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Journal of Drug Targeting Jul 2024Rheumatoid arthritis (RA) is a chronic autoimmune inflammation. Excessive proliferation and inadequate apoptosis of synovial macrophages are the crucial events of RA....
Rheumatoid arthritis (RA) is a chronic autoimmune inflammation. Excessive proliferation and inadequate apoptosis of synovial macrophages are the crucial events of RA. Therefore, delivering therapeutic molecules to synovial macrophages specifically to tackle apoptotic insufficiency probably can be an efficient way to reduce joint inflammation and bone erosion. Based on the characteristics of dextran sulphate (DS) specifically binding scavenger receptor A (SR-A) on macrophage and celastrol (CLT) inducing apoptosis, we designed synovial macrophage-targeted nano-emulsions encapsulated with CLT (SR-CLTNEs) and explored their anti-RA effect. After intravenous injection, fluorescence-labelled SR-CLTNEs successfully targeted inflammatory joints and synovial macrophages in a mouse model of RA, with the macrophage targeting efficiency of SR-CLTNEs, CLTNEs and free DID was 20.53%, 13.93% and 9.8%, respectively. and studies showed that SR-CLTNEs effectively promoted the apoptosis of macrophages, reshaped the balance between apoptosis and proliferation, and ultimately treated RA in a high efficiency and low toxicity manner. Overall, our work demonstrates the efficacy of using SR-CLTNEs as a novel nanotherapeutic approach for RA therapy and the great translational potential of SR-CLTNEs.
Topics: Animals; Pentacyclic Triterpenes; Arthritis, Rheumatoid; Apoptosis; Mice; Macrophages; Emulsions; Nanoparticles; Male; Triterpenes; Synovial Membrane; Disease Models, Animal; Humans; Cell Proliferation; Dextran Sulfate
PubMed: 38712874
DOI: 10.1080/1061186X.2024.2352757 -
Materials Today. Bio Jun 2024Rheumatoid arthritis (RA) is known to be caused by autoimmune disorders and can be partially alleviated through Disease-Modifying Antirheumatic Drugs (DMARDs) therapy....
Rheumatoid arthritis (RA) is known to be caused by autoimmune disorders and can be partially alleviated through Disease-Modifying Antirheumatic Drugs (DMARDs) therapy. However, due to significant variations in the physical environment and condition of each RA patient, the types and doses of DMARDs prescribed can differ greatly. Consequently, there is a need for a platform based on patient-derived cells to determine the effectiveness of specific DMARDs for individual patient. In this study, we established an RA three-dimensional (3D) spheroid that mimics the human body's 3D environment, enabling high-throughput assays by culturing patient-derived synovial cells on a macroscale-patterned polycaprolactone (PCL) scaffold. Fibroblast-like synoviocytes (FLSs) from patient and human umbilical vein endothelial cells (HUVECs) were co-cultured to simulate vascular delivery. Additionally, RA characteristics were identified at both the genetic and cytokine levels using real-time polymerase chain reaction (RT-qPCR) and dot blot assay. The similarities in junctions and adhesion were demonstrated in both actual RA patient tissues and 3D spheroids. The 3D RA spheroid was treated with representative DMARDs, observing changes in reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH) levels, and inflammatory cytokine responses to confirm the varying cell reactions depending on the DMARDs used. This study underscores the significance of the 3D drug screening platform, which can be applied to diverse inflammatory disease treatments as a personalized drug screening system. We anticipate that this platform will become an indispensable tool for advancing and developing personalized DMARD treatment strategies.
PubMed: 38711937
DOI: 10.1016/j.mtbio.2024.101061 -
Frontiers in Immunology 2024Rheumatoid arthritis (RA) is a systemic immune-related disease characterized by synovial inflammation and destruction of joint cartilage. The pathogenesis of RA remains...
BACKGROUND
Rheumatoid arthritis (RA) is a systemic immune-related disease characterized by synovial inflammation and destruction of joint cartilage. The pathogenesis of RA remains unclear, and diagnostic markers with high sensitivity and specificity are needed urgently. This study aims to identify potential biomarkers in the synovium for diagnosing RA and to investigate their association with immune infiltration.
