Visceral adipocyte-derived extracellular vesicle miR-27a-5p elicits glucose intolerance by inhibiting pancreatic ß-cell insulin secretion.

Pancreatic ß-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (miRNAs). However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs' miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic ß-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in ß-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs' miR-27a-5p in visceral adipocyte-mediated pancreatic ß-cell dysfunction in obesity-associated type 2 diabetes mellitus.

Allopurinol is Associated with an Increased Risk of Cerebral Infarction: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: Previous studies have reported that the inappropriate use of allopurinol may increase the risk of cerebrovascular accidents, but some studies have also confirmed that allopurinol is a protective factor against stroke. To clarify whether there is a relevant causal relationship between allopurinol and cerebral infarction, we conducted a two-sample Mendelian randomization (MR) study. METHODS: Data on single nucleotide polymorphisms (SNPs) associated with allopurinol and genome-wide association studies of cerebral infarction were obtained from the genome-wide association study (GWAS) web site. Five basic MR analyses were performed using MR-Egger regression, weighted median (WM1), inverse variance weighting (IVW), weighted mode (WM2), and simple mode. Sensitivity analysis was subsequently performed to detect horizontal pleiotropy, heterogeneity, and potential outliers. The final analysis results were mainly based on the IVW estimates. RESULTS: A total of 10 SNPs were used as instrumental variables (IVs). MR analysis [(IVW: odds ratio (OR) = 1.053, 95% confidence interval (CI): 1.019-1.088, P = 0.002), (WM1: OR = 1.053, 95% CI: 1.009-1.098, P = 0.017), (WM2: OR = 1.050, 95% CI: 1.008-1.095, P = 0.044), (MR Egger: Q = 4.285, P = 0.830)] showed a positive causal association between allopurinol and the risk of cerebral infarction. Sensitivity analysis such as horizontal pleiotropy and heterogeneity increased the reliability of this result. CONCLUSION: The results of this study provide direct evidence that there is a causal relationship between allopurinol and cerebral infarction and that allopurinol may increase the risk of cerebral infarction.

Serum 25-hydroxyvitamin D levels and dermatomyositis: A 2-sample mendelian randomization study.

BACKGROUND: Previous studies have reported low serum 25-hydroxyvitamin D [25(OH)D] levels in dermatomyositis (DM) patients, but the exact causal relationship between them remains elusive. Our aim is to confirm the causal relationship between 25(OH)D and DM risk through a Mendelian randomization study. METHODS: Retrieve genome-wide association study (GWAS) data on 25(OH)D (n = 441 291) and DM (n cases = 201, n controls = 172 834) from the GWAS database (https://gwas.mrcieu.ac.uk/). Select single-nucleotide polymorphisms (SNPs) strongly correlated with 25(OH)D as instrumental variables (IVs). The primary analytical approach involves the use of the inverse-variance weighted method (IVW), supplemented by MR-Egger regression and weighted median methods to enhance the reliability of the results. Heterogeneity and sensitivity analyses were conducted using Cochran's Q and leave-one-out approaches, respectively. RESULTS: The IVW analysis confirmed a positive causal relationship between genetic variation in 25(OH)D levels and DM (OR = 2.36, 95% CI = 1.01-5.52, p = .048). Although not statistically significant (all p > .05), the other methods also suggested a protective effect of 25(OH)D on DM. Based on MR-Egger intercepts and Cochran's Q analysis, the selected SNPs showed no horizontal pleiotropy and heterogeneity. Sensitivity analysis demonstrated the robustness of the results against individual SNPs. CONCLUSION: We provide the first evidence of a causal relationship between 25(OH)D levels and DM. Our findings support the importance of measuring serum 25(OH)D levels and considering vitamin D supplementation in clinical practice for patients with DM.

Risk of dyslipidemia and major adverse cardiac events with tofacitinib versus adalimumab in rheumatoid arthritis: a real-world cohort study from 7580 patients.

