Targeted siRNA Therapy for Psoriasis: Translating Preclinical Potential into Clinical Treatments.

Psoriasis is a chronic inflammatory skin disease characterized by the excessive proliferation of keratinocytes and heightened immune activation. Targeting pathogenic genes through small interfering RNA (siRNA) therapy represents a promising strategy for the treatment of psoriasis. This mini-review provides a comprehensive summary of siRNA research targeting the pathogenesis of psoriasis, covering aspects such as keratinocyte function, inflammatory cell roles, preclinical animal studies, and siRNA delivery mechanisms. It details recent advancements in RNA interference that modulate key factors including keratinocyte proliferation (Fibroblast Growth Factor Receptor 2, FGFR2), apoptosis (Interferon Alpha Inducible Protein 6, G1P3), differentiation (Grainyhead Like Transcription Factor 2, GRHL2), and angiogenesis (Vascular Endothelial Growth Factor, VEGF); immune cell infiltration and inflammation (Tumor Necrosis Factor-Alpha, TNF-α; Interleukin-17, IL-17); and signaling pathways (JAK-STAT, Nuclear Factor Kappa B, NF-κB) that govern immunopathology. Despite significant advances in siRNA-targeted treatments for psoriasis, several challenges persist. Continued scientific developments promise the creation of more effective and safer siRNA medications, potentially enhancing the quality of life for psoriasis patients and revolutionizing treatments for other diseases. This article focuses on the most recent research advancements in targeting the pathogenesis of psoriasis with siRNA and explores its future therapeutic prospects.

Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key effector cells that play a central role in RA pathogenesis through their ability to polarize into distinct functional phenotypes. An imbalance favoring pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages disrupts immune homeostasis and exacerbates joint inflammation. Multiple signaling pathways, including Notch, JAK/STAT, NF-κb, and MAPK, regulate macrophage polarization towards the M1 phenotype in RA. Metabolic reprogramming also contributes to this process, with M1 macrophages prioritizing glycolysis while M2 macrophages utilize oxidative phosphorylation. Redressing this imbalance by modulating macrophage polarization and metabolic state represents a promising therapeutic strategy. Furthermore, complex bidirectional interactions exist between synovial macrophages and fibroblast-like synoviocytes (FLS), forming a self-perpetuating inflammatory loop. Macrophage-derived factors promote aggressive phenotypes in FLS, while FLS-secreted mediators contribute to aberrant macrophage activation. Elucidating the signaling networks governing macrophage polarization, metabolic adaptations, and crosstalk with FLS is crucial to developing targeted therapies that can restore immune homeostasis and mitigate joint pathology in RA.

Identification of clinical characteristics biomarkers for rheumatoid arthritis through targeted DNA methylation sequencing.

