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BACKGROUND: The association between psoriasis and pulmonary fibrosis has been reported in observational studies. However, the association is vulnerable to bias from using immunosuppressants such as methotrexate, which can cause fibrosis in multiple organs. The present study is to investigate whether psoriasis could independently increase the risk of idiopathic pulmonary fibrosis (IPF). METHODS: We conducted a two-sample Mendelian randomization (MR) study using summary statistics from genome-wide association studies. The random-effects inverse variance weighted analysis was used as the primary method. Some secondary analyses were further performed, including a sensitivity analysis using a genetic instrument that excluded extended single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) gene region. RESULTS: Our study included 9267 cases and 364,071 controls for psoriasis, 2018 cases, and 373,064 controls for IPF of European ancestry, respectively. Genetically predicted psoriasis was associated with a higher risk of IPF (odds ratio (OR), 1.14; 95% confidence interval (CI), 1.08-1.22; P < 0.001). Sensitivity analyses did not uncover any statistically significant evidence of bias resulting from pleiotropy or the genetic instruments, including SNPs in the MHC gene region. CONCLUSIONS: These MR analyses support that genetically predicted psoriasis was associated with the risk of IPF, implying that pulmonary fibrosis in patients with psoriasis should not be neglected, even if they are not receiving immunosuppressant therapy.
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Fibroblasts are crucial components of the skin structure. They were traditionally believed to maintain the skin's structure by producing extracellular matrix and other elements. Recent research illuminated that fibroblasts can respond to external stimuli and exhibit diverse functions, such as the secretion of pro-inflammatory factors, adipogenesis, and antigen presentation, exhibiting remarkable heterogeneity and plasticity. This revelation positions fibroblasts as active contributors to the pathogenesis of skin diseases, challenging the traditional perspective that views fibroblasts solely as structural entities. Based on their diverse functions, fibroblasts can be categorized into six subtypes: pro-inflammatory fibroblasts, myofibroblasts, adipogenic fibroblasts, angiogenic fibroblasts, mesenchymal fibroblasts, and antigen-presenting fibroblasts. Cytokines, metabolism, and epigenetics regulate functional abnormalities in fibroblasts. The dynamic changes fibroblasts exhibit in different diseases and disease states warrant a comprehensive discussion. We focus on dermal fibroblasts' aberrant manifestations and pivotal roles in inflammatory and autoimmune skin diseases, including psoriasis, vitiligo, lupus erythematosus, scleroderma, and atopic dermatitis, and propose targeting aberrantly activated fibroblasts as a potential therapeutic strategy for inflammatory and autoimmune skin diseases.
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BACKGROUND: The pathogenesis and treatment of colorectal cancer (CRC) continue to be areas of ongoing research, especially the benefits of traditional Chinese medicine (TCM) in slowing the progression of CRC. This study was conducted to investigate the effectiveness and mechanism of action of modified Lichong decoction (MLCD) in inhibiting CRC progression. METHODS: We established CRC animal models using azoxymethane/dextran sodium sulfate (AOM/DSS) and administered high, medium, or low doses of MLCD or mesalazine (MS) for 9 weeks to observe MLCD alleviation of CRC. The optimal MLCD dose group was then subjected to metagenomic and RNA sequencing (RNA-seq) to explore the differentially abundant flora and genes in the control, model and MLCD groups. Finally, the mechanism of action was verified using WB, qRTâPCR, immunohistochemistry and TUNEL staining. RESULTS: MLCD inhibited the progression of CRC, and the optimal effect was observed at high doses. MLCD regulated the structure and function of the intestinal flora by decreasing the abundance of harmful bacteria and increasing that of beneficial bacteria. The differentially expressed genes were mainly associated with the Wnt/ß-catenin pathway and the cell cycle. Molecular biology analysis indicated that MLCD suppressed the Wnt/ß-catenin pathway and the epithelial-mesenchymal transition (EMT), inhibited abnormal cell proliferation and promoted intestinal epithelial cell apoptosis. CONCLUSION: MLCD mitigated the abnormal growth of intestinal epithelial cells and promoted apoptosis, thereby inhibiting the progression of CRC. This inhibition was accomplished by modifying the intestinal microbiota and disrupting the Wnt/ß-catenin pathway and the EMT. Therefore, MLCD could serve as a potential component of TCM prescriptions for CRC treatment.