METHODS
We downloaded four datasets containing 51 RA and 36 healthy synovium samples from the Gene Expression Omnibus database. Differentially expressed genes were identified using R. Then, various enrichment analyses were conducted. Subsequently, weighted gene co-expression network analysis (WGCNA), random forest (RF), support vector machine-recursive feature elimination (SVM-RFE), and least absolute shrinkage and selection operator (LASSO) were used to identify the hub genes for RA diagnosis. Receiver operating characteristic curves and nomogram models were used to validate the specificity and sensitivity of hub genes. Additionally, we analyzed the infiltration levels of 28 immune cells in the expression profile and their relationship with the hub genes using single-sample gene set enrichment analysis.
RESULTS
Three hub genes, namely, ribonucleotide reductase regulatory subunit M2 (), DLG-associated protein 5 (), and kinesin family member 11 (), were identified through WGCNA, LASSO, SVM-RFE, and RF algorithms. These hub genes correlated strongly with T cells, natural killer cells, and macrophage cells as indicated by immune cell infiltration analysis.
CONCLUSION
, , and could serve as potential diagnostic indicators and treatment targets for RA. The infiltration of immune cells offers additional insights into the underlying mechanisms involved in the progression of RA.
Topics: Humans; Arthritis, Rheumatoid; Gene Regulatory Networks; Machine Learning; Gene Expression Profiling; Transcriptome; Synovial Membrane; Kinesins; Biomarkers; Databases, Genetic; Computational Biology; Support Vector Machine; Ribonucleoside Diphosphate Reductase
PubMed: 38711508
DOI: 10.3389/fimmu.2024.1387311 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Apr 2024To explore the inhibitory effect of , a traditional Miao herbal medicine formula, on articular bone and cartilage destruction and synovial neovascularization in rats...
OBJECTIVE
To explore the inhibitory effect of , a traditional Miao herbal medicine formula, on articular bone and cartilage destruction and synovial neovascularization in rats with collagen-induced arthritis (CIA).
METHODS
In a SD rat model of CIA, we tested the effects of daily gavage of at low, moderate and high doses (10, 20, and 40 g/kg, respectively) for 21 days, with Tripterygium glycosides (GTW) as the positive control, on swelling in the hind limb plantar regions by arthritis index scoring. Pathologies in joint synovial membrane of the rats were observed with HE staining, and serum TNF-α and IL-1β levels were detected with ELISA. The expressions of NF-κB p65, matrix metalloproteinase 1 (MMP1), MMP2 and MMP9 at the mRNA and protein levels in the synovial tissues were detected using real-time PCR and Western blotting. Network pharmacology analysis was conducted to identify the important target proteins in the pathways correlated with the therapeutic effects of topical treatment for RA, and the core target proteins were screened by topological analysis.
RESULTS
Treatment with GTW and at the 3 doses all significantly alleviated plantar swelling, lowered arthritis index scores, improved cartilage and bone damage and reduced neovascularization in CIA rats (<0.05), and the effects of showed a dose dependence. Both GTW and treatments significantly lowered TNF-α, IL-1β, NF-κB p65, MMP1, MMP2, and MMP9 mRNA and protein expressions in the synovial tissues of CIA rats (<0.05). Network pharmacological analysis identified MMPs as the core proteins associated with topical treatment of RA.
CONCLUSION
alleviates articular bone and cartilage damages and reduces synovial neovascularization in CIA rats possibly by downregulating MMPs the TNF-α/IL-1β/NF-κB-MMP1, 2, 9 signaling pathway, and MMPs probably plays a key role in mediating the effect of though the therapeutic pathways other than oral administration.
