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The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth.
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Refractory temporal lobe epilepsy (TLE) is one of the most frequently observed subtypes of epilepsy and endangers more than 50 million people world-wide. Although electroencephalogram (EEG) had been widely recognized as a classic tool to screen and diagnose epilepsy, for many years it heavily relied on identifying epileptic discharges and epileptogenic zone localization, which however, limits the understanding of refractory epilepsy due to the network nature of this disease. This work hypothesizes that the microstate dynamics based on resting-state scalp EEG can offer an additional network depiction of the disease and provide potential complementary evaluation tool for the TLE even without detectable epileptic discharges on EEG. We propose a novel framework for EEG microstate spatial-temporal dynamics (EEG-MiSTD) analysis based on machine learning to comprehensively model millisecond-changing whole-brain network dynamics. With only 100 seconds of resting-state EEG even without epileptic discharges, this approach successfully distinguishes TLE patients from healthy controls and is related to the lateralization of epileptic focus. Besides, microstate temporal and spatial features are found to be widely related to clinical parameters, which further demonstrate that TLE is a network disease. A preliminary exploration suggests that the spatial topography is sensitive to the following surgical outcomes. From such a new perspective, our results suggest that spatiotemporal microstate dynamics is potentially a biomarker of the disease. The developed EEG-MiSTD framework can probably be considered as a general tool to examine dynamical brain network disruption in a user-friendly way for other types of epilepsy.
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Objective: The purpose of this systematic bioinformatics analysis was to describe the compositions and differences in submucosal microbial profiles of peri-implants' diseases and healthy implant. Material and methods: PubMed, Embase, ETH Z, Scopus, CNKI, and Wanfang databases were searched to screen relevant literature on the analysis of peri-implant microflora based on the sequencing analysis technique of 16S ribosomal RNA (16S rRNA) gene. High-throughput sequencing of the 16S rRNA gene of microorganisms from healthy implants, peri-implant mucositis, and peri-implantitis was downloaded from the screened articles. EasyAmplicon and Usearch global algorithm were used to match the reads from each dataset to a full length of 16S rRNA or ITS gene sequence. The microorganisms based on the Human Oral Microbiome Database (HOMD) were re-classified, and the microbial diversity, flora composition, and differential species of the samples were re-analyzed, including taxonomic classification and alpha and beta diversity calculations. The co-occurrence network was also re-analyzed. Results: A total of seven articles with 240 implants were included. Among them, 51 were healthy implants (HI), 43 were in the peri-implant mucositis (PM) group, and 146 were in the peri-implantitis (PI) group. A total of 26,483 OTUs were obtained, and 877 microorganisms were annotated. The alpha diversity including Chao1 (healthy implants, 121.04 ± 92.76; peri-implant mucositis, 128.21 ± 66.77; peri-implantitis, 131.15 ± 84.69) and Shannon (healthy implants, 3.25 ± 0.65; peri-implant mucositis, 3.73 ± 0.61; peri-implantitis, 3.53 ± 0.67) of the samples from the three groups showed a significant difference. The beta diversity of the three samples was statistically different among groups. The genera of Treponema and Fretibacterium were significantly more abundant in the PI group than in the other two groups, and the genus of Streptococcus was more abundant in the HI group. The relative abundance of Porphyromonas in the peri-implantitis group was 6.1%. The results of the co-occurrence network showed differences in the network topology among the three groups of samples. The most connected three genera in the healthy implants were Halomonas, Fusobacterium, and Fretibacterium. The most connected three genera in peri-implant mucositis were Alistipes, Clostridia UCG-014, and Candidatus Saccharimonas. The most connected three genera in the peri-implantitis group were Lachnoanaerobaculum, Fusobacterium, and Atopobium. The betweenness of Porphvromonas gingivalis (red complex) in the PI group (7,900) was higher than in the HI group (23). Conclusions: The community compositions of peri-implant submucosal microorganisms were significantly different in healthy implants, peri-implant mucositis, and peri-implantitis. The submucosal microbial communities in peri-implantitis were characterized by high species richness and diversity compared with the healthy implants; the relative abundance of red complex, some members of the yellow complex, and some novel periodontal pathogens was higher in the peri-implantitis and peri-implant mucositis groups than in the healthy implant group. The core flora of the co-occurrence network of healthy implants, peri-implant mucositis, and peri-implantitis varied considerably. The peri-implantitis site presented a relative disequilibrium microbial community, and Porphyromonas may play an important role in the co-occurrence network.