OBJECTIVES: Rheumatoid arthritis (RA) is a complex disease with a challenging diagnosis, especially in seronegative patients. The aim of this study is to investigate whether the methylation sites associated with the overall immune response in RA can assist in clinical diagnosis, using targeted methylation sequencing technology on peripheral venous blood samples. METHODS: The study enrolled 241 RA patients, 30 osteoarthritis patients (OA), and 30 healthy volunteers control (HC). Fifty significant cytosine guanine (CG) sites between undifferentiated arthritis and RA were selected and analyzed using targeted DNA methylation sequencing. Logistic regression models were used to establish diagnostic models for different clinical features of RA, and six machine learning methods (logit model, random forest, support vector machine, adaboost, naive bayes, and learning vector quantization) were used to construct clinical diagnostic models for different subtypes of RA. Least absolute shrinkage and selection operator regression and detrended correspondence analysis were utilized to screen for important CGs. Spearman correlation was used to calculate the correlation coefficient. RESULTS: The study identified 16 important CG sites, including tumor necrosis factort receptor associated factor 5 (TRAF5) (chr1:211500151), mothers against decapentaplegic homolog 3 (SMAD3) (chr15:67357339), tumor endothelial marker 1 (CD248) (chr11:66083766), lysosomal trafficking regulator (LYST) (chr1:235998714), PR domain zinc finger protein 16 (PRDM16) (chr1:3307069), A-kinase anchoring protein 10 (AKAP10) (chr17:19850460), G protein subunit gamma 7 (GNG7) (chr19:2546620), yes1 associated transcriptional regulator (YAP1) (chr11:101980632), PRDM16 (chr1:3163969), histone deacetylase complex subunit sin3a (SIN3A) (chr15:75747445), prenylated rab acceptor protein 2 (ARL6IP5) (chr3:69134502), mitogen-activated protein kinase kinase kinase 4 (MAP3K4) (chr6:161412392), wnt family member 7A (WNT7A) (chr3:13895991), inhibin subunit beta B (INHBB) (chr2:121107018), deoxyribonucleic acid replication helicase/nuclease 2 (DNA2) (chr10:70231628) and chromosome 14 open reading frame 180 (C14orf180) (chr14:105055171). Seven CG sites showed abnormal changes between the three groups (P < 0.05), and 16 CG sites were significantly correlated with common clinical indicators (P < 0.05). Diagnostic models constructed using different CG sites had an area under the receiver operating characteristic curve (AUC) range of 0.64-0.78 for high-level clinical indicators of high clinical value, with specificity ranging from 0.42 to 0.77 and sensitivity ranging from 0.57 to 0.88. The AUC range for low-level clinical indicators of high clinical value was 0.63-0.72, with specificity ranging from 0.48 to 0.74 and sensitivity ranging from 0.72 to 0.88. Diagnostic models constructed using different CG sites showed good overall diagnostic accuracy for the four subtypes of RA, with an accuracy range of 0.61-0.96, a balanced accuracy range of 0.46-0.94, and an AUC range of 0.46-0.94. CONCLUSIONS: This study identified potential clinical diagnostic biomarkers for RA and provided novel insights into the diagnosis and subtyping of RA. The use of targeted deoxyribonucleic acid (DNA) methylation sequencing and machine learning methods for establishing diagnostic models for different clinical features and subtypes of RA is innovative and can improve the accuracy and efficiency of RA diagnosis.

Case report: Whole exome sequencing and genome-wide methylation profiling of Czech dysplasia in a Chinese pedigree.

Background: Czech dysplasia is a rare skeletal disorder with symptomatology including platyspondyly, brachydactyly of the third and fourth toes, and early-onset progressive pseudorheumatoid arthritis. The disorder segregates in an autosomal dominant fashion. A specific missense mutation (R275C, c.823C > T) in exon 13 of the COL2A1 gene has been identified in German and Japanese families. Case summary: We present the case of a Chinese woman diagnosed with Czech dysplasia (proband) who carried a variant in the COL2A1 gene. Whole-exome sequencing (WES) identified the COL2A1 missense mutation (R275C, c.823C > T) in close relatives of the proband who also exhibited the same disorder. Conclusion: This study is a thorough clinical and physiological description of Czech dysplasia in a Chinese patient.

Role of signaling lymphocytic activation molecule family of receptors in the pathogenesis of rheumatoid arthritis: insights and application.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and joint damage. The signaling lymphocytic activation molecule (SLAMF) family of receptors are expressed on various hematopoietic and non-hematopoietic cells and can regulate both immune cell activation and cytokine production. Altered expression of certain SLAMF receptors contributes to aberrant immune responses in RA. In RA, SLAMF1 is upregulated on T cells and may promote inflammation by participating in immune cell-mediated responses. SLAMF2 and SLAMF4 are involved in regulating monocyte tumor necrosis factor production and promoting inflammation. SLAMF7 activates multiple inflammatory pathways in macrophages to drive inflammatory gene expression. SLAMF8 inhibition can reduce inflammation in RA by blocking ERK/MMPs signaling. Of note, there are differences in SLAMF receptor (SFR) expression between normal and arthritic joint tissues, suggesting a role as potential diagnostic biomarkers. This review summarizes recent advances on the roles of SLAMF receptors 1, 2, 4, 7, and 8 in RA pathogenesis. However, further research is needed to elucidate the mechanisms of SLAMF regulation of immune cells in RA. Understanding interactions between SLAMF receptors and immune cells will help identify selective strategies for targeting SLAMF signaling without compromising normal immunity. Overall, the SLAMF gene family holds promise as a target for precision medicine in RA, but additional investigation of the underlying immunological mechanisms is needed. Targeting SLAMF receptors presents opportunities for new diagnostic and therapeutic approaches to dampen damaging immune-mediated inflammation in RA.

Circulating DNA methylation level of CXCR5 correlates with inflammation in patients with rheumatoid arthritis.