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Neoplasias Colorrectales , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Vía de Señalización Wnt , Vía de Señalización Wnt/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ratones , Humanos , Masculino , Apoptosis/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sulfato de Dextran , beta Catenina/metabolismo , Modelos Animales de EnfermedadRESUMEN
Gut-tropic T cells primarily originate from gut-associated lymphoid tissue (GALT), and gut-tropic integrins mediate the trafficking of the T cells to the gastrointestinal tract, where their interplay with local hormones dictates the residence of the immune cells in both normal and compromised gastrointestinal tissues. Targeting gut-tropic integrins is an effective therapy for inflammatory bowel disease (IBD). Gut-tropic T cells are further capable of entering the peripheral circulatory system and relocating to multiple organs. There is mounting evidence indicating a correlation between gut-tropic T cells and extra-intestinal autoimmune disorders. This review aims to systematically discuss the origin, migration, and residence of gut-tropic T cells and their association with extra-intestinal autoimmune-related diseases. These discoveries are expected to offer new understandings into the development of a range of autoimmune disorders, as well as innovative approaches for preventing and treating the diseases.
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In the field of contemporary medicine, autoimmune diseases (AIDs) are a prevalent and debilitating group of illnesses. However, they present extensive and profound challenges in terms of etiology, pathogenesis, and treatment. A major reason for this is the elusive pathophysiological mechanisms driving disease onset. Increasing evidence suggests the indispensable role of B cells in the pathogenesis of autoimmune diseases. Interestingly, B-cell receptor (BCR) repertoires in autoimmune diseases display a distinct skewing that can provide insights into disease pathogenesis. Over the past few years, advances in high-throughput sequencing have provided powerful tools for analyzing B-cell repertoire to understand the mechanisms during the period of B-cell immune response. In this paper, we have provided an overview of the mechanisms and analytical methods for generating BCR repertoire diversity and summarize the latest research progress on BCR repertoire in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), and type 1 diabetes (T1D). Overall, B-cell repertoire analysis is a potent tool to understand the involvement of B cells in autoimmune diseases, facilitating the creation of innovative therapeutic strategies targeting specific B-cell clones or subsets.
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Artritis Reumatoide , Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Síndrome de Sjögren , Humanos , Linfocitos B , Receptores de Antígenos de Linfocitos BRESUMEN
BACKGROUND: Increasing evidence has highlighted the significant role of histone modifications in pathogenesis of systemic lupus erythematosus (SLE). However, few studies have comprehensively analyzed trimethylation of histone H3 lysine 4 (H3K4me3) features at specific immune gene loci in SLE patients. METHODS: We conducted H3K4me3 chromatin immunoprecipitation sequencing (ChIP-seq) on CD4+ T cells from SLE patients and healthy controls (HC). Differential H3K4me3 peaks were identified, followed by enrichment analysis. We integrated online RNA-seq and DNA methylation datasets to explore the relationship between H3K4me3 modification, DNA methylation and gene expression. We validated several upregulated peak regions by ChIP-qPCR and confirmed their impact on gene expression using RT-qPCR. Finally, we investigated the impact of H3K4 methyltransferases KMT2A on the expression of immune response genes. RESULTS: we identified 147 downregulated and 2701 upregulated H3K4me3 peaks in CD4+ T cells of SLE. The upregulated peaks primarily classified as gained peaks and enriched in immune response genes such as FCGR2A, C5AR1, SERPING1 and OASL. Genes with upregulated H3K4me3 and downregulated DNA methylations in the promoter were highly expressed in SLE patients. These genes, including OAS1, IFI27 and IFI44L, were enriched in immune response pathways. The IFI44L locus also showed increased H3K27ac modification, chromatin accessibility and chromatin interactions in SLE. Moreover, knockdown of KMT2A can downregulate the expression of immune response genes in T cells. CONCLUSION: Our study uncovers dysregulated H3K4me3 modification patterns in immune response genes loci, which also exhibit downregulated DNA methylation and higher mRNA expression in CD4+ T cells of SLE patients.
