Fibroblast expression of neurotransmitter receptor HTR2A associates with inflammation in rheumatoid arthritis joint.

The study of neuroimmune crosstalk and the involvement of neurotransmitters in inflammation and bone health has illustrated their significance in joint-related conditions. One important mode of cell-to-cell communication in the synovial fluid (SF) is through extracellular vesicles (EVs) carrying microRNAs (miRNAs). The role of neurotransmitter receptors in the pathogenesis of inflammatory joint diseases, and whether there are specific miRNAs regulating differentially expressed HTR2A, contributing to the inflammatory processes and bone metabolism is unclear. Expression of neurotransmitter receptors and their correlated inflammatory molecules were identified in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium from a scRNA-seq dataset. Immunohistochemistry staining of synovial tissue (ST) from RA and OA patients was performed for validation. Expression of miRNAs targeting HTR2A carried by SF EVs was screened in low- and high-grade inflammation RA from a public dataset and validated by qPCR. HTR2A reduction by target miRNAs was verified by miRNAs mimics transfection into RA fibroblasts. HTR2A was found to be highly expressed in fibroblasts derived from RA synovial tissue. Its expression showed a positive correlation with the degree of inflammation observed. 5 miRNAs targeting HTR2A were decreased in RA SF EVs compared to OA, three of which, miR-214-3p, miR-3120-5p and miR-615-3p, mainly derived from monocytes in the SF, were validated as regulators of HTR2A expression. The findings suggest that fibroblast HTR2A may play a contributory role in inflammation and the pathogenesis of RA. Additionally, targeting miRNAs that act upon HTR2A could present novel therapeutic strategies for alleviating inflammation in RA.

The transcription factor ZEB2 drives the formation of age-associated B cells.

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.

Efficacy and safety of abatacept for interstitial lung disease associated with antisynthetase syndrome: a case series.

OBJECTIVES: This study investigated the efficacy and safety of abatacept (ABA) in interstitial lung disease (ILD) associated with antisynthetase syndrome (ASS). METHODS: Eight patients were identified through retrospective analysis of the medical records of our centre. All patients fulfilled the Solomon criteria and had a disease complicated with ILD. Lung function, imaging, serum markers, clinical evaluation indicators of ILD, peripheral blood cell classification, cytokines, and prednisone doses were analysed. RESULTS: Seven of the eight patients were female. The mean age was 54.4 (standard deviation [SD] 6.0) years. Antibodies against Jo-1, PL-12, and PL-7 were present in three, three, and two patients respectively. At baseline, the mean diffusing lung capacity for carbon monoxide (DLCO) was 53.8% (SD 9.2%), the mean score of King's Brief Interstitial Lung Disease (KBILD) was 40.6 (SD 13.8), the median Krebs Von den Lungen-6 (KL-6) was 1612.5 (interquartile range [IQR] 1180.5-2431.5) U/ml. All patients experienced symptom alleviation after ABA therapy. The mean and median changes in DLCO percentage, KBILD, and KL-6 were 12.3% (p<0.05), 21.4 (p<0.01), and 174.5U/ml (p<0.01), respectively. No obvious adverse events related to ABA were observed during the treatment. CONCLUSIONS: Our study offers preliminary, but encouraging, clinical evidence in favour of ABA as a therapy for ASS-ILD. ABA demonstrated favourable effects on ILD and was well-tolerated. Well-designed randomised controlled studies are required to confirm the efficacy and safety of this strategy.

Biomarkers for systemic lupus erythematosus - a focus on organ damage.