Topics: Animals; Rats; Arthritis, Rheumatoid; Rats, Sprague-Dawley; Arthritis, Experimental; Drugs, Chinese Herbal; Matrix Metalloproteinase 1; Synovial Membrane; Tumor Necrosis Factor-alpha; Interleukin-1beta; Matrix Metalloproteinase 2; Down-Regulation; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Tripterygium; Transcription Factor RelA
PubMed: 38708508
DOI: 10.12122/j.issn.1673-4254.2024.04.16 -
Cureus Apr 2024Introduction Pigmented villonodular synovitis (PVNS) is a relatively rare disorder affecting the synovial membrane and tendon sheath of a joint. It rarely affects the...
Introduction Pigmented villonodular synovitis (PVNS) is a relatively rare disorder affecting the synovial membrane and tendon sheath of a joint. It rarely affects the shoulder joint. This prospective study aims to document the challenges encountered in achieving total synovectomy and assesses the clinical outcomes of arthroscopic synovectomy for PVNS in shoulder patients. Methods This is a prospective study conducted from April 2017 to September 2023. This monoarticular disease was observed among six patients (four females and two males). All patients underwent arthroscopic extensile synovectomy with biopsy and culture. The outcomes were measured using Constant score, American Shoulder and Elbow Surgeons (ASES), and University of California Los Angeles (UCLA) scores. All patients were followed up for a minimum of 36 months after arthroscopic synovectomy. Results All intraoperative findings were consistent with PVNS and confirmed with histopathological examination. All patients achieved a satisfactory, painless range of movements following surgery. The individual Constant score improved from a mean value of 64.83 to 94.50, the ASES score improved from a mean value of 81.15 to 99.73, and the UCLA score improved from a mean value of 23.16 to 34.83 post-arthroscopic intervention, proving its effectiveness. No recurrences were reported after 36 months of follow-up. Conclusion PVNS can be easily missed, and one must have a high index of suspicion to diagnose early. Delayed presentation of the disease had led to severe destruction of the joint. Early diagnosis and arthroscopic intervention prior to joint destruction are crucial for achieving a good functional outcome. Incomplete excision may lead to recurrence of the disease. Therefore, we propose extensile arthroscopic synovectomy of the shoulder, wherein by expecting and addressing the intraoperative challenges, complete excision can be achieved, thus preventing recurrence.
PubMed: 38707076
DOI: 10.7759/cureus.57492 -
The American Journal of Sports Medicine Jun 2024The incremental biological changes in the synovial microenvironment of the shoulder in acute and chronic instability that may contribute to joint degeneration are poorly...
BACKGROUND
The incremental biological changes in the synovial microenvironment of the shoulder in acute and chronic instability that may contribute to joint degeneration are poorly understood. Proteomic analysis of synovial fluid in patients with shoulder instability may improve our understanding of proteins that are shed into shoulder synovial fluid after an injury.
HYPOTHESIS
Injury-specific factors such as the direction of instability and the severity of glenoid and humeral bone loss are associated with the proteome of synovial fluid in patients with shoulder instability.
STUDY DESIGN
Descriptive laboratory study.
METHODS
Synovial fluid lavage samples were compared between patients with anterior (n = 12) and posterior (n = 8) instability and those without instability (n = 5). Synovial proteins were identified with liquid chromatography-tandem mass spectrometry. Orthogonal validation of protein targets found to be significant on tandem mass spectrometry was performed in a separate set of prospective patients with Western blotting. Data were processed and analyzed, and values were adjusted with the Benjamini-Hochberg method for multiple comparisons.
RESULTS
A total of 25 patients were included. Tandem mass spectrometry identified 720 protein groups in synovial fluid of patients with shoulder instability. There were 4 synovial proteins that were significantly expressed in patients with anterior instability relative to posterior instability: periostin (POSTN) (adjusted value = .03; log fold change [logFc] = 4.7), transforming growth factor beta-induced protein ig-h3 (adjusted value = .05; logFc = 1.7), collagen type VI alpha-3 chain (adjusted value = .04; logFc = 2.6), and coagulation factor V (adjusted value = .04; logFc = -3.3). Among these targets, POSTN showed a moderate correlation with the Hill-Sachs lesion size ( = 0.7). Prospective validation with Western blotting confirmed a significantly higher level of POSTN in synovial fluid of patients with anterior instability ( = .00025; logFc = 5.1).
