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The interleukin 1 (IL-1) pathway signals through IL-1 receptor type 1 (IL-1R1) and emerges as a central mediator for systemic inflammation. Aberrant IL-1 signaling leads to a range of autoinflammatory diseases. Here, we identified a de novo missense variant in IL-1R1 (p.Lys131Glu) in a patient with chronic recurrent multifocal osteomyelitis (CRMO). Patient PBMCs showed strong inflammatory signatures, particularly in monocytes and neutrophils. The p.Lys131Glu substitution affected a critical positively charged amino acid, which disrupted the binding of the antagonist ligand, IL-1Ra, but not IL-1α or IL-1ß. This resulted in unopposed IL-1 signaling. Mice with a homologous mutation exhibited similar hyperinflammation and greater susceptibility to collagen antibody-induced arthritis, accompanied with pathological osteoclastogenesis. Leveraging the biology of the mutation, we designed an IL-1 therapeutic, which traps IL-1ß and IL-1α, but not IL-1Ra. Collectively, this work provides molecular insights and a potential drug for improved potency and specificity in treating IL-1-driven diseases.
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Osteomielite , Receptores de Interleucina-1 , Camundongos , Animais , Receptores de Interleucina-1/genética , Osteomielite/tratamento farmacológico , Osteomielite/genética , Osteomielite/patologia , Inflamação/genética , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Transdução de Sinais , MutaçãoRESUMO
Behçet's disease (BD) is a chronic vasculitis characterized by systemic immune aberrations. However, a comprehensive understanding of immune disturbances in BD and how they contribute to BD pathogenesis is lacking. Here, we performed single-cell and bulk RNA sequencing to profile peripheral blood mononuclear cells (PBMCs) and isolated monocytes from BD patients and healthy donors. We observed prominent expansion and transcriptional changes in monocytes in PBMCs from BD patients. Deciphering the monocyte heterogeneity revealed the accumulation of C1q-high (C1qhi) monocytes in BD. Pseudotime inference indicated that BD monocytes markedly shifted their differentiation toward inflammation-accompanied and C1qhi monocyte-ended trajectory. Further experiments showed that C1qhi monocytes enhanced phagocytosis and proinflammatory cytokine secretion, and multiplatform analyses revealed the significant clinical relevance of this subtype. Mechanistically, C1qhi monocytes were induced by activated interferon-γ (IFN-γ) signaling in BD patients and were decreased by tofacitinib treatment. Our study illustrates the BD immune landscape and the unrecognized contribution of C1qhi monocytes to BD hyperinflammation, showing their potential as therapeutic targets and clinical assessment indexes.
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Síndrome de Behçet , Complemento C1q , Monócitos , Síndrome de Behçet/genética , Síndrome de Behçet/imunologia , Complemento C1q/genética , Complemento C1q/imunologia , Humanos , Monócitos/imunologia , RNA-Seq , Análise de Célula ÚnicaRESUMO
This study aims to explore the molecular regulation mechanism of ubiquitination-specific protease 7 (USP7) in facilitating the stemness properties of hepatocellular carcinoma (HCC). Gain-of-function and loss-of-function assays were conducted in SK-Hep1 and HepG2 cells transfected with USP7 overexpression/knockdown plasmids and USP7 inhibitor P22077. The proliferation, migration, invasion, and self-renewal capacity of hepatocellular carcinoma cells were detected by CCK-8, colony formation, Transwell, scratch, and tumor sphere formation, respectively. MS was performed to identify the potential substrate of USP7 following P22077 treatment. Co-IP assay was used to verify the interaction between USP7 and basic transcription factor 3 (BTF3) in HCC cells. The overexpression of USP7 could promote the proliferation, migration, invasion, and colony formation capacity of SK-Hep1 and HepG2 cells. Additionally, ectopic UPS7 enhanced the epithelial-mesenchymal transition (EMT) and stem-like characteristics of the HCC cells. In contrast, USP7 depletion by knockdown of USP7 or administrating inhibitor P22077 significantly inhibited these malignant phenotypes of SK-Hep1 and HepG2 cells. Following MS analysis, BTF3 was identified as a potential substrate for USP7. USP7 could interact with BTF3 and upregulate its protein level, while USP7 depletion significantly upregulated the ubiquitination levels. Overexpression of BTF3 partially rescue the inhibitory effects of USP7 depletion on the malignant phenotypes and stemness properties of SK-Hep1 and HepG2 cells. USP7 can promote the stemness and malignant phenotype of HCC by stabilizing BTF3.