INTRODUCTION: Systemic lupus erythematosus (SLE) is complex autoimmune disease with heterogenous manifestations, unpredictable disease course and response to treatment. One of the critical needs in SLE management is the identification of reliable biomarkers that can aid in early diagnosis, accurate monitoring of disease activity, and assessment of treatment response. AREAS COVERED: In the current review, we focus on the commonly affected organs (skin, kidney, and nervous system) in SLE to summarize the emerging biomarkers that show promise in disease diagnosis, monitoring and treatment response assessment. The subtitles within each organ domain were determined based on the most relevant and promising biomarkers for that specific organ damage. EXPERT OPINION: Biomarkers have the potential to significantly benefit the management of SLE by aiding in diagnosis, disease activity monitoring, prognosis, and treatment response assessment. However, despite decades of research, none has been validated and implemented for routine clinical use. Novel biomarkers could lead to the development of precision medicine for SLE, guide personalized treatment, and improve patient outcomes. Challenges in biomarker research in SLE include defining clear and clinically relevant questions, accounting for the heterogeneity of SLE, and confirming initial findings in larger, multi-center, multi-ethnic, independent cohorts that reflect real-world clinical scenarios.

WDFY4 polymorphisms in Chinese patients with anti-MDA5 dermatomyositis is associated with rapid progressive interstitial lung disease.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM), is susceptible to development of rapidly progressive interstitial lung disease (RPILD), which has been predominantly reported in East Asia. A Japanese genome-wide study has identified a WDFY4 variant rs7919656 linkage. We sought to evaluate this genetic marker and exploit its possible clinical relevance in Chinese MDA5+DM. METHODS: We genotyped and compared the minor allele A frequency of WDFY4 rs7919656 in patients with MDA5+DM (n = 254) including 190 clinically amyopathic dermatomyositis (CADM), MDA5-DM (n = 53), anti-synthetases syndrome (ASyS, n = 72) and healthy controls (n = 192). Association of the WDFY4 variant with clinical phenotype was evaluated using logistic regression. RESULTS: Although the minor allele A frequencies of WDFY4 rs7919656 in MDA5+DM and CADM were comparable to that in healthy controls, we observed a significant correlation between the WDFY4 variant (GA+AA genotype) and the incidence of RPILD in MDA5+DM (OR: 2.11; 95% CI: 1.21, 3.69; P = 0.007). Moreover, this variant was an independent risk factor for RPILD in multivariate analysis (OR: 4.98; 95% CI: 1.59, 17.19; P = 0.008), along with other well-recognized risk factors, i.e. forced vital capacity % predicted, diffusing capacity for carbon monoxide % predicted, serum ferritin and prednisolone exposure. In addition, this variant was associated with higher expression of WDFY4 in PBMCs of MDA5+DM, especially those with RPILD. WDFY4 overexpression was also observed in lung biopsy of MDA5+DM-RPILD bearing the variant genotype. CONCLUSION: We found that the WDFY4 variant was associated with an increased risk of RPILD, not with disease susceptibility in Chinese MDA5+DM.

Amelioration of Autoimmunity in a Lupus Mouse Model by Modulation of T-Bet-Promoted Energy Metabolism in Pathogenic Age/Autoimmune-Associated B Cells.

OBJECTIVE: Emerging evidence indicates that a distinct CD11c+T-bet+ B cell subset, termed age/autoimmune-associated B cells (ABCs), is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors and metabolic programs to meet specific functional requirements is unclear. We undertook this study to characterize the metabolism of ABCs and to identify the regulators of their metabolic pathways in an effort to develop new therapies for ABC-mediated autoimmunity. METHODS: We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from bm12 mice to induce lupus. We next sorted CD11c+tdTomato+ B cells and conducted RNA sequencing and an extracellular flux assay. A metabolic restriction to constrain ABC formation was tested in human and mouse B cells. We used a bm12-induced lupus mouse model to conduct the metabolic intervention. RESULTS: ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by interferon-γ (IFNγ) signaling. T-bet, a downstream transcription factor of IFNγ, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells. Administration of a glycolysis inhibitor ameliorated ABC accumulation and autoantibody production in the lupus-induced bm12 mouse model. CONCLUSION: T-bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulation of ABCs favored a metabolic program that could be a novel therapeutic approach for lupus.

Bulk RNA Sequencing With Integrated Single-Cell RNA Sequencing Identifies BCL2A1 as a Potential Diagnostic and Prognostic Biomarker for Sepsis.