CONCLUSION
Proteomic analysis enriched our understanding of proteins that were secreted into shoulder synovial fluid of patients with shoulder instability. The identification of POSTN, a proinflammatory catabolic protein involved with tissue remodeling and repair, as a significant target in anterior shoulder instability is a novel finding. Therefore, further study is warranted to determine the role that POSTN may play in the progression of bone loss and posttraumatic osteoarthritis.
CLINICAL RELEVANCE
Proteomic analysis of synovial fluid in patients with shoulder instability improved our understanding of this abnormality after an injury.
Topics: Humans; Synovial Fluid; Joint Instability; Female; Biomarkers; Male; Cell Adhesion Molecules; Proteomics; Adult; Young Adult; Shoulder Joint; Adolescent; Tandem Mass Spectrometry; Periostin
PubMed: 38702960
DOI: 10.1177/03635465241246258 -
Cureus Apr 2024One of the hallmarks of rheumatoid arthritis (RA) is inflammation of the synovial membrane, and oxidative stress is a mediator of tissue damage. RA is characterized by... (Review)
Review
Comparison of Adenosine Deaminase, C-reactive Protein, Uric Acid, and Rheumatoid Arthritis Levels in Patients With Rheumatoid Arthritis and Those Without Arthritis: A Review.
One of the hallmarks of rheumatoid arthritis (RA) is inflammation of the synovial membrane, and oxidative stress is a mediator of tissue damage. RA is characterized by persistent joint inflammation, which leads to pain, edema, and finally joint destruction. Numerous biochemical markers can cause RA because of their impact on systemic and local inflammation. Numerous biomarkers have been investigated for their potential application in the diagnosis and prognosis of RA. In this review article, we evaluate the role of RA factor or rheumatoid factor (RF), uric acid, C-reactive protein (CRP), and adenosine deaminases (ADAs) as biomarkers in patients with and without arthritis. Studies that analyze and compare the levels of uric acid, ADAs, CRP, and RF in patients with and without arthritis. Although recent research has shown higher levels of uric acid, ADA, CRP, and RA in patients with RF compared to healthy controls, these findings may indicate a role for these markers in reflecting inflammation and disease activity. In the metabolism of purines, the enzyme ADA is involved. The liver produces CRP, which is then released into the bloodstream. In inflammatory situations, there is a rise in CRP levels. This biomarker is frequently used for systemic inflammatory assessment in RA. The pathophysiology and severity of RA have both been connected to uric acid, which has historically been linked to gout. One particular biomarker for RA is RF. When compared to a healthy control group of individuals with arthritis, this review provides valuable insights into the diagnostic and prognostic use of uric acid, CRP, ADAs, and RF.
PubMed: 38699124
DOI: 10.7759/cureus.57433 -
Tissue Engineering. Part A May 2024Previously, chitosan reduces the senescence-related phenotypes in human foreskin fibroblasts through the transforming growth factor beta (TGF-β) pathway, and enhances...
Previously, chitosan reduces the senescence-related phenotypes in human foreskin fibroblasts through the transforming growth factor beta (TGF-β) pathway, and enhances the proliferation and migration capabilities of these cells are demonstrated. In this study, we examined whether the senescence-delaying effect of chitosan could be applied to primary knee-related fibroblasts, such as human synovial membrane derived cells (SCs) and anterior cruciate ligament fibroblasts (ACLs). These two types of cells were obtained from donors who needed ACL reconstruction or knee replacement. We found that chitosan treatment effectively reduced aging-associated β-galactosidase (SA-β-gal)-positive cells, downregulated the expression of senescence-related proteins pRB and p53, and enhanced the 5-bromo-2'-deoxyuridine (BrdU) incorporation ability of SCs and ACLs. Moreover, chitosan could make SCs secret more glycosaminoglycans (GAGs) and produce type I collagen. The ability of ACLs to close the wound was also enhanced, and the TGF-β and alpha smooth muscle actin (αSMA) protein expression decreased after chitosan treatment. In summary, chitosan not only delayed the senescence but also enhanced the functions of SCs and ACLs, which is beneficial to the application of chitosan in cell expansion and cell therapy.