OBJECTIVES: To assess the differences in circulating DNA methylation levels of CXCR5 between rheumatoid arthritis (RA) and osteoarthritis (OA) and healthy controls (HC), and the correlation of methylation changes with clinical characteristics of RA patients. METHODS: Peripheral blood samples were collected from 239 RA patients, 30 patients with OA, and 29 HC. Target region methylation sequencing to the promoter region of CXCR5 was achieved using MethylTarget. The methylation level of cg04537602 and methylation haplotype were compared among the three groups, and the correlation between methylation levels and clinical characteristics of RA patients was performed by Spearman's rank correlation analysis. RESULTS: The methylation level of cg04537602 was significantly higher in the peripheral blood of RA patients compared with OA patients (p = 1.3 × 10-3 ) and in the HC group (p = 5.5 × 10- 4 ). The sensitivity was enhanced when CXCR5 methylation level combined with rheumatoid factor and anti-cyclic citrullinated peptide with area under curve (AUC) of 0.982 (95% confidence interval 0.970-0.995). The methylation level of cg04537602 in RA was positively correlated with C-reactive protein (CRP) (r = .16, p = .01), and in RA patients aged 60 years and above, cg04537602 methylation levels were positively correlated with CRP (r = .31, p = 4.7 × 10- 4 ), tender joint count (r = .21, p = .02), visual analog scales score (r = .21, p = .02), Disease Activity Score in 28 joints (DAS28) using the CRP level DAS28-CRP (r = .27, p = 2.1 × 10- 3 ), and DAS28-ESR (r = .22, p = .01). We also observed significant differences of DNA methylation haplotypes in RA patients compared with OA patients and HC, which was consistent with single-loci-based CpG methylation measurement. CONCLUSION: The methylation level of CXCR5 was significantly higher in RA patients than in OA and HC, and correlated with the level of inflammation in RA patients, our study establishes a link between CXCR5 DNA methylation and clinical features that may help in the diagnosis and disease management of RA patients.

Role of the granzyme family in rheumatoid arthritis: Current Insights and future perspectives.

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by chronic inflammation that affects synovial tissues of multiple joints. Granzymes (Gzms) are serine proteases that are released into the immune synapse between cytotoxic lymphocytes and target cells. They enter target cells with the help of perforin to induce programmed cell death in inflammatory and tumor cells. Gzms may have a connection with RA. First, increased levels of Gzms have been found in the serum (GzmB), plasma (GzmA, GzmB), synovial fluid (GzmB, GzmM), and synovial tissue (GzmK) of patients with RA. Moreover, Gzms may contribute to inflammation by degrading the extracellular matrix and promoting cytokine release. They are thought to be involved in RA pathogenesis and have the potential to be used as biomarkers for RA diagnosis, although their exact role is yet to be fully elucidated. The purpose of this review was to summarize the current knowledge regarding the possible role of the granzyme family in RA, with the aim of providing a reference for future research on the mechanisms of RA and the development of new therapies.

Multicentric reticulohistiocytosis with eosinophilic gastroenteritis: An unusual relationship.

Multicentric reticulohistiocytosis (MRH) is a rare disease with poorly defined therapeutic strategies. Here, we report the case of a patient with eosinophilic gastroenteritis who developed MRH after 5 years. The patient presented with disabling and rapidly progressive polyarthralgia, eosinophilic gastroenteritis, and resistance to first-line therapies. However, there was a marked improvement in the arthritis symptoms following treatment with tofacitinib. This presentation provides a useful perspective for the therapeutic management of complex scenarios involving MRH.

Circulating Level of Blood Iron and Copper Associated with Inflammation and Disease Activity of Rheumatoid Arthritis.

