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Neutrophils are important in the context of innate immunity and actively contribute to the progression of diverse autoimmune disorders. Distinct death mechanisms of neutrophils may exhibit specific and pivotal roles in autoimmune diseases and disease pathogenesis through the orchestration of immune homeostasis, the facilitation of autoantibody production, the induction of tissue and organ damage, and the incitement of pathological alterations. In recent years, more studies have provided in-depth examination of various neutrophil death modes, revealing nuances that challenge conventional understanding and underscoring their potential clinical utility in diagnosis and treatment. This review explores the multifaceted processes and characteristics of neutrophil death, with a focus on tailored investigations within various autoimmune diseases. It also highlights the potential interplay between neutrophil death and the landscape of autoimmune disorders. The review encapsulates the pertinent pathways implicated in various neutrophil death mechanisms across diverse autoimmune diseases while also charts possible avenues for future research.
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Doenças Autoimunes , Neutrófilos , Humanos , Imunidade InataRESUMO
Non-small-cell lung cancer (NSCLC), which has a high rate of metastatic spread and drug resistance, is the most common subtype of lung cancer. Therefore, NSCLC patients have a very poor prognosis and a very low chance of survival. Human cancers are closely linked to regulated cell death (RCD), such as apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Currently, small-molecule compounds targeting various types of RCD have shown potential as anticancer treatments. Moreover, RCD appears to be a specific part of the antitumor immune response; hence, the combination of RCD and immunotherapy might increase the inhibitory effect of therapy on tumor growth. In this review, we summarize small-molecule compounds used for the treatment of NSCLC by focusing on RCD and pharmacological systems. In addition, we describe the current research status of an immunotherapy combined with an RCD-based regimen for NSCLC, providing new ideas for targeting RCD pathways in combination with immunotherapy for patients with NSCLC in the future.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Morte Celular Regulada , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Imunoterapia , ApoptoseRESUMO
Rheumatoid arthritis (RA) is a typical autoimmune disease characterized by synovial inflammation, synovial tissue hyperplasia, and destruction of bone and cartilage. Protein glycosylation plays key roles in the pathogenesis of RA but in-depth glycoproteomics analysis of synovial tissues is still lacking. Here, by using a strategy to quantify intact N-glycopeptides, we identified 1260 intact N-glycopeptides from 481 N-glycosites on 334 glycoproteins in RA synovium. Bioinformatics analysis revealed that the hyper-glycosylated proteins in RA were closely linked to immune responses. By using DNASTAR software, we identified 20 N-glycopeptides whose prototype peptides were highly immunogenic. We next calculated the enrichment scores of nine types of immune cells using specific gene sets from public single-cell transcriptomics data of RA and revealed that the N-glycosylation levels at some sites, such as IGSF10_N2147, MOXD2P_N404, and PTCH2_N812, were significantly correlated with the enrichment scores of certain immune cell types. Furthermore, we showed that aberrant N-glycosylation in the RA synovium was related to increased expression of glycosylation enzymes. Collectively, this work presents, for the first time, the N-glycoproteome of RA synovium and describes immune-associated glycosylation, providing novel insights into RA pathogenesis.
