Efficacy of Juanbi capsule on ameliorating knee osteoarthritis:a network pharmacology and experimental verification-based study

Background:The purpose of the study was to investigate the active ingredients and potential biochemical mechanisms of Juanbi capsule in knee osteoarthritis based on network pharmacology,molecular docking and animal experiments.Methods:Chemical components for each drug in the Juanbi capsule were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,while the target proteins for knee osteoarthritis were retrieved from the Drugbank,GeneCards,and OMIM databases.The study compared information on knee osteoarthritis and the targets of drugs to identify common elements.The data was imported into the STRING platform to generate a protein-protein interaction network diagram.Subsequently,a“component-target”network diagram was created using the screened drug components and target information with Cytoscape software.Common targets were imported into Metascape for GO function and KEGG pathway enrichment analysis.AutoDockTools was utilized to predict the molecular docking of the primary chemical components and core targets.Ultimately,the key targets were validated through animal experiments.Results:Juanbi capsule ameliorated Knee osteoarthritis mainly by affecting tumor necrosis factor,interleukin1β,MMP9,PTGS2,VEGFA,TP53,and other cytokines through quercetin,kaempferol,andβ-sitosterol.The drug also influenced the AGE-RAGE,interleukin-17,tumor necrosis factor,Relaxin,and NF-κB signaling pathways.The network pharmacology analysis results were further validated in animal experiments.The results indicated that Juanbi capsule could decrease the levels of tumor necrosis factor-αand interleukin-1βin the serum and synovial fluid of knee osteoarthritis rats and also down-regulate the expression levels of MMP9 and PTGS2 proteins in the articular cartilage.Conclusion:Juanbi capsule may improve the knee bone microstructure and reduce the expression of inflammatory factors of knee osteoarthritis via multiple targets and multiple signaling pathways.

Comparison of Three Experimental Models for Rat Osteoarthritis Induction

Background: Osteoarthritis is a slowly progressive and debilitating disease with high prevalence in adult population. Knee is one of the joints most affected by this disorder. There are several models for animals’ osteoarthritis induction, however it is not identified any paper that compares these techniques. The present study was aimed to define the most appropriate model for rats osteoarthritis induction. Material and Methods: 40 Wistar rats were distributed into 4 groups of 10 animals each: normality group (NG);meniscectomy group (MG);quinolone group (QG) and iodoacetate group (IG). Radiographic images of the rat’s knees were analyzed as well as the amount of chondrocytes in the epiphyseal and articular cartilage. Results: In the radiographic analysis, there was a low correlation between the raters. Regarding the amount of chondrocytes in the epiphyseal cartilage, it was noticed that the IG and QG groups had fewer chondrocytes than NG, in contrast to MG that reported similar results to normality (p > 0.05). There was no significant difference between IG and QG groups (p > 0.05). Regarding the amount of chondrocytes in articular cartilage, it was noticed that the IG group showed fewer chondrocytes than NG (p 0.05). There was no significant difference between QG and MG groups (p > 0.05). Conclusion: Intraarticular injection of iodoacetate in rats is the model with greatest effect on reduction of chondrocytes amount.

Experimental Study on Anti-adjuvant Arthritis in Rats of Kadsura coccinea

[Objectives] To investigate the therapeutic effect of Kadsura coccinea on adjuvant arthritis( AA) rats and its mechanism from cytokine levels. [Methods] The complete Freund's adjuvant( CFA)-induced AA model of rats was used. The therapeutic effect of K. coccinea on AA rats was evaluated by the articular swelling,arthritis score,immune organ index and hematoxylin-eosin( HE) staining. The content of inflammatory factors TNF-α,IL-6,and IL-1β in the serum of AA rats was detected by enzyme-linked immunosorbent assay( ELISA) respectively. [Results]Compared with the model group,the total extract of K. coccinea( KCTE) could significantly inhibit the primary and secondary articular swelling of AA rats,lower the arthritis score and immune organ index,and improve the pathological state of ankles of AA rats. In the groups with a high and middle dosage of KCTE( KCTE-H and KCTE-M),KCTE could significantly reduce the content of TNF-α and IL-6 in the serum of rats,exhibiting a certain dose-effect relationship. [Conclusions]KCTE had significant therapeutic effect on the AA of rats,and the mechanism might be associated with the modulation of immune function and the decrease in the secretion of inflammatory cytokines TNF-α and IL-6.

