Synovial Hyperplasia Research Articles

The Effect of T-Cell Transcription Factors on the Immunopathogenesis of Rheumatoid Arthritis

Objective: This looks at investigates the impact of T-cell transcription factors at the immunopathogenesis of rheumatoid arthritis (RA). Methods: An overall of 60 sufferers diagnosed with RA and handled in our health center between January 2022 and January 2024 had been selected because the remark organization, whilst 60 healthy those who underwent routine health test-usual through the equal length had been distinct as the manipulate group. Peripheral blood samples from each organization were analyzed to measure the proportion and proliferative interest of regulatory T cells (Tregs), as well as their inhibitory feature on effector T cells. Levels of the T-cell transcription component STAT3 and associated inflammatory factors were additionally tested. RA patients had been handled with a STAT3 inhibitor to take a look at changes in Treg proliferation, inhibitory function, and the secretion stages of seasoned-inflammatory factors. Additionally, synovial tissue from RA patients changed into received for histopathological evaluation the usage of mild microscopy to assess synovial infection and hyperplasia. Results: The peripheral blood of the remark organization confirmed substantially decrease Treg counts compared to the manipulate group (P < 0.05). The in vitro proliferation charge of Tregs in the remark group was additionally decrease than within the manipulate group (P < 0.05). Levels of p-STAT3, TNF-α, IFN-γ, and IL-17A in Tregs have been higher within the commentary group, and the expression tiers of TNF-α, IFN-γ, and IL-17A mRNA have been also improved in comparison to the manage group (P < 0.05). RA sufferers handled with 50 μg/L STAT3 inhibitor confirmed a substantially better Tresp suppression price in comparison to untreated sufferers (P < 0.05). However, there has been no statistically tremendous distinction in Treg proliferation charges among the treated institution and the control institution (P > 0.05). The expression of p-STAT3 protein in Tregs became lower in the treated group compared to untreated sufferers (P < 0.05), and not using a big difference as compared to the manage organization (P > 0.05). Similarly, TNF-α, IFN-γ, and IL-17A mRNA stages had been reduced in the dealt with organization compared to untreated sufferers (P < 0.05), but no great distinction turned into found whilst in comparison to the manage group (P > 0.05). Histopathological evaluation discovered mentioned inflammatory responses in the synovial tissue of the statement organization, inclusive of congestion and edema of the synovial stroma, full-size lymphocyte and plasma cellular infiltration, focal necrosis, epithelial hyperplasia, fibrinous exudation, and necrotic particles accumulation. Conclusion: RA patients show off synovial inflammation and hyperplasia, together with a lack of ability to efficiently suppress Tresp cells thru Tregs. The mechanism is intently related to peculiar STAT3 expression. Inhibiting aberrant STAT3 expression extensively influences the immunopathogenesis of RA, probably restoring Treg feature, assuaging seasoned-inflammatory thing secretion, and preventing the development of RA.

Olive oil and castor oil-based self-nanoemulsifying drug delivery system of flurbiprofen can relieve peripheral pain and inflammation through reduction of oxidative stress and inflammatory biomarkers: a comprehensive formulation and pharmacological insights.

Flurbiprofen (FBP) is poorly water-soluble BCS class II drug with anti-inflammatory and analgesic effects, used to treat arthritis and degenerative joint diseases. This study was aimed to develop SNEDDS loaded with FBP. Six SNEDDS using two oils olive oil (F1OLV, F2OLV, F3OLV) and castor oil (F4CAS, F5CAS, F6CAS) with three different Smix ratios consisting of Tween 20 and PEG 400 (1:1, 1:2, 2:1) were prepared and characterized. Compatibility between FBP and polymers was investigated using FTIR. SNEDDS were characterized for physicochemical attributes. Two optimized formulations were investigated at 10mg/kg dose given orally in Wistar rats for analgesic activity by hot plate and tail flick methods, and anti-inflammatory activity by carrageenan induced paw edema method. Anti-inflammatory activity was further explored by motor coordination and motility by Rota rod and cage activity tests. Following anesthesia blood samples were collected before dissection to measure inflammatory mediators and oxidative stress markers. Sciatica nerves and hind paws of rats were also removed for histopathological evaluation.FTIR studies revealed compatibility of FBP with other components. Droplet size of F1OLV, F2OLV, F3OLV was 128.5 ± 0.7 nm, 202.5 ± 1.3 nm, and 541.5 ± 1.7 nm, whereas it was 142.5 ± 1.1 nm, 215.4 ± 1.2 nm and 349.9 ± 1.8 nm for F4CAS, F5CAS, F6CAS. %EE of F1OLV, F2OLV, F3OLV was found 85 ± 4.89%-91 ± 4.67%, whereas the %EE F4CAS, F5CAS, F6CAS was 84 ± 4.15%-90 ± 4.21%. DSC curves of F1OLVand F4CASrevealed amorphous nature of the FBP. SEM showed spherical shape of globules. % of drug released in the pH medium 1.2 for plain FBP, F1OLVand F4CASwas 25%, 59% and 57%. % drug released in the pH 6.8 for plain FBP, F1OLVand F4CASwas 59%, 85% and 83%. Oral administration of FBP-loaded SNEDDS (F1OLV and F4CAS) significantly decreased paw diameter and enhanced motor coordination in rats when compared to the disease control group. This was linked to the ability of FBP to reduce inflammation and oxidative stress, with histological studies indicating decreased tissue damage in SNEDDS treated groups, implying the possibility of tissue recovery. Administration of both formulations started to demonstrate analgesic and anti-inflammatory effects after one hour of administration. In addition to anti-inflammatory effect, both formulations improved motor coordination, motility, and reduced infiltration of inflammatory cells in the inflamed paws. The anti-inflammatory and analgesic activities were attributed to decreased serum levels of IL-6 and TNF-α, increased activity of SOD and reduced nitrite content in sciatic nerves. Histopathological evaluation revealed reduced vascularity, inflammation and synovial hyperplasia. The overall findings suggest that the FBP loaded SNEDDS can be used as carriers for improved delivery of FBP which can effectively be used to cure pain and inflammation.