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Artrite Reumatoide , Glicoproteínas , Proteoma , Membrana Sinovial , Humanos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Glicopeptídeos/análise , Glicoproteínas/análise , Glicosilação , Osteoartrite/patologia , Proteômica , Membrana Sinovial/química , Membrana Sinovial/patologia , Proteoma/análiseRESUMO
OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) DM complicated by rapidly progressive interstitial lung disease (RP-ILD) has a high incidence and poor prognosis. The objective of this study was to establish a model for the prediction and early diagnosis of anti-MDA5+ DM-associated RP-ILD based on clinical manifestations and imaging features. METHODS: A total of 103 patients with anti-MDA5+ DM were included. The patients were randomly split into training and testing sets of 72 and 31 patients, respectively. After image analysis, we collected clinical, imaging and radiomics features from each patient. Feature selection was performed first with the minimum redundancy and maximum relevance algorithm and then with the best subset selection method. The final remaining features comprised the radscore. A clinical model and imaging model were then constructed with the selected independent risk factors for the prediction of non-RP-ILD and RP-ILD. We also combined these models in different ways and compared their predictive abilities. A nomogram was also established. The predictive performances of the models were assessed based on receiver operating characteristics curves, calibration curves, discriminability and clinical utility. RESULTS: The analyses showed that two clinical factors, dyspnoea (P = 0.000) and duration of illness in months (P = 0.001), and three radiomics features (P = 0.001, 0.044 and 0.008, separately) were independent predictors of non-RP-ILD and RP-ILD. However, no imaging features were significantly different between the two groups. The radiomics model built with the three radiomics features performed worse than the clinical model and showed areas under the curve (AUCs) of 0.805 and 0.754 in the training and test sets, respectively. The clinical model demonstrated a good predictive ability for RP-ILD in MDA5+ DM patients, with an AUC, sensitivity, specificity and accuracy of 0.954, 0.931, 0.837 and 0.847 in the training set and 0.890, 0.875, 0.800 and 0.774 in the testing set, respectively. The combination model built with clinical and radiomics features performed slightly better than the clinical model, with an AUC, sensitivity, specificity and accuracy of 0.994, 0.966, 0.977 and 0.931 in the training set and 0.890, 0.812, 1.000 and 0.839 in the testing set, respectively. The calibration curve and decision curve analyses showed satisfactory consistency and clinical utility of the nomogram. CONCLUSION: Our results suggest that the combination model built with clinical and radiomics features could reliably predict the occurrence of RP-ILD in MDA5+ DM patients.
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Doenças Pulmonares Intersticiais , Radiômica , Humanos , Nomogramas , Algoritmos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Tomografia Computadorizada por Raios XRESUMO
Lathyrane-based diterpenoid is one of the critical bioactive elements of Euphorbia lathyris L., a widely used traditional Chinese medicine for the treatment of inflammation and infection. In this study, we introduced and evaluated seven synthetic or natural lathyrane-based diterpenoids with the same core structure but notable structural variations at specific positions, for their anti-inflammatory and gout-alleviating properties. There was no significant cytotoxicity below 10 µM among the initial test of the cell counting kit 8 of the seven candidate derivatives (compounds 13 to 19) in this work. Furthermore, maintaining the acyloxy group at 15-C position and the strongly hydrophobic aryl structure at 3-C and 5-C positions, compounds 15 (Euphorbia factor L3, EFL3) and 17 strikingly inhibited the production of IL-1ß related to the actuation of the inflammasome in our study. The ELISA assay indicated that the anti-inflammatory effects of EFL3 were better associated with MSU stimulation than other second-line pathways triggered by inflammasome. Further examinations on the acute paw gout model in C57BL/6 mice showed that EFL3 had a significantly inflammatory retarding effect by intraperitoneal injection. It decreased swelling volume as well as the cleavage and activation of local IL-1ß and casepas-1 in the paw. To conclude, our findings reveal several potential key structure-activity relationships that govern the anti-inflammatory effects of lathyrane-type diterpenoids, the dispensable acyl group at the 15-C position, the importance of maintaining the spatial structure of the B-ring, and the potential importance of hydrophobic substituents at the 3-C position. These insights may provide guidance for the structural design of lathyrane-type agents in the future; furthermore, we found that the lathyrane-based diterpenoid EFL3 is a potential agent for gout that is expected to provide a novel therapeutic strategy for inflammation intervention.
