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Immune-related skin diseases represent a collective of dermatological disorders intricately linked to dysfunctional immune system processes. These conditions are primarily characterized by an immoderate activation of the immune system or deviant immune responses, involving diverse immune components including immune cells, antibodies, and inflammatory mediators. However, the precise molecular dysregulation underlying numerous individual cases of these diseases and unique subsets respond under disease conditions remains elusive. Comprehending the mechanisms and determinants governing the homeostasis and functionality of diseases could offer potential therapeutic opportunities for intervention. Mass cytometry enables precise and high-throughput quantitative measurement of proteins within individual cells by utilizing antibodies labeled with rare heavy metal isotopes. Imaging mass cytometry employs mass spectrometry to obtain spatial information on cell-to-cell interactions within tissue sections, simultaneously utilizing more than 40 markers. The application of single-cell mass cytometry presents a unique opportunity to conduct highly multiplexed analysis at the single-cell level, thereby revolutionizing our understanding of cell population heterogeneity and hierarchy, cellular states, multiplexed signaling pathways, proteolysis products, and mRNA transcripts specifically in the context of many autoimmune diseases. This information holds the potential to offer novel approaches for the diagnosis, prognostic assessment, and monitoring responses to treatment, thereby enriching our strategies in managing the respective conditions. This review summarizes the present-day utilization of single-cell mass cytometry in studying immune-related skin diseases, highlighting its advantages and limitations. This technique will become increasingly prevalent in conducting extensive investigations into these disorders, ultimately yielding significant contributions to their accurate diagnosis and efficacious therapeutic interventions.
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Espectrometría de Masas , Análisis de la Célula Individual , Enfermedades de la Piel , Humanos , Análisis de la Célula Individual/métodos , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/diagnóstico , Espectrometría de Masas/métodos , Animales , Citometría de Flujo/métodos , BiomarcadoresRESUMEN
BACKGROUND/OBJECTIVES: Ultrasonography is a new method for subjective and qualitative assessment of true vocal fold movement, and true vocal fold visualization with the lateral approach could be better than that with the anterior approach. Our aim was to explore the feasibility of lateral-approach ultrasonography in objective and quantitative assessment of true vocal fold movement. METHODS: The lateral-approach laryngeal ultrasonography was performed during calm breathing and breath-holding on young healthy adult volunteers in Shanghai, China. The morphology and anatomical position of false vocal fold, true vocal fold, and arytenoid cartilage were observed and measured through the ultrasonic self-contained measurement function. All parameters, including the distance from false vocal fold to thyroid cartilage lamina, true vocal fold length, and the distance from true vocal fold to thyroid cartilage lamina, were obtained at the end of the calm inspiratory and breath-holding phases. Data were analyzed using a t test (P < 0.05). RESULTS: Forty healthy adult volunteers (age 20 to 34 years, body mass index 19.5 to 23.8 kg/m2, 20 males and 20 females) with satisfactory ultrasonic images were included in the study. There were no significant differences in all laryngeal parameters between the left and right sides in either phase (P > 0.05). From the end of the calm inspiratory phase to the breath-holding phase, changes in all laryngeal parameters were significantly different (P < 0.05), regardless of gender. CONCLUSIONS: This study demonstrated that the lateral-approach laryngeal ultrasonography seemed feasible to quantify and objectively assess true vocal fold movement, utilizing differences between laryngeal parameters before and after true vocal fold movement.
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Psoriasis is a chronic and recurrent inflammatory skin disorder. The primary manifestation of psoriasis arises from disturbances in the cutaneous immune microenvironment, but the specific functions of the cellular components within this microenvironment remain unknown. Recent advancements in single-cell technologies have enabled the detection of multi-omics at the level of individual cells, including single-cell transcriptome, proteome, and metabolome, which have been successfully applied in studying autoimmune diseases, and other pathologies. These techniques allow the identification of heterogeneous cell clusters and their varying contributions to disease development. Considering the immunological traits of psoriasis, an in-depth exploration of immune cells and their interactions with cutaneous parenchymal cells can markedly advance our comprehension of the mechanisms underlying the onset and recurrence of psoriasis. In this comprehensive review, we present an overview of recent applications of single-cell technologies in psoriasis, aiming to improve our understanding of the underlying mechanisms of this disorder.