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Peptidase 7 Específica de Ubiquitina , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Tiofenos , Peptidase 7 Específica de Ubiquitina/genética , Peptidase 7 Específica de Ubiquitina/metabolismo , Ubiquitinação , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Inflammatory diseases are often initiated by the activation of inflammasomes triggered by pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs), which mediate pyroptosis. Although pyroptosis resulting from aberrant inflammasome triggering in thyroid follicular cells (TFCs) has been observed in Hashimoto's thyroiditis (HT) patients, the underlying mechanisms remain largely unknown. Given the extensive involvement of protein ubiquitination and deubiquitination in inflammatory diseases, we aimed to investigate how deubiquitinating enzymes regulate thyroid follicular cell pyroptosis and HT pathogenesis. METHODS: Our study specifically investigated the role of Ubiquitin-specific peptidase 1 (USP1), a deubiquitinase (DUB), in regulating the inflammasome components NLRP3 and AIM2, which are crucial in pyroptosis. We conducted a series of experiments to elucidate the function of USP1 in promoting pyroptosis associated with inflammasomes and the progression of HT. These experiments involved techniques such as USP1 knockdown or inhibition, measurement of key pyroptosis indicators including caspase-1, caspase-1 p20, and GSDMD-N, and examination of the effects of USP1 abrogation on HT using a mouse model. Furthermore, we explored the impact of USP1 on NLRP3 transcription and its potential interaction with p65 nuclear transportation. RESULTS: Our findings provide compelling evidence indicating that USP1 plays a pivotal role in promoting inflammasome-mediated pyroptosis and HT progression by stabilizing NLRP3 and AIM2 through deubiquitination. Furthermore, we discovered that USP1 modulates the transcription of NLRP3 by facilitating p65 nuclear transportation. Knockdown or inhibition of USP1 resulted in weakened cell pyroptosis, as evidenced by reduced levels of caspase-1 p20 and GSDMD-N, which could be restored upon AIM2 overexpression. Remarkably, USP1 abrogation significantly ameliorated HT in the mice model, likely to that treating mice with pyroptosis inhibitors VX-765 and disulfiram. CONCLUSIONS: Our study highlights a regulatory mechanism of USP1 on inflammasome activation and pyroptosis in TFCs during HT pathogenesis. These findings expand our understanding of HT and suggest that inhibiting USP1 may be a potential treatment strategy for managing HT.
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Doença de Hashimoto , Inflamassomos , Piroptose , Proteases Específicas de Ubiquitina , Animais , Inflamassomos/metabolismo , Camundongos , Doença de Hashimoto/metabolismo , Doença de Hashimoto/patologia , Humanos , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Progressão da Doença , Modelos Animais de Doenças , Glândula Tireoide/metabolismo , Glândula Tireoide/patologiaRESUMO
Major histocompatibility complex (MHC) could serve as a potential biomarker for tumor immunotherapy, however, it is not yet known whether MHC could distinguish potential beneficiaries. Single-cell RNA sequencing datasets derived from patients with immunotherapy were collected to elucidate the association between MHC and immunotherapy response. A novel MHCsig was developed and validated using large-scale pan-cancer data, including The Cancer Genome Atlas and immunotherapy cohorts. The therapeutic value of MHCsig was further explored using 17 CRISPR/Cas9 datasets. MHC-related genes were associated with drug resistance and MHCsig was significantly and positively associated with immunotherapy response and total mutational burden. Remarkably, MHCsig significantly enriched 6% top-ranked genes, which were potential therapeutic targets. Moreover, we generated Hub-MHCsig, which was associated with survival and disease-special survival of pan-cancer, especially low-grade glioma. This result was also confirmed in cell lines and in our own clinical cohort. Later low-grade glioma-related Hub-MHCsig was established and the regulatory network was constructed. We provided conclusive clinical evidence regarding the association between MHCsig and immunotherapy response. We developed MHCsig, which could effectively predict the benefits of immunotherapy for multiple tumors. Further exploration of MHCsig revealed some potential therapeutic targets and regulatory networks.