Objective: To compare the effects of tofacitinib and adalimumab on the risk of adverse lipidaemia outcomes in patients with newly diagnosed rheumatoid arthritis (RA). Methods: Data of adult patients newly diagnosed with RA who were treated with tofacitinib or adalimumab at least twice during a 3-year period from 1 January 2018 to 31 December 2020, were enrolled in the TriNetX US Collaborative Network. Patient demographics, comorbidities, medications, and laboratory data were matched by propensity score at baseline. Outcome measurements include incidental risk of dyslipidemia, major adverse cardiac events (MACE) and all-cause mortality. Results: A total of 7,580 newly diagnosed patients with RA (1998 receiving tofacitinib, 5,582 receiving adalimumab) were screened. After propensity score matching, the risk of dyslipidaemia outcomes were higher in the tofacitinib cohort, compared with adalimumab cohort (hazard ratio [HR] with 95% confidence interval [CI], 1.250 [1.076-1.453]). However, there is no statistically significant differences between two cohorts on MACE (HR, 0.995 [0.760-1.303]) and all-cause mortality (HR, 1.402 [0.887-2.215]). Conclusion: Tofacitinib use in patients with RA may increase the risk of dyslipidaemia to some extent compared to adalimumab. However, there is no differences on MACE and all-cause mortality.

Intradermal acupuncture in the treatment of rheumatoid arthritis with liver and kidney deficiency syndrome - A sham-controlled, randomized, clinical trial.

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is called "immortal cancer", and it affects the quality of life, disability rate and even the survival of patients. This study aimed to observe the clinical efficacy, and adverse reactions of intradermal acupuncture (IA) in the treatment of RA patients with liver and kidney deficiency syndrome. MATERIALS AND METHODS: 132 RA patients were split into an IA group and a sham IA group at a 1:1 ratio. Both groups were assessed before and after the intervention with the assessments: a traditional Chinese medicine (TCM) syndrome evaluation, the Health Assessment Questionnaire (HAQ), the Disease Activity Score 28 (DAS28) and serum C-reactive protein (CRP). RESULTS: There was a statistically significant difference in TCM syndrome evaluation, HAQ, DAS28, and CRP between both groups before and after treatment (P < 0.01). The improvement of TCM syndrome evaluation (95% CI [1.14(0.38-1.89)]; P = 0.001), HAQ (95% CI [2.00(1.00-3.00)]; P = 0.003), and DAS28 (95% CI [0.11(0.02-0.20)]; P = 0.021) in the IA group was more obvious than that in the sham IA group (P < 0.05), except for CRP (95% CI [0.50(- 2.09 to 7.08)], P = 0.786). The difference in CRP outcome changes between the two groups was not statistically significant (P > 0.05). Both groups had comparable results in the implementation of RA in the upper and lower extremity acupoints and did not differ due to different sites (IA group: P = 0.852; sham IA group: P = 0.861). The comparison of effective rate of the upper limb as well as that of the lower limb was statistically significant (P = 0.001). Besides, patients reported no adverse effects. CONCLUSION: The IA intervention was associated with a promising effect on the decrease in RA disease activity and delayed overall disease progression.

Methotrexate and the Risk of Dementia: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Recent studies have suggested a potential association between methotrexate use and an increased risk of dementia. However, the causal relationship between methotrexate and dementia remains unclear. This study aims to investigate the potential causal effect of methotrexate use on the risk of dementia using a two-sample Mendelian randomization (TSMR) approach. METHODS: We conducted a TSMR study using summary statistics from genome-wide association studies (GWAS) of methotrexate use and dementia. We obtained genetic instruments for methotrexate use from a large-scale GWAS meta-analysis and genetic instruments for dementia from a separate GWAS meta-analysis. We performed several statistical analyses, including inverse-variance weighted (IVW), weighted median (WM1), weighted mode (WM2), and MR-Egger regression methods, to estimate the causal effect of methotrexate on dementia risk. RESULTS: Our TSMR analysis showed a significant positive association between genetic predisposition to methotrexate use and dementia risk. The IVW method estimated a causal odds ratio (OR) of 0.476 [95% confidence interval (CI) 0.362-0.626] per unit increase in the log odds ratio of methotrexate use. WM1, WM2, and MR-Egger methods provided consistent results. CONCLUSION: The findings of this mendelian randomization (MR) study suggest a potential causal effect of methotrexate use on the risk of dementia. However, further research is needed to validate these findings and explore the underlying mechanisms. Since methotrexate is widely prescribed for various autoimmune diseases, a better understanding of its potential impact on dementia risk is crucial for optimizing treatment strategies and addressing potential adverse effects.