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Psoriasis , Análisis de la Célula Individual , Psoriasis/inmunología , Humanos , Análisis de la Célula Individual/métodos , Transcriptoma , Piel/inmunología , Piel/patología , AnimalesRESUMEN
BACKGROUND Aberrant lipid metabolism alterations in skin tissue, blood, or urine have been implicated in psoriasis. Here, we examined lipid metabolites related to psoriasis and their association with the age of disease onset. MATERIAL AND METHODS Differences in lipid metabolites before and after methotrexate (MTX) treatment were evaluated. The discovery cohort and validation cohort consisted of 50 and 46 patients, respectively, with moderate-to-severe psoriasis. After MTX treatment, the patients were divided into response (Psoriasis Area and Severity Index [PASI] 75 and above) and non-response (PASI below 75) groups, blood was collected for serum metabolomics, and multivariate statistical analysis was performed. RESULTS We detected 1546 lipid metabolites. The proportion of the top 3 metabolites was as follows: triglycerides (TG, 34.8%), phospholipids (PE, 14.5%), phosphatidylcholine (PC, 12.4%); diglycerides (DG) (16: 1/18: 1), and DG (18: 1/18: 1) showed strong positive correlations with onset age. There were marked changes in TG (16: 0/18: 0/20: 0), TG (18: 0/18: 0/22: 0), TG (14: 0/18: 0/22: 0), TG (14: 0/20: 0/20: 0), lysophosphatidylcholine (LPC) (16: 0/0: 0), LPC (18: 0/0: 0), LPC (14: 0/0: 0), and LPC (18: 1/0: 0) levels before and after 12 weeks of MTX treatment. The glycerophospholipid metabolic pathway was implicated in psoriasis development. Of the 96 recruited patients, 35% were MTX responders and 65% non-responders. PE (34: 4) and PE (38: 1) levels were significantly different between the groups. Obvious differences in lipid metabolism were found between early-onset (<40 years) and late-onset (≥40 years) psoriasis. Significant changes in serum lipid profile before and after MTX treatment were observed. CONCLUSIONS The specific lipid level changes in responders may serve as an index for MTX treatment efficacy evaluation.
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Metabolismo de los Lípidos , Metabolómica , Metotrexato , Psoriasis , Índice de Severidad de la Enfermedad , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Psoriasis/sangre , Metotrexato/uso terapéutico , Masculino , Femenino , Metabolómica/métodos , Persona de Mediana Edad , Adulto , Metabolismo de los Lípidos/efectos de los fármacos , Metaboloma/efectos de los fármacos , Lípidos/sangre , AncianoRESUMEN
Psoriasis is a chronic inflammatory skin disease characterized by the activation of keratinocytes and the infiltration of immune cells. Overexpression of the transcription factor LIM-domain only protein 4 (LMO4) promoted by IL-23 has critical roles in regulating the proliferation and differentiation of psoriatic keratinocytes. IL-6, an autocrine cytokine in psoriatic epidermis, is a key mediator of IL-23/T helper 17-driven cutaneous inflammation. However, little is known about how IL-6 regulates the up-regulation of LMO4 expression in psoriatic lesions. In this study, human immortalized keratinocyte cells, clinical biopsy specimens, and an animal model of psoriasis induced by imiquimod cream were used to investigate the role of IL-6 in the regulation of keratinocyte proliferation and differentiation. Psoriatic epidermis showed abnormal expression of IL-6 and LMO4. IL-6 up-regulated the expression of LMO4 and promoted keratinocyte proliferation and differentiation. Furthermore, in vitro and in vivo studies showed that IL-6 up-regulates LMO4 expression by activating the mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK)/NF-κB signaling pathway. These results suggest that IL-6 can activate the NF-κB signaling pathway, up-regulate the expression of LMO4, lead to abnormal proliferation and differentiation of keratinocytes, and promote the occurrence and development of psoriasis.