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Imunoterapia , Aprendizado de Máquina , Complexo Principal de Histocompatibilidade , Neoplasias , Análise de Célula Única , Humanos , Imunoterapia/métodos , Análise de Célula Única/métodos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/imunologia , Complexo Principal de Histocompatibilidade/genética , Análise de Sequência de RNA/métodos , Biomarcadores Tumorais/genética , PrognósticoRESUMO
OBJECTIVES: This study aims to evaluate the efficacy and safety of infliximab (IFX) in patients with parenchymal neuro-Behçet's syndrome (p-NBS). METHODS: We retrospectively analysed eleven p-NBS patients treated with IFX at our institution and combined them with studies from database searches for a meta-analysis. Pooled estimates of clinical response (complete and partial remission) and MRI improvement at months 3, 6, and 12 were calculated. RESULTS: One patient achieved CR and the other ten patients achieved PR at our institution. 8 studies (77 patients) were included in the meta-analysis. At 3, 6, and 12 months, 97% (95%CI 61.9-100%), 89.6% (95%CI 45.9-100%), 100% (95%CI 96.0-100%) of patients showed clinical response and 100% (95%CI 89.7-100%), 89.1% (95% CI 26.3-100%), 99.5% (95% CI 96.0-100%) of patients showed radiological improvement, respectively. Severe adverse events were observed in 7 patients. CONCLUSIONS: IFX was effective and relatively safe for p-NBS. Patients should be re-evaluated after 3 months of IFX to determine further therapy.
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This five-wave longitudinal study examined the between- and within-family dynamic associations between father, mother, and child anxiety and the moderating effects of child gender in Chinese culture. Five hundred and twenty-two father-mother dyads of children (59% boys; Mage T1 = 8.34 years) completed measures of father, mother, and child anxiety at five time points, 6 months apart. Between-family associations suggested that children whose parents had more anxiety symptoms showed higher anxiety levels, and mothers or fathers whose partners had more anxiety symptoms showed higher anxiety levels. At the within-family level, after periods with higher child anxiety symptoms, mothers reported higher anxiety symptoms and vice versa. However, no reciprocal associations were found between father and child anxiety and between father and mother anxiety. Finally, the associations between father, mother, and child anxiety did not differ across boys and girls. Our findings highlight the importance of distinguishing among between-family and within-family associations and help to develop effective programs to prevent anxiety disorders in families.
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The migrasome is a new organelle discovered by Professor Yu Li in 2015. When cells migrate, the membranous organelles that appear at the end of the retraction fibres are migrasomes. With the migration of cells, the retraction fibres which connect migrasomes and cells finally break. The migrasomes detach from the cell and are released into the extracellular space or directly absorbed by the recipient cell. The cytoplasmic contents are first transported to the migrasome and then released from the cell through the migrasome. This release mechanism, which depends on cell migration, is named 'migracytosis'. The main components of the migrasome are extracellular vesicles after they leave the cell, which are easy to remind people of the current hot topic of exosomes. Exosomes are extracellular vesicles wrapped by the lipid bimolecular layer. With extensive research, exosomes have solved many disease problems. This review summarizes the differences between migrasomes and exosomes in size, composition, property and function, extraction method and regulation mechanism for generation and release. At the same time, it also prospects for the current hotspot of migrasomes, hoping to provide literature support for further research on the generation and release mechanism of migrasomes and their clinical application in the future.