The use of belimumab on patients with both systemic lupus erythematosus and immune thrombocytopenia: A retrospective cohort study.

OBJECTIVE: The objective of this study is to provide a description of a group of retrospective cohort outcomes in patients with systemic lupus erythematosus (SLE) complicated with immune thrombocytopenia (ITP) receiving belimumab. METHODS: This study reports on the treatment of 10 female patients (mean age 34.3 ± 14.0 years, mean weight 58.7 ± 18.2 kg) with both SLE and ITP who received belimumab in addition to basic drug therapy. The belimumab treatment regimen consisted of a dosage of 10 mg/kg, with an initial infusion every 2 weeks for the first 3 doses, followed by an infusion every 4 weeks. RESULTS: Ten patients were included in the study. The overall response rate of thrombocytopenia was 90% after treatment. The parameters such as platelet count, lymphocyte count, erythrocyte count, hemoglobin, dsDNA, C3, and C4 were significantly improved (p < .05). The SLE Disease Activity Index (SLEDAI), British Islet lupus Assessment Group 2004 (BILAG-2004), and Physician Global assessment (PGA) scores were significantly decreased (p < .05). There were no significant differences in glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), and serum creatinine (Scr) before and after treatment (p > .05). CONCLUSION: Belimumab shows promising clinical outcomes in the treatment on patients with both SLE and ITP. Further studies are needed to validate these findings in larger patient populations and compare the efficacy of belimumab with other treatments for SLE complicated with ITP. Long-term response rates and adverse events associated with belimumab treatment also warrant further investigation.

A bibliometric analysis of the research status and trends in studies on polymyositis and dermatomyositis with interstitial lung disease from 2000 to 2022 using Web of Science.

BACKGROUND: The main subtypes of idiopathic inflammatory myopathies (IIMs)-polymyositis (PM) and dermatomyositis (DM)-are often presented as interstitial lung disease (ILD) in clinical practice; therefore, many researchers have combined the three studies into PM/DM with ILD. METHODS: Using bibliometrics, the research status, progress, and hotspots of PM/DM with ILD between 2000 and 2022 were studied. Literature data on PM/DM with ILD were retrieved from the Web of Science (WoS) database for the research period. Visualization software, including VOSviewer, Pajek, CiteSpace, and Scimago Graphica were used for bibliometric analysis. RESULTS: A total of 1555 relevant articles were obtained, and the overall research in this field showed an increasing trend. Regarding contributing countries and venues, Japan published the most articles while Rheumatology was the most prolific journal. Regarding authors, the most published article was by Wang Guochun from Changchun University of Technology in China. Keyword analysis and cocited literature cluster analysis showed that diagnosis, classification, autoantibodies, antibodies, prognosis, complications, and treatment of PM/DM with ILD have been hot topics in this field recently. Moreover, our study shows that anti-mda5 antibody, mortality, gene 5 antibody, IIMs, double-blind, and prognostic factors, among others, may be new hot topics. CONCLUSION: This study found that research on PM/DM with ILD has increased over time, and scholars are paying more attention to this field. The development of new drugs for the management, treatment, and prevention of PM/DM with ILD is the primary task of researchers and a direction for future research in this field.

Periplogenin inhibits pathologic synovial proliferation and infiltration in rheumatoid arthritis by regulating the JAK2/3-STAT3 pathway.

Rheumatoid arthritis (RA) is an autoimmune disease that affects joints, causing inflammation, synovitis, and erosion of cartilage and bone. Periplogenin is an active ingredient in the anti-rheumatic and anti-inflammatory herb, cortex periplocae. We conducted a study using a CIA model and an in vitro model of fibroblast-like synoviocytes (FLS) induced by Tumor Necrosis Factor-alpha (TNF-α) stimulation. We evaluated cell activity, proliferation, and migration using the CCK8 test, EDU kit, and transwell assays, as well as network pharmacokinetic analysis of periplogenin targets and RA-related effects. Furthermore, we measured inflammatory factors and matrix metalloproteinases (MMPs) expression using ELISA and qRT-PCR assays. We also evaluated joint destruction using HE and Safranin O-Fast Green Staining and examined the changes in the JAK2/3-STAT3 pathway using western blot. The results indicated that periplogenin can effectively inhibit the secretion of inflammatory factors, suppress the JAK2/3-STAT3 pathway, and impede the proliferation and migration of RA FLS. Thus, periplogenin alleviated the Synovial inflammatory infiltration of RA.