Background: Sepsis is one of the leading causes of morbidity and mortality worldwide in the intensive care unit (ICU). The prognosis of the disease strongly depends on rapid diagnosis and appropriate treatment. Thus, some new and accurate sepsis-related biomarkers are pressing needed and their efficiency should be carefully demonstrated. Methods: Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were applied to detect sepsis and monocyte/macrophage-related genes. Least absolute shrinkage and selection operator (LASSO) and random forest regression analyses were used in combination to screen out prognostic genes. Single-cell RNA sequence profiling was utilized to further verify the expression of these genes on a single cell level. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were also applied to verify the diagnostic value of the target biomarkers. Results: The intersections of the genes detected by differential expression and WGCNA analyses identified 141 overlapping candidate genes that were closely related to sepsis and macrophages. The LASSO and random forest regression analyses further screened out 17 prognostic genes. Single-cell RNA sequencing analysis detected that FCGR1A and BCL2A1 might be potential biomarkers for sepsis diagnosis and the diagnostic efficacy of BCL2A1 was further validated by ROC curve and DCA. Conclusions: It was revealed that BCL2A1 had good diagnostic and prognostic value for sepsis, and that it can be applied as a potential and novel biomarker for the management of the disease.

Novel Mutations in ACP5 and SAMHD1 in a Patient With Pediatric Systemic Lupus Erythematosus.

Background: The study of genetic predisposition to pediatric systemic lupus erythematosus (pSLE) has brought new insights into the pathophysiology of SLE, as it is hypothesized that genetic predisposition is greater in children. Furthermore, identifying genetic variants and linking disrupted genes to abnormal immune pathways and clinical manifestations can be beneficial for both diagnosis and treatment. Here, we identified genetic alterations in a patient with childhood-onset SLE and analyzed the immunological mechanisms behind them to support future diagnosis, prognosis, and treatment. Methods: Whole exome sequencing (WES) was adopted for genetic analysis of a patient with childhood-onset SLE. Gene mutations were confirmed by Sanger sequencing. Clinical data of this patient were collected and summarized. Ingenuity Pathway Analysis was used to provide interacting genes of the perturbed genes. Online Enrichr tool and Cytoscape software were used to analysis the related pathways of these genes. Results: We present a case of a 2-year-old girl who was diagnosed with idiopathic thrombocytopenic purpura (ITP) and SLE. The patient was characterized by cutaneous bleeding spots on both lower extremities, thrombocytopenia, decreased serum complements levels, increased urinary red blood cells, and positive ANA and dsDNA. The patient was treated with methylprednisolone and mycophenolate, but clinical remission could not be achieved. The genomic analysis identified three novel mutations in this pSLE patient, a double-stranded missense mutation in ACP5 (c.1152G>T and c.420G>A) and a single-stranded mutation in SAMHD1 (c.1423G>A). Bioinformatic analysis showed that these two genes and their interacting genes are enriched in the regulation of multiple immune pathways associated with SLE, including cytokine signaling and immune cell activation or function. Analysis of the synergistic regulation of these two genes suggests that abnormalities in the type I interferon pathway caused by genetic variants may contribute to the pathogenesis of SLE. Conclusion: The combined complexity of polymorphisms in the coding regions of ACP5 and SAMHD1 influences the susceptibility to SLE. Alterations in these genes may lead to abnormalities in the type I interferon pathway. Our study extends the spectrum of mutations in the ACP5 and SAMHD1 genes. The identification of these mutations could aid in the diagnosis of SLE with genetic counseling and suggest potential precise treatments for specific pathways.

MicroRNAs in Systemic Lupus Erythematosus: a Perspective on the Path from Biological Discoveries to Clinical Practice.

PURPOSE OF REVIEW: MicroRNAs (miRNAs) play essential roles in immune abnormalities and organ damage of systemic lupus erythematosus (SLE). Current findings have indicated potential clinical applications of miRNAs for combating SLE. Here, we review recent evidence which support the notions that miRNAs can be novel biomarkers and therapeutic agents for SLE. RECENT FINDINGS: Following years of the studies of the expression patterns of miRNAs in both peripheral blood cells and body fluids, such as plasma and urine, several miRNAs or miRNA combinations have been associated with disease activity and specific organ damage. In depth analysis reveals complex and multiple roles of certain miRNAs in the pathogenesis of SLE. Manipulating miRNA expression shows in vivo therapeutic effects in lupus mouse models. MiRNAs contribute to the immune disorders and organ damage in SLE. MiRNA based biomarkers and therapies have the potential to be viable options for the treatment of SLE.