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Exossomos , Vesículas Extracelulares , Humanos , Exossomos/metabolismo , Organelas/metabolismo , Movimento Celular/fisiologia , Transporte BiológicoRESUMO
Behçet's disease (BD) is a multisystemic chronic vasculitis. Sustained and enhanced immune responses were reportedly associated with active BD. Although genetic polymorphisms increase development risk, genetic factors alone cannot account for BD development, suggesting the involvement of exogenous factors. Also, how various infectious agents promote BD in high-risk populations is not fully understood. In this review, we summarized the current findings on the associations of infectious agents with BD pathogenesis. The review also highlights the potential microbial risk factors and their pathogenic role in BD progression. Interactions between genetic and infectious risk factors was also discussed. Furthermore, evidence implied that after the eradication of infectious agents, BD symptoms and recurrence decreased, thus highlighting that combined use of antibiotics may be an effective therapy for BD. Finally, we summarized the main limitation of the current related studies, providing valuable insights and a basis for future studies on BD pathogenic factors.
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Síndrome de Behçet , Vasculite , Humanos , Vasculite/complicações , Fatores de RiscoRESUMO
NLRC4 gain-of-function variants are known to cause various autoinflammatory phenotypes, including familial cold autoinflammatory syndrome (FCAS4) and NLRC4 macrophage activation syndrome (NLRC4-MAS). However, to date, no study has linked NLRC4 gain-of-function variants to systemic lupus erythematosus (SLE). In this study, we identified a novel NLRC4 W655S variant in an SLE patient and her son, who had neonatal lupus complicated with macrophage activation syndrome. Our in vitro experiments demonstrated that the W655S NLRC4 increased ASC speck formation and mature IL-1ß secretion compared to the wild-type NLRC4. In addition, the patient had elevated levels of IL-1ß and IL-18 in both serum and PBMCs. RNA sequencing showed that NF-κB and interferon signaling pathways were significantly activated in the patient compared to healthy controls. Furthermore, gene set enrichment analysis revealed upregulation of NLRC4-related pathways in patient PBMCs. In conclusion, our study identified the NLRC4 W655S variant in a patient with SLE. This is the first report linking inflammasomopathy to monogenic SLE. Our findings suggest that inflammasome activation may be a critical driver in the pathogenicity of lupus, and autoinflammatory pathways may play important roles in the development of the disease.
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Síndromes Periódicas Associadas à Criopirina , Inflamassomos , Lúpus Eritematoso Sistêmico , Síndrome de Ativação Macrofágica , Feminino , Humanos , Recém-Nascido , Proteínas de Ligação ao Cálcio/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Mutação com Ganho de Função , Inflamassomos/genética , Inflamassomos/metabolismo , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Síndrome de Ativação Macrofágica/genéticaRESUMO
OBJECTIVES: The pilot study aims to explore the efficacy and safety of baricitinib in treating refractory intestinal Behçet's disease (BD). METHODS: We consecutively enrolled patients with refractory intestinal BD from October 2020 to September 2022. They were treated with baricitinib 2-4 mg daily, with background glucocorticoids and immunosuppressants. Efficacy assessment included the global gastrointestinal symptom scores, the endoscopy scores, the Disease activity index for intestinal Behçet's disease (DAIBD), and the inflammatory parameters. Side effects were recorded. RESULTS: The thirteen patients (six males and seven females) had a median follow-up of eleven months, 76.92% (10/13) patients achieved complete remission of global gastrointestinal symptom scores, and 66.7% (6/9) had mucosal healing on endoscopy. The DAIBD scores decreased significantly, as well as the C-reactive protein level. Baricitinib showed a glucocorticoid-sparing effect, and the safety profile is favorable. CONCLUSION: Baricitinib might be a potential choice in treating refractory intestinal BD.