Leonurine alleviates rheumatoid arthritis by regulating the Hippo signaling pathway.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause joint inflammation and damage. Leonurine (LE) is an alkaloid found in Leonurus heterophyllus. It has anti-inflammatory effects. HYPOTHESIS/PURPOSE: The molecular mechanisms by which LE acts in RA are unclear and further investigation is required. METHODS: Mice with collagen-induced arthritis (CIA), and RA-fibroblast-like synoviocytes (FLSs) isolated from them were used as in vivo and in vitro models of RA, respectively. The therapeutic effects of LE on CIA-induced joint injury were investigated by micro-computed tomography, and staining with hematoxylin and eosin and Safranin-O/Fast Green. Cell Counting Kit-8, a Transwell® chamber, enzyme-linked immunosorbent assays, RT-qPCR, and western blotting were used to investigate the effects of LE on RA-FLS viability, migratory capacity, inflammation, microRNA-21 (miR-21) levels, the Hippo signaling pathway, and the effects and intrinsic mechanisms of related proteins. Dual luciferase was used to investigate the binding of miR-21 to YOD1 deubiquitinase (YOD1) and yes-associated protein (YAP). Immunofluorescence was used to investigate the localization of YAP within the nucleus and cytoplasm. RESULTS: Treatment with LE significantly inhibited joint swelling, bone damage, synovial inflammation, and proteoglycan loss in the CIA mice. It also reduced the proliferation, cell colonization, migration/invasion, and inflammation levels of RA-FLSs, and promoted miR-21 expression in vitro. The effects of LE on RA-FLSs were enhanced by an miR-21 mimic and reversed by an miR-21 inhibitor. The dual luciferase investigation confirmed that both YOD1 and YAP are direct targets of miR-21. Treatment with LE activated the Hippo signaling pathway, and promoted the downregulation and dephosphorylation of MST1 and LATS1 in RA, while inhibiting the activation of YOD1 and YAP. Regulation of the therapeutic effects of LE by miR-21 was counteracted by YOD1 overexpression, which caused the phosphorylation of YAP and prevented its nuclear ectopic position, thereby reducing LE effect on pro-proliferation-inhibiting apoptosis target genes. CONCLUSION: LE regulates the Hippo signaling pathway through the miR-21/YOD1/YAP axis to reduce joint inflammation and bone destruction in CIA mice, thereby inhibiting the growth and inflammation of RA-FLSs. LE has potential for the treatment of RA.

Identifying NFKB1, STAT3, and CDKN1A as Baicalein's Potential Hub Targets in Parkinson's Disease-related α-synuclein-mediated Pathways by Integrated Bioinformatics Strategies.

BACKGROUND: The overexpression, accumulation, and cell-to-cell transmission of α-synuclein leads to the deterioration of Parkinson's disease (PD). Previous studies suggest that Baicalein (BAI) can bind to α-synuclein and inhibit α-synuclein aggregation and secretion. However, it is still unclear whether BAI can intervene with the pathogenic molecules in α-synuclein-mediated PD pathways beyond directly targeting α-synuclein per se. METHODS: This study aimed to systematically investigate BAI's potential targets in PD-related A53T mutant α-synuclein-mediated pathways by integrating data mining, network pharmacological analysis, and molecular docking simulation techniques. RESULTS: The results suggest that BAI may target genes that are dysregulated in synaptic transmission, vesicle trafficking, gene transcription, protein binding, extracellular matrix formation, and kinase activity in α-synucleinmediated pathways. NFKB1, STAT3, and CDKN1A are BAI's potential hub targets in these pathways. CONCLUSION: Our findings highlight BAI's potentiality to modulate α-synuclein-mediated pathways beyond directly targeting α-synuclein per se.

Proton pump inhibitor use associated with an increased risk of gout: A population-based case-control study.

OBJECTIVES: In previous reports, proton pump inhibitor (PPI) use increased the risk of gout. However, there is no epidemiological study investigating this association. We aimed to examine the potential impact of PPI treatment on the risk of developing gout. METHODS: A population-based case-control study was performed using a Longitudinal Health Insurance Database 2000 from Taiwan (population 23 million). We identified gout cases and non-gout controls through propensity score matching at 1:1, which was matched by sex and age. We used a conditional logistic regression model to estimate an odds ratio and 95% confidence intervals (CI) for gout population versus controls. RESULTS: Esomeprazole increased the risk of gout after adjusting confounding variables (adjusted odds ratio [aOR] 1.3; 95% CI 1.0-1.6). The risk of gout was highest within 30 days of PPI treatment (aOR 1.7; 95% CI 1.4-1.9) and attenuated thereafter. The risk of gout was increased among female users of PPI compared with male users (aOR 2.2; 95% CI 1.7-2.8). The aOR of gout in people with PPI use was higher in middle-aged individuals (41-60 years: aOR 2.1; 95% CI 1.7-2.7) than in the older group (≥60 years: aOR 1.8; 95% CI 1.5-2.2). CONCLUSIONS: Our findings provide population-level evidence for the hypothesis that PPI treatment is positively associated with the risk of developing gout. Further research on the mechanism underlying this association is warranted.

Methotrexate is associated with decreased total thyroxine in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint swelling, pain, and deformation. RA patients have an increased risk of thyroid dysfunction, and drugs of RA treatment may have potential effects on thyroid function. METHODS: This is a single-center cross-sectional study including 281 inpatients with RA in the First Affiliated Hospital of Guangzhou University of Chinese Medicine. The purpose of this study is to explore the correlation between RA therapeutic drugs and thyroid function. The medical records of 281 inpatients with RA were collected, including general data, laboratory examination, complications, and RA treatment. Spearman correlation analysis was used to explore the association of independent variables with thyroid function and antibodies in RA patients. Multinomial logistics and binary logistic regression were used for multivariate analysis. The statistically significance level was set as P < 0.05. SPSS 22.0 was used for statistical analysis. RESULTS: Patients taking methotrexate (OR = 0.067, 95%CI: 0.008-0.588, P = 0.015) had lower levels of total thyroxine (TT4) (TT4 < 78.38 nmol/L). There was a negative correlation between glucocorticoids (r = - 0.153, P = 0.010) and total triiodothyronine (TT3) level (TT3 ≥ 1.34 nmol/L), but it was not significant in the multivariate regression model of TT3, although the regression model was statistically significant (P = 0.001). CONCLUSION: Methotrexate is associated with decreased TT4 levels in RA patients, and glucocorticoids is associated with decreased TT3 levels. Drugs of RA treatment may affect the thyroid function of patients while treating RA, which may be one of the causes of secondary thyroid diseases in RA patients.

The Underlying Mechanism of Duanteng Yimu Decoction in Inhibiting Synovial Hyperplasia in Rheumatoid Arthritis.

Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of rheumatoid arthritis (RA). Our previous studies confirmed that Duanteng Yimu decoction (DTYMT) effectively inhibits RA fibroblast-like synoviocyte (FLS) proliferation. In this study, we investigated the influence of DTYMT on miR-221 in RA individuals. Hematoxylin-eosin (HE) staining was performed to assess histopathological alterations in collagen-induced arthritis (CIA) mice. The expression of miR-221-3p and TLR4 in PBMC, FLS, and cartilage was measured by RT-qPCR. In the in vitro experiments, DTYMT-containing serum was incubated with FLS-transfected miR-221 mimic or inhibitor. CCK-8 was performed to determine FLS proliferation, and the secretion of IL-1ß, IL-6, IL-18, and TNF-α was quantified by ELISA assay. In addition, the regulation of miR-221 expression on FLS apoptosis was assessed using flow cytometry. Finally, western blot was employed to reflect TLR4/MyD88 protein levels. HE results showed that DTYMT effectively reduced synovial hyperplasia in the joints of CIA mice. RT-qPCR assay of FLS and cartilage of the model group showed that miR-221-3p and TLR4 significantly increased compared with those in the normal group. All outcomes were improved by DTYMT. The miR-221 mimic reversed the inhibitory effect of DTYMT-containing serum on FLS proliferation, the release of IL-1ß, IL-18, IL-6, and TNF-α, and FLS apoptosis, as well as TLR4/MyD88 protein levels. The results showed that miR-221 promotes the activity of RA-FLS by activating TLR4/MyD88 signaling, and DTYMT treats RA by reducing miR-221 in CIA mice.

Mechanism underlying the action of Duanteng-Yimu Tang in regulating Treg/Th17 imbalance and anti-rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic immune disease characterised by synovitis and cartilage destruction. Currently, many patients experience poor remission after new antirheumatic drug treatments. Duanteng-Yimu Tang (DTYMT), a traditional Chinese medicine, is effective in the treatment of RA. In this research, we designed to investigate the anti-RA effects of DTYMT and explore its potential mechanisms. Methods: Network pharmacology was adopted to explore the main pathways of DTYMT in patients with RA. Collagen-induced arthritis models of male DBA/1 mice were established, and their histopathological changes were observed by hematoxylin-eosin staining and micro-CT. qRT-PCR was performed to detect the expression of Foxp3 and RORγt in the serum and synovial tissue and IL-17, IL-1ß, TNF-α, and IL-10 mRNA in vivo. The proliferation and invasion of synovial cells were analyzed using Cell Counting Kit-8 and transwell assays, respectively. The ratio of T helper 17 (Th17) to regulatory T (Treg) cells was analyzed by flow cytometry. Results: Network pharmacology analysis revealed that Th17 cell differentiation may be the key pathway of DTYMT in RA. DTYMT ameliorated joint damage, inhibited RORγt expression, and increased Foxp3 expression in CIA mice. DTYMT significantly decreased IL-1ß, IL-17, and TNF-α mRNA levels, and increased IL-10 mRNA levels in IL-6-induced cells. Additionally, DTYMT inhibited Th17 cell differentiation and promoted Treg cell production, thus improving the Treg/Th17 imbalance. DTYMT also inhibited the proliferation, migration, and invasion of RA fibroblast-like synovial cells. Conclusions: These results indicate that DTYMT could regulate the Treg/Th17 cell balance, which is a possible mechanism of DTYMT in treating RA.

A patient with refractory proliferative lupus nephritis treated with telitacicept: A case report.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Lupus nephritis (LN) is a common type of organ damage which occurs in SLE patients and is characterized by recurrent proteinuria. Activation of B lymphocytes can lead to refractory LN, which is an important pathogenic factor in SLE. B lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL) are predominantly produced by myeloid cells (monocytes, dendritic cells, neutrophils, etc) to regulate B lymphocyte function. Telitacicept was the first dual-targeting biological drug which targeted both BLyS and APRIL. Telitacicept has passed a phase II clinical trial and has since been approved for the treatment of SLE. CASE PRESENTATION: We report a case of SLE confirmed by renal biopsy as proliferative lupus nephritis (PLN) with massive proteinuria, which was treated with telitacicept (European League Against Rheumatism / American College of Rheumatology 2019 standard). During the 19 months of follow-up, the patient's renal function was stable, massive proteinuria was relieved, and creatinine and blood pressure did not increase. CONCLUSIONS: During the 19 months of telitacicept treatment (160 mg once weekly), PLN reduced blood system damage and proteinuria without increasing the risk of infection.

Triptolide improves chondrocyte proliferation and secretion via down-regulation of miR-221 in synovial cell exosomes.

BACKGROUND: Rheumatoid arthritis (RA), the most common type of inflammatory arthritis, can cause bone damage and disability. Triptolide, a prominent treatment for RA, has satisfactory anti-inflammatory effects. However, the mechanism of action of triptolide in RA remains unknown. PURPOSE: This study aimed to explore the molecular mechanisms underlying triptolide-mediated improvements in RA and identify the miRNA pathway responsible for these effects. METHODS: We identified various dysregulated miRNAs associated with RA by mining previously described microarray data and verified and screened these candidates using RT-qPCR. Hematoxylin-eosin staining was then applied to identify pathological changes in the affected joints, and cell counting kit-8 analysis and flow cytometry were employed to examine cell proliferation and apoptosis, respectively. Extracted exosomes were verified using transmission electron microscopy. RESULTS: Our results revealed that the legs of rats with collagen-induced arthritis presented with obvious swelling and bone damage, a high degree of inflammatory cell infiltration into the synovium, and structural changes to the cartilage. Data mining identified 39 dysregulated miRNAs in these tissues, and RT-qPCR further refined these observations to highlight miR-221 as a potential RA biomarker. Subsequent evaluations revealed that fibroblast-like synovial (FLS) cells secrete Exs carrying dysregulated miR-221 in vitro. These Exs mediate miR-221 levels, inflammation, and TLR4/MyD88 signaling via their fusion with chondrocytes, leading to changes in chondrocyte growth and metabolic factor levels. Additionally, the addition of triptolide impaired miR-221 expression, cell proliferation, inflammatory factors, and the protein levels of TLR4/MyD88 in RA-FLS and promoted the apoptosis of FLS. The therapeutic effect of triptolide on miR-221 Exs was reversed by miR-221 inhibitor in both normal and RA FLS. CONCLUSION: Our research shows that effective treatment with triptolide is mediated by its regulation of growth and secretory functions of chondrocytes via the inhibition of miR-221 secretion by FLS, providing a new target and natural medicinal candidate for future RA treatments.