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Bacterias , Biología Computacional , Implantes Dentales , Microbiota , Periimplantitis , ARN Ribosómico 16S , Humanos , Periimplantitis/microbiología , ARN Ribosómico 16S/genética , Implantes Dentales/microbiología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Biología Computacional/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Estomatitis/microbiologíaRESUMEN
Mesenchymal stromal/stem cells (MSC) have emerged as a promising therapeutic avenue for treating autoimmune diseases, eliciting considerable interest and discussion regarding their underlying mechanisms. This study revealed the distinctive ability of human umbilical cord MSC to aggregate within the lymph nodes of mice afflicted with autoimmune diseases, but this phenomenon was not observed in healthy mice. The specific distribution is driven by the heightened expression of the CCL21-CCR7 axis in mice with autoimmune diseases, facilitating the targeted homing of MSC to the lymph nodes. Within the lymph nodes, MSC exhibit a remarkable capacity to modulate Th17 cell function, exerting a pronounced anti-inflammatory effect. Transplanted MSC stimulates the secretion of L-amino-acid oxidase (LAAO), a response triggered by elevated levels of tumor necrosis factor-α (TNF-α) in mice with autoimmune diseases through the NF-κB pathway. The presence of LAAO is indispensable for the efficacy of MSC, as it significantly contributes to the inhibition of Th17 cells. Furthermore, LAAO-derived indole-3-pyruvic acid (I3P) serves as a potent suppressor of Th17 cells by activating the aryl hydrocarbon receptor (AHR) pathway. These findings advance our understanding of the global immunomodulatory effects exerted by MSC, providing valuable information for optimizing therapeutic outcomes.
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L-Aminoácido Oxidasa , Ganglios Linfáticos , Células Madre Mesenquimatosas , Células Th17 , Animales , Células Madre Mesenquimatosas/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , L-Aminoácido Oxidasa/metabolismo , Ganglios Linfáticos/metabolismo , Ratones , Humanos , Ratones Endogámicos C57BL , Receptores CCR7/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , FN-kappa B/metabolismo , Trasplante de Células Madre Mesenquimatosas , Transducción de Señal , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Factor de Necrosis Tumoral alfa/metabolismo , Quimiocina CCL21/metabolismoRESUMEN
Based on the principle of cascade reaction, a fusion enzyme of dextransucrase and dextranase was designed without linker to catalyze the production of oligo-dextran with homogeneous molecular weight from sucrose in one catalytic step. Due to the different effects of temperature on the two components of the fusion enzyme, temperature served as the "toggle switch" for the catalytic efficiency of the two-level fusion enzyme, regulating the catalytic products of the fusion enzyme. Under optimal conditions, the fusion enzyme efficiently utilized 100 % of the sucrose, and the yield of oligo-dextran with a homogeneous molecular weight reached 70 %. The product has been purified and characterized. The probiotic potential of the product was evaluated by analyzing the growth of 10 probiotic species. Its cytotoxic and anti-inflammatory activities were also determined. The results showed that the long-chain oligo-dextran in this study had significantly better probiotic potential and anti-inflammatory activity compared to other oligosaccharides. This study provides a strategy for the application of oligo-dextran in the food and pharmaceutical industries.