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Síndrome de Behçet , Enteropatias , Masculino , Feminino , Humanos , Projetos Piloto , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/diagnóstico , Intestinos , Sulfonamidas/uso terapêutico , Enteropatias/tratamento farmacológico , Glucocorticoides/uso terapêuticoRESUMO
Neuro-Behçet's disease (NBD) contributes to poor prognosis in BD patients which lacks reliable laboratory biomarkers in assessing intrathecal injury. This study aimed to determine the diagnostic value of myelin basic protein (MBP), an indicator of central nervous system (CNS) myelin damage, in NBD patients and disease controls. Paired samples of cerebrospinal fluid (CSF) and serum MBP were measured using ELISA, while IgG and Alb were routinely examined before the MBP index was developed. CSF and serum MBP in NBD were significantly higher than in NIND, which could distinguish NBD from NIND with a specificity exceeding 90%, moreover, they could also be excellent discriminators for acute NBD and chronic progressive ones. We found positive linkage between MBP index and IgG index. Serial MBP monitoring confirmed serum MBP's sensitive response to disease recurrences and drug effects, whereas MBP index suggests relapses prior to clinical symptoms. MBP has high diagnostic yield for NBD with demyelination and identifies CNS pathogenic processes before imaging or clinical diagnosis.
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Síndrome de Behçet , Proteína Básica da Mielina , Humanos , Síndrome de Behçet/sangue , Síndrome de Behçet/diagnóstico , Biomarcadores/sangue , Biomarcadores/metabolismo , Sistema Nervoso Central/metabolismo , Imunoglobulina G , Proteína Básica da Mielina/sangue , Proteína Básica da Mielina/metabolismoRESUMO
OBJECTIVE: The pilot study aims to evaluate the effectiveness and safety of baricitinib in Behcet's Disease (BD) patients with refractory vascular involvement. METHODS: We consecutively enrolled vascular/cardiac BD patients who received baricitinib (2 mg/day) along with glucocorticoids (GCs) and immunosuppressants in our center. Efficacy assessment mainly depends on the proportion of clinical remission and side effects were recorded. RESULTS: 17 patients (12 males) were included with a mean follow-up of 10.7 ± 5.3 months. At 3 months of follow-up, 76.5% of patients achieved a complete response and the proportion increased to 88.2% at the last visit. During follow-up, ESR (p < 0.01) and hsCRP (p < 0.0001) decreased significantly, as well as Behçet's Disease Current Activity Form score (p < 0.01). In addition, baricitinib showed a GCs-sparing effect. No serious adverse events were noted. CONCLUSIONS: Our study suggests that baricitinib is well-tolerated and effective in treating refractory vascular/cardiac BD patients.
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Síndrome de Behçet , Masculino , Humanos , Síndrome de Behçet/tratamento farmacológico , Projetos Piloto , Imunossupressores/uso terapêutico , Sulfonamidas/uso terapêutico , Glucocorticoides/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.
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Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Humanos , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estudos de Coortes , Estudos Retrospectivos , MutaçãoRESUMO
OBJECTIVES: To investigate the potential role of shelterin dysfunction in naïve CD4+ T cells in the pathogenesis of Behçet's disease (BD). METHODS: Naïve CD4+ T cells were isolated from 40 BD patients and 40 sex- and age-matched healthy controls (HC). Senescent profiles, shelterin subunits expression, telomere length, telomerase activity, and critical DNA damage response (DDR) was evaluated. TRF2 silencing was conducted for further validation. RESULTS: Compared to HC, BD patients had significantly decreased naïve CD4+ T cells, increased cell apoptosis, senescence, and productions of TNF-α and IFN-γ upon activation. Notably, BD naïve CD4+ T cells had shortened telomere, impaired telomerase activity, and expressed lower levels of shelterin subunits TRF2, TIN2, and RAP1. Furthermore, BD naïve CD4+ T cells exhibited significantly increased DDR, evidenced by elevated phosphorylated ataxia telangiectasia (AT) mutated (pATM), pp53, and p21. Finally, TRF2-silencing markedly upregulated DDR, apoptosis, and proinflammatory cytokines production in HC naïve CD4+ T cells. CONCLUSION: Our study demonstrated that TRF2 deficiency in BD naïve CD4+ T cells promoted cell apoptosis and senescence, leading to proinflammatory cytokines overproduction. Therefore, restoring TRF2 might be a promising therapeutic strategy for BD.