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Artrite Gotosa , Diterpenos , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Relação Estrutura-Atividade , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/síntese química , Artrite Gotosa/tratamento farmacológico , Animais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamação/tratamento farmacológico , Estrutura Molecular , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos Endogâmicos C57BL , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/síntese químicaRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease characterized by enigmatic pathogenesis. Polyunsaturated fatty acids (PUFAs) are implicated in RA's development and progression, yet their exact mechanisms of influence are not fully understood. Soluble epoxide hydrolase (sEH) is an enzyme that metabolizes anti-inflammatory epoxy fatty acids (EpFAs), derivatives of PUFAs. In this study, we report elevated sEH expression in the joints of CIA (collagen-induced arthritis) rats, concomitant with diminished levels of two significant EpFAs. Additionally, increased sEH expression was detected in both the synovium of CIA rats and in the synovium and fibroblast-like synoviocytes (FLS) of RA patients. The sEH inhibitor TPPU attenuated the migration and invasion capabilities of FLS derived from RA patients and to reduce the secretion of inflammatory factors by these cells. Our findings indicate a pivotal role for sEH in RA pathogenesis and suggest that sEH inhibitors offer a promising new therapeutic strategy for managing RA.
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Artrite Reumatoide , Sinoviócitos , Animais , Humanos , Ratos , Artrite Reumatoide/enzimologia , Artrite Reumatoide/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Epóxido Hidrolases/metabolismo , Fibroblastos/metabolismo , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismoRESUMO
Fatty acids (FAs) and fatty alcohols (FOHs) are essential compounds for maintaining life. Due to the inherent poor ionization efficiency, low abundance, and complex matrix effect, such metabolites are challenging to precisely quantify and explore deeply. In this study, a pair of novel isotope derivatization reagents known as d0/d5-1-(2-oxo-2-(piperazin-1-yl) ethyl) pyridine-1-ium (d0/d5-OPEPI) were designed and synthesized, and an in-depth screening strategy for FAs and FOHs was established based on d0/d5-OPEPI coupled with liquid chromatography-tandem high-resolution mass spectrometry (LC-HRMS/MS). Using this approach, a total of 332 metabolites were identified and annotated (some of the FAs and FOHs were reconfirmed by standards). Our results demonstrated that OPEPI labeling could significantly enhance the MS response of FAs and FOHs via the introduction of permanently charged tags. The detection sensitivities of FAs were increased by 200-2345-fold compared with the nonderivatization method. At the same time, for FOHs, due to the absence of ionizable functional groups, sensitive detection was achieved utilizing OPEPI derivatization. One-to-one internal standards were provided by using d5-OPEPI labeling to minimize the errors in quantitation. Moreover, the method validation results showed that the method was stable and reliable. Finally, the established method was successfully applied to the study of the FA and FOH profiles of two heterogeneous severe clinical disease tissues. This study would improve our understanding of the pathological and metabolic mechanisms of FAs and FOHs for inflammatory myopathies and pancreatic cancer and also prove the generality and accuracy of the developed analytical method for complex samples.
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Miosite , Neoplasias Pancreáticas , Humanos , Ácidos Graxos/análise , Espectrometria de Massas em Tandem/métodos , Álcoois Graxos , Isótopos , Neoplasias PancreáticasRESUMO
In the past decade, an increasing number of studies have found a relationship between the occurrence and development of depression and autoimmune diseases, and the high prevalence of depression in patients with connective tissue diseases has also been confirmed. Primary Sjögren's syndrome (pSS) is a chronic autoimmune exocrinopathy characterised by lymphocytic infiltration and exocrine gland destruction. Depression in pSS patients is common, and the factors contributing to this condition are complicated. pSS patients with depression generally have a lower quality of life than pSS patients without depression. Several pathophysiological mechanisms involved in the condition have been proposed in recent years. Thus, in this review, we summarised recent progress on the impact of depression on pSS patients' quality of life, the possible pathogenesis underlying the development of depression in pSS patients and the management of such patients.