Dendropanax morbifera Léveille extract facilitates cadmium excretion and prevents oxidative damage in the hippocampus by increasing antioxidant levels in cadmium-exposed rats.

BACKGROUND: Dendropanax morbifera Léveille is used in herbal medicine as a cancer treatment. In this study, we investigated the effects of Dendropanax morbifera stem extract (DMS) on cadmium (Cd) excretion from the blood and kidney and brain tissues of rats exposed to cadmium, as well as the effects of DMS on oxidative stress and antioxidant levels in the hippocampus after Cd exposure. METHODS: Seven-week-old Sprague-Dawley rats were exposed to 2 mg/kg of cadmium by intragastric gavage and were orally administered 100 mg/kg of DMS for 4 weeks. Animals were sacrificed and Cd determination was performed using inductively coupled plasma mass spectrometry. In addition, the effects of Cd and/or DMS on oxidative stress were assayed by measuring reactive oxygen species production, protein carbonyl modification, lipid peroxidation levels, and antioxidant levels in hippocampal homogenates. RESULTS: Exposure to Cd significantly increased Cd content in the blood, kidneys, and hippocampi. DMS treatment significantly reduced Cd content in the blood and kidneys, but not in the hippocampi. Exposure to Cd significantly increased reactive oxygen species production, protein carbonyl modification, lipid peroxidation, total sulfhydryl content, reduced glutathione content, and glutathione reductase activity. In contrast, Cu, Zn-superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) activity in the hippocampus were significantly decreased after exposure to Cd, and administration of DMS significantly inhibited these Cd-induced changes. CONCLUSION: These results indicate that DMS facilitates cadmium excretion from the kidneys, reduces cadmium-induced oxidative stress in the hippocampus, and modulates SOD1, CAT, GPx, and glutathione-S-transferase activities.

Postoperative stability after setback of sagittal split ramus osteotomy: a comparison of three techniques.

PURPOSE: The aim of the present study was to evaluate the postoperative stability after bilateral sagittal split ramus osteotomy (BSSRO) for the treatment of mandibular prognathism, in addition to a posterior ostectomy of the distal segment and mandibular angle resection. PATIENTS AND METHODS: The present retrospective study included patients with mandibular prognathism who were treated with BSSRO at Kangdong Sacred Heart Hospital from July 2007 to July 2011. We assessed the linear changes in the chin position in 17 patients with BSSRO only (control group), 10 with BSSRO and posterior ostectomy of the distal segment (experimental group 1), and 13 with BSSRO and mandibular angle resection (experimental group 2). A cephalogram was taken 2 weeks before surgery and 1 day and 2 months postoperatively. Differences among the groups were determined using 1-way analysis of variance. RESULTS: The demographic and surgical variables were similar among the groups. With regard to the changes observed 1 day to 2 months postoperatively, no statistically significant differences were found; however, the proportion of patients who had highly significant changes (>4 mm) was different. Point B moved forward and upward more than 4 mm in approximately 18% and 12% of patients, respectively, in the control group. However, such movement was not observed in any patient in the experimental group. CONCLUSIONS: Less postoperative instability was present in the experimental groups than in the control group. This might have resulted from the reduced tension in the pterygomasseteric sling and the minimized interference between the bony segments. Therefore, improved stability can be obtained regardless of the type of additional procedures.

Recent updates in redox regulation and free radical scavenging effects by herbal products in experimental models of Parkinson's disease.