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Quinasas MAP Reguladas por Señal Extracelular , Psoriasis , Animales , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Interleucina-23/efectos adversos , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Queratinocitos/patología , Proteínas con Dominio LIM/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Psoriasis/patologíaRESUMEN
The covalently cross-linked network gives thermosets superior thermal, mechanical, and electrical properties, which, however, squarely makes the large residual stress that is inevitably induced during preparation hardly relieved in the glassy state. In this work, an incredible reduction in residual stress is successfully achieved in bulk thermosets in the glassy state through introducing highly dynamic thiocarbamate bonds by "click" reactions of thiols and isocyanates. Due to the excellent dynamic behaviors of thiocarbamate bonds, local network rearrangement is achieved through thermal stimulation, while the strong 3D cross-linked network is well maintained. Ultimately, a decrease by 44% in residual stress is detected by simply annealing samples at 30 °C below glass transition temperature (Tg), during which they could well maintain more than 98.4% of the storage modulus. After the annealing, more uniform residual stress distribution is also observed, showing a 32% decline in sample standard deviation. However, the residual stress of epoxy resin, a typical thermoset as a reference, changes little even after annealing at Tg. The results prove it a feasible strategy to reduce residual stress in bulk thermosets in the glassy state by introducing proper dynamic covalent bonds.
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Vidrio , Vidrio/química , Temperatura de Transición , Compuestos de Sulfhidrilo/química , Estructura Molecular , Isocianatos/química , Estrés Mecánico , TemperaturaRESUMEN
GFH009 is a potent, highly selective, small molecule that targets and inhibits the activity of the CDK9/cyclin T1 regulatory complex of P-TEFb. This study aimed to develop and validate a highly selective and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for precise quantification of GFH009 in rat plasma. This method was subsequently employed for conducting toxicokinetic studies of GFH009 in rats. Plasma was prepared using a simple protein precipitation method by acetonitrile. Chromatographic separation of the analytes was achieved on a BEH C18 analytical column with a rapid 3.0 min run time and a flow rate of 0.5 ml/min. The calibration curves for plasma samples exhibited excellent linearity over a wide concentration range of 1.0-1,000 ng/ml for GFH009. Intra- and inter-day accuracies were within 92.7-105.7%, and precisions were no more than 6.7%. Furthermore, the analyte demonstrated stability under four different storage conditions, with variations of <15.0%. This study pioneers a methodological innovation by introducing a highly reliable, specific and sensitive analytical method for GFH009 in rat plasma. The successful application of this method in toxicokinetic studies further underscores its significance, offering valuable insights for the methodology of clinical pharmacokinetic research.
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Cromatografía Líquida con Espectrometría de Masas , Espectrometría de Masas en Tándem , Ratas , Animales , Espectrometría de Masas en Tándem/métodos , Ratas Sprague-Dawley , Cromatografía Liquida , Toxicocinética , Cromatografía Líquida de Alta Presión/métodos , Inhibidores de Proteínas Quinasas , Reproducibilidad de los ResultadosRESUMEN
To evade cell cycle controls, malignant cells rely upon rapid expression of select proteins to mitigate proapoptotic signals resulting from damage caused by both cancer treatments and unchecked over-proliferation. Cyclin-dependent kinase 9 (CDK9)-dependent signaling induces transcription of downstream oncogenes promoting tumor growth, especially in hyperproliferative 'oncogene-addicted' cancers, such as human hematological malignancies (HHMs). GFH009, a potent, highly selective CDK9 small molecule inhibitor, demonstrated antiproliferative activity in assorted HHM-derived cell lines, inducing apoptosis at IC50 values below 0.2 µM in 7/10 lines tested. GFH009 inhibited tumor growth at all doses compared to controls and induced apoptosis in a dose-dependent manner. Twice-weekly injections of GFH009 maleate at 10 mg/kg significantly prolonged the survival of MV-4-11 xenograft-bearing rodents, while their body weight remained stable. There was marked reduction of MCL-1 and c-MYC protein expression post-drug exposure both in vitro and in vivo. Through rapid 'on-off' CDK9 inhibition, GFH009 exerts a proapoptotic effect on HHM preclinical models triggered by dynamic deprivation of crucial cell survival signals. Our results mechanistically establish CDK9 as a targetable vulnerability in assorted HHMs and, along with the previously shown superior class kinome selectivity of GFH009 vs other CDK9 inhibitors, strongly support the rationale for currently ongoing clinical studies with this agent in acute myeloid leukemia and other HHMs.