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Linfocitos T CD4-Positivos , Cromatina , Histonas , Lupus Eritematoso Sistémico , Humanos , Linfocitos T CD4-Positivos/inmunología , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Metilación de ADN , Histonas/metabolismo , Inmunidad/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunologíaRESUMEN
BACKGROUND AND AIMS: Atherosclerosis (AS) is a continuously low-grade inflammatory disease, and monocyte-derived macrophages play a vital role in AS pathogenesis. Regulatory factor X1 (RFX1) has been reported to participate in differentiation of various cells. Our previous report showed that RFX1 expression in CD14+ monocytes from AS patients was decreased and closely related to AS development. Macrophages mostly derive from monocytes and play an important role in AS plaque formation and stability. However, the functions of RFX1 in the formation of macrophage-derived foam cells and consequent AS development are unclear. METHODS: We explored the effects of RFX1 on oxidation low lipoprotein (ox-LDL)-stimulated foam cell formation and CD36 expression by increasing or silencing Rfx1 expression in mouse peritoneal macrophages (PMAs). The ApoE-/-Rfx1f/f or ApoE-/-Rfx1f/f Lyz2-Cre mice fed a high-fat diet for 24 weeks were used to further examine the effect of RFX1 on AS pathogenesis. We then performed dual luciferase reporter assays to study the regulation of RFX1 for CD36 transcription. RESULTS: Our results demonstrate that RFX1 expression was significantly reduced in ox-LDL induced foam cells and negatively correlated with lipid uptake in macrophages. Besides, Rfx1 deficiency in myeloid cells aggravated atherosclerotic lesions in ApoE-/- mice. Mechanistically, RFX1 inhibited CD36 expression by directly regulating CD36 transcription in macrophages. CONCLUSIONS: The reduction of RFX1 expression in macrophages is a vital determinant for foam cell formation and the initiation of AS, proving a potential novel approach for the treatment of AS disease.
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Aterosclerosis , Antígenos CD36 , Células Espumosas , Animales , Humanos , Ratones , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Células Espumosas/citología , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Factor Regulador X1/metabolismo , Antígenos CD36/metabolismoRESUMEN
Rationale: Macrophage-associated inflammation and keratinocytes excessive proliferation and inflammatory cytokines secretion induced by stimulation play an important role in the progression of psoriasiform dermatitis. However, how these two types of cells communicate remains obscure. Methods: We induced a mouse model with experimental psoriasiform dermatitis by Imiquimod (IMQ). To investigate whether damaged keratinocytes promote macrophage polarization and accelerate skin lesions by releasing extracellular vesicle (EV), purified EV were isolated from the primary epidermis of 5-day IMQ-induced psoriasiform dermatitis model mice, and then fluorescence-labeled the EV with PKH67. The EV was injected into the skin of mice treated with IMQ or vehicle 2 days in situ. In addition, we established a co-culture system of the human monocytic cell line (THP-1) and HaCaT, and THP-1/HaCaT conditioned media culture model in vitro respectively. Subsequently, we evaluated the effect of Leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EV on macrophage activation. Results: We demonstrated macrophages can significantly promote keratinocyte inflammation and macrophage polarization may be mediated by intercellular communication with keratinocytes. Interestingly, IMQ-induced 5-day, keratinocyte-derived EV recruited macrophage and enhanced the progression of skin lesions. Similar to results in vivo, EV released from M5-treated HaCaT significantly promotes Interleukin 1ß (IL-1ß) and Tumor necrosis factor α (TNF-α) expression of THP-1 cells. Importantly, we found that LRG1-enriched EV regulates macrophages via TGF beta Receptor 1 (TGFßR1) dependent process. Conclusion: Our findings indicated a novel mechanism for promoting psoriasiform dermatitis, which could be a potential therapeutic target.