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OBJECTIVE: This study aimed to analyse long term outcomes and risk factors for endovascular repair of aortic pseudoaneurysms in patients with vascular Behçet's disease (BD). METHODS: Medical records of 26 aortic vascular BD patients who underwent endovascular treatment at the vascular department of Peking Union Medical College Hospital between January 2002 and December 2021 were reviewed retrospectively. Erythrocyte sedimentation rate (ESR) and C reactive protein were used to assess BD activity. Computed tomography angiography (CTA) was obtained pre- and post-operatively for almost all patients. Univariable logistic regression analysis was used to analyse risk factors for endovascular repair, such as inflammatory indicators, drug usage, and stent graft parameters. RESULTS: The abdominal aorta (n = 17) was the most common site of 27 vascular BD pseudoaneurysms in this study. CTA also revealed one aortic arch pseudoaneurysm, seven descending thoracic aortic pseudoaneurysms, one thoraco-abdominal aortic pseudoaneurysm, and one pseudoaneurysm at the aortic bifurcation. Most of the pseudoaneurysms were treated with covered stent grafts. The technical success rate was 96% and no deaths occurred during hospital stay. The mean follow up was 5.8 ± 5.5 years and 31% (8/26) experienced post-operative complications. Overall one, three, and five year event free survival rates were 87%, 78%, and 74%, respectively. Univariable logistic regression analysis revealed that pre-operative ESR ≥ 16.0 mm/h (p = .040), pre-operative glucocorticoid (GC) use ≤ 11.5 days (p = .024), pre-operative immunosuppressant use ≤ 15.5 days (p = .028), and length of proximal landing zone ≤ 1.95 cm (p = .034) were associated with a worse prognoses following endovascular treatment. Proximal oversize ≥ 9.5% (p = .074) was also regarded as a risk factor, although not statistically significant. CONCLUSION: This study further confirmed the feasibility of endovascular repair for aortic vascular BD patients. Risk factors predicting poor prognoses included elevated pre-operative ESR, insufficient pre-operative GC use or immunosuppressant use, inadequate proximal landing zone, and larger proximal oversize percentage.
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Falso Aneurisma , Síndrome de Behçet , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/cirurgia , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Estudos Retrospectivos , Implante de Prótese Vascular/efeitos adversos , Resultado do Tratamento , Stents/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Fatores de Risco , Imunossupressores/uso terapêutico , Prótese Vascular/efeitos adversosRESUMO
BACKGROUND: Globally, millions of patients suffer from regenerative deficiencies, such as refractory wound healing, which is characterized by excessive inflammation and abnormal angiogenesis. Growth factors and stem cells are currently employed to accelerate tissue repair and regeneration; however, they are complex and costly. Thus, the exploration of new regeneration accelerators is of considerable medical interest. This study developed a plain nanoparticle that accelerates tissue regeneration with the involvement of angiogenesis and inflammatory regulation. METHODS: Grey selenium and sublimed sulphur were thermalized in PEG-200 and isothermally recrystallised to composite nanoparticles (Nano-Se@S). The tissue regeneration accelerating activities of Nano-Se@S were evaluated in mice, zebrafish, chick embryos, and human cells. Transcriptomic analysis was performed to investigate the potential mechanisms involved during tissue regeneration. RESULTS: Through the cooperation of sulphur, which is inert to tissue regeneration, Nano-Se@S demonstrated improved tissue regeneration acceleration activity compared to Nano-Se. Transcriptome analysis revealed that Nano-Se@S improved biosynthesis and ROS scavenging but suppressed inflammation. The ROS scavenging and angiogenesis-promoting activities of Nano-Se@S were further confirmed in transgenic zebrafish and chick embryos. Interestingly, we found that Nano-Se@S recruits leukocytes to the wound surface at the early stage of regeneration, which contributes to sterilization during regeneration. CONCLUSION: Our study highlights Nano-Se@S as a tissue regeneration accelerator, and Nano-Se@S may provide new inspiration for therapeutics for regenerative-deficient diseases.