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Dextranasa , Dextranos , Glucosiltransferasas , Temperatura , Dextranos/química , Dextranasa/metabolismo , Dextranasa/química , Dextranasa/genética , Glucosiltransferasas/metabolismo , Glucosiltransferasas/química , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Probióticos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Animales , Sacarosa/química , Sacarosa/metabolismo , Peso MolecularRESUMEN
Biomass-related airborne fine particulate matter (PM2.5) is an important risk factor for chronic obstructive pulmonary disease (COPD). Macrophage polarization has been reported to be involved in PM2.5-induced COPD, but the dynamic characteristics and underlying mechanism of this process remain unclear. Our study established a PM2.5-induced COPD mouse model and revealed that M2 macrophages predominantly presented after 4 and 6 months of PM2.5 exposure, during which a notable increase in MMP12 was observed. Single cell analysis of lung tissues from COPD patients and mice further revealed that M2 macrophages were the dominant macrophage subpopulation in COPD, with MMP12 being involved as a hub gene. In vitro experiments further demonstrated that PM2.5 induced M2 polarization and increased MMP12 expression. Moreover, we found that PM2.5 increased IL-4 expression, STAT6 phosphorylation and nuclear translocation. Nuclear pSTAT6 then bound to the MMP12 promoter region. Furthermore, the inhibition of STAT6 phosphorylation effectively abrogated the PM2.5-induced increase in MMP12. Using a coculture system, we observed a significantly reduced level of E-cadherin in alveolar epithelial cells cocultured with PM2.5-exposed macrophages, while the decrease in E-cadherin was reversed by the addition of an MMP12 inhibitor to the co-culture system. Taken together, these findings indicated that PM2.5 induced M2 macrophage polarization and MMP12 upregulation via the IL-4/STAT6 pathway, which resulted in alveolar epithelial barrier dysfunction and excessive extracellular matrix (ECM) degradation, and ultimately led to COPD progression. These findings may help to elucidate the role of macrophages in COPD, and suggest promising directions for potential therapeutic strategies.
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Interleucina-4 , Macrófagos , Metaloproteinasa 12 de la Matriz , Material Particulado , Enfermedad Pulmonar Obstructiva Crónica , Factor de Transcripción STAT6 , Regulación hacia Arriba , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Metaloproteinasa 12 de la Matriz/metabolismo , Animales , Material Particulado/toxicidad , Factor de Transcripción STAT6/metabolismo , Ratones , Macrófagos/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Contaminantes Atmosféricos/toxicidadRESUMEN
Background: Mild cognitive impairment (MCI) is a heterogeneous condition that can precede various forms of dementia, including Alzheimer's disease (AD). Identifying MCI subjects who are at high risk of progressing to AD is of major clinical relevance. Enlarged perivascular spaces (EPVS) on MRI are linked to cognitive decline, but their predictive value for MCI to AD progression is unclear. Objective: This study aims to assess the predictive value of EPVS for MCI to AD progression and develop a predictive model combining EPVS grading with clinical and laboratory data to estimate conversion risk. Methods: We analyzed 358 patients with MCI from the ADNI database, consisting of 177 MCI-AD converters and 181 non-converters. The data collected included demographic information, imaging data (including perivascular spaces grade), clinical assessments, and laboratory test results. Variable selection was conducted using the Least Absolute Shrinkage and Selection Operator (LASSO) method, followed by logistic regression to develop predictive model. Results: In the univariate logistic regression analysis, both moderate (ORâ=â5.54, 95% CI [3.04-10.18]) and severe (ORâ=â25.04, 95% CI [10.07-62.23]) enlargements of the centrum semiovale perivascular space (CSO-PVS) were found to be strong predictors of disease progression. LASSO analyses yielded 12 variables, refined to six in the final model: APOE4 genotype, ADAS11 score, CSO-PVS grade, and volumes of entorhinal, fusiform, and midtemporal regions, with an AUC of 0.956 in the training and 0.912 in the validation cohort. Conclusions: Our predictive model, emphasizing EPVS assessment, provides clinicians with a practical tool for early detection and management of AD risk in MCI patients.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Progresión de la Enfermedad , Sistema Glinfático , Imagen por Resonancia Magnética , Humanos , Disfunción Cognitiva/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Femenino , Masculino , Anciano , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/patología , Valor Predictivo de las Pruebas , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The performance of host immune responses biomarkers and clinical scores was compared to identify infection patient populations at risk of progression to sepsis, ICU admission and mortality. METHODS: Immune response biomarkers were measured and NEWS, SIRS, and MEWS. Logistic and Cox regression models were employed to evaluate the strength of association. RESULTS: IL-10 and NEWS had the strongest association with sepsis development, whereas IL-6 and CRP had the strongest association with ICU admission and in-hospital mortality. IL-6 [HR (95%CI) = 2.68 (1.61-4.46)] was associated with 28-day mortality. Patient subgroups with high IL-10 (≥ 5.03 pg/ml) and high NEWS (> 5 points) values had significantly higher rates of sepsis development (88.3% vs 61.1%; p < 0.001), in-hospital mortality (35.0% vs. 16.7%; p < 0.001), 28-day mortality (25.0% vs. 5.6%; p < 0.001), and ICU admission (66.7% vs. 38.9%; p < 0.001). CONCLUSIONS: Patients exhibiting low severity signs of infection but high IL-10 levels showed an elevated probability of developing sepsis. Combining IL-10 with the NEWS score provides a reliable tool for predicting the progression from infection to sepsis at an early stage. Utilizing IL-6 in the emergency room can help identify patients with low NEWS or SIRS scores.