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Dermatitis , Vesículas Extracelulares , Humanos , Animales , Ratones , Queratinocitos , Macrófagos , Glicoproteínas , InflamaciónRESUMEN
Abnormal macrophage polarization is generally present in autoimmune diseases. Overwhelming M1 macrophage activation promotes the continuous progression of inflammation, which is one of the reasons for the development of autoimmune diseases. However, the underlying mechanism is still unclear. Here we explore the function of Regulatory factor X1 (RFX1) in macrophage polarization by constructing colitis and lupus-like mouse models. Both in vivo and in vitro experiments confirmed that RFX1 can promote M1 and inhibit M2 macrophage polarization. Furthermore, we found that RFX1 promoted DNA demethylation of macrophage polarization-related genes by increasing APOBEC3A/Apobec3 expression. We identified a potential RFX1 inhibitor, adenosine diphosphate (ADP), providing a potential strategy for treating autoimmune diseases.
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Enfermedades Autoinmunes , Activación de Macrófagos , Animales , Ratones , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Desmetilación del ADN , Inflamación/metabolismo , Macrófagos/metabolismo , Factor Regulador X1/metabolismoRESUMEN
As an autoimmune disease, systemic lupus erythematosus (SLE) can affect multiple organs and systems. Whether SLE can increase the risk of coeliac disease (CeD) was not evaluated until now. We performed a two-sample Mendelian randomisation study to evaluate the relationship between SLE and CeD, and found that SLE can significantly increase the risk of CeD, suggesting the association between SLE and abnormal intestinal immune microenvironment.
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Enfermedades Autoinmunes , Enfermedad Celíaca , Lupus Eritematoso Sistémico , Humanos , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/genética , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/genéticaRESUMEN
A variety of immune cells or tissues are present in the gut to form the gut immune microenvironment by interacting with gut microbiota, and to maintain the gut immune homeostasis. Accumulating evidence indicated that gut microbiota dysbiosis might break the homeostasis of the gut immune microenvironment, which was associated with many health problems including autoimmune diseases. Moreover, disturbance of the gut immune microenvironment can also induce extra-intestinal autoimmune disorders through the migration of intestinal pro-inflammatory effector cells from the intestine to peripheral inflamed sites. This review discussed the composition of the gut immune microenvironment and its association with autoimmunity. These findings are expected to provide new insights into the pathogenesis of various autoimmune disorders, as well as novel strategies for the prevention and treatment against related diseases.
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BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4+ T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m6A) modification and CD4+ T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m6A methyltransferase like 3 (METTL3) in CD4+ T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo. METHODS: The expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4+ T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m6A RNA-immunoprecipitation qPCR was applied to confirm the m6A modification of METTL3 targets. RESULTS: METTL3 was defective in the CD4+ T cells of SLE patients. METTL3 expression varied following CD4+ T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4+ T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m6A-dependent manner, hence suppressing Treg cell differentiation. CONCLUSION: In summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m6A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4+ T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE.
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Lupus Eritematoso Sistémico , Metiltransferasas , Linfocitos T Reguladores , Animales , Ratones , Diferenciación Celular , Factores de Transcripción Forkhead/genética , Metiltransferasas/genética , Metiltransferasas/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
The macrophage is an essential part of the innate immune system and also serves as the bridge between innate immunity and adaptive immune response. As the initiator and executor of the adaptive immune response, macrophage plays an important role in various physiological processes such as immune tolerance, fibrosis, inflammatory response, angiogenesis and phagocytosis of apoptotic cells. Consequently, macrophage dysfunction is a vital cause of the occurrence and development of autoimmune diseases. In this review, we mainly discuss the functions of macrophages in autoimmune diseases, especially in systemic lupus erythematosus (SLE), rheumatic arthritis (RA), systemic sclerosis (SSc) and type 1 diabetes (T1D), providing references for the treatment and prevention of autoimmune diseases.