WTAP-Mediated m6A Modification of TRAIL-DR4 Suppresses MH7A Cell Apoptosis.

N6-methyladenosine (m6A) is one of the most conserved internal RNA modifications, which has been implicated in many biological processes, such as apoptosis and proliferation. Wilms tumor 1-associating protein (WTAP), as a key component of m6A methylation, is a nuclear protein that has been associated with the regulation of proliferation and apoptosis. Rheumatoid arthritis (RA), a systemic, infiltrating autoimmune disease, is characterized by synovial hyperplasia. However, little is known about the precise role of WTAP in RA. This study investigated the role of the WTAP-mediated m6A modification of TNF-related apoptosis-inducing ligand death receptor 4 (TRAIL-DR4) in RA. Methyltransferase WTAP overexpression plasmids and small interfering RNAs were constructed and transfected into MH7A cells. Immunofluorescence (IF) staining, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and Western blot were used to detect changes in the expression of WTAP, the B-cell lymphoma 2 (BCL2) gene family, BCL2-associated X (BAX) and TRAIL-DR4 expression, and the effects of WTAP overexpression on cell viability, cell cycle, apoptosis, and proliferation were assessed by a cell counting kit-8 (CCK-8), flow cytometry, and transmission electron microscopy (TEM). The m6A modification of TRAIL-DR4 was verified by m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and its stability was assessed by an actinomycin D assay. Overexpression of WTAP not only increased the levels of WTAP and BCL2, and decreased the levels of BAX and TRAIL-DR4, but also significantly inhibited MH7A cell apoptosis and promoted cell viability and proliferation, while WTAP silencing led to the opposite trend. The SRAMP online database predicted that TRAIL-DR4 has multiple potential methylation-binding sites, and fluorescence insitu hybridization (FISH) combined with IF showed that WTAP and TRAIL-DR4 were mainly expressed in both the nucleus and cytoplasm. MeRIP-qPCR and actinomycin D analysis experiments revealed that WTAP could promote the m6A level of TRAIL-DR4, decrease the stability of TRAIL-DR4 mRNA, and subsequently inhibit apoptosis. This study suggests that WTAP-mediated m6A modification of TRAIL-DR4 suppresses MH7A cell apoptosis. This discovery offers a new focus and avenue for the clinical treatment of RA, while also extending our understanding of the pathophysiology of RA from the standpoint of m6A alteration.

Research progress of Sinomenium in the treatment of rheumatoid arthritis and suggestions for future research.

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease. Its main pathological manifestations are joint cartilage, bone tissue injury, synovial hyperplasia, and chronic inflammation. At present, the pathogenesis of the disease has not been fully defined, and delaying the disease to improve joint function is the existing treatment. Sinomenium (SIN) is an effective ingredient in Sinomenium acutum (Thunb.) Rehd. et Wils., with anti-inflammatory, analgesic, immunosuppressive, anti-tumor, and other pharmacological activities, which is quite effective in the treatment of RA. There are many SIN compound preparations in the market, such as Zhengqing Fengtongning capsule, Zhubi Huoluo prescription, and Qinxitong tablet. They all exhibit good anti-RA effect with less adverse reactions. This study summarized the mechanism of action of SIN in the treatment of RA and further explored the possibility of SIN in the treatment of RA combined with other diseases for future research.

Efficacy and safety of ultrasound-guided percutaneous radiofrequency ablation for synovial hyperplasia

Purpose This study aimed to investigate the efficacy and safety of ultrasound-guided percutaneous radiofrequency ablation (RFA) for the treatment of synovial hyperplasia in the knee joints of antigen-induced arthritis (AIA) model rabbits. Methods Forty Japanese large-eared white rabbits were divided into AIA and control groups. After successful induction of the AIA model, the knee joints were randomly assigned to RFA and non-RFA groups. The RFA group underwent ultrasound-guided RFA to treat synovial hyperplasia in the knee joint. Dynamic observation of various detection indices was conducted to evaluate the safety and effectiveness of the RFA procedure. Results Successful synovial ablation was achieved in the RFA group, with no intraoperative or perioperative mortality. Postoperative the circumference of the knee joint reached a peak before decreasing in the third week after surgery. The incidence and diameter of postoperative skin ulcers were not significantly different compared to the non-RFA group (p > .05). Anatomical examination revealed an intact intermuscular fascia around the ablated area in the RFA group. The ablated synovial tissue initially presented as a white mass, which subsequently liquefied into a milky white viscous fluid. Gross articular cartilage was observed, along with liquefied necrosis of the synovium on pathological histology and infiltration of inflammatory cells in the surrounding soft tissue. Conclusion The experimental results demonstrated that ultrasound-guided RFA of the knee in the treatment of synovial hyperplasia in AIA model animals was both effective and safe.