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Biomarcadores , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Interleucina-10 , Interleucina-6 , Sepsis , Humanos , Sepsis/sangre , Sepsis/inmunología , Sepsis/mortalidad , Sepsis/diagnóstico , Biomarcadores/sangre , Masculino , Femenino , Persona de Mediana Edad , Interleucina-10/sangre , Anciano , Interleucina-6/sangre , Unidades de Cuidados Intensivos/estadística & datos numéricos , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Índice de Severidad de la Enfermedad , Pronóstico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/mortalidadRESUMEN
Chronic neuropathic pain has been one of the prominent causes of disability, and acupuncture has shown promise in treatment. The present study aimed to characterize acupuncture modulation of chronic neuropathic pain and explore the related functional brain changes. Sixty chronic sciatica patients were divided into acupuncture- or sham acupuncture groups and received 10 sessions of treatment during 4 weeks. The visual analog scale for leg pain, oswestry disability index (ODI), and resting-state functional magnetic resonance images were assessed at baseline and after treatment. Then, fractional amplitudes of low-frequency fluctuations (fALFF) and support vector regression analyses were performed. Compared with sham acupuncture, acupuncture significantly improved symptoms, including visual analog scale for leg pain and ODI. In addition, acupuncture exhibited increased fALFF of the right superior parietal lobule (SPL) and right postcentral gyrus. Furthermore, the actual 4-week ODI values were positively correlated with the support vector regression-predicted values based on the right SPL fALFF and baseline clinical measurements. These results indicate that the spontaneous neural activity of the right SPL and right postcentral gyrus may be involved in the modulation of acupuncture in chronic neuropathic pain. In addition, the spontaneous neural activity of the right SPL might be used as the predictor of response to acupuncture therapy. PERSPECTIVE: This clinical neuroimaging study elucidated the neural basis of acupuncture in chronic sciatica. Neurological indicators and clinical measurements could be used as potential predictors of acupuncture response. This study combines neuroimaging and artificial intelligence techniques to highlight the potential of acupuncture for the treatment of chronic neuropathic pain. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR2100044585, http://www.chictr.org.cn.