This study aims to compare the concentrations of circulating levels of iron, zinc, and copper in blood samples of rheumatoid arthritis (RA) patients which determine the correlations with inflammation and disease activity. A total of 102 RA patients and 66 healthy controls were enrolled. Circulation of iron, zinc, and copper levels in whole blood were assessed. Hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anticyclic citrullinated peptide antibody (anti-CCP) levels were collected. A meta-analysis was performed to validate our findings. Single and multiple variate generalized linear regression were applied to identify the correlation between trace elements and clinical characteristics. Blood copper level was significantly higher in RA patients (P < 0.001), while iron and zinc levels were decreased (P < 0.001 and P = 0.02, respectively). Meta-analysis confirmed our findings for zinc (SMD = - 1.17, P < 0.001) and copper (SMD = 1.24, P < 0.001). Copper level was positively correlated with DAS28-CRP (r = 0.35, P < 0.01), CRP (r = 0.45, P < 0.01) and ESR (r = 0.58, P < 0.01). Iron level was negatively correlated with DAS28-CRP (r = - 0.37, P < 0.01), CRP (r = - 0.46, P < 0.01) and ESR (r = - 0.55, P < 0.01). Circulating blood copper was significantly higher and positively correlated with DAS28-CRP and inflammatory markers, while circulating blood iron was decreased and negatively correlated with DAS28-CRP and inflammatory markers in RA patients.

Absent in melanoma 2 (AIM2) in rheumatoid arthritis: novel molecular insights and implications.

Absent in melanoma 2 (AIM2), a member of the Pyrin and HIN domain protein family, is a cytoplasmic receptor that recognizes double-stranded DNA. AIM2 exhibits limited expression under physiological conditions but is widely expressed in many human diseases, including autoimmune diseases, and plays an essential role in the immune response. Rheumatoid arthritis (RA) is an autoimmune disease that poses a severe threat to physical and mental health, and is caused by several genetic and metabolic factors. Multiple immune cells interact to form a complex inflammatory network that mediates inflammatory responses and bone destruction. Abnormal AIM2 expression in multiple immune cell populations (T cells, B cells, fibroblast-like synoviocytes, monocytes, and macrophages) may regulate multiple functional responses in RA through mechanisms such as pyroptosis, PANoptosis, and regulation of other molecules. In this review, we describe and summarize the functional regulation and impact of AIM2 expression in immune cells to improve our understanding of the complex pathological mechanisms. These insights may provide potential directions for the development of new clinical diagnostic strategies for RA.

Cuproptosis and cuproptosis-related genes in rheumatoid arthritis: Implication, prospects, and perspectives.

Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients' physical and mental health, leading to chronic synovitis and destruction of bone joints. Although various available clinical treatment options exist, patients respond with varying efficacies due to multiple factors, and there is an urgent need to discover new treatment options to improve clinical outcomes. Cuproptosis is a newly characterized form of cell death. Copper causes cuproptosis by binding to lipid-acylated components of the tricarboxylic acid cycle, leading to protein aggregation, loss of iron-sulfur cluster proteins, and eventually proteotoxic stress. Targeting copper cytotoxicity and cuproptosis are considered potential options for treating oncological diseases. The synovial hypoxic environment and the presence of excessive glycolysis in multiple cells appear to act as inhibitors of cuproptosis, which can lead to excessive survival and proliferation of multiple immune cells, such as fibroblast-like synoviocytes, effector T cells, and macrophages, further mediating inflammation and bone destruction in RA. Therefore, in this study, we attempted to elaborate and summarize the linkage of cuproptosis and key genes regulating cuproptosis to the pathological mechanisms of RA and their effects on a variety of immune cells. This study aimed to provide a theoretical basis and support for translating preclinical and experimental results of RA to clinical protocols.

G-Protein-Coupled Receptors in Rheumatoid Arthritis: Recent Insights into Mechanisms and Functional Roles.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint damage and even disability. Although there are various clinical therapies for RA, some patients still have poor or no response. Thus, the development of new drug targets remains a high priority. In this review, we discuss the role of G-protein-coupled receptors (GPCRs), including chemokine receptors, melanocortin receptors, lipid metabolism-related receptors, adenosine receptors, and other inflammation-related receptors, on mechanisms of RA, such as inflammation, lipid metabolism, angiogenesis, and bone destruction. Additionally, we summarize the latest clinical trials on GPCR targeting to provide a theoretical basis and guidance for the development of innovative GPCR-based clinical drugs for RA.

SFRP1 Negatively Modulates Pyroptosis of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis: A Review.