PubMed: 38695112
DOI: 10.1089/ten.TEA.2024.0077 -
Frontiers in Medicine 2024Osteoarthritis (OA) is distinguished by pathological alterations in the synovial membrane, articular cartilage, and subchondral bone, resulting in physical symptoms such... (Review)
Review
Osteoarthritis (OA) is distinguished by pathological alterations in the synovial membrane, articular cartilage, and subchondral bone, resulting in physical symptoms such as pain, deformity, and impaired mobility. Numerous research studies have validated the effectiveness of low-intensity pulsed ultrasound (LIPUS) in OA treatment. The periodic mechanical waves generated by LIPUS can mitigate cellular ischemia and hypoxia, induce vibration and collision, produce notable thermal and non-thermal effects, alter cellular metabolism, expedite tissue repair, improve nutrient delivery, and accelerate the healing process of damaged tissues. The efficacy and specific mechanism of LIPUS is currently under investigation. This review provides an overview of LIPUS's potential role in the treatment of OA, considering various perspectives such as the synovial membrane, cartilage, subchondral bone, and tissue engineering. It aims to facilitate interdisciplinary scientific research and further exploration of LIPUS as a complementary technique to existing methods or surgery. Ongoing research is focused on determining the optimal dosage, frequency, timing, and treatment strategy of LIPUS for OA. Additional research is required to clarify the precise mechanism of action and potential impacts on cellular, animal, and human systems prior to its integration into therapeutic applications.
PubMed: 38695024
DOI: 10.3389/fmed.2024.1292473 -
In Vivo (Athens, Greece) 2024Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and management of it is still a challenge. The present investigation assessed the potential preventive...
BACKGROUND/AIM
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and management of it is still a challenge. The present investigation assessed the potential preventive effect of phlorizin on rats with RA.
MATERIALS AND METHODS
A total of 40 healthy Wistar rats were used for this study. Bovine type II collagen and Freund's incomplete adjuvant (1:1 and 1 mg/ml) were administered on days 1 and 8 of the protocol to induce RA in rats; treatment with phlorizin at 60 or 120 mg/kg was started after the 4th week of the protocol, and its effect on inflammation, level of inflammatory cytokines, and expression of proteins were estimated in RA rats. Moreover, an in vitro study was performed on fibroblast-like synoviocytes (FLSs), and the effects of phlorizin on proliferation, apoptosis, and expression of the mechanistic target of rapamycin kinase pathway protein after stimulating these cells with tumor necrosis factor α (TNF-α) were estimated.
RESULTS
The data obtained from the study indicate that phlorizin has the potential to mitigate inflammation and enhance weight management in rats with RA induced by bovine type II collagen (CII). The level of inflammatory cytokines in the serum and the expression of protein kinase B (AKT), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and mechanistic target of rapamycin kinase (mTOR) proteins in the joint tissue were reduced in phlorizin-treated rats with RA. In this investigation, phlorizin was shown to reverse the histological abnormalities in the joint tissue of rats with RA. The in-vitro study showed that phlorizin reduced proliferation and had no apoptotic effect on TNF-α-stimulated FLSs. Expression of AKT, PI3K, and mTOR proteins was also down-regulated in phlorizin-treated TNF-α-stimulated FLSs.
CONCLUSION
Phlorizin protects against inflammation and reduces injury to synovial tissues in RA by modulating the AKT/PI3K/mTOR pathway.
Topics: Animals; Arthritis, Rheumatoid; TOR Serine-Threonine Kinases; Rats; Hyperplasia; Signal Transduction; Phlorhizin; Inflammation; Synoviocytes; Synovial Membrane; Disease Models, Animal; Cytokines; Cell Proliferation; Apoptosis; Male; Arthritis, Experimental; Rats, Wistar; Proto-Oncogene Proteins c-akt
PubMed: 38688626
DOI: 10.21873/invivo.13553