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BACKGROUND: Irreversible pulmonary fibrosis induced by paraquat is the most prevalent cause of death in patients with paraquat poisoning. Pulmonary fibrosis is characterized by abnormal deposition of extracellular matrix (ECM). Currently, the role of fibrotic ECM microenvironment in paraquat-induced pulmonary fibrosis has not been established. METHODS: Rat pulmonary fibrosis model was induced by paraquat, ATN-161 (an integrin-ß1 antagonist) was given to investigate their effect on Rat survival and pulmonary fibrosis. Lungs were decellularized to generate normal and fibrotic acellular ECM scaffolds using Triton and SDS. Fibroblasts were cocultured with ECM scaffolds to established 3D culture systems to investigate the relationship between fibrotic ECM and the differentiation of fibroblasts. Then we explored the effect of fibrotic ECM microenvironment systematically promoting on integrin-ß1/FAK/ERK1/2 pathway and established 3D culture systems to investigate the relationship between fibrotic ECM and the differentiation of fibroblasts. RESULTS: Antagonism of integrin-ß1 could alleviate paraquat-induced pulmonary fibrosis and ameliorate survival status of rats. Compared to normal ECM, fibrotic extracellular microenvironment promoted the differentiation of fibroblasts to myofibroblasts. Antagonism of integrin-ß1 could also ameliorate the promotion of fibrotic extracellular microenvironment on differentiation of fibroblasts to myofibroblasts. Fibrotic ECM microenvironment promotes fibroblasts transforming into myofibroblasts through integrin-ß1/FAK/ERK1/2 signaling pathway. Moreover, this phenomenon holds independent on exogenous integrin-ß1. CONCLUSIONS: Activation of integrin-ß1/FAK/ERK1/2 pathway aggravates paraquat-induced pulmonary fibrosis depend on fibrotic ECM and integrin-ß1 may be a prospective therapeutic target for paraquat-induced pulmonary fibrosis in the future.
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Matriz Extracelular , Fibroblastos , Integrina beta1 , Sistema de Señalización de MAP Quinasas , Paraquat , Fibrosis Pulmonar , Ratas Sprague-Dawley , Animales , Paraquat/toxicidad , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Matriz Extracelular/metabolismo , Masculino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Fibroblastos/metabolismo , Ratas , Integrina beta1/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinasa 1 de Adhesión Focal/metabolismo , Pulmón/patología , Pulmón/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Miofibroblastos/efectos de los fármacos , Células Cultivadas , Modelos Animales de EnfermedadRESUMEN
Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts.
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Bleomicina , Diferenciación Celular , Sistema Enzimático del Citocromo P-450 , Fibroblastos , Galectina 1 , Ratones Endogámicos C57BL , Miofibroblastos , Fibrosis Pulmonar , Animales , Miofibroblastos/metabolismo , Miofibroblastos/patología , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Ratones , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Galectina 1/metabolismo , Galectina 1/genética , Pulmón/patología , Pulmón/metabolismo , Masculino , Matriz Extracelular/metabolismo , Humanos , Transducción de Señal , Modelos Animales de Enfermedad , Células Cultivadas , Técnicas de CocultivoRESUMEN
BACKGROUND: In this study, we used immune repertoire (IR) sequencing technology to profile the diversity of peripheral blood T cell receptors and used transcriptomics to profile the gene expression of peripheral blood neutrophil mRNA in patients with mild-moderate knee osteoarthritis (KOA) before and after electroacupuncture (EA) treatment. METHODS: An 8-week intervention with EA was performed on 3 subjects with KOA. IR sequencing of complementarity determining region 3 (CDR3) was performed using RNA extracted from peripheral blood T cells of KOA subjects prior to and at the end of the intervention, as well as healthy volunteers (controls) who matched the subjects in sex and age. Neutrophils were extracted from the plasma of healthy individuals, pretreatment patients, and posttreatment patients for further transcriptome sequencing. RESULTS: The D50, diversity index (DI), and Shannon entropy values of circulatory T-cells were significantly lower in pretreatment KOA patients compared to healthy controls. Posttreatment KOA samples displayed significant decreases in serum proinflammatory factors, IL-8 and IL-18 (P < 0.01), as well as a substantial reduction in serum matrix MMP-3 and MMP-13 (P < 0.01, P < 0.05). Transcriptome analysis revealed that the expression of CXCL2, IRF8, and PEAR1 (P < 0.05) was significantly higher in patients before the treatment than in the healthy population and was significantly down-regulated after the treatment. In contrast, the expression of SMPD3 (P < 0.05) showed the opposite trend. CONCLUSION: EA may alleviate KOA by rebalancing T-cell homeostasis and improving systemic inflammation. At the same time, EA treatment can significantly enhance TCR diversity, reduce levels of proinflammatory factors, and increase levels of anti-inflammatory factors, thereby achieving therapeutic effects.