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Artritis Reumatoide , Enfermedades Autoinmunes , Diabetes Mellitus Tipo 1 , Lupus Eritematoso Sistémico , Humanos , Enfermedades Autoinmunes/etiología , Macrófagos , Diabetes Mellitus Tipo 1/etiologíaRESUMEN
Discoid lupus erythematosus (DLE) and systemic lupus erythematosus (SLE) are both types of lupus, yet the characteristics, and differences between them are not fully understood. Here we show single-cell RNA sequencing data of cutaneous lesions from DLE and SLE patients and skin tissues from healthy controls (HCs). We find significantly higher proportions of T cells, B cells and NK cells in DLE than in SLE. Expanded CCL20+ keratinocyte, CXCL1+ fibroblast, ISGhiCD4/CD8 T cell, ISGhi plasma cell, pDC, and NK subclusters are identified in DLE and SLE compared to HC. In addition, we observe higher cell communication scores between cell types such as fibroblasts and macrophage/dendritic cells in cutaneous lesions of DLE and SLE compared to HC. In summary, we clarify the heterogeneous characteristics in cutaneous lesions between DLE and SLE, and discover some specific cell subtypes and ligand-receptor pairs that indicate possible therapeutic targets of lupus erythematosus.
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Lupus Eritematoso Discoide , Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Discoide/genética , Lupus Eritematoso Discoide/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Piel/metabolismo , Linfocitos T CD8-positivosRESUMEN
Subacute cutaneous lupus erythematosus (SCLE) is a clinical subtype of cutaneous lupus erythematosus with psoriatic-like or annular papules with scaly erythemas, the pathological mechanism of which is poorly understood. To investigate the immune pathogenesis of SCLE, we performed single-cell RNA sequencing (scRNA-seq) of SCLE skin lesions and integrated the scRNA-seq data from skin tissues of healthy controls (HCs). Our results identified expanded fibroblasts and keratinocytes subtypes, abnormally activated lymphocyte and inflammatory M1 macrophages in SCLE. In SCLE, stromal cells, such as keratinocytes and fibroblasts, showed enhanced chemotactic functions for recruiting immune cells. Importantly, interferon-related genes were identified as key intermediate genes in the potential trajectory of fibroblasts, keratinocytes, and B cells from HCs to SCLE. Our investigation provides a comprehensive description of cell composition in SCLE and highlights several important clues for understanding the pathogenesis of SCLE.
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Lupus Eritematoso Cutáneo , Transcriptoma , Humanos , Lupus Eritematoso Cutáneo/genética , Piel , Queratinocitos , Linfocitos B/patologíaRESUMEN
OBJECTIVE: The perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin plus docetaxel (FLOT) was recommended by the Chinese Society of Clinical Oncology Guidelines for gastric cancer (2018 edition) for patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (class IIA). However, the economic impact of FLOT chemotherapy in China remains unclear. The analysis aimed to compare the cost-effectiveness of FLOT versus epirubicin, cisplatin plus fluorouracil or capecitabine (ECF/ECX) in patients with locally advanced resectable tumours. DESIGN: We developed a Markov model to compare the healthcare and economic outcomes of FLOT and ECF/ECX in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. Costs were estimated from the perspective of Chinese healthcare system. Clinical and utility inputs were derived from the FLOT4 phase II/III clinical trial and published literature. Sensitivity analyses were employed to assess the robustness of our result. The annual discount rate for costs and health outcomes was set at 5%. OUTCOME MEASURES: The primary outcome of incremental cost-effectiveness ratios (ICERs) was calculated as the cost per quality-adjusted life years (QALYs). RESULTS: The base-case analysis found that compared with ECF/ECX, the use of FLOT chemotherapy was associated with an additional 1.08 QALYs, resulting in an ICER of US$851/QALY. One-way sensitivity analysis results suggested that the HR of overall survival and progression-free survival had the greatest impact on the ICER. Probabilistic sensitivity analysis demonstrated that FLOT was more likely to be cost-effective compared with ECF/ECX at a willingness-to-pay threshold of US$31 513/QALY. CONCLUSIONS: For patients with locally advanced resectable tumours, the FLOT chemotherapy is a cost-effective treatment option compared with ECF/ECX in China. TRIAL REGISTRATION NUMBER: NCT01216644.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/uso terapéutico , Análisis Costo-Beneficio , Docetaxel/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/patología , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patologíaRESUMEN