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Nanocompostos , Nanopartículas , Selênio , Embrião de Galinha , Humanos , Camundongos , Animais , Selênio/farmacologia , Selênio/química , Peixe-Zebra/metabolismo , Espécies Reativas de Oxigênio , Cicatrização , Nanopartículas/química , Inflamação , EnxofreRESUMO
Two-dimensional transition metal dichalcogenides (TMDs) have shown great importance in the development of novel ultrathin optoelectronic devices owing to their exceptional electronic and photonic properties. Effectively tuning their electronic band structures is not only desired in electronics applications but also can facilitate more novel properties. In this work, we demonstrate that large electronic tuning on a WSe2 monolayer can be realized by different facets of a Au-foil substrate, forming in-plane p-n junctions with remarkable built-in electric fields. This facet-dependent tuning effect is directly visualized by using scanning tunneling microscopy and differential conductance (dI/dV) spectroscopy. First-principles calculations reveal that the atomic arrangement of the Au facet effectively changes the interfacial coupling and charge transfer, leading to different magnitudes of charge doping in WSe2. Our study would be beneficial for future customized fabrication of TMD-junction devices via facet-specific construction on the substrate.
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Behçet's disease (BD) is a systemic vasculitis characterized by neutrophil activation with unclear pathogenesis. This study aimed to explore the transcriptional profiles of BD neutrophils and identify specific gene signatures. We performed RNA sequencing on neutrophils from treatment-naive active BD patients and healthy controls, then analyzed differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) and transcription regulatory network. Quantitative real-time PCR and Western Blot were used to validate chemotaxis-related DEGs expression. We detected 567 DEGs, including 520 upregulated genes and 47 downregulated genes. 9 KEGG pathways were enriched, dominated by the NF-κB pathway and chemotaxis. The transcription regulatory network suggests ETS1 regulated the enhanced chemotaxis of BD neutrophils. Validation experiments demonstrated the overexpression of ETS1, CCR6 and CCL5 in BD neutrophils compared with HC, and ETS1 was significantly increased in vascular BD compared with other BD subgroups. Our study revealed increased activation and chemotaxis of BD neutrophils characterized by the overexpression of CCL5, CCR6 and ETS1.
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Síndrome de Behçet , Neutrófilos , Humanos , Neutrófilos/metabolismo , Síndrome de Behçet/genética , Síndrome de Behçet/metabolismo , Quimiotaxia/genética , Ativação de Neutrófilo/genéticaRESUMO
PURPOSE: A variety of studies have connected circadian rhythm to the initiation and progression of hepatocellular carcinoma (HCC). The purpose of this study was to figure out about the circadian genes' profile characteristics, prognostic significance, and targeted values in HCC. METHODS: The expression profiles and prognostic significance of circadian genes in the cancer genome atlas liver hepatocellular carcinoma (TCGA-LIHC) database were investigated using bioinformatics analysis. The expression features of Casein Kinase 1 Delta (CSNK1D), a robust signature gene, was further detected by immunohistochemistry, western blotting and Real-time quantitative PCR (RT-qPCR) in a local HCC cohort. The effect of CSNK1D on corresponding phenotypes of HCC cells was evaluated using Cell Counting Kit-8 (CCK8), flowcytometry, clone assay, Transwell assay, and xenograft assay. In addition, the underlying mechanisms of CSNK1D in the Wnt/ß-catenin signaling were validated by multiple molecular experiments. RESULTS: Abnormal expression of the Circadian genome was associated with the malignant clinicopathological characteristics of HCC patients. A 10 circadian gene-based signature with substantial prognostic significance was developed using Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. Of them, CSNK1D, significantly elevated in a local HCC cohort, was chosen for further investigation. Silencing or overexpression of CSNK1D significantly reduced or increased proliferation, invasion, sorafenib resistance, xenograft development, and epithelial-mesenchymal transformation (EMT) of HCC cells, respectively. Mechanically, CSNK1D exacerbated the aggressiveness of HCC cells by activating Wnt/ß-catenin signaling through interacting with Dishevelled Segment Polarity Protein 3 (DVL3). CONCLUSIONS: The Circadian gene CSNK1D was found to contribute to HCC progression by boosting the Wnt/ß-catenin pathway, hinting that it could be a prospective therapeutic target for HCC.