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Antineoplásicos , Quinasa 9 Dependiente de la Ciclina , Neoplasias Hematológicas , Humanos , Antineoplásicos/farmacología , Apoptosis , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias Hematológicas/tratamiento farmacológico , OncogenesRESUMEN
Room temperature vulcanised (RTV) silicone rubber coatings effectively enhance the insulation properties of electrical equipment. However, RTV coatings are prone to internal defects caused by the coating process and the effects of aging during service, which can lead to debonding of the coatings. Internal debonding defects are challenging to detect and can ultimately lead to accidents due to a reduction in the insulation capacity of the equipment. To visualize the internal defect morphology of RTV coatings and quantify the defect size, an ultrasonic pulse-echo-based method for detecting and imaging debonding defects is proposed. The method involves the development of a finite element model to investigate how ultrasonic waves propagate in RTV coatings and the influence of ultrasonic probes and inspection conditions on defect echoes. Furthermore, an ultrasonic detection system specifically designed for RTV coating debonding defects is constructed. This system utilizes wavelet packets in the time-frequency domain to analyze the echo signals in both normal and defective regions. The three-dimensional reconstruction of the debonding defect morphology is accomplished by integrating ultrasonic echo amplitude and position information. Finally, the size of the debonding defects is quantified using an adaptive threshold segmentation method. The findings indicate that ultrasound waves reflected in RTV materials propagate as spherical waves, with the acoustic energy primarily concentrated near the acoustic axis. As the propagation distance increases, the sound beam disperses along the axis and extends beyond the transducer, resulting in a decrease in the sound field's directionality. The developed visual reconstruction method in this study offers the capability of three-dimensional visualization for defects present within RTV coatings, including their length, width, and depth. The accurate determination of defect size is achieved through the utilization of the adaptive threshold segmentation method, yielding an average error rate of 5.7 % across different defect types. In comparison, the maximal interclass variance method (OTSU) and the fuzzy C-means (FCM) method produced results with error rates of 9.8 % and 7.9 %, respectively. The research presented in this paper enables precise assessment of debonding defect severity and establishes a reliable foundation for on-site inspection, operation, and maintenance of RTV coatings.
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OBJECTIVES: Several studies have assessed adult vocal fold movement using transcutaneous laryngeal ultrasonography (TLUSG) during the perioperative period of thyroidectomy. However, the movement was not objectively quantified. This study aimed to provide a feasible and objective method for assessing vocal fold movement using TLUSG. STUDY DESIGN: Feasibility study. METHODS: TLUSG was performed during calm breathing and breath-holding in healthy adult volunteers. The morphology and anatomy of the larynx were observed and measured using an ultrasonic self-contained measurement function. At the end of the calm inspiratory and breath-holding phases, vocal fold angle, vocal fold length, distance from vocal process to the midline, distance from anterior vocal commissure to arytenoid cartilage, distance from false vocal fold to the midline, and distance from the anterior horn of thyroid cartilage to false vocal fold were measured. Data were analyzed using a t test (significance <0.05). RESULTS: The ultrasonic images were satisfactory in all 40 healthy adult volunteers (age 19-35 years; body mass index 18.55-23.93 kg/m2; 20 men and 20 women). There were no significant differences in all laryngeal parameters between the left and right sides in both phases (P > 0.05). Moreover, all differences in laryngeal parameters between the end of the calm inspiratory phase and the breath-holding phase were statistically significant (P < 0.05), regardless of sex. CONCLUSION: The relevant positional parameters of the vocal fold, arytenoid cartilage, and false vocal fold and their differences before and after vocal fold movement in healthy adult volunteers can be obtained objectively using TLUSG.
