effect. METHODS: Hypoxia was induced in vitro by incubating human proximal tubular epithelial cell line HK-2 cells in 1% O2 and 5% CO2. Western blotting and reverse transcription polymerase chain reaction analyses were used to evaluate the expression of epithelial and mesenchymal markers in the cell samples. The expression of miR-200b in the HK-2 cells under hypoxia or treatment with EPO was examined. RESULTS: EPO represses hypoxia-induced EMT by upregulating miR-200b in HK-2 cells. Overexpression of miR-200b represses the effect of ETS proto-oncogene 1 (Ets-1)-induced EMT in HK-2 cells. CONCLUSION: miR-200 mediates the protective effects of EPO on EMT in hypoxic HK-2 cells. EPO attenuated hypoxia-induced EMT by increasing miR-200 expression via the repression of Ets-1.
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Hipoxia de la Célula , Transición Epitelial-Mesenquimal/efectos de los fármacos , Eritropoyetina/farmacología , MicroARNs/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Actinas/metabolismo , Antagomirs/metabolismo , Cadherinas/metabolismo , Línea Celular , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Microscopía Fluorescente , Proto-Oncogenes Mas , Proteína Proto-Oncogénica c-ets-1/metabolismo , Proteína smad7/metabolismoRESUMEN
The notion that animals can detect the Earth's magnetic field was once ridiculed, but is now well established. Yet the biological nature of such magnetosensing phenomenon remains unknown. Here, we report a putative magnetic receptor (Drosophila CG8198, here named MagR) and a multimeric magnetosensing rod-like protein complex, identified by theoretical postulation and genome-wide screening, and validated with cellular, biochemical, structural and biophysical methods. The magnetosensing complex consists of the identified putative magnetoreceptor and known magnetoreception-related photoreceptor cryptochromes (Cry), has the attributes of both Cry- and iron-based systems, and exhibits spontaneous alignment in magnetic fields, including that of the Earth. Such a protein complex may form the basis of magnetoreception in animals, and may lead to applications across multiple fields.
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Proteínas Hierro-Azufre/metabolismo , Magnetismo , Animales , Anticuerpos , Materiales Biocompatibles , Biofisica , Columbidae/metabolismo , Simulación por Computador , Drosophila melanogaster/metabolismo , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Proteínas Hierro-Azufre/genética , Microscopía Electrónica , Modelos Moleculares , Mutagénesis , Conformación Proteica , Transporte de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Retina/metabolismoRESUMEN
BACKGROUND AND AIMS: We aimed to investigate outcomes of pancreatic extracorporeal shock wave lithotripsy (P-ESWL) for the removal of large pancreatic stones coexisting with pancreatic pseudocysts (PPCs) in chronic pancreatitis (CP). METHODS: This is a prospective study performed in CP patients with at least 1 stone (≥5 mm). Patients were divided into the PPC group (stones coexisting with PPCs) or the control group (stones alone). Patients were initially subjected to successive P-ESWL treatments, followed by ERCP. Primary outcomes were P-ESWL adverse events, and secondary outcomes were stone clearance, long-term pain relief, improved quality-of-life scores, and PPC regression. RESULTS: A total of 849 patients (59 in the PPC group and 790 in the control group) was subjected to P-ESWL between March 2011 and October 2013. Occurrences of P-ESWL adverse events were similar between the PPC group and the control group (11.86% vs 12.41%, P = .940). After the treatment of initial P-ESWL combined with ERCP, the complete, partial, and nonclearance of stones occurred in 67.24%, 20.69%, and 12.07%, respectively, of patients in PPC group, with no significant difference from the control group (complete, partial, and nonclearance: 83.17%, 10.40%, and 11.39%, respectively; P = .106). Fifty-five of 59 patients (93.22%) with PPCs were followed for a median period of 21.9 months (range, 12.0-45.1). PPCs disappeared in 56.36% (31/55) and 76.36% (42/55) of patients after 3 months and 1 year of follow-up visits, respectively. Moreover, complete and partial pain relief were achieved in 63.64% (35/55) and 25.45% (14/55) of patients, respectively. The scores for quality of life (P < .001), physical health (P < .001), and weight loss (P < .001) improved. CONCLUSIONS: In our multispecialty tertiary center, initial P-ESWL followed by ERCP was safe in patients with coexisting pancreatic stones and PPCs and effective for stone clearance, main pancreatic duct drainage, and pain relief.