Secreted frizzled-related protein 1 (SFRP1) is a member of secretory glycoprotein SFRP family. As a primitive gene regulating cell growth, development and transformation, SFRP1 is widely expressed in human cells, including various cancer cells and fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA). Deletion or silencing of SFRP1 involves epigenetic and other mechanisms, and participates in biological behaviors such as cell proliferation, migration and cell pyroptosis, which leads to disease progression and poor prognosis. In this review, we discuss the role of SFRP1 in the pathogenesis of RA-FLS and summarize different experimental platforms and recent research results. These are helpful for understanding the biological characteristics of SFRP1 in RA, especially the mechanism by which SFRP1 regulates RA-FLS pyroptosis through Wnt/ß-catenin and Notch signaling pathways. In addition, the epigenetic regulation of SFRP1 in RA-FLS is emphasized, which may be considered as a promising biomarker and therapeutic target of RA.

Inflammatory Response to Regulated Cell Death in Gout and Its Functional Implications.

Gout, a chronic inflammatory arthritis disease, is characterized by hyperuricemia and caused by interactions between genetic, epigenetic, and metabolic factors. Acute gout symptoms are triggered by the inflammatory response to monosodium urate crystals, which is mediated by the innate immune system and immune cells (e.g., macrophages and neutrophils), the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pro-inflammatory cytokine (e.g., IL-1ß) release. Recent studies have indicated that the multiple programmed cell death pathways involved in the inflammatory response include pyroptosis, NETosis, necroptosis, and apoptosis, which initiate inflammatory reactions. In this review, we explore the correlation and interactions among these factors and their roles in the pathogenesis of gout to provide future research directions and possibilities for identifying potential novel therapeutic targets and enhancing our understanding of gout pathogenesis.

Assessment of four screening tools and retrieval of key questions to detect undiagnosed psoriatic arthritis in Chinese patients with psoriasis: A multicenter study.

Several screening tools have been developed to facilitate early diagnosis of psoriatic arthritis (PsA); however, their performance varied greatly across different studies. In this study, we validated and compared the performance of four screening tools in detecting undiagnosed PsA Chinese patients with psoriasis, and determined the key questions and their weights. The four screening tools were the Early Arthritis for Psoriatic Patients (EARP) questionnaire, Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire, Psoriasis and Arthritis Screening Questionnaire (PASQ), and Psoriasis Epidemiology Screening Tool (PEST). The receiver-operator curve (ROC) with area under curve (AUC) was used to determine sensitivity, specificity, and accuracy. Least absolute shrinkage and selection operator and logistic regression were utilized to retrieve key questions, and a nomogram was utilized to visualize their weights. Of 482 psoriasis patients from dermatology clinics, 77 were newly diagnosed with PsA. Another 68 patients with newly diagnosed PsA from rheumatology clinics were incorporated in the analysis. ROC analysis indicated that the optimal cut-off values for EARP, PASE, PASQ, and PEST were 3, 40, 7, and 3, with corresponding sensitivities of 91.4%, 88.6%, 86.2%, and 88.5%, and specificities of 88.6%, 75.2%, 80.2%, and 83.6%, respectively. The AUC of EARP (0.925) was higher than those of PASE (0.885), PASQ (0.905), and PEST (0.827). However, none of them were sufficiently sensitive to identify pure axial PsA (sensitivities of EARP, PASQ, and PASE were 25.0%, 36.8%, and 42.1%, respectively). Twelve key questions were retrieved from these four tools to establish a nomogram with a high discrimination (C-index = 0.993) and a good calibration (mean absolute error = 0.014). In conclusion, to screen undiagnosed PsA, EARP has slightly better balanced sensitivity and specificity, and higher accuracy. The retrieval of key questions and nomogram signify the necessity of attributing different scores to differently weighted questions when developing a new screening tool to make it function more efficiently.

MicroRNA-106b overexpression suppresses synovial inflammation and alleviates synovial damage in patients with rheumatoid arthritis.

OBJECTIVES: To explore the effect of miR-106b on synovial inflammation and damage in rheumatoid arthritis (RA) patients and further to investigate its possible mechanism. METHODS: Quantitative real-time polymerase chain reaction, immunofluorescence, in situ hybridization, and immunohistochemistry assay were used to verify the levels of miR-106b and cytokines. Pearson's correlation analysis was conducted to examine bivariate relationship between miR-106b and cytokines or receptor activator of nuclear factor-κ B ligand (RANKL). Following the isolation of fibroblast-like synoviocytes (FLS), the cultured cells were separately transfected with or without miR-106b mimic. Thereafter, cell proliferation, invasion and migration were measured by Cell Counting Kit-8 assay and Transwell assay, respectively. Furthermore, concentration and expression of cytokines were separately detected by enzyme-linked immunosorbent assay and Western blot. RESULTS: Compared with osteoarthritis, RA patients had a lower level of miR-106b and higher levels of RANKL, tumour necrosis factor-a (TNF-a), and interleukin-6 (IL-6). The relative transcription of miR-106b level was negatively correlated to TNF-a, IL-6, and RNKAL levels in both patients (all P < 0.05). Furthermore, miR-106b overexpression suppressed cell proliferation, migration, and invasion capacity of RA-FLS. CONCLUSIONS: miR-106b overexpression suppresses synovial inflammation and alleviates synovial damage; thus, it may be served as a potential therapeutic target for RA patients.