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Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of autoantibodies, immune complex deposition, and tissue/organ damage. In this study, we aimed to identify molecular features and signaling pathways associated with SLE severity using RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and clinical parameters. Methods: We analyzed transcriptome profiles of 45 SLE patients, grouped into mild (mSLE, SLEDAI ≤ 9) and severe (sSLE, SLEDAI > 9) based on SLE Disease Activity Index (SLEDAI) scores. We also collected clinical data on anti-dsDNA, ANA, ESR, CRP, snRNP, AHA, and anti-Smith antibody status for each patient. Results: By comparing gene expression across groups, we identified 12 differentially expressed genes (DEGs), including 7 upregulated (CEACAM6, UCHL1, ARFGEF3, AMPH, SERPINB10, TACSTD2, and OTX1) and 5 downregulated (SORBS2, TRIM64B, SORCS3, DRAXIN, and PCDHGA10) DEGs in sSLE compared to mSLE. Furthermore, using the CIBERSORT algorithm, we found that Treg cells were significantly decreased in sSLE and negatively correlated with AMPH expression, which was mainly expressed in Treg cells from SLE patients according to public scRNA-seq data (GSE135779). Discussion: Overall, our findings shed light on the molecular mechanisms underlying SLE severity and provide insight into potential therapeutic targets.
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Purpose: Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. This study aimed to investigate the molecular mechanism of SLE. Patients and Methods: We retrieved genome-wide gene expression levels from five public datasets with relatively large sample sizes from the Gene Expression Omnibus (GEO), and we compared the expression profiles of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls (HCs). The expression of seven target genes in PBMCs from 25 cases and 3 HCs was further validated by reverse-transcription quantitative PCR (RTâqPCR). Flow cytometry was used for verifying the proportion of naive CD4(+) T cells and M2 macrophages in PBMCs from 5 cases and 4 HCs. Results: We found 14 genes (TRIM5, FAM8A1, SHFL, LHFPL2, PARP14, IFIT5, PARP12, DDX60, IRF7, IF144, OAS1, OAS3, RHBDF2, and RSAD2) that were differentially expressed among all five datasets. The heterogeneity test under the fixed effect model showed no obvious heterogeneity of TRIM5, FAM8A1, and SHFL across different populations. TRIM5 was positively correlated with the remaining 13 genes. By separating patient samples into TRIM5-high and TRIM5-low groups, we found that up-regulated genes in the TRIM5-high group were mainly enriched in virus-related pathways. Immune cell proportion analysis and flow cytometry revealed that naive CD4(+) T cells were significantly decreased while M2 macrophages were increased in the SLE group. TRIM5 expression levels were negatively correlated with naive CD4(+) T cells but positively correlated with M2 macrophages. Conclusion: Our data indicated that TRIM5 might be a key factor that modulates SLE etiology, possibly through naive CD4(+) T cells and M2 macrophages.
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Inflammatory bowel disease (IBD) affects millions of individuals worldwide annually. Enteric reactive oxygen species (ROS) play critical roles in the physiology and pathology of IBD. Nanozymes hold great promise for the treatment of IBD because of their exceptional ability to regulate redox homeostasis during ROS-related inflammation. However, the rapid development of orally administered, acid-tolerant, antioxidant nanozymes for IBD therapy is challenging. Here, a nine-tier high-throughput screening strategy is established to address the multifaceted IBD treatment demands, including intrinsic stability, radioactivity, solubility, gut microbiome toxicity, biomimetic elements, intermediate frontier molecular orbitals, reaction energy barriers, negative charges, and acid tolerance. Ni3 S4 is selected as the best matching material from 146 323 candidates, which exhibits superoxide dismutase-catalase bienzyme-like activity and is 3.13- and 1.80-fold more active than natural enzymes. As demonstrated in a mouse model, Ni3 S4 is stable in the gastrointestinal tract without toxicity and specifically targets the diseased colon to alleviate oxidative stress. RNA and 16S rRNA sequencing analyses show that Ni3 S4 effectively inhibits the cellular pathways of pro-inflammatory factors and restores the gut microbiota. This study not develops a highly efficient orally administered cascade nanozyme for IBD therapy and offers a next-generation paradigm for the rational design of nanomedicine through data-driven approaches.