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Doenças Autoimunes , Síndrome de Sjogren , Doenças Autoimunes/complicações , Depressão/epidemiologia , Depressão/etiologia , Humanos , Prevalência , Qualidade de Vida , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnósticoRESUMO
Gut dysbiosis precedes clinic symptoms in rheumatoid arthritis (RA) and has been implicated in the initiation and persistence of RA. The early treatment of RA is critical to better clinical outcome especially for joint destruction. Although dietary interventions have been reported to be beneficial for RA patients, it is unclear to whether diet-induced gut microbiome changes can be a preventive strategy to RA development. Here, we investigated the effect of a high fiber diet (HFD) rich with resistant starch (RS) on collagen-induced arthritis (CIA) and gut microbial composition in mice. RS-HFD significantly reduced arthritis severity and bone erosion in CIA mice. The therapeutic effects of RS-HFD were correlated with splenic regulatory T cell (Treg) expansion and serum interleukin-10 (IL-10) increase. The increased abundance of Lactobacillus and Lachnoclostridium genera concomitant with CIA were eliminated in CIA mice fed the RS-HFD diet. Notably, RS-HFD also led to a predominance of Bacteroidetes, and increased abundances of Lachnospiraceae_NK4A136_group and Bacteroidales_S24-7_group genera in CIA mice. Accompanied with the gut microbiome changes, serum levels of the short-chain fatty acid (SCFA) acetate, propionate and isobutyrate detected by GC-TOFMS were also increased in CIA mice fed RS-HFD. While, addition of ß-acids from hops extract to the drinking water of mice fed RS-HFD significantly decreased serum propionate and completely eliminated RS-HFD-induced disease improvement, Treg cell increase and IL-10 production in CIA mice. Moreover, exogenous propionate added to drinking water replicated the protective role of RS-HFD in CIA including reduced bone damage. The direct effect of propionate on T cells in vitro was further explored as at least one mechanistic explanation for the dietary effects of microbial metabolites on immune regulation in experimental RA. Taken together, RS-HFD significantly reduced CIA and bone damage and altered gut microbial composition with concomitant increase in circulating propionate, indicating that RS-rich diet might be a promising therapy especially in the early stage of RA.
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Artrite Experimental/prevenção & controle , Dieta Hiperlipídica , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Propionatos/metabolismo , Amido Resistente/administração & dosagem , Animais , Artrite Experimental/sangue , Artrite Experimental/metabolismo , Bactérias/classificação , Bactérias/genética , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Ácidos Graxos Voláteis/sangue , Microbioma Gastrointestinal/genética , Humanos , Interleucina-10/sangue , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/microbiologia , Masculino , Camundongos Endogâmicos DBA , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
The production of ß-lactamases represents the main cause of resistance to clinically important ß-lactam antibiotics. Boron containing compounds have been demonstrated as promising broad-spectrum ß-lactamase inhibitors to combat ß-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which manifested broad-spectrum inhibition to representative serine-ß-lactamases (SBLs) and metallo-ß-lactamases (MBLs). The most potent inhibitor 9f displayed an IC50 value of 86 nM to KPC-2 SBL and micromolar inhibitory activity towards other tested enzymes. Cell-based assays further revealed that 9f was able to significantly reduce the MICs of meropenem in clinically isolated KPC-2-producing bacterial strains and it showed no apparent toxicity in HEK293T cells.
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Compostos de Boro/farmacologia , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/farmacologia , Sítios de Ligação , Compostos de Boro/síntese química , Compostos de Boro/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Células HEK293 , Humanos , Concentração Inibidora 50 , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/metabolismo , Meropeném/farmacologia , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Inibidores de beta-Lactamases/químicaAssuntos
Artrite Reumatoide , Fibroblastos , Glicólise , Lipopolissacarídeos , Metotrexato , Sinoviócitos , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Metotrexato/farmacologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Glicólise/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Lipopolissacarídeos/farmacologia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Células CultivadasRESUMO
OBJECTIVE: The present study was performed to localize the articular deposition of monosodium urate (MSU) crystal in joints. We compare the detection efficiencies of dual-energy CT (DECT) and ultrasound scans. METHODS: Analyses by DECT and ultrasound were performed with 184 bilateral joints of the lower limbs of 54 consecutive gout patients. All joints were categorized into (1) knee, (2) ankle, (3) MTP1, and (4) MTP2, and sorted into those with and those without detectable MSU deposition. The comparison of the positive rate between DECT and ultrasound and the agreement was performed using the McNemar test and the Cohen's κ coefficient, respectively. Next, we listed the MSU crystal deposition as assessed by ultrasound between the DECT-positive and -negative joints according to their interior structure. We included tendons, synovia, cartilage, subcutaneous tissue, etc. RESULTS: Among all joints, the percentages with MSU crystal deposition detected by DECT (99/184, 53.8%) and ultrasound (106/184, 57.6%) were comparable (P = 0.530 > 0.05). For MTP1 (21/34, 61.8%; 12/34, 35.3%; P < 0.05) and MTP2-5 (17/34, 50.0%; 10/34, 29.4%, P < 0.05), ultrasound and DECT were more efficient, respectively. The data concordance in 46 of 50 joints (92.00%; κ = 0.769, P < 0.05) for knee; and 27 of 34 joints (79.41%; κ = 0.588, P < 0.05) for MTP2-5 and suggested that tendons were the most frequent anatomical location of MSU crystal deposition. CONCLUSIONS: The tendons are the most frequent anatomical location of MSU crystal depositions. The concordance rate of knee joints and MTP2-5 joints shows good agreement between DECT and ultrasound depending on the location.
Assuntos
Articulação do Tornozelo/diagnóstico por imagem , Gota/diagnóstico por imagem , Articulação do Joelho/diagnóstico por imagem , Tendões/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Ultrassonografia , Ácido Úrico/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Articulação do Tornozelo/química , Cristalização , Feminino , Gota/metabolismo , Humanos , Articulação do Joelho/química , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Tendões/química , Adulto JovemRESUMO
BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved. METHODS: The expression of synovial genes from six control individuals, seven OA patients, and nineteen PVNS patients was analyzed via RNA sequencing. Protein profiles from five control individuals, ten OA patients, and thirty-two PVNS patients were analyzed using label-free proteomics. Microarray and RT-PCR analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from PVNS tissue. Various signaling pathway inhibitors, siRNAs, and western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed. RESULTS: In total, 522 differentially expressed proteins were identified in the PVNS tissues. By integrating RNA sequencing and microarray analyses, significant changes in the expression of EMT-related genes, including TGFBI, N-cadherin, E-cadherin, SNAIL, and TWIST, were confirmed in the PVNS tissue compared to the control tissue. In vitro, TGF-ß induced EMT and increased epithelial cell migration and invasion. Moreover, TGF-ß not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways. CONCLUSION: This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGF-ß in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy.
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Euphorbia L. is a traditionally used herb and contains many newly identified compounds with novel chemical structures. Euphorbia factor L2 (EFL2), a diterpenoid derived from Euphorbia seeds, is reported to alleviate acute lung injury and arthritis by exerting anti-inflammatory effects. In this study, we aimed to test the therapeutic benefit and mechanisms of EFL2 in NLRP3 inflammasome-mediated gouty models and identified the potential molecular mechanism. A cell-based system was used to test the specific inhibitory effect of EFL2 on NLRP3-related inflammation. The gouty arthritis model and an air pouch inflammation model induced by monosodium urate monohydrate (MSU) crystals were used for in vivo experiments. Nlrp3-/- mice and in vitro studies were used for mechanistic exploration. Virtual molecular docking and biophysical assays were performed to identify the direct binding and regulatory target of EFL2. The inhibitory effect of EFL2 on inflammatory cell infiltration was determined by flow cytometry in vivo. The mechanism by which EFL2 activates the NLRP3 inflammasome signaling pathway was evaluated by immunological experiment and transmission electron microscopy. In vitro, EFL2 specifically reduced NLRP3 inflammasome-mediated IL-1ß production and alleviated MSU crystal-induced arthritis, as well as inflammatory cell infiltration. EFL2 downregulated NF-κB phosphorylation and NLRP3 inflammasome expression by binding to glucocorticoid receptors. Moreover, EFL2 could specifically suppress the lysosome damage-mediated NLRP3 inflammasome activation process. It is expected that this work may be useful to accelerate the development of anti-inflammatory drugs originated from traditional herbs and improve therapeutics in gout and its complications.
Assuntos
Anti-Inflamatórios , Euphorbia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/imunologia , Artrite Gotosa/metabolismo , Artrite Gotosa/induzido quimicamente , Modelos Animais de Doenças , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Euphorbia/química , Gota/tratamento farmacológico , Gota/imunologia , Gota/patologia , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido ÚricoRESUMO
To evaluate and optimize antigen retrieval (AR) methods for the detection of NF-κB, interleukin-1ß, interleukin-6, interferon regulatory factor 5 and matrix metalloproteinase-3 expression in mouse joint tissue using immunohistochemistry (IHC). This study evaluated the differences in several AR methods, including pressure cooking (PC), microwave treatment (MW), water bath cooking (WB), trypsin retrieval (TYR), improved water bath cooking (IWB), and enhanced alkaline pH of IWB (EIWB), in tissue integrity maintenance and IHC staining specificity. The AR methods of TYR and IWB maintained the integrity of the tissue to a great extent. The PC, MW, WB, and EIWB resulted in tissue detachment and were not appropriate for subsequent IHC staining. TYR maintained better tissue morphology and staining intensity than IWB, while the IWB retrieval method had a higher percentage of IHC-positive staining and a less nonspecific background. Both the TYR and IWB AR methods were suitable for IHC staining and could effectively resolve the challenges of tissue detachment, insufficient staining, and nonspecific background in paraffin sections of mouse decalcified joint tissues.
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Antígenos , Água , Animais , Camundongos , Imuno-Histoquímica , Inclusão em Parafina , Coloração e Rotulagem , Fixação de Tecidos/métodosRESUMO
B cells play an important role in adaptive immunity and participate in the process of humoral immunity mainly by secreting antibodies. The entire development and differentiation process of B cells occurs in multiple microenvironments and is regulated by a variety of environmental factors and immune signals. Differentiation biases or disfunction of B cells participate in the process of many autoimmune diseases. Emerging studies report the impact of altered metabolism in B cell biology, including lipid metabolism. Here, we discuss how extracellular lipid environment and metabolites, membrane lipid-related components, and lipid synthesis and catabolism programs coordinate B cell biology and describe the crosstalk of lipid metabolic programs with signal transduction pathways and transcription factors. We conclude with a summary of therapeutic targets for B cell lipid metabolism and signaling in autoimmune diseases and discuss important future directions.
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Interstitial lung disease (ILD) is a highly fatal manifestation of idiopathic inflammatory myopathies (IIMs). Th cells play important roles in the initiation of ILD. Here, we investigated the clinical significance of peripheral blood Th cells in IIMs-ILD patients. Eleven healthy controls (HC) and 53 patients diagnosed with IIMs were included, including 30 with ILD (IIMs-ILD) and 23 without ILD (IIMs-non-ILD). Circulating Th1, Th2, Th17, and Treg cells were examined by flow cytometry, and their correlation with clinical and laboratory findings was analyzed by Spearman's correlation and logistic regression. The proportion of Th1 cells decreased and Th2 cells increased in IIMs-ILD compared with IIMs-non-ILD (median (quartile): 2.99 (1.59-5.39) vs. 6.91 (3.48-10.04), p < 0.001; 2.67 (1.79-4.67) vs. 1.62 (0.85-2.66), p = 0.006) and correlated with disease activity. The Th1-cell proportion decreased in anti-MDA5 antibody-positive patients, while the Th2 cell proportion increased in patients with nonspecific interstitial pneumonia compared with IIMs-non-ILD (2.66 (1.06-4.35) vs. 6.91 (3.48-10.04), p = 0.002; 3.09 (2.03-5.72) vs. 1.62 (0.85-2.66), p = 0.016). Univariate analysis showed that a lower Th1 proportion, higher Th2 proportion increased, lower CK level, positivity for ARS, or anti-Ro52 antibodies (OR = 0.7122; OR = 1.679; OR = 0.9993; OR = 9.188; and OR = 6.161, respectively) were associated with the occurrence of ILD in IIMs patients. Decreased Th1 cells and elevated Th2 cells in peripheral blood may be involved in the pathogenesis of ILD in IIMs patients and have different effects on different serological and imaging subtypes.
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Pneumonias Intersticiais Idiopáticas , Doenças Pulmonares Intersticiais , Miosite , Humanos , Células Th2 , Células Th1 , Doenças Pulmonares Intersticiais/complicações , Miosite/complicações , AutoanticorposRESUMO
In this study, the available data from published randomized, controlled trials (RCTs) of the use of intestinal microecological regulators as adjuvant therapies to relieve the disease activity of rheumatoid arthritis (RA) are systematically compared. An English literature search was performed using PubMed, Embase, Scopus, Web of Science and the Cochrane Central Registry of Controlled Trials and supplemented by hand searching reference lists. Three independent reviewers screened and assessed the quality of the studies. Among the 2355 citations identified, 12 RCTs were included. All data were pooled using a mean difference (MD) with a 95% CI. The disease activity score (DAS) showed a significant improvement following microecological regulators treatment (MD (95% CI) of -1.01 (-1.81, -0.2)). A borderline significant reduction in the health assessment questionnaire (HAQ) scores was observed (MD (95% CI) of -0.11 (-0.21, -0.02)). We also confirmed the known effects of probiotics on inflammatory parameters such as the C-reactive protein (CRP) (MD -1.78 (95% CI -2.90, -0.66)) and L-1ß (MD -7.26 (95% CI -13.03, -1.50)). No significant impact on visual analogue scale (VAS) of pain and erythrocyte sedimentation rate (ESR) reduction was observed. Intestinal microecological regulators supplementation could decrease RA activity with a significant effect on DAS28, HAQ and inflammatory cytokines. Nevertheless, these findings need further confirmation in large clinical studies with greater consideration of the confounding variables of age, disease duration, and individual medication regimens.
Assuntos
Artrite Reumatoide , Probióticos , Humanos , Artrite Reumatoide/tratamento farmacológico , Probióticos/uso terapêutico , Suplementos Nutricionais , Proteína C-Reativa , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Patients with idiopathic inflammatory myopathies (IIMs), referred to as myositis, are prone to infectious complications, which hinder the treatment of the disease and worsen the outcome of patients. The purpose of this study was to explore the different types of infectious complications in patients with myositis and to determine the predisposing factors for clinical reference. A retrospective study was conducted on 66 patients with IIM who were divided into different subpopulations by an unsupervised analysis of their clinical manifestations, laboratory features, and autoantibody characteristics. Combined with the incidence of infectious complications, the types of infectious pathogens and the sites of infection, the characteristics of infection, and susceptibility factors were explored. Three clusters with significantly different clinical characteristics and coinfection rates were identified (76.2% vs. 41.6% vs. 36.4%, p = 0.0139). Cluster 1 (n = 12) had a moderate risk of infection, with an infection rate of 41.6%. The patients in cluster 1 had a high probability of positive mechanic's hands, periungual erythema, anti-Ro52 antibody, and anti-Jo1 antibody. CD3 and CD4 were the highest among the three groups. Cluster 2 (n = 21) had a high risk of infection, and the incidence of infection was 76.2%. Almost all patients in this cluster had a rash, prominent clinical symptoms, and decreased WBC, PMN, LYM, CD3, and CD4 counts. Cluster 3 (n = 33) had a low risk of infection, with an infection rate of 36.4%. Compared with the other two clusters, cluster 3 (n = 33) lacked a typical rash but had a high ANA-positive rate. The patients in cluster 1 and cluster 3 were mainly infected by viruses, followed by bacterial infections. In cluster 2 patients, bacterial infections were the most prevalent. Fungal and Pneumocystis carinii were common causes of cluster 2 and 3 infections. In addition, the patients within a cluster often have a single infection, and pulmonary infections are the most common. We clustered the patients with IIM complicated with infection into three different types by their clinical symptoms and found that there were differences in the infection risk and infection types among the different cluster groups.