Does lifting female piglets by one hind leg increase the risk of umbilical and hind leg lesions?

BackgroundUmbilical lesions in pigs have a negative impact on animal welfare and productivity. It has been suggested that lifting young piglets by one hind leg may be a risk factor for developing omphalitis and umbilical hernia. However, the hypothesis that lifting piglets by one hind leg should stretch the umbilical wall and impede the healing of the umbilicus has not yet been investigated. The present study examined if piglets caught, lifted, and carried by one hind leg have an increased risk of developing lesions in the umbilicus and the hind legs compared to piglets caught, lifted, and carried with support under the abdomen.Materials and methodsIn a commercial indoor sow herd, 1901 piglets were randomly allocated into two groups on the day of birth. Piglets in Group 1 (986 piglets) were caught, lifted, and carried by one hind leg (either left or right, as the same leg was not necessarily used each time). Piglets in Group 2 (915 piglets), were caught, lifted, and carried with support under the abdomen. All piglets were lifted 8–10 times during the first 14 days of life as a part of routine management procedures. From each group, 50 female piglets, 14 days old, were randomly selected and euthanised for necropsy and histopathological evaluation.ResultsThe risk of having haemosiderophages in the umbilicus was 1.4 times higher in piglets caught, lifted, and carried by one hind leg compared to piglets caught, lifted, and carried with support under the abdomen (p = 0.01). No other variable differed significantly between the groups. Omphalitis was present in 68% and 58% of piglets in Groups 1 and 2, respectively. Moreover, umbilical herniation was present in 14% and 12% of piglets in Groups 1 and 2, respectively. Lesions were present in the hind legs of piglets in both groups and included synovial hyperplasia, neutrophilic granulocyte infiltration, oedema, and haemorrhage.ConclusionFemale piglets caught, lifted, and carried by one hind leg did not have an increased risk of umbilical hernia, omphalitis, or joint lesions compared to piglets caught, lifted, and carried with support under the abdomen.

Proteoglycan 4 (Lubricin) and regulation of xanthine oxidase in synovial macrophage as a mechanism of controlling synovitis

BackgroundSynovial macrophages (SMs) are important effectors of joint health and disease. A novel Cx3CR1 + TREM2 + SM population expressing the tight junction protein claudin-5, was recently discovered in synovial lining. Ablation of these SMs was associated with onset of arthritis. Proteoglycan 4 (PRG4) is a mucinous glycoprotein that fulfills lubricating and homeostatic roles in the joint. The aim of this work is to study the role of PRG4 in modulating synovitis in the context of SM homeostasis and assess the contribution of xanthine oxidase (XO)-hypoxia inducible factor alpha (HIF-1a) axis to this regulation.MethodsWe used Prg4FrtloxP/FrtloxP;R26FlpoER/+, a novel transgenic mouse, where the Prg4Frt allele normally expresses the PRG4 protein and was designed to flank the first two exons of Prg4 with a flippase recognition target and “LOXP” sites. Inducing flippase activity with tamoxifen (TAM) inactivates the Frt allele and thus creates a conditional knockout state. We studied anti-inflammatory SMs and XO by quantitative immunohistochemistry, isolated RNA and studied immune pathway activations by multiplexed assays and isolated SMs and studied PRG4 signaling dysfunction in relation to glycolytic switching due to pro-inflammatory activation. Prg4 inactivated mice were treated with oral febuxostat, a specific XO inhibitor, and quantification of Cx3CR1 + TREM2 + SMs, XO immunostaining and synovitis assessment were conducted.ResultsPrg4 inactivation induced Cx3CR1 + TREM2 + SM loss (p < 0.001) and upregulated glycolysis and innate immune pathways in the synovium. In isolated SMs, Xdh (p < 0.01) and Hif1a (p < 0.05) were upregulated. Pro-inflammatory activation of SMs was evident by enhanced glycolytic flux and XO-generated reactive oxygen species (ROS). Febuxostat reduced glycolytic flux (p < 0.001) and HIF-1a levels (p < 0.0001) in SMs. Febuxostat also reduced systemic inflammation (p < 0.001), synovial hyperplasia (p < 0.001) and preserved Cx3CR1 + TREM2 + SMs (p < 0.0001) in synovia of Prg4 inactivated mice.ConclusionsPRG4 is a biologically significant modulator of synovial homeostasis via inhibition of XO expression and downstream HIF-1a activation. PRG4 signaling is anti-inflammatory and promotes synovial homeostasis in chronic synovitis, where direct XO inhibition is potentially therapeutic in chronic synovitis.