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Enfermedades Inflamatorias del Intestino , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , ARN Ribosómico 16S/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Inflamación , Estrés OxidativoRESUMEN
Psoriasis is a chronic inflammatory skin disease occurring worldwide, with multiple systemic complications, which seriously affect the quality of life and physical and mental health of patients. The pathogenesis of psoriasis is related to the environment, genetics, epigenetics, and dysregulation of immune cells such as T cells, dendritic cells (DCs), and nonimmune cells such as keratinocytes. Absent in melanoma 2 (AIM2), a susceptibility gene locus for psoriasis, has been strongly linked to the genetic and epigenetic aspects of psoriasis and increased in expression in psoriatic keratinocytes. AIM2 was found to be activated in an inflammasome-dependent way to release IL-1ß and IL-18 to mediate inflammation, and to participate in immune regulation in psoriasis, or in an inflammasome-independent way by regulating the function of regulatory T(Treg) cells or programming cell death in keratinocytes as well as controlling the proliferative state of different cells. AIM2 may also play a role in the recurrence of psoriasis by trained immunity. In this review, we will elaborate on the characteristics of AIM2 and how AIM2 mediates the development of psoriasis.
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Proteínas de Unión al ADN , Psoriasis , Humanos , Proteínas de Unión al ADN/metabolismo , Inflamasomas/metabolismo , Queratinocitos , Psoriasis/patología , Calidad de VidaRESUMEN
Introduction: Munro's microabscess is a typical pathological feature in the early psoriatic lesion, mainly characterized by the accumulation of neutrophils in the epidermis. DNA methylation microenvironment of Munro's microabscess and the crosstalk with transcription and its effect on neutrophils have not yet been revealed. Methods: Performed genome-wide DNA methylation analysis and further differential methylation analysis of psoriatic skin lesions with and without Munro's microabscess from two batch samples consisting of 114 former samples in the discovery stage and 21 newly-collected samples in the validation stage. Utilized GO, MEME, and other tools to conduct downstream analysis on differentially methylated sites (DMSs). Correlation analysis of methylation level and transcriptome data was also conducted. Results: We observed 647 overlapping DMSs associated with Munro's microabscess. Subsequently, GO pathway analysis revealed that DNA methylation might affect the physical properties associated with skin cells through focal adhesion and cellsubstrate junction and was likely to recruit neutrophils in the epidermis. Via the MEME tool, used to investigate the possible binding transcription factors (TFs) of 20 motifs around the 647 DMSs, it was found that DNA methylation regulated the binding of AP1 family members and the recruitment of neutrophils in the epidermis through the TGF-beta pathway and the TH17 pathway. Meanwhile, combined with our earlier transcriptome data, we found DNA methylation would regulate the expressions of CFDP, SIRT6, SMG6, TRAPPC9, HSD17B7, and KIAA0415, indicating these genes would potentially promote the process of Munro's microabscess. Discussion: In conclusion, DNA methylation may affect the course of psoriasis by regulating the progression of Munro's microabscess in psoriatic skin lesions.
