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Aim: To investigate the association between plasma AAT level and glaucoma. Methods: 163 glaucoma patients and 111 healthy controls were recruited. The plasma AAT levels were measured by ELISA. Results: Plasma AAT level was significantly higher in glaucoma patients than those in healthy controls (p < 0.001). Patients with higher plasma AAT level exhibited severer disease stage (early vs. severe: p < 0.05; H-P-A; early vs. severe: p < 0.05; early vs. end-stage: p < 0.01; AGIS). ROC curves yielded that AAT can distinguish patients with early glaucoma from those with advanced glaucoma (early vs. severe: AUC: 0.616; H-P-A; early vs. severe: AUC: 0.763; early vs. end-stage: AUC: 0.660; AGIS). Conclusion: Plasma AAT is a useful biomarker for the identification of glaucoma severity.
[Box: see text].
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The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients' quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.
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Enfermedades Cardiovasculares , Lipoproteínas , Triglicéridos , Humanos , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/etiología , Lipoproteínas/metabolismo , Triglicéridos/metabolismo , Triglicéridos/sangre , Aterosclerosis/metabolismo , Animales , Dislipidemias/metabolismo , Factores de RiesgoRESUMEN
(-)-Epigallocatechin-3-gallate (EGCG) is remarkably efficacious in inhibiting the browning of red meat. We therefore propose a hypothesis that EGCG forms complexes with myoglobin, thereby stabilizing its structure and thus preventing browning. This study investigated the interaction mechanism between EGCG and myoglobin. EGCG induced static quenching of myoglobin. Noncovalent forces, including hydrogen bonds and van der Waals, primarily governing the interactions between myoglobin and EGCG. The interactions primarily disrupted myoglobin's secondary structure, thus significantly reducing surface hydrophobicity by 53% (P < 0.05). The modification augmented the solubility and thermal stability of myoglobin. The radius of gyration (Rg) value fluctuated between 1.47 and 1.54 nm, and the hydroxyl groups in EGCG formed an average of 2.93 hydrogen bonds with myoglobin. Our findings elucidated the formation of stable myoglobin-EGCG complexes and the myoglobin-EGCG interaction, thus confirming our initial hypothesis.
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Catequina , Catequina/análogos & derivados , Interacciones Hidrofóbicas e Hidrofílicas , Mioglobina , Mioglobina/química , Catequina/química , Enlace de Hidrógeno , Animales , Unión ProteicaRESUMEN
The present study investigated the impact of plasma-activated water (PAW), slightly acidic electrolytic water (SAEW) and plasma-activated slightly acidic electrolytic water (PASW) treatment on myofibrillar protein (MP) in salmon fillets. Additionally, the interaction mechanism between myosin and reactive oxygen species was explored by molecular docking. Compared with the control group (719.26 nm), PASW treatment group exhibited the smallest particle size (408.97 nm). The PASW treatment exhibited efficacy in reducing MP aggregation and inhibiting protein oxidation. In comparison with other treatments, PASW treatment demonstrated a greater ability to mitigate damage to the secondary and tertiary structures of MP. O3 and H2O2 interact with myosin through hydrogen bonding. Specifically, O3 interacts with Lys676, Gly677, and Met678 of myosin while H2O2 binds to Thr681, Asp626, Arg680, and Met678. This study offers novel insights into the impact of PASW on MP, and provides a theoretical foundation for its application in aquatic product processing.
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OBJECTIVES: To understand the status quo and related influencing factors of machine alarm fatigue of hemodialysis nurses in tertiary hospitals in Liaoning Province. METHODS: This cross-sectional study employed convenience sampling to select 460 nurses from 29 tertiary hospitals in Liaoning Province, who are involved in hemodialysis care. Surveys were conducted using the General Information Questionnaire, Alarm Fatigue Scale, National Aeronautics and Space Administration Task Load Index, and Maslach Burnout Inventory Scale. RESULTS: The overall machine alarm fatigue score for 460 hemodialysis nurses from 29 tertiary hospitals in Liaoning Province was 17.04 ± 3.21, indicating a moderate level. The multiple linear regression analysis shows that years of experience in hemodialysis nursing, the number of patients managed per shift, whether specialized nursing training has been received, self-reported health status, emotional exhaustion, and workload have statistically significant associations with alarm fatigue among hemodialysis nurses (p < 0.05). Among them, the years of experience in hemodialysis nursing are negatively correlated with alarm fatigue among hemodialysis nurses, whereas the number of patients managed per shift and workload are positively correlated with alarm fatigue among hemodialysis nurses. CONCLUSION: This study indicates that certain demographic factors, workload, and occupational burnout are associated with machine alarm fatigue among hemodialysis nurses. Therefore, hemodialysis-related managers should establish a Machine Alarm Management System, implement Personalized Thresholds and Delayed Alarms, ensure reasonable staffing arrangements, improve compassion fatigue, and enhance anticipatory care. Our findings have implications for improving the health and well-being of hemodialysis nurses, providing a conducive environment for professional training in hemodialysis, and ultimately addressing the current situation of machine alarm fatigue among hemodialysis nurses.