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BACKGROUND: Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects. METHODS: First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-ß1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD. RESULTS: The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-ß1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-ß1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis. CONCLUSIONS: MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-ß1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.
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Diferenciación Celular , Colitis , Ganglios Linfáticos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Linfocitos T Reguladores , Células Th17 , Factor de Crecimiento Transformador beta1 , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Humanos , Colitis/terapia , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Ganglios Linfáticos/metabolismo , Células Th17/metabolismo , Células Th17/inmunología , Cordón Umbilical/citología , Mesenterio/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos BALB C , Masculino , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patologíaRESUMEN
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.
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BACKGROUND: Aiming to measure and compare asymmetry of facial hard and soft tissues in patients with HFM and isolated microtia, examining how it evolves. METHODS: This cross-sectional study assessed facial asymmetry in male East Asian patients aged 5-12 diagnosed with unilateral hemifacial microsomia (Pruzansky-Kaban types I and IIA) or isolated microtia. Using 3D imaging of computed tomography scans, it measured root-mean-square (RMS) values for surface deviations across facial regions. Statistical analyses explored differences between conditions and the relationship of age with facial asymmetry. RESULTS: A total of 120 patients were categorized into four groups by condition (HFM or isolated microtia) and age (5-7 and 8-12 years). Patients with HFM exhibited the greatest asymmetry in the lower cheek, while those with isolated microtia showed primarily upper face asymmetry. Significant differences, except in the forehead and nasal soft tissue, were noted between the groups across age categories. Notable distinctions in hard tissue were found between age groups in the nasal and mid-cheek areas for patients with HFM (median RMS (mm) 0.9 vs. 1.1, P = 0.02; 1.5 vs. 1.7, P = 0.03) and in the nasal and upper lip areas for patients with isolated microtia (median RMS (mm) 0.8 vs. 0.9, P = 0.002; 0.8 vs. 1.0, P = 0.002). Besides these areas for HFM, no significant age-asymmetry correlation was detected. CONCLUSIONS: Significant differences in facial asymmetry were observed between HFM and isolated microtia, with the asymmetry in specific area evolving over time. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Background: The American College of Radiology (ACR) developed the contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) for pure blood contrast agents, but Sonazoid was not included. Modifications to LI-RADS have been proposed for Sonazoid. The purpose of this meta-analysis was to identify and compare the diagnostic efficacy of the two LI-RADS algorithms of Sonazoid. Methods: We searched the PubMed, MEDLINE, Web of Science, Embase, and Cochrane Library databases from databases inception to August 31, 2023, to find original studies on the ACR LI-RADS and/or modified LI-RADS algorithm with Sonazoid used as the contrast agent in patients with high-risk hepatocellular carcinoma (HCC). A bivariate random-effects model was used. Data pooling, meta-regression, and sensitivity analysis were performed for meta-analysis. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool was used to assess the methodological quality, and the Deeks funnel plot asymmetry test was used to evaluate the publication bias. Results: A meta-analysis of 10 studies with 1,611 observations was conducted. The pooled data for ACR LI-RADS category 5 (LR-5) and modified LR-5 were respectively as follows: pooled sensitivity, 0.70 [95% confidence interval (CI): 0.64-0.75] and 0.81 (95% CI: 0.76-0.86) (P<0.05); pooled specificity, 0.90 (95% CI: 0.82-0.94) and 0.87 (95% CI: 0.81-0.91) (P>0.05); and pooled area under the summary receiver operating characteristic curve, 0.84 and 0.91. The diagnostic performance of LI-RADS category M (LR-M) of the two algorithms was comparable. Study heterogeneity was observed. Conclusions: The results indicated that modified LR-5 algorithm demonstrated improved diagnostic sensitivity compared with the ACR LR-5 algorithm of Sonazoid, with differences observed between the different versions. Further research is needed to validate and explore the optimal diagnostic criteria for HCC using Sonazoid. Before the database search was conducted, this study was registered on PROSPERO (International Prospective Register of Systematic Reviews; CRD42023455220).