Background: Infection with Helicobacter pylori (H. pylori) can cause chronic gastritis and other digestive tract diseases, and represents a public health concern. Current anti-H. pylori treatment can result in antibiotic resistance and other adverse reactions. Huangqi Jianzhong decoction (HQJZD) is a prescription form of traditional Chinese medicine for chronic gastritis that increases probiotics and inhibits H. pylori. In this study, its anti-bacterial activity against H. pylori receives a preliminary evaluation, and a pharmacology analysis is performed to predict its underlying mechanisms. Methods: Human GES-1 cells are divided into a blank control group, a model group, a HQJZD low-dose (2.08 mg·mL-1), a high-dose group (4.16 mg·mL-1), and a positive control group (amoxicillin, 5 µg·mL-1). After culture, the CCK-8 method is used to detect cell viability; flow cytometry is used to detect cell apoptosis rate; and RT-qPCR is used to detect the expression of mRNA virulence factors, including HpPrtC, OPiA, IceA1, and BabA2. Network pharmacology analysis and molecular docking were performed to explore the mechanisms of HQJZD in treating H. pylori gastritis, based on its anti-H. pylori infection effect. Results: We noted lower cell survival rates in the model group, but higher apoptosis rates and mRNA expressions of HpPrtC, OPiA, IceA1, and BabA2 than in the control group (p < 0.05). Compared to the model group, the cell survival rate of each dosage group of Huangqi Jianzhong decoction and the positive control group increased significantly, while the apoptosis rate and the mRNA expressions of HpPrtC, OPiA, IceA1, and BabA2 were decreased significantly. The effect in each HQJZD group was dose-dependent (p < 0.05). Network pharmacological analysis involving 159 signaling pathways was used to screen 6 key active components of HQJZD and 102 potential target proteins for the treatment of H. pylori-related gastritis. The molecular docking results revealed that the 6 active compounds had a strong binding ability with the target proteins of ALB, IL-6, AKT1, IL-1B, and JUN. Conclusion: HQJZD effectively increases the proliferation rate of human GES-1 cells after infection, while reducing the level of apoptosis. The mechanism may be related to multiple components, multiple targets and pathways, which provides a scientific basis for further elucidating the mechanism of action, the pharmacodynamic material basis, and the clinical application of HQJZD against H. pylori infection.
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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects various organs or systems. We performed metabolomic and lipidomic profiles analyses of 133 SLE patients and 30 HCs. Differential metabolites and lipids were integrated, and then the biomarker panel was identified using binary logistic regression. We found that a combination of four metabolites or lipids could distinguish SLE from HC with an AUC of 0.998. Three lipids were combined to differentiate inactive SLE and active SLE. The AUC was 0.767. In addition, we also identified the biomarkers for different organ phenotypes of SLE. The AUCs for diagnosing SLE patients with only kidney involvement, skin involvement, blood system involvement, and multisystem involvement were 0.766, 0.718, 0.951, and 0.909, respectively. Our study succeeded in identifying biomarkers associated with different clinical phenotypes in SLE patients, which could facilitate a more precise diagnosis and assessment of disease progression in SLE.
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Lipidómica , Lupus Eritematoso Sistémico , Biomarcadores , Humanos , Lípidos , Lupus Eritematoso Sistémico/genética , MetabolómicaRESUMEN
The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.
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Hierro , Lupus Eritematoso Sistémico , Animales , Diferenciación Celular , Epigénesis Genética , Humanos , Hidroxibutirato Deshidrogenasa/genética , Ratones , Linfocitos T Colaboradores-InductoresRESUMEN
Trace element iron affects T cell biology, but the knowledge about the role of iron in regulating Treg cell expansion is limited. Treg cells play an important role in keeping peripheral T cell tolerance, increasing Treg cell expansion is a promising therapeutic method for SLE. Here we showed that iron deficiency promotes Treg cell expansion by reducing ROS accumulation, improving the disease progression of pristane-induced lupus. Increased oxidative stress inhibits Treg cell differentiation by inducing cell apoptosis. Our data suggest that altering iron metabolism promotes Treg cell expansion by preventing oxidation-induced cell death, which may provide a potential therapeutic strategy for SLE.