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Psoriasis , Sirtuinas , Humanos , Metilación de ADN , Epigénesis Genética , Psoriasis/patología , Piel/patología , Absceso/patología , Sirtuinas/metabolismoRESUMEN
Background: Whether circRAN, which acts as a microRNA sponge, plays a role in 5-fluorouracil (5-Fu) resistant gastric cancer has not been reported. In this study, a 5-Fu resistant cell line with an IC50 of 16.59 µM was constructed. Methods: Using comparative analysis of circRNA in the transcriptomics of resistant and sensitive strains, 31 differentially expressed circRNAs were detected, and the microRNA interacting with them was predicted. Results: Hsacirc_004413 was selected for verification in drug resistant and sensitive cells. By interfering with hsacirc_004413 using antisense RNA, the sensitivity of drug resistant cells to 5-Fu was significantly promoted, and the apoptosis and necrosis of the cells were significantly increased. In sensitive cells, inhibition by inhibitors enhanced the resistance of cells to 5-Fu. We hypothesize that hsacirc_004413 makes gastric cancer cells resistant to 5-Fu mainly through adsorption of miR-145-5p.
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MicroARNs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Fluorouracilo/farmacología , ARN Circular/genética , Proliferación Celular/genéticaRESUMEN
BACKGROUND: Psoriasis is a chronic and hyperproliferative skin disease featured by hyperkeratosis with parakeratosis, Munro micro-abscess, elongation of rete pegs, granulosa thinning, and lymphocyte infiltration. We previously profiled gene expression and chromatin accessibility of psoriatic skins by transcriptome sequencing and ATAC-seq. However, integrating both of these datasets to unravel gene expression regulation is lacking. Here, we integrated transcriptome and ATAC-seq of the same psoriatic and normal skin tissues, trying to leverage the potential role of chromatin accessibility and their function in histopathology features. RESULTS: By inducing binding and expression target analysis (BETA) algorithms, we explored the target prediction of transcription factors binding in 15 psoriatic and 19 control skins. BETA identified 408 upregulated genes (rank product < 0.01) and 133 downregulated genes linked with chromatin accessibility. We noticed that cumulative fraction of genes in upregulation group was statistically higher than background, while that of genes in downregulation group was not significant. KEGG pathway analysis showed that the upregulated 408 genes were enriched in TNF, NOD, and IL-17 signaling pathways. In addition, the motif module in BETA suggested the 57 upregulated genes are targeted by transcription factor AP-1, indicating that increased chromatin accessibility facilitated the binding of AP-1 to the target regions and further induced expression of relevant genes. Among these genes, SQLE, STRN, EIF4, and MYO1B expression was increased in patients with hyperkeratosis, parakeratosis, and acanthosis thickening. CONCLUSIONS: In summary, with the advantage of BETA, we identified a series of genes that contribute to the disease pathogenesis, especially in modulating histopathology features, providing us with new clues in treating psoriasis.
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Paraqueratosis , Psoriasis , Cromatina/genética , Metilación de ADN , Humanos , Paraqueratosis/genética , Psoriasis/genética , Factor de Transcripción AP-1/genética , TranscriptomaRESUMEN
BACKGROUND Psoriasis is a chronic, immune-mediated and hyperproliferative skin disease with both genetic and environmental components. Copy number variations (CNV) of IL22 and LCE3C-LCE3B deletion have been confirmed to be predisposed to psoriasis vulgaris (PsV) in several ethnic groups. However, it remains to be clarified whether CNVs of IL22 and LCE3C are associated with different subtypes of psoriasis (psoriatic arthritis, PsA; erythrodermic psoriasis, EP; and generalized pustular psoriasis, GPP). MATERIAL AND METHODS We enrolled 897 Han Chinese individuals, including 478 patients and 419 healthy controls, and detected CNVs of IL22 and LCE3C using the comparative CT method by real-time PCR, and Pearson's χ² test was used to evaluated the copy number difference among subtypes. RESULTS CNVs of IL22 were significantly higher in PsV than in healthy controls (P<0.001). CNV of LCE3C in PsV, PsA, and GPP groups were significantly lower compared to healthy controls. When linked with clinical parameters, mild psoriasis carried less IL22 copy numbers than that in severe psoriasis (P=0.043). Neither IL22 or LCE3C CNVs were associated with age of onset. CONCLUSIONS CNVs of LCE3C and IL22 might differentially contribute to subtypes of psoriasis. These findings suggest complex and diverse genetic variations in and among different clinical subtypes of psoriasis.