Carvone-loaded chitosan nanoparticles alleviate joint destruction by downregulating the expression of pro, inflammatory cytokines and MMP-13 in adjuvant-induced rat model.

Rheumatoid arthritis is an autoimmune illness causing deformity, edema, and joint tenderness. Its long-term treatment burdens the healthcare system and leads to toxicity, and thus, finding safe, effective, and affordable therapies is essential. The current study aimed to exhibit the anti-arthritic activity of Carvone-loaded chitosan nanoparticles to treat Freund's complete adjuvant (FCA) arthritis in rats. Healthy albino rats (n = 35) were distributed into seven groups. The 1st group worked as normal control, while the 2nd was arthritic control. The 3rd group received methotrexate (10mg/kg/week). The 4th group received Carvone (60mg/kg/day), while the 5th (30mg/kg/day), 6th (45mg/kg/day), and 7th (60mg/kg/day) groups received Carvone-C-NPs, respectively. Nanoparticles, prepared by the ion gelation method, were characterized by zeta size, potential, scanning electron microscopy, and Fourier transform infrared microscopy. NPs have zeta size (78.82 ± 0.02nm) and potential (19.96 ± 0.02mV). A significant reduction was shown in paw swelling (5.52 ± 0.05mm), arthritic score (2.81 ± 0.23), and rheumatoid factor (14.56 ± 0.68IU/L) by Carvone-C-NPs. qRT-PCR results showed significant down-regulation of pro-inflammatory cytokines [TNF-α (0.25 ± 0.03), IL-1β (0.21 ± 0.06), IL-17a (0.16 ± 0.12), and IL-33 (0.15 ± 0.01)] and up-regulation of anti-inflammatory cytokines [IL-4 (0.85 ± 0.06) and IL-10 (0.66 ± 0.04)] in ankle joint of Carvone-C-NPs treated group. The radiographical and histopathological findings showed reduced pannus formation, joint swelling, and synovial hyperplasia in the Carvone-C-NPs treated group. Overall, it is concluded that Carvone-C-NPs have remarkable anti-arthritic activity and promising anti-inflammatory properties.

Emerging influence of RNA post-transcriptional modifications in the synovial homeostasis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an important autoimmune disease that affects synovial tissues, accompanied by redness, pain, and swelling as main symptoms, which will limit the quality of daily life and even cause disability. Multiple coupling effects among the various cells in the synovial micro-environment modulate the poor progression and development of diseases. Respectively, synovium is the primary target tissue of inflammatory articular pathologies; synovial hyperplasia, and excessive accumulation of immune cells lead to joint remodelling and destroyed function. In general, epigenetic modification is an effective strategy to regulate dynamic balance of synovial homeostasis. Several typical post-transcriptional changes in cellular RNA can control the post-transcriptional modification of RNA structure. It can inhibit important processes, including degradation of RNA and nuclear translocation. Recent studies have found that RNA modification regulates the homeostasis of the synovial micro-environment and forms an intricate network in the "bone-cartilage-synovium" feedback loop. Aberrant regulation of RNA methylation triggers the pathological development of RA. Collectively, this review summarises recent advanced research about RNA modification in modulating synovial homeostasis by making close interaction among resident synovial macrophages, fibroblasts, T cells, and B cells, which could display the dramatic role of RNA modifications in RA pathophysiological process and perform the promising therapeutic target for treating RA.

Study on the mechanism of moxibustion regulating ferroptosis-lipid metabolism pathway to improve synovitis inflammatory injury in rheumatoid arthritis rats

To explore the mechanism of moxibustion in improving synovitis inflammatory injury in rheumatoid arthritis (RA) model rats based on the ferroptosis-lipid metabolism pathway. Forty-eight SD rats were randomly divided into normal, model, moxibustion and moxibustion + long-chain acyl-CoA synthetase 4 (ACSL4) inhibitor groups, with 12 rats in each group. The RA model was replicated using environmental factors of wind, cold, and dampness combined with Freund's complete adjuvant injection. The moxibustion group received moxibustion at "Shenshu" (BL23) and "Zusanli" (ST36) for 20 minutes per acupoint each time, once daily at a single acupoint (both sides) with alternating acupoints over 15 consecutive days. The moxibustion + ACSL4 inhibitor group received intraperitoneal injection of the ACSL4 inhibitor rosiglitazone (0.4 mg/kg) after moxibustion, once daily for 15 consecutive days. Histopathological changes in synovial tissue were observed using HE staining；serum contents of glutathione (GSH) and malondialdehyde (MDA) were detected using biochemical methods；reactive oxygen species (ROS) levels in synovial tissues were detected using flow cytometry；the expressions of glutathione peroxidase 4 (GPX4), ACSL4, and lysophosphatidylcholine acyltransferase 3 (LPCAT3) proteins in synovial tissues were detected using Western blot；and serum contents of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were detected using ELISA. Compared with the normal group, the serum contents of GSH decreased (P<0.01) while MDA, IL-6, and TNF-α contents increased (P<0.01)；the ROS levels, ACSL4 and LPCAT3 protein expressions increased (P<0.01) while GPX4 protein expression decreased (P<0.01) in synovial tissue in the model group. Compared with the model group, the serum contents of GSH increased (P<0.01) while MDA, IL-6, and TNF-α contents decreased (P<0.01)；the ROS levels, ACSL4 and LPCAT3 protein expressions decreased (P<0.01) while GPX4 protein expression increased (P<0.01) in synovial tissue in the moxibustion group and moxibustion + ACSL4 inhibitor group. Compared with the moxibustion group, the serum contents of GSH increased (P<0.01) while MDA, IL-6, and TNF-α contents decreased (P<0.01)；the ROS levels, ACSL4 and LPCAT3 protein expressions decreased (P<0.01, P<0.05) while GPX4 protein expression increased (P<0.05) in synovial tissue in the moxibustion + ACSL4 inhibitor group. HE staining showed that the model group had significantly increased synovial hyperplasia and inflammatory cell infiltration；the moxibustion group and moxibustion + ACSL4 inhibitor group showed varying degrees of alleviation in inflammatory cell infiltration and hyperplasia in synovial tissue；compared with the moxibustion group, the moxibustion + ACSL4 inhibitor group showed more significant improvements in inflammatory infiltration and hyperplasia of synovial cells, reduced layers of synovium. Moxibustion at BL23 and ST36 can alleviate synovial inflammatory injury, and its mechanism may be related to reducing lipid peroxidation and ROS levels, and inhibiting the occurrence of ferroptosis.

Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice

BackgroundWomen have a higher risk of developing osteoarthritis (OA) than men, including with obesity. To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA.MethodsMale and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age (n = 12 per diet and sex). We performed broad metabolic phenotyping, 16 S gut microbiome analysis, targeted gene expression analysis of synovium-infrapatellar fat tissue, targeted gene expression and proteomic analysis of articular cartilage, chondrocyte metabolic profiling, and OA histopathology. Two-way ANOVA statistics were utilized to determine the contribution of sex and diet and their interaction on outcomes.ResultsMice fed HFD weighed 1.76-fold (p < 0.0001) and 1.60-fold (p < 0.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 ± 2.2%; female: 44.1 ± 3.8%). HFD caused greater cartilage pathology (p < 0.024) and synovial hyperplasia (p < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (p = 0.048), and only male mice developed osteophytes with HFD (p = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (p < 0.0001), fatty liver (p < 0.0001), and elevated serum amylase (p < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (p = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of Bifidobacterium only in male mice. In knee synovium and infrapatellar fat tissue, HFD upregulated the expression of pro-inflammatory and pro-fibrotic genes predominantly in female mice. In cartilage, lipid metabolism proteins were more abundant with HFD in male mice, whereas proteins involved in glycolysis/gluconeogenesis and biosynthesis of amino acids were greater in cartilage of female mice. Sex-dependent metabolic differences were observed in cartilage from young, healthy mice prior to pubertal maturation, but not in primary juvenile chondrocytes studied in vitro.ConclusionsHFD induced numerous sex differences in metabolic and inflammatory outcomes, especially in joint tissues, suggesting that sex-specific cellular processes are involved during development of early-stage OA with obesity.

Sea Hare Hydrolysate Reduces PD-L1 Levels in Cancer Cells and Mitigates Rheumatoid Arthritis Ina Collagen-Induced Arthritis Mouse Model.

Our previous study highlighted the anticancer potential of sea hare hydrolysate (SHH), particularly its role in regulating macrophage polarization and inducing pyroptotic death in lung cancer cells through the inhibition of signal transducer and activator of transcription 3 (STAT3). These findings prompted us to investigate additional features of immune-oncology (I-O) agents or adjuvants, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibition and their association with rheumatoid arthritis (RA) risk, to explore the potential of SHH as an I-O agent or adjuvant. In this study, we investigated the effects of SHH on PD-L1 levels in various cancer cell types and assessed its effectiveness in treating RA, a common side effect of I-O agents. Our results showed a marked reduction in PD-L1 levels in multiple cancer cell lines and decreased PD-1 and PD-L1 levels in tumor-associated macrophages. In a mouse model with collagen-induced arthritis (CIA), SHH exhibited anti-inflammatory effects comparable to methotrexate (MTX), a first-line treatment for RA. Both the SHH and MTX groups had significantly lower arthritis scores and paw thickness compared to the CIA group. Additionally, SHH or MTX treatment effectively reduced elevated levels of anticollagen type II (CII) antibodies and proinflammatory cytokines (IL-1β, IL-6, and TNF-α). Histopathological analysis revealed that SHH and MTX treatments notably mitigated arthritic inflammation, synovial hyperplasia, and loss of articular cartilage and bone. Micro-CT scans showed reduced articular destruction in the SHH and MTX groups. These findings indicate that SHH treatment decreases PD-L1 levels in cancer cells and reduces the severity of CIA by exerting anti-inflammatory effects. Therefore, SHH holds promise as an I-O agent without side effects such as exacerbation of RA.

Study on the value of enhanced magnetic resonance imaging in the International Prophylaxis Study Group (IPSG) score of the synovium in hemophilic arthropathy

Objective: To evaluate the value of enhanced magnetic resonance imaging (MRI) on the assessment of synovial hyperplasia and International Prophylaxis Study Group (IPSG) score of hemophilic arthropathy (HA). Methods: This was a retrospective case series study. Briefly, 54 joints of 46 male patients with hemophilia type A and diagnosed with HA in Henan Provincial People's Hospital from August 2016 to September 2017 were selected. Plain and enhanced MRI were performed at the same time. The IPSG score of synovial hyperplasia and the total joint before and after enhancement were calculated, and the enhancement rate of the synovium and muscles at the same level were also calculated. The differences in synovial hyperplasia and joint total IPSG scores before and after enhancement were compared by paired rank sum test. The correlation between enhancement joint total IPSG score, synovial IPSG score, synovial enhancement rate, total joint bleeding number, course of disease, and Hemophilia Joint Health Score (HJHS) score were analyzed by Spearman's correlation analysis. Results: Enhanced MRI could more clearly show synovial hyperplasia and ensure better accuracy of joint total IPSG score (Z=-2.24, P=0.025). The enhancement extent of synovial hyperplasia was higher than that of the same level muscle. There was no correlation between synovial enhancement rate and total number of joint bleeding, course of disease, and HJHS score. After enhancement, the joint total IPSG score was highly positively correlated with the total number of joint bleeding and the disease course (r=0.96, 0.84, P<0.001) and moderately positively correlated with the HJHS score (r=0.58, P<0.001). The enhanced synovial IPSG score showed a low positive correlation with the total number of joint bleeding and the disease course (r=0.37, 0.36, P=0.006, 0.008), but no correlation with HJHS score. Conclusion: Enhanced MRI can provide accurate imaging of synovial hyperplasia of HA and make joint IPSG score more accurate.

Effect of Aconitum diphtheria on the Proliferation, Apoptosis, and Inflammatory Response of Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Rheumatoid arthritis (RA), a highly disabling autoimmune disease, is characterized by joint damage and synovial hyperplasia. This paper was designed to explore the effect and mechanisms of Aconitum diphtheria on the proliferation and apoptosis of RA fibroblast-like synoviocytes (RA-FLS). First, RA-FLS was treated with different doses of A. diphtheria extracts. Then, an inverted biological microscope was adopted to observe the RA-FLS morphology. Subsequently, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining, Cell Counting Kit-8 and western blot were utilized to analyze the apoptosis, proliferation, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway-related proteins in RA-FLS, respectively. The experimental results disclosed that, after treatment of RA-FLS with A. diphtheria extracts, the cells became round and the intercellular space was increased. Besides, the RA-FLS proliferation was effectively inhibited by A. diphtheria extracts, while the apoptosis was promoted. Additionally, A. diphtheria extracts could effectively downregulate the expression levels of p-NF-κB (p50), NF-κB (p50), p-NF-κB (p65), and NF-κB (p65). Collectively, A. diphtheria can effectively inhibit RA-FLS proliferation and promote apoptosis in a dose-dependent manner. Similarly, A. diphtheria is able to downregulate p-NF-κB and NF-κB protein expression, but there is no dose-response relationship.

Unveiling the Therapeutic Potential of Berberine in Rheumatoid Arthritis: A Comprehensive Study of Network Pharmacology, Metabolomics, and Intestinal Flora.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by environmental triggers, including the commensal microbiota. Recent research has highlighted distinctive features of the gut microbiota in RA patients. This study investigates the therapeutic potential of berberine (BBR), a gut microbiota modulator known for its significant anti-RA effects, and elucidates the underlying mechanisms. Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of BBR in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. Employing network pharmacology, we identified potential targets involved in RA alleviation by BBR. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. An integrated network encompassing metabolomics and network pharmacology data was constructed using Cytoscape. The potential therapeutic targets and signaling pathways of BBR in the management of RA were predicted using network pharmacology. Key targets and pathways were further validated by molecular docking and immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16S rDNA sequencing and investigated the effects of BBR on the microbiota of CIA rats through bioinformatics and statistical methods. Our results showed that BBR demonstrated significant efficacy in alleviating RA symptoms in CIA rats, as evidenced by improvements in paw redness and swelling, attenuation of bone and cartilage damage, reduction in synovial hyperplasia, inflammatory cell infiltration, and suppression of proinflammatory cytokines IL-1β, IL-6, IL-17A, and TNF-α. KEGG analysis highlighted the PI3K/AKT signaling pathway as a key mediator of BBR's anti-RA effects. Metabolomics profiling via LC-MS revealed 22 potential biomarkers. Arginine and proline metabolism, cutin, suberine and wax biosynthesis, glycine, serine and threonine metabolism and taurine and hypotaurine metabolism are the most related pathways of BBR anti-RA. Molecular docking studies corroborated high affinities between BBR and key targets. Furthermore, 16S analysis demonstrated BBR's capacity to modulate gut bacteria composition, including an increase in the abundance of Lachnoclostridium, Akkermansia, Blautia, Romboutsia, and Faecalibacterium genera, alongside a decrease in Prevotella_9 abundance in genus level. Integrated analysis underscored a strong correlation between serum microbiota and fecal metabolites. Our findings elucidate the multifaceted mechanisms underlying BBR's therapeutic efficacy in RA, involving inhibition of the PI3K/AKT pathway, modulation of intestinal flora, and regulation of host metabolites. These insights provide novel perspectives on BBR's role in RA management.

Ferroportin inhibits the proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis via regulating ROS/PI3K/AKT signaling pathway.

The aberrant proliferation of fibroblast-like synoviocytes (FLS) significantly contributes to excessive synovial hyperplasia and joint deformity in rheumatoid arthritis (RA). It has been observed that the membrane iron transporter protein, ferroportin (FPN), is commonly downregulated in tumor cells, while its overexpression can inhibit tumor cell proliferation. However, limited studies have investigated the role of iron in the pathogenesis of RA. In this study, we examined the functional relevance of FPN in RA. The expression of FPN in RA tissue specimens and primary cells was assessed using western blotting and RT-PCR. An adjuvant-induced arthritis (AIA) rat model was established to further validate the expression level of FPN. Phenotypic analysis of FLS cell proliferation was performed via CCK-8, clonogenic formation, and cell scratch assays. The involvement of membrane iron transporter proteins was analyzed through RNAseq and reactive oxygen species (ROS) detection. The results demonstrated decreased expression of FPN in the synovial tissue of RA patients compared to the normal group. Overexpression of FPN can inhibit RA-FLS proliferation and migration by suppressing the PI3K/AKT pathway, and this effect is associated with the elevation of ROS levels. Our findings suggest that the downregulation of FPN may contribute to the pathogenesis of RA, indicating a potential role of iron dysregulation in this disease, and FPN regulates the proliferation and migration of FLS by promoting the levels of ROS in FLS as well as suppressing the PI3K/AKT signaling pathway. These results suggest that FPN could be a potential target for alleviating joint damage in RA.

Exploring the correlation between knee osteoarthritis and musculoskeletal ultrasound manifestations based on changes in traditional Chinese medical syndrome types.

This study explores the correlation between knee osteoarthritis and musculoskeletal ultrasound manifestations based on changes in traditional Chinese medicine (TCM) syndrome types. The study enrolled 104 patients with knee osteoarthritis admitted to the Gansu Provincial Hospital of TCM between January 2019 and January 2021. According to the principle of syndrome differentiation and treatment in TCM, the patients were divided into wind-cold-damp obstruction (n = 17), damp-heat accumulation (n = 22), qi-stagnation and blood stasis (n = 31), and liver and kidney deficiency (n = 34) types. The degrees of cartilage injury, synovial hyperplasia, synovial blood flow, and joint effusion in patients with different TCM syndrome types were compared using ultrasound. There were no significant differences in the degree of cartilage injury or synovial hyperplasia among the 4 TCM syndrome types (P > .05). The proportion of grade III blood flow signals in the liver and kidney deficiency group was lower than that in the damp-heat accumulation and wind-cold-damp obstruction groups, and the proportion of no blood flow and grade I blood flow signals were higher than those in the damp-heat accumulation and wind-cold-damp obstruction groups (P < .05). The proportion of non-joint effusion in the liver and kidney deficiency and wind-cold-damp obstruction groups was higher than that in the damp-heat accumulation and qi-stagnation and blood stasis groups (P < .05), and the proportion of grade I effusion in the damp-heat accumulation group was higher than that in the liver and kidney deficiency group (P < .05). Musculoskeletal ultrasound manifestations of knee osteoarthritis are related to TCM syndrome differentiation and classification and can provide a reference for TCM syndrome differentiation and treatment of knee osteoarthritis.

Phytochemical, Cytoprotective Profiling, and Anti-Inflammatory Potential of Colchicum luteum in Rheumatoid Arthritis: An Experimental and Simulation Study.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by severe pain, inflammation, and joint deformity. Currently, it affects 1% of the population, with a projection to exceed 23 million cases by 2030. Despite significant advancements, non-steroidal anti-inflammatory drugs (NSAIDs), the first line of treatment, are associated with a range of adverse effects. Consequently, plant-based derivatives are being utilized as an effective alternative. This study evaluates the anti-inflammatory and safety profile of Colchicum luteum hydroethanolic extract (CLHE) in comparison to NSAIDs, with a focus on COX-2 and TNFα inhibition. CLHE potential was evaluated by phytochemical screening and in vitro bioactivity assays. Toxicity profile was conducted in Human Colon Epithelial Cells (HCEC) and Balb/c mice. Anti-inflammatory potential was explored in a collagen-induced arthritic (CIA) mice model. Bioactive compounds were identified computationally from GCMS data and subjected to docking and simulation studies against COX2 and TNFα. CLHE demonstrated significant antioxidant (IC-50 = 6.78 µg/mL) and anti-inflammatory (IC-50 = 97.39 µg/mL) activity. It maintained 50% cell viability at 78.5 μg/µL in HCEC cells and exhibited no toxicity at a dose of 5000 mg/kg in mice. In the CIA model, CLHE significantly reduced paw swelling, arthritic scoring, C-reactive protein levels, and spleen indices, outperforming ibuprofen. Expression analysis confirmed the downregulation of COX-2, TNFα, and MMP-9. Histopathological analysis indicated the superior efficacy of CLHE compared to ibuprofen in reducing inflammation, synovial hyperplasia, and bone erosion. Computational studies identified compound-15 (CL15), (4-(4,7-dimethoxy-1,3-benzodioxol-5-yl)-2-oxo pyrrolidine-3-carboxylic acid), a non-toxic compound with strong binding affinities to COX-2 (-12.9 KJ/mol), and TNF-α (-5.8 KJ/mol). The findings suggest the potential of Colchicum luteum as a safer, anti-inflammatory, and multi-targeted alternative to NSAIDs for RA treatment.