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Alarmas Clínicas , Enfermeras y Enfermeros , Diálisis Renal , Centros de Atención Terciaria , Humanos , Alarmas Clínicas/estadística & datos numéricos , Femenino , Adulto , Masculino , Enfermeras y Enfermeros/estadística & datos numéricos , Agotamiento Profesional , Estudios Transversales , Persona de Mediana Edad , Carga de TrabajoRESUMEN
Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.
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Glaucoma , Células Ganglionares de la Retina , Humanos , Ratones , Animales , Células Ganglionares de la Retina/patología , Molécula 1 de Adhesión Celular Vascular/metabolismo , Células TH1/patología , Glaucoma/metabolismo , Retina/patología , Trastornos de la Visión/patología , Modelos Animales de EnfermedadRESUMEN
This study focused on non-covalent complex of myoglobin-chlorogenic acid (Mb-CA) and the changes in conformation, oxidation, and microstructure induced by varying concentrations of CA (10-40 µmol/g Mb). Employing molecular docking and dynamics simulations, further insights into the interaction between Mb and CA were obtained. The findings revealed that different CA concentrations enhanced Mb's thermal stability, while diminishing particle size, solubility, and relative content of metmyoglobin (MetMb%). The optimal interaction occurred at 40 µmol/g Mb. Furthermore, CA exhibited static quenching of Mb, with thermodynamic analysis confirming a 1:1 complex formation. These insights deepen our understanding of interaction between Mb and CA, providing valuable clarity.
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Ácido Clorogénico , Mioglobina , Mioglobina/química , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Metamioglobina/químicaRESUMEN
ATG4B is a core protein and essential for cleaving precursor MAP1LC3/LC3 or deconjugating lipidated LC3-II to drive the formation of autophagosomes. The protein stability and activity of ATG4B regulated by post-translational modification (ubiquitination) will directly affect macroautophagy/autophagy. However, the mechanism involved in ATG4B ubiquitination is largely unclear. In this study, a new E3 ligase of ATG4B, UBE3C, was identified by mass spectra. UBE3C mainly assembles K33-branched ubiquitin chains on ATG4B at Lys119 without causing ATG4B degradation. In addition, the increased ubiquitination of ATG4B caused by UBE3C overexpression inhibits autophagy flux in both normal and starvation conditions, which might be due to the reduced activity of ATG4B and ATG4B-LC3 interaction. This reduction could be reversed once the lysine 119 of ATG4B was mutated to arginine. More important, under starvation conditions the interaction between ATG4B and UBE3C apparently decreased followed by the removal of the K33-branched ubiquitin chain of ATG4B. Thus, starvation-induced autophagy could be partially suppressed by an increased ubiquitination level of ATG4B. In conclusion, our research reveals a novel modification mode of ATG4B in which UBE3C can fine tune ATG4B activity by specific ubiquitination regulating autophagy without causing ATG4B degradation.Abbreviation: ATG: autophagy-related; Baf: bafilomycin A1; CBB: Coomassie Brilliant Blue; CM: complete medium; CQ: chloroquine; GFP: green fluorescent protein; HA-Ub: HA-tagged ubiquitin; IF: immunofluorescence; IP: immunoprecipitation; K: lysine; KO: knockout; K0: all K-to-R mutant; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MS: mass spectrometry; NC: negative control; R: arginine; WCL: whole cell lysate; WT: wild-type.
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Autofagia , Lisina , Autofagia/fisiología , Lisina/metabolismo , Ubiquitinación , Ubiquitina/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Arginina/metabolismoRESUMEN
Dexamethasone (Dex) is a type of glucocorticoid drug. Long term use can induce growth plate chondrocytes (GPCs) apoptosis, impair differentiation, and inhibit cell proliferation and bone growth. It has been reported that Krüppel-like factor 2 (KLF2) inhibits osteoblast damage induced by Dex, but the role in Dex-induced GPCs remains unclear. Dex was used to construct a model of growth plate injury in vitro. CCK-8 and TUNEL kits were used to determine cell viability and apoptosis. A model of growth plate injury was established by intraperitoneal injection of Dex. Immunohistochemistry was used to investigate the expression of KLF2 in rats. The results showed that KLF2 expression of rat tibial GPCs was down-regulated after Dex stimulation. Overexpression of KLF2 promoted cell viability and cell cycle, while inhibited apoptosis of growth plate Dex-induced chondrocytes. Moreover, KLF2 inhibited Runx2-mediated PI3K/AKT and ERK signalling pathways. And PI3K/AKT and ERK signalling pathways, which were involved in the regulation of KLF2 on GPCs. Further studies showed that KLF2 alleviated growth plate injury in vivo. In conclusion, our study found that KLF2 promoted proliferation and inhibited apoptosis of Dex-induced GPCs by targeting the Runx2-mediated PI3K/AKT and ERK signalling pathways.
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Condrocitos , Fracturas de Salter-Harris , Ratas , Animales , Condrocitos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Placa de Crecimiento/metabolismo , Fracturas de Salter-Harris/metabolismo , Dexametasona/efectos adversos , Factores de Transcripción/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismoRESUMEN
Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children. Activated platelets predispose patients to coronary artery structural lesions that may lead to thrombotic cardiovascular events. To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay of 34 cytokines and discovered thymic stromal lymphopoietin (TSLP) was aberrantly expressed, which remained elevated after intravenous immunoglobulin G (IVIG) treatment and during convalescence in KD patients in comparison to healthy controls. Enzyme-linked immunosorbent assay (ELISA) corroborated the upregulation of TSLP in KD patients, which was exacerbated in convalescent patients complicated with thrombosis. TSLP receptors on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in convalescence KD patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy in healthy blood donors, as observed in KD patients. TSLP, similar to mitophagy agonist carbonyl cyanide 3-chlorophenyl hydrazone (CCCP), promoted thrombosis, which was attenuated by the mitophagy inhibitor Mdivi-1. Co-immunoprecipitation in TSLP-treated platelets revealed TSLP receptor (TSLPR) bound to mitophagy regulators, Parkin and Voltage Dependent Anion Channel Protein 1 (VDAC1).Thus, our results demonstrated that TSLP induced platelet mitophagy via a novel TSLPR/Parkin/VDAC1 pathway that promoted thrombosis in KD. These results suggest TSLP as a novel therapeutic target against KD-associated thrombosis.
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Plaquetas , Síndrome Mucocutáneo Linfonodular , Lactante , Niño , Humanos , Plaquetas/metabolismo , Linfopoyetina del Estroma Tímico , Mitofagia , Síndrome Mucocutáneo Linfonodular/terapia , Convalecencia , Citocinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
INTRODUCTION: It has been reported that people seeking bariatric surgery have poor health-related quality of life (HRQoL). Weight bias internalization (WBI) is prevalent in this population and strongly associated with psychopathology and health status. However, the psychological mechanisms underlying the relationship between WBI and the physical and mental dimensions of HRQoL remain to be clarified. METHODS: A preoperative sample of patients with obesity (N = 246; women = 75.2%; Mage = 32.07) completed validated measures as part of a routine preoperative psychological assessment to assess their WBI, self-esteem, anxiety symptoms, depressive symptoms, and HRQoL. RESULTS: After controlling for the effects of gender, age, and BMI, WBI was linked to poorer physical and mental HRQoL through low self-esteem and increased psychological distress, including anxiety and depressive symptoms. CONCLUSION: In pre-bariatric surgery patients with obesity, high WBI may predict impairments in mental and physical HRQoL by lowering self-esteem, and further increasing anxiety and depressive symptoms. Interventions targeting WBI may be an important aspect to consider in the clinical treatment of pre-bariatric surgery patients. Further longitudinal studies are warranted to determine causality.
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Cirugía Bariátrica , Obesidad Mórbida , Prejuicio de Peso , Humanos , Femenino , Adulto , Calidad de Vida/psicología , Obesidad Mórbida/cirugía , Cirugía Bariátrica/psicología , Obesidad/cirugía , Obesidad/psicología , Trastornos de AnsiedadRESUMEN
Background: In early-stage breast cancer (BC) patients, 40-70% of lymph node metastases are limited to the sentinel lymph nodes (SLNs). Patients at low risk for nonsentinel lymph node (NSLN) metastasis should be exempt from axillary lymph node dissection (ALND) or regional lymph node radiotherapy (RNI). Methods: The present study included 237 female early-stage BC patients with positive SLNs who received ALND. Based on the clinicopathological factors of the 158 patients in the training cohort, multivariate analysis was used to determine the independent risk factors for NSLN metastasis, which were used to establish the NSLN metastasis prediction model. The calibration and discrimination of this model were tested with the training and validation cohorts and compared to the Memorial Sloan Kettering Cancer Center (MSKCC) model. Results: Tumor size, neural invasion, lymphovascular invasion, expression of matrix metalloproteinase 15 (MMP15) in the cytoplasm, and the number of positive SLNs were statistically significant by multivariate analysis (P < 0.05), which were used to establish the new model. The MSKCC model was verified by the training cohort, and the area under the receiver-operating characteristic (ROC) curve was 0.733 (95% CI: 0.650-0.816), which was less than that of the new model (0.824; 95% CI: 0.760-0.889). The area under the ROC curve in the validation cohort for the new model was 0.773 (95% CI: 0.669-0.877), and the calibration performed well. The false-negative rates were 3.2%, 6.5%, and 14.5% for the predicted probability cut-offs of 50%, 60%, and 70%, respectively. Conclusions: The new model included five variables: tumor size, neural invasion, lymphovascular invasion, cytoplasmic MMP15 expression, and the number of positive SLNs. The model with a cut-off of 60% could accurately identify low-risk patients with NSLN metastasis.
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Purpose: This study examined the importance of hematological parameters as prognostic markers for people with esophageal cancer receiving radical concurrent chemoradiation. Methods: 106 patients with esophageal cancer are included in this study. Cox regression analysis, Kaplan-Meier method, and chi-square test were used to analyze our data. Results: The median follow-up time for patients was 15.5 months (3-55). Univariate and multivariate analyses showed that age, the change of platelet-to-lymphocyte ratio (ΔPLR), and the change rate of circulating lymphocyte count (ΔCLC%) were independent influencing factors of OS and DFS. The patients were grouped according to the median of ΔPLR and ΔCLC%, and analysis showed that a higher ΔPLR and a higher ΔCLC% was related to poor OS and DFS (P < 0.001, P < 0.001 and P < 0.001, P < 0.001). By subgroup analysis, the OS of T1-4N1-2 were better in the low ΔPLR group than the high one (P = 0.03, P < 0.001, P = 0.001, P < 0.001, and P = 0.008). DFS of T3-4N1-2 in the low ΔPLR group were better than the high one (P < 0.001, P = 0.016 and P < 0.001, P = 0.022). For patients with T1-4N0-2, the OS in the low ΔCLC% group were better than in the high ΔCLC% group (P = 0.01, P < 0.001, P < 0.002, P = 0.012, P < 0.001, and P = 0.024). For T1-4N1-2, the DFS were better in the low ΔCLC% group than others (P = 0.042, P < 0.001, P < 0.001, P < 0.001, and P = 0.006). Conclusion: ΔPLR and ΔCLC% are independent factors of OS and DFS, and a lower ΔPLR and ΔCLC% are associated with a better OS and DFS. And T3-4N1-2 patients in the low ΔPLR group and low ΔCLC% group have greater survival benefit.
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MicroRNAs (miRNAs) are considered important in the pathogenesis of colon cancer. But the mechanism of their role in colon cancer is still largely unknown. Here, we aimed to explore the function of miR-503-5p in the pathogenesis of colon cancer. This study analyzed miRNA microarray of colon cancer. Then, we performed EdU, CCK-8, flow cytometry, Transwell invasion assays and in vivo assays to explore the exact role of miR-503-5p in colon cancer. We observed considerable downregulation of miR-503-5p expression in colon cancer cells and tissues and significant correlation with the TNM stage, differentiation grade and lymph node metastasis of colon cancer. Overexpression of miR-503-5p promoted the apoptosis and G1 arrest of colon cancer cells, and inhibited migration, proliferation, invasion and colony formation. Interestingly, ectopic miR-503-5p overexpression could significantly inhibit vascular endothelial growth factor (VEGF)-A expression and reduce the activity of a luciferase reporter containing the VEGF-A 3'-untranslated region. Furthermore, overexpressed miR-503-5p in human umbilical vein endothelial cells (HUVECs) and colon cancer cells resulted in lower expression levels of VEGFR-2, and subsequently inhibited AKT signaling pathway. Additionally, overexpression of miR-503-5p suppressed both lymphangiogenesis and angiogenesis in vivo and significantly inhibited the tumorigenicity of HT-29 cells in nude mice. In summary, our study shows downregulation of miR-503-5p at least partially contributes to the tumorigenesis of colon cancer through modulating the angiogenesis and lymphangiogenesis by targeting VEGF-A while stimulating AKT signaling pathways. Therapeutic strategies to restore miR-503-5p in colon cancer could be useful to inhibit tumor progression.
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Neoplasias del Colon , MicroARNs/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Células Endoteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Linfangiogénesis , Ratones , Ratones Desnudos , MicroARNs/genética , Neovascularización Patológica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
PURPOSE: To evaluate the prognosis of estrogen receptor-positive breast cancer patients with CYP2D6*10 mutant genotypes under tamoxifen or toremifen therapy. METHODS: Estrogen receptor-positive breast cancer patients were selected and CYP2D6*10 genotypes (C/C, C/T, and T/T) were determined by Sanger sequencing. Patients were divided into tamoxifen, toremifene, or tamoxifen + toremifene groups according to prior therapy. The correlation between CYP2D6*10 genotype and disease-free survival was analyzed. RESULTS: In total, 293 estrogen receptor-positive breast cancer patients treated with tamoxifen or toremifene between 2008 and 2017 were studied. Median follow-up was 39 months (10-141). Of these, 107 (36.52%), 112 (38.23%), and 74 (25.26%) patients had C/C, C/T, and T/T genotypes, respectively. Genotype was significantly associated with disease-free survival in tamoxifen patients. Patients with C/T and T/T genotypes showed worse disease-free survival than patients with a C/C genotype. Genotype and disease-free survival in toremifene and tamoxifen+toremifene patients were not correlated. Of patients with a C/T genotype, toremifene or tamoxifen+toremifene groups showed better disease-free survival than tamoxifen patients. Although disease-free survival of patients with a T/T genotype in the three groups was not statistically different, tamoxifen patients showed worse disease-free survival. There was no correlation between different treatments and disease-free survival in patients with a C/C genotype. Cox proportional hazard analysis revealed toremifene patients had a better prognosis than tamoxifen patients; toremifene was an independent protective factoremifene for disease-free survival. CONCLUSIONS: Tamoxifen was less effective in patients with CYP2D6*10 C/T and T/T genotypes. Estrogen receptor-positive breast cancer patients with a CYP2D6*10 mutation genotype have a better prognosis with toremifen than tamoxifen.
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Neoplasias de la Mama , Tamoxifeno , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , China , Citocromo P-450 CYP2D6/genética , Femenino , Genotipo , Humanos , Pronóstico , Receptores de Estrógenos/uso terapéutico , Tamoxifeno/uso terapéutico , Toremifeno/uso terapéuticoRESUMEN
Objectives: Psoriasis is a common chronic recurrent dermatitis. Accumulating observations show gut microbiota dysbiosis in psoriasis. We intend to further investigate the relationship between intestinal microbiota and psoriasis development. Design: We first performed an epidemiological investigation on differences of gastrointestinal discomfort symptoms between patients with psoriasis and general population. Then variation of gut microbiota in patients with psoriasis (un)treated with acitretin plus narrow-band ultraviolet B (NB-UVB) was analyzed by 16S rRNA sequencing. We last compared recovery status and vital cytokines (lesion and intestine) of mouse psoriasiform models, which were transplanted with fecal microbiota from patients with psoriasis or healthy controls. Results: (1) About 85.5% of patients with psoriasis vs. 58.1% of healthy controls presented with at least one gastrointestinal symptom. The prevalence of investigated symptoms (e.g., abdominal distension and constipation) were significantly higher in patients, compared with controls (p < 0.05). Passing flatus and constipation were significantly correlated with psoriasis (p < 0.05 in both cases). (2) The abundance of Ruminococcaceae family, Coprococcus_1 genus, and Blautia genus were decreased with psoriasis improvement (p < 0.05, respectively), which had been demonstrated significantly increased in psoriasis. (3) Mice receiving psoriatic microbes transplantation showed delayed recovery of psoriasiform dermatitis and less reduction of interleukin (IL)-17A than those receiving healthy microbiota or blank control (p < 0.05 and p < 0.01, respectively). Conclusion: Multiple evidence we provided here preliminarily demonstrates the involvement of gut microbiota in the different degree of psoriasis activity. The strategy based on overall microbial communities is expected to be a promising supplementary for long-term management of psoriasis.