Dihydroartemisinin alleviates skin fibrosis and endothelial dysfunction in bleomycin-induced skin fibrosis models.

OBJECTIVE: The present study was to investigate whether dihydroartemisinin (DHA), which is a highly effective and safe drug in the treatment of malaria, could be repurposed for the treatment of skin fibrosis and vascular dysfunction in systemic sclerosis (SSc). METHODS: The value of DHA was determined using a bleomycin-induced model of skin fibrosis. mRNA transcriptome analysis was performed, and the targets of DHA on fibroblasts were identified. Immunofluorescence staining was used to identify dermal vessels undergoing endothelial-to-mesenchymal transition (EndoMT). Autophagic flux was detected by western blot and mRFP-GFP-LC3 adenovirus vector transfection. RESULTS: Both systemic and topical administration of DHA decreased dermal thickness and collagen deposition and alleviated EndoMT in bleomycin-induced skin fibrosis mice model. Treatment of human umbilical vein endothelial cells (HUVECs) with TGF-ß1 resulted in the acquisition of the activation marker (α-SMA) and loss of endothelial markers (CD31 and VE-cadherin), a process that was restored by DHA. DHA significantly suppressed skin fibroblast activation and collagen-1 production mainly through regulating PI3K-Akt pathway. DHA also induced fibroblast autophagic flux and that autophagy dependently suppressed collagen-1 production. CONCLUSION: The results of the present study revealed that oral and topical DHA administration ameliorated tissue fibrosis and protected dermal blood vessels from bleomycin-induced EndoMT. Our study has elucidated the value of repurposing DHA for the treatment of SSc. Key Points • Oral or topical usage of DHA alleviated dermal fibrosis and EndoMT in bleomycin-induced skin fibrosis mice models. • DHA autophagy dependently inhibited fibroblast activation and collagen deposition via PI3K-ATK pathway. • DHA inhibited EndoMT of HUVECs induced by TGF-ß1 by the downregulation of α-SMA and the upregulation of CD31 and VE-cadherin.

Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis.

Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.

Changes in Efficacy Indicators for Adalimumab Biosimilar Candidate (HS016) for the Treatment of Active Ankylosing Spondylitis at Various Time Points.

Objectives: A phase III, 24-weeks Chinese clinical trial demonstrated that efficacy and safety outcomes of treatments with 40 mg/0.8 ml HS016 (n = 416) or adalimumab (n = 232) for active ankylosing spondylitis (AS) patients was comparable. In the present study, a subanalysis of the clinical trial was conducted to determine whether also individual efficacy indicators were comparable between HS016 and adalimumab. Methods: The individual efficacy indicators total and nocturnal back pain, global assessment of disease activity, swollen joint count, Maastricht AS Enthesitis Score, Bath AS Disease Activity Index, Bath AS Functional Index, Bath AS Metrology Index and chest expansion, were assessed at baseline and every 2 weeks during the treatment period. Results: This subanalysis revealed no significant difference between the patient groups treated with HS016 or adalimumab for any individual efficacy indicator investigated at any time point (all p > 0.05) beside faster total back pain score improvements in the adalimumab group on week 10, 12 and 22, which became equal at week 24. Among these indicators, chest expansion showed a significant increase at each time point compared with baseline, whereas all other efficacy indicators showed significant decreases compared with baseline at each time point (all p < 0.05). All efficacy indicators had increased or decreased rapidly by week 2, and the values continued to increase/decrease up to week 12, with subsequent smaller changes thereafter up to week 24 of treatment. Conclusion: The response trajectory of most individual efficacy indicators was comparable between HS016 and adalimumab at each time point during the 24 weeks of the trial. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=37910, identifier [ChiCTR1900022520].