Inula viscosa (L). Aiton leaves extract ameliorate arthritis by antioxidative and anti-inflammatory effects in formaldehyde-induced arthritis in mice

Ethnopharmacological relevanceInula viscosa (L.) Aiton is a traditional medicinal plant widely distributed and used in Mediterranean countries, its leaves are prepared by maceration to treat, rheumatic pain, inflammatory diseases, diabetes, anemia and cancer. Aim of the studyThe present study purpose to investigate the anti-inflammatory efficacy of I. viscosa leaves methanol extract (IVME) at three different doses on formaldehyde-induced arthritis in NMRI albinos mice. Materials and methodsMice were divided into six groups (n = 6) as follows: normal control, disease control, Diclofenac group (10 mg/kg, p.o. daily) and three groups, daily treated with 50, 100 and 200 mg/kg IVME (p.o.); Formaldehyde models were obtained by a sub-plantar administration of 20 μl of formaldehyde (3.75% v/v) into the right hind paws of NMRI albino mice on 1st and 3rd days of the 10 experimental days. Joint diameter was measured, arthritis severity was evaluated by inhibition of paw edema, histological changes, synovial hyperplasia and immune cells infiltration was evaluated by histological and immunohistochemical analyses of CD3+, CD20+ and CD68+. Post-mitochondrial supernatants (PMS) from liver tissues homogenates were collected for the assessment of enzymatic and non-enzymatic antioxidants: Catalase (CAT) & Myeloperoxidase (MPO) activities, glutathione (GSH) and an oxidative stress biomarker (nitric-oxide (NO)) level. ResultsAdministration of I. visocsa (at low dose: 50 mg/kg) significantly (∗∗∗p < 0.001) ameliorated the induced arthritis severity, reduced hyperplasia of synovial membrane, bone erosion and immune cells infiltration (∗p < 0.05), resulted by restoration of paw diameter. It also decreased levels of NO (∗∗∗p < 0.001) and MPO activity (∗∗∗p < 0.001), and significantly restored GSH levels (∗p < 0.05) and CAT activity (∗∗∗p < 0.001) in liver tissues. ConclusionThese findings suggest that I. viscosa leaves have an anti-arthritic property. Which is due to the combination of antioxidant activity regulating oxidative stress and anti-inflammatory effect by probably cytokines regulation.

Prediction model for bone erosion in rheumatoid arthritis based on musculoskeletal ultrasound and clinical risk factors.

Progressive bone erosion (BE) is a prominent manifestation of structural damage in rheumatoid arthritis (RA). This study aimed to construct and validate a BE prediction model (BEPM) for RA based on musculoskeletal ultrasound and clinical risk factors. A total of 312 RA patients without BE were consecutively collected and followed up for 2years, who were divided into BE group and non-bone erosion group, as confirmed by two radiology experts based on at least two imaging techniques. Relevant clinical information, such as anti-cyclic citrullinated peptide (ACCP) antibody and disease duration, was collected. Musculoskeletal ultrasound examinations were performed on all patients upon admission. Univariate and binary logistic regression analyses were conducted to identify risk factors for BE and to establish the prediction model. The calibration, diagnostic efficacy, and clinical effectiveness of BEPM were evaluated by calibration curve plots, receiver-operating characteristic curve, and decision curve analysis (DCA). Binary logistic regression analysis screened four variables, including synovial hyperplasia, synovial blood flow, ACCP + , and disease duration, into the prediction model. BEPM exhibited good diagnostic performance in both the training and validation groups, with area under the curve values of 0.949 (95% CI 0.924-0.973) and 0.965 (95% CI 0.935-0.996), respectively. Using 0.376 as the optical cutoff value for BE, the sensitivity, specificity, and Youden index of the model in the training group were 86.0%, 90.4%, and 76.4%, respectively. In the DCA curves, BEPM indicated overall good population benefit. BEPM demonstrates high diagnostic performance and clinical utility, and may be a useful clinical model for predicting BE in patients with RA. Key Points • Synovial hyperplasia, synovial blood flow, ACCP+ , and disease duration are independent risk factors for bone erosion in RA patients. • BEPM exhibits good diagnostic performance in both the training and validation groups. • Combining musculoskeletal ultrasound parameters with key clinical risk factors to construct a bone erosion model is feasible.