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Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by intrahepatic ectopic steatosis. Due to the increase in high-calorie diets and sedentary lifestyles, NAFLD has surpassed viral hepatitis and become the most prevalent chronic liver disease globally. Silibinin, a natural compound, has shown promising therapeutic potential for the treatment of liver diseases. Nevertheless, the ameliorative effects of silibinin on NAFLD have not been completely understood, and the underlying mechanism is elusive. Therefore, in this study, we used high-fat diet (HFD)-induced mice and free fatty acid (FFA)-stimulated HepG2 cells to investigate the efficacy of silibinin for the treatment of NAFLD and elucidate the underlying mechanisms. In vivo, silibinin showed significant efficacy in inhibiting adiposity, improving lipid profile levels, ameliorating hepatic histological aberrations, healing the intestinal epithelium, and restoring gut microbiota compositions. Furthermore, in vitro, silibinin effectively inhibited FFA-induced lipid accumulation in HepG2 cells. Mechanistically, we reveal that silibinin possesses the ability to ameliorate hepatic lipotoxicity by suppressing the heat shock protein 90 (Hsp90)/peroxisome proliferator-activated receptor-γ (PPARγ) pathway and alleviating gut dysfunction by inhibiting the Hsp90/NOD-like receptor pyrin domain-containing 3 (NLRP3) pathway. Altogether, our findings provide evidence that silibinin is a promising candidate for alleviating the "multiple-hit" in the progression of NAFLD.
RESUMEN
PURPOSE: To investigate the effect of Morinda officinalis polysaccharides(MOP) on the expression of fibronectin(FN) and fibronectin containing extra domain A(FN-EDA) in inflammatory periodontal ligament fibroblasts. METHODS: Thirty six rats were randomly divided into a control group(n=12) and a model group (n=24). The model group used orthodontic wire ligation to establish periodontitis. After three weeks, 6 rats from each group were selected and confirmed by Micro-CT to complete the modeling. The remaining rats in the model group were randomly divided into periodontitis group, normal saline(NS) group, and MOP group. In the MOP group, MOP (200 mg/kg for 3 d, 50 µL for 4 weeks) was injected into the palatal side of the left maxillary first molar of the rats. In the NS group, same volume of NS was injected, and no treatment was performed in the periodontitis group. The left maxillary tissue of rats were taken and the pathological changes of periodontal tissue were observed by H-E staining. The expression of FN and FN-EDA was detected by immunohistochemistry. Periodontal ligament fibroblasts were cultured in vitro, the effect of MOP on cell activity detected by CCK-8. The fourth generation cells were divided into control group, inflammation group (10 mg/mL lipopolysaccharide), and experimental group (12.5 µg/mL MOP, 12.5 µg/mL MOP+10 mg/mL lipopolysaccharide). The expression of FN and FN-EDA was detected by qRT-PCR and Western blot. The data were statistically analyzed using Prism 8.0 software package. RESULTS: In vivo experiments, the expression of FN-EDA in the MOP group was significantly lower than that in the periodontitis group and NS group(Pï¼0.05), and the infiltration of inflammatory cells was reduced. However, there was no significant difference in the expression of FN in each group. In vitro experiments, compared with the control group, the expression of FN-EDA mRNA and protein in the inflammation group was significantly increased(Pï¼0.000 1). MOP significantly reduced the expression of FN-EDA in inflammatory cells, but had no significant effect on FN expression. CONCLUSIONS: With increased expression of FN-EDA in inflammatory periodontal ligament tissues and cells, MOP may play a role in inhibiting inflammation by down-regulating FN-EDA.
Asunto(s)
Fibroblastos , Fibronectinas , Morinda , Ligamento Periodontal , Polisacáridos , Animales , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Polisacáridos/farmacología , Ligamento Periodontal/efectos de los fármacos , Ligamento Periodontal/metabolismo , Ligamento Periodontal/citología , Ratas , Morinda/química , Fibronectinas/metabolismo , Fibronectinas/genética , Periodontitis/tratamiento farmacológico , Periodontitis/metabolismo , Inflamación/tratamiento farmacológico , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/ß-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application. RESULTS: The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest. CONCLUSIONS: The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization.