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Immune Network Apr 2024We have reported that anterior cruciate ligament (ACL) injury leads to the differential dysregulation of the complement system in the synovium as compared to meniscus...
We have reported that anterior cruciate ligament (ACL) injury leads to the differential dysregulation of the complement system in the synovium as compared to meniscus tear (MT) and proposed this as a mechanism for a greater post-injury prevalence of post traumatic osteoarthritis (PTOA). To explore additional roles of complement proteins and regulators, we determined the presence of decay-accelerating factor (DAF), C5b, and membrane attack complexes (MACs, C5b-9) in discarded surgical synovial tissue (DSST) collected during arthroscopic ACL reconstructive surgery, MT-related meniscectomy, osteoarthritis (OA)-related knee replacement surgery and normal controls. Multiplexed immunohistochemistry was used to detect and quantify complement proteins. To explore the involvement of body mass index (BMI), after these 2 injuries, we examined correlations among DAF, C5b, MAC and BMI. Using these approaches, we found that synovial cells after ACL injury expressed a significantly lower level of DAF as compared to MT (p<0.049). In contrast, C5b staining synovial cells were significantly higher after ACL injury (p<0.0009) and in OA DSST (p<0.039) compared to MT. Interestingly, there were significantly positive correlations between DAF & C5b (r=0.75, p<0.018) and DAF & C5b (r=0.64 p<0.022) after ACL injury and MT, respectively. The data support that DAF, which should normally dampen C5b deposition due to its regulatory activities on C3/C5 convertases, does not appear to exhibit that function in inflamed synovia following either ACL injury or MT. Ineffective DAF regulation may be an additional mechanism by which relatively uncontrolled complement activation damages tissue in these injury states.
PubMed: 38725672
DOI: 10.4110/in.2024.24.e17 -
Journal of Ethnopharmacology Oct 2024Di-Long (Pheretima vulgaris) is a classic animal sourced traditional Chinese medicine. It has been used for the treatment of joint inflammation and arthralgia for over...
ETHNOPHARMACOLOGICAL RELEVANCE
Di-Long (Pheretima vulgaris) is a classic animal sourced traditional Chinese medicine. It has been used for the treatment of joint inflammation and arthralgia for over two thousand years due to its effects of Tong-Luo-Zhi-Tong (dredging collaterals and alleviating pain). Our previous study showed that Chinese medicine Di-Long has significant anti-rheumatoid arthritis (RA) effects.
AIM OF THE STUDY
Considering Di-Long as a potential source of active compounds with specific anti-RA therapeutic effects, this research was to obtain the anti-RA target-specific active fraction from Di-Long extracts (DL), and to further explore the chemical basis and verify the anti-RA mechanism of this active fraction.
MATERIALS AND METHODS
Transcriptomic was applied to obtain the main anti-RA targets of DL on human RA fibroblast-like synoviocytes (FLS) and validated by qPCR. The target-corresponding active fraction was isolated from DL by ethanol precipitation and gel chromatography, and analyzed by nanoliter chromatography-mass spectrometry. Anti-RA effects of this active fraction was investigated by collagen-induced arthritis (CIA) in mice, and anti-RA mechanisms were verified in cocultured model of rat FLS and peripheral blood lymphocytes.
RESULTS
We confirmed that CXCL10/CXCR3 was the main anti-RA target of DL. The active fraction - A (2182 - 890 Da) was isolated from DL based on its CXCL10 inhibiting effects in RA-FLS. Fraction A contains 195 peptides (192 were newly discovered), 26 of which might be bioactive and were considered to be the chemical basis of its anti-RA effects. Fraction A significantly ameliorated the joint destruction and overall inflammation in CIA mice, and downregulated CXCR3 expression in mice joint. Fraction A inhibited the chemotaxis of Th-cells in rat peripheral blood lymphocytes towards the TNF-α-induced rat FLS through CXCL10/CXCR3 pathway.
CONCLUSIONS
Our work indicated that active fraction from DL containing small peptides exhibits promising therapeutic effects for RA through inhibiting CXCL10/CXCR3 chemotaxis.