Parkinson's disease (PD) is a complex multifactorial disease marked by extensive neuropathology in the brain with selective yet prominent and progressive loss of mid-brain dopaminergic neurons. The etiological factors involved in the development of PD are still elusive, but oxidative stress arising when reactive oxygen species (ROS) exceed amounts required for normal redox signaling is considered one of the major factors. ROS cause oxidative damage to proteins, lipids, and DNA and are one of the most prominent factors related to neurodegeneration. Pre-clinical and clinical studies clearly demonstrate the effectiveness of oxidative stress in the pathogenesis of PD. Therefore, regulation of redox signaling and inhibiting excess ROS would contribute greatly not only to extend longevity but also to ameliorate the progression of dopaminergic cell death seen in patients with PD. Several herbal products are beneficial for maintaining nerve cell function and for treating various neurodegenerative disorders by reducing oxidative stress. Here, we summarize the recent knowledge concerning promising herbs that have shown significant beneficial effects based on regulation of redox status and ROS inhibition in toxin-induced PD models.

Three-dimensional changes in pharyngeal airway in skeletal class III patients undergoing orthognathic surgery.

PURPOSE: It has often been hypothesized that mandibular setback surgery causes narrowing of the pharyngeal airway. We examined whether the pharyngeal airway narrowed after orthognathic surgery in patients undergoing either mandibular setback surgery or bimaxillary surgery and whether the amount of narrowing of the pharyngeal airway was any different after mandibular setback surgery or bimaxillary surgery. MATERIALS AND METHODS: Cone-beam computed tomography scans were obtained for 21 patients who were assigned to either mandibular setback surgery or bimaxillary surgery. The anteroposterior dimension, lateral width, cross-sectional area, and volume of each subject's pharyngeal airway were measured before and after surgery. RESULTS: The pharyngeal airway showed significant narrowing after both mandibular setback surgery and bimaxillary surgery. The amount of change in the anteroposterior dimension and cross-sectional area on the posterior nasal spine plane and the length of the pharyngeal airway showed significant differences between the 2 groups. CONCLUSION: The amount of narrowing of the pharyngeal airway was smaller in patients undergoing bimaxillary surgery than in the patients undergoing mandibular setback surgery.

Pressurized liquid extraction for the simultaneous analysis of polychlorinated biphenyls and polybrominated diphenyl ethers from soil by GC-TOF-MS detection.

Pressurized liquid extraction (PLE) system was optimized to simultaneously determine polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in soil samples by gas chromatography with time-of-flight mass spectrometry. PLE parameters (temperature, pressure, static time, and flush volume) and packing materials (activated copper and sorbents such as: Florisil, silica gel, and a combination of Florisil and silica gel) were studied to achieve a one-step extraction and cleanup that could be analytically rapid and reliable. Method detection limit was found to be in the range of 0.1-0.4 mg/kg for PCBs and 0.1-0.6 mg/kg for PBDEs with a relative standard deviation of 1.7-7.3% for PCBs and 2.6-6.3% for PBDEs. A standard reference material for PCBs, NIST-SRM 1939a, spiked with PBDEs standard, was analyzed to substantiate the validity of the optimized method. Experimental values agreed well with the certified values with recoveries of 71.6-117%, and the optimized PLE system has been proven to be useful for the simultaneous determination of PCBs and PBDEs with various congeners in soil samples.

Determination of mono- to octachlorobiphenyls in fish oil using florisil adsorption followed by headspace solid-phase microextraction and gas chromatography with time-of-flight mass spectrometric detection.

A simple and reliable method for the determination of polychlorinated biphenyls (PCBs) from mono- to octachlorobiphenyls in fish oil for dietary supplement is described. The method combines Florisil clean up and headspace solid-phase microextraction on 65 microm polydimethylsiloxane-divinylbenzene (PDMS-DVB). Analyte detection was carried out using GC-time-of-flight mass spectrometry (GC-TOF-MS). Fifty three PCB congeners including the seven indicator PCBs (IUPAC Nos. 28, 52, 101, 118, 138, 153 and 180) were analyzed. Under optimal conditions, the method detection limit (MDL) of each congener in the range from 0.8 to 31 ng/g was found. A certified reference material (BCR-349) was analyzed and it showed good agreement with the certified data.