Radiomics features based on internal and marginal areas of the tumor for the preoperative prediction of microsatellite instability status in colorectal cancer.

Objectives: To explore whether the preoperative CT radiomics can predict the status of microsatellite instability (MSI) in colorectal cancer (CRC) patients and identify the region with the most stable and high-efficiency radiomics features. Methods: This retrospective study involved 230 CRC patients with preoperative computed tomography scans and available MSI status between December 2019 and October 2021. Image segmentation and radiomic feature extraction were performed as follows. First, slices with the maximum tumor area (region of interest, ROI) were manually contoured. Subsequently, each ROI was shrunk inward by 1, 2, and 3 mm, respectively, where the remaining ROIs were considered as the internal region of the tumor (named as IROI1, IROI2, and IROI3), and the shrunk regions were considered as marginal regions of the tumor (named as MROI1, MROI2, and MROI3). Finally, radiomics features were extracted from each of the ROI. The intraclass correlation coefficient and least absolute shrinkage and selection operator method were used to choose the most reliable and relevant features of MSI status. Clinical, radiomics, and combined clinical radiomics models have been established. Calibration curve and decision curve analyses (DCA) were generated to explore the correction effect and assess the clinical applicability of the above models, respectively. Results: In the testing cohort, the radiomics model based on IROI3 yielded the highest average area under the curve (AUC) value of 0.908, compared with the remaining radiomics models. Additionally, hypertension and N stage were considered as clinically independent factors of MSI status. The combined clinical radiomics model achieved excellent diagnostic efficacy (AUC: 0.928; sensitivity: 0.840; specificity: 0.867) in the testing cohort, as well as favorable calibration and clinical utility by calibration curve and DCA analyses. Conclusions: The IROI3 model, which is based on a 3-mm shrink in the largest areas of the tumor, could noninvasively reflect the heterogeneity and genetic instability within the tumor. This suggests that it is an important biomarker for the preoperative prediction of MSI status. The model can extract more robust and effective radiomics features, which lays a foundation for the radiomics study of hollow organs, such as in CRC.

Case report: Joint deformity associated with systemic lupus erythematosus.

OBJECTIVE: Typically, Jaccoud arthropathy (JA) is characterized by joint deformation without bone erosion. However, some recent studies have shown that bone erosion also occurs in JA; however, this remains controversial. To date, there have been no unified diagnostic standards for JA. Herein, we report a case of systemic lupus erythematosus complicated with JA without bone erosion. METHODS: A 27-year-old woman was admitted to our department with a 2-year history of pain, swelling, and progressive deformities of her hands and feet. She was diagnosed with systemic lupus erythematosus and class V lupus nephritis 5 years prior. Upon examination, her erythrocyte sedimentation rate and C-reactive protein levels were found to be increased. She was positive for antinuclear antibodies, antidouble stranded DNA antibodies, and antiextractable nuclear antigen antibodies, with a decreased complement C3 and C4. Radiography and magnetic resonance imaging revealed no bone erosion. The patient was diagnosed with JA. She was treated with oral prednisone (10 mg daily), tofacitinib (5 mg twice daily), methotrexate (10 mg weekly), and celecoxib (0.2 g twice daily). RESULTS: The patient's joint symptoms improved after treatment. No further progress was observed during the 4-month follow-up period. CONCLUSION: We believe that bone erosion is the key to distinguish rhupus syndrome from JA. However, this needs to be confirmed with further long-term follow-up studies. We found that the use tofacitinib, MTX, and celecoxib in combination with prednisone may be an effective regimen for the treatment of JA.