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Cálculos/terapia , Colangiopancreatografia Retrógrada Endoscópica/métodos , Seudoquiste Pancreático/cirugía , Pancreatitis Crónica/complicaciones , Adolescente , Adulto , Cálculos/diagnóstico por imagen , Cálculos/etiología , Estudios de Casos y Controles , Endosonografía , Femenino , Hemorragia/epidemiología , Humanos , Litotricia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades Pancreáticas/diagnóstico por imagen , Enfermedades Pancreáticas/etiología , Enfermedades Pancreáticas/terapia , Seudoquiste Pancreático/diagnóstico por imagen , Seudoquiste Pancreático/etiología , Pancreatitis/epidemiología , Complicaciones Posoperatorias/epidemiología , Estudios Prospectivos , Infección de la Herida Quirúrgica/epidemiología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
microRNAs (miRNAs), through negatively regulating their target genes, influence the development and progression of many cancers. Previously, we found miR-483 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues, and its overexpression was negatively correlated with the prognosis and positively correlated with multidrug resistance of ESCC, but whether it could affect the biological role of proliferation and migration in ESCC cell lines is unknown. In the present study, we found miR-483-3p was overexpressed in ESCC cell lines as compared with the normal esophageal squamous epithelial cell line. Functional experiments in vitro showed that miR-483-3p could promote the proliferation, migration, transformation of cell cycle from G1 phase to G2 phase of ESCC cells and could inhibit cells' sensitivity to chemotherapy drugs. Nude mouse tumorigenicity assay indicated that miR-483-3p could promote the growth of ESCC cells in vivo. Western blot assay showed that ectopic expression of miR-483-3p in ESCC cells could downregulate the protein level of etoposide induced 2.4 (EI24), which is a tumor suppressor and has not been reported in ESCC. Luciferase reporter assay demonstrated that EI24 was a direct target of miR-483-3p. Collectively, our study demonstrated that miR-483-3p could promote ESCC progression at least in part through directly targeting EI24, supplying a potential strategy for miRNA-based ESCC therapy.
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MicroARNs/metabolismo , Regiones no Traducidas 3' , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Secuencia de Bases , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/toxicidad , Regulación hacia Abajo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Puntos de Control de la Fase G1 del Ciclo Celular , Genes Reporteros , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligonucleótidos Antisentido/metabolismo , Alineación de Secuencia , Trasplante HeterólogoRESUMEN
BACKGROUND: Endothelial-to-mesenchymal transition (EndoMT) is a crucial event during kidney interstitial fibrosis and it is believed to be inhibited by netrin-1. Our aim was to determine the influence of netrin-1 on renal EndoMT in chronic kidney disease by studying its effect in 5/6 nephrectomized (Nx) rats. METHODS: Male Sprague-Dawley rats were divided into three groups (10 rats/group): sham-operated rats treated with control adenovirus; 5/6 Nx rats treated with control adenovirus; and 5/6 Nx rats treated with recombinant adenovirus expressing the netrin-1 gene (Ad-netrin-1). Rats were sacrificed 13 weeks after surgery. Blood urea nitrogen (BUN) and serum creatinine (Scr) levels were measured regularly after surgery. After the rats were sacrificed, pathological changes in renal tissues were analyzed histologically. Immunofluorescence was performed to evaluate the co-expression of CD31 and α-SMA. CD31, α-SMA and Snail mRNA were detected by RT-PCR. Protein expression was detected by western blot. RESULTS: Renal function and histopathological damage were significantly improved in Ad-netrin-1-treated 5/6 Nx rats. In the sham and control-treated 5/6 Nx rats, the percentage of CD31(+)/α-SMA(+) cells increased, which indicated EndoMT. However, the percentage of CD31(+)/α-SMA(+) cells were reduced in the netrin-1-treated 5/6 Nx rats, which indicates netrin-1-induced blocking of EndoMT. CONCLUSION: From the results, it seems that netrin-1 attenuates the progression of renal dysfunction by inhibiting EndoMT in 5/6 Nx rats. Netrin-1 can therefore be considered as a potential therapeutic agent for the treatment of renal fibrosis.
Asunto(s)
Endotelio/fisiopatología , Transición Epitelial-Mesenquimal , Riñón/patología , Netrina-1/genética , Netrina-1/metabolismo , ARN Mensajero/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Actinas/genética , Actinas/metabolismo , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Transición Epitelial-Mesenquimal/genética , Fibrosis , Masculino , Nefrectomía , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/patología , Transducción de Señal , Factores de Transcripción de la Familia Snail/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: In practice, small bowel cancer is a rare entity. The most common histologic subtype is adenocarcinoma. Adenocarcinoma of the small bowel (SBA) is challenging to diagnose, often presents at a late stage and has a poor prognosis. The treatment of early-stage SBA is surgical resection. No standard protocol has been established for unresectable or metastatic disease. CASE PRESENTATION: We report here on a 26-year-old man with SBA in the jejunum, lacking specific symptoms and with a delay of 6 months in diagnosis. The diagnosis was finally achieved with a combination of balloon-assisted enteroscopy, computed tomography scans, positron emission computed tomography scans and the values of carcino-embryonic antigen and carbohydrate antigen 19-9. The patient underwent segmental intestine with lymph node resection, followed by eight cycles of FOLFOX palliative chemotherapy with good tolerance. As of the 11-month postoperative follow-up, there has been no evidence of recurrent disease. CONCLUSIONS: This case is reported to arouse a clinical suspicion of SBA in patients with abdominal pain of unknown cause. We also provided evidence in this case of a response to palliative chemotherapy with FOLFOX. Because the incidence of SBA is very low, there is a need for further studies to evaluate the possible application of newer investigative agents and strategies to obtain a better outcome within the framework of international collaborations.