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Trained immunity, induced by ß-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR-9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that ß-glucan-trained miR-9-5p-/- monocytes showed decreased IL-1ß, IL-6, and TNF-α production after LPS stimulation. Trained miR-9-5p-/- mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR-9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR-9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. ß-Glucan-trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR-9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity.
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Epigénesis Genética/genética , Inmunidad Innata/genética , Memoria Inmunológica/genética , Isocitrato Deshidrogenasa/metabolismo , Redes y Vías Metabólicas/genética , MicroARNs/genética , Monocitos/metabolismo , Animales , Candida albicans , Candidiasis/genética , Candidiasis/inmunología , Epigénesis Genética/inmunología , Fumaratos/metabolismo , Glucólisis/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunidad Innata/inmunología , Memoria Inmunológica/inmunología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ácidos Cetoglutáricos/metabolismo , Lipopolisacáridos/farmacología , Redes y Vías Metabólicas/inmunología , Ratones , Ratones Noqueados , MicroARNs/metabolismo , Monocitos/efectos de los fármacos , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Ácido Succínico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , beta-Glucanos/inmunologíaRESUMEN
Owing to the serious threat of aflatoxin B1 (AFB1) to public health, development of a reliable method for accurate determination of it is extremely necessary and urgent. In this study, a simple, rapid and highly-sensitive quantum dot nanobeads (QBs) based lateral flow fluorescent strip immunosensor was developed for on-site detection of AFB1 in edible and medicinal lotus seeds. Carboxylated QBs were used as the fluorescent markers to prepare the fluorescent probe through coupling QBs with anti-AFB1 antibodies. Bovine serum albumin (BSA)-AFB1 antigens and goat anti-mouse IgG antibodies were coated on the nitrocellulose (NC) membrane to prepare the test (T) and control (C) lines, respectively. Qualitative analysis of AFB1 was realized by naked eye, and the quantitative determination was achieved with a portable strip reader. Results showed that the newly-developed test strip sensor could achieve rapid detection of AFB1 within 15 min, allowing a limit of detection (LOD) of 1 ng/mL (2 µg/kg) and a linear range of 1-19 ng/mL (2-38 µg/kg). Recovery rates from the fortified lotus seeds with low, medium and high spiking concentrations (2.5, 5 and 10 µg/kg) ranged from 94.0% to 116.0% with relative standard deviations less than 10%. All the results were confirmed by a standard LC-MS/MS method. The QBs-based fluorescent strip immunosensor with high sensitivity, easy operation, and low cost provided a preferred solution for rapid, on-site screening and highly-sensitive quantitation of AFB1 in a large number of lotus seed samples.
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Aflatoxina B1/análisis , Lotus/química , Nanoestructuras/química , Puntos Cuánticos , Aflatoxina B1/química , Técnicas Biosensibles , Colorantes Fluorescentes/análisis , Inmunoensayo , Límite de Detección , Semillas/química , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: The involvement of the nerve in psoriasis development was suggested by sporadic case reports. OBJECTIVES: To provide multiple evidence for the nerve in psoriasis development with a retrospective case review, a literature review and a mouse-based experimental experiment. METHODS: Psoriatic patients who had concomitant nerve injuries and such cases from literatures were reviewed. And, on wild-type mouse level, unilateral denervation surgery was performed on the dorsal skin before and after the induction of psoriasiform dermatitis, respectively. Lesion visual scores were calculated, and biopsies were taken for hematoxylin-eosin (HE) staining, immunofluorescence analysis, and RNA sequencing & bioinformatics analysis before denervation surgery and the 2nd, 4th, 6th, 8th day after the surgery. RESULTS: All clinical cases (20/20) showed that local lesions under the control of injured nerves relieved spontaneously or even cleared/spared, and only about 1/3 experienced partial recurrence. Next, mouse psoriasiform experiments demonstrated that unilateral denervation prior to imiquimod application attenuated the enhancement of inflammatory reactions (e.g. adaptive immune response and Th17 cell differentiation pathway) and the induction of ipsilateral psoriasiform dermatitis. On the other hand, unilateral denervation after psoriasiform dermatitis induction promoted the regression of inflammatory reactions (e.g. T cell activation, TNF signaling, and Th17 cell differentiation pathway) and ipsilateral dermatitis recovery. CONCLUSION: Our study based on both retrospective clinical case review and wild-type mouse experiments provides multiple evidence for the involvement of the nerve in psoriasis development. Regulation of immune events, including TNF signaling and Th17 cell differentiation, may be the mechanisms of the nerve in psoriasis.