Topics: Animals; Receptors, CXCR3; Chemokine CXCL10; Arthritis, Experimental; Arthritis, Rheumatoid; Male; Antirheumatic Agents; Rats; Humans; Chemotaxis; Synovial Membrane; Mice; Mice, Inbred DBA; Drugs, Chinese Herbal; Synoviocytes
PubMed: 38723919
DOI: 10.1016/j.jep.2024.118286 -
Scientific Reports May 2024Histone lysine methylation is thought to play a role in the pathogenesis of rheumatoid arthritis (RA). We previously reported aberrant expression of the gene encoding...
Histone lysine methylation is thought to play a role in the pathogenesis of rheumatoid arthritis (RA). We previously reported aberrant expression of the gene encoding mixed-lineage leukemia 1 (MLL1), which catalyzes methylation of histone H3 lysine 4 (H3K4), in RA synovial fibroblasts (SFs). The aim of this study was to elucidate the involvement of MLL1 in the activated phenotype of RASFs. SFs were isolated from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee joint replacement. MLL1 mRNA and protein levels were determined after stimulation with tumor necrosis factor α (TNFα). We also examined changes in trimethylation of H3K4 (H3K4me3) levels in the promoters of RA-associated genes (matrix-degrading enzymes, cytokines, and chemokines) and the mRNA levels upon small interfering RNA-mediated depletion of MLL1 in RASFs. We then determined the levels of H3K4me3 and mRNAs following treatment with the WD repeat domain 5 (WDR5)/MLL1 inhibitor MM-102. H3K4me3 levels in the gene promoters were also compared between RASFs and OASFs. After TNFα stimulation, MLL1 mRNA and protein levels were higher in RASFs than OASFs. Silencing of MLL1 significantly reduced H3K4me3 levels in the promoters of several cytokine (interleukin-6 [IL-6], IL-15) and chemokine (C-C motif chemokine ligand 2 [CCL2], CCL5, C-X-C motif chemokine ligand 9 [CXCL9], CXCL10, CXCL11, and C-X3-C motif chemokine ligand 1 [CX3CL1]) genes in RASFs. Correspondingly, the mRNA levels of these genes were significantly decreased. MM-102 significantly reduced the promoter H3K4me3 and mRNA levels of the CCL5, CXCL9, CXCL10, and CXCL11 genes in RASFs. In addition, H3K4me3 levels in the promoters of the IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 genes were significantly higher in RASFs than OASFs. Our findings suggest that MLL1 regulates the expression of particular cytokines and chemokines in RASFs and is associated with the pathogenesis of RA. These results could lead to new therapies for RA.
Topics: Aged; Female; Humans; Male; Middle Aged; Arthritis, Rheumatoid; Cells, Cultured; Chemokines; Cytokines; Fibroblasts; Gene Expression Regulation; Histone-Lysine N-Methyltransferase; Histones; Myeloid-Lymphoid Leukemia Protein; Osteoarthritis; Promoter Regions, Genetic; RNA, Messenger; Synovial Membrane; Tumor Necrosis Factor-alpha
PubMed: 38719857
DOI: 10.1038/s41598-024-60860-7 -
Diagnostic Microbiology and Infectious... Jul 2024Lecanicillium dimorphum and Lecanicillium psalliotae are fungi that exist naturally in plants or insects, and are generally considered non-pathogenic to humans. However,...
Lecanicillium dimorphum and Lecanicillium psalliotae are fungi that exist naturally in plants or insects, and are generally considered non-pathogenic to humans. However, in this case, we cultured Lecanicillium from the synovial fluid of a patient, and identified it through genome sequencing and sequence alignment as Lecanicillium dimorphum or Lecanicillium psalliotae. Due to the conservation of sequences, we can only identify the genus and not the species. There are very few reports on the human infection and pathogenicity of these two fungi, and this case also cannot completely prove that the pathogenic agent is this fungus. But this case also holds clinical significance, as the discovery of Lecanicillium in a human sample can alert the clinician to the presence of an uncommon mold with unclear clinical significance.
Topics: Humans; Hypocreales; Mycoses; Synovial Fluid; Male; Phylogeny; Sequence Analysis, DNA; DNA, Fungal
PubMed: 38718662
DOI: 10.1016/j.diagmicrobio.2024.116337 -
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 -
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 -
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