Structural Changes in Vertebrae of Mice Based on Experimental Model of Rheumatoid Arthritis

Studies have shown that autoimmunity causes pathogenesis of more than 100 diseases. Among these diseases, approximately 1-2% of the world’s population has rheumatoid arthritis disease, which is a chronic disease that affects 45 out of every 3000 people who have autoimmune diseases. The aim of this research is to address the possible treatment of rheumatoid arthritis disease by comparing and contrasting the effectiveness and influence that treatments have on treating the disease. This study will be conducted by inducing the following treatments: ibuprofen and Boigor-10 on model animal subjects (mice) to determine the outcomes of the treatment. We will assess the outcomes by investigate the structural changes on vertebrae and joints of these subjects and the clinical manifestation score of each treatment. We hypothesize that these treatments will improve the treatment of rheumatoid arthritis disease. Furthermore, we hope that this research contributes to further understanding autoimmune disease and promotes proper treatment of the disease.

A NEAR-INFRARED FLUORESCENT DEOXYGLUCOSE DERIVATIVE FOR OPTICAL IMAGING OF EXPERIMENTAL ARTHRITIS

The purpose of this study is to investigate whether a near-infrared fluorescence(NIRF)probe,Cy5.5-d-glucosamine(Cy5.5-2DG),can image arthritis in collagen-induced arthritic(CIA)mice.The presence of arthritis was verified by both visual examination and micro-computed tomography(MicroCT)imaging.CIA mice were imaged by a micro-positron emission tomography(MicroPET)scanner one hour after intravenous injection of 2-deoxy-2-[18F]fluoro-d-glucose([18F]FDG).After radioactivity of[18F]FDG decayed away,Cy5.5-2DG was injected into a lateral tail vein of the mice.Arthritic tissue targeting and retention of Cy5.5-2DG in CIA mice were evaluated and quantified by an optical imaging system.Inflammatory tissue in CIA mice was clearly visualized by[18F]FDG-MicroPET scan.NIRF imaging of Cy5.5-2DG in the same mice revealed that the pattern of localization of Cy5.5-2DG in the arthritic tissue was very similar to that of[18F]FDG.Quantification analysis further showed that[18F]FDG uptake in arthritic tissues at one hour post-injection(p.i.)and Cy5.5-2DG uptakes at different time points p.i.were all well correlated(r2 over 0.65).In conclusion,Cy5.5-DG can detect arthritic tissues in living mice.The good correlation between the[18F]FDG uptake and Cy5.5-2DG accumulation in the same arthritic tissue warrants further investigation of Cy5.5-2DG as an approach for assessment of anti-inflammatory treatments.

Arava Treatment,between Beneficial Action on Joint Inflammation and Side Effects on Liver,Myocardium and Kidney in Experimental Murine Arthritis

The purpose of the experiment was the follow-up in time of the course of joint inflammation phenomena in laboratory animals (white female adult Wistar rats) by determining particular biological, hematological, radiological, osteodensitometric, immunological and anatomic-pathological parameters and by assessing the effects of Leflunomide (Arava) on the course of the disease. ARAVA®(Leflunomide) is a pyrimidine synthesis inhibitor. The experimental study was conducted for 8 weeks. We have also assessed the side effects of the therapy on their liver, myocardium and kidney. Leflunomide therapy improved the course of the clinical and paraclinical parameters, but it did not cure the condition. The positive results in the joints were accompanied by many histological alterations. The experiment revealed the toxic visceral effects of Leflunomide on the liver, heart and kidney.

The effect of compound sage root injection on pathology of rumatoid arthritis in experimental rats

Objective To investigate the effect of compound sage root injection on pathology of arthritis induced by collagen II in experimental rats.Method Articular and synovium tissues were routinely fixed,embedded,stained and mounted.Result Pathological changes were mild in sage root group.There were no significant differences in pathology of synovium tissue between groups. Conclusion Compound sage root is effective in protecting and managing CIA model.

Attenuation of the Activation of NLRP3 Inflammasome in Fibroblast Like Synoviocytes of Rheumatoid Arthritis by Baicalin through Regulating the Let-7i-3p/PI3K/Akt/NF-κB Signaling Axis

[Objectives]To study the effect and mechanism of baicalin on the activation of NLRP3 inflammasome in human fibroblast like synoviocytes of rheumatoid arthritis(HFLS-RA).[Methods]To confirm that baicalin alleviated the activation of NLRP3 inflammasome in HFLS-RA,the expression of NLRP3 before and after baicalin treatment was observed by immunofluorescence.Western blot was used to detect the protein expression of p-PI3K,p-Akt,NF-κB p65,NLRP3,ASC and caspase-1 after baicalin treatment for 48 h,and the contents of IL-1 and IL-18 in the supernatents were detected by ELISA.In order to explore the mechanism of baicalin alleviating the activation of NLRP3 inflammasome,the corresponding relationship between let-7i-3p and PIK3CA was verified by double luciferin and Westen blot analysis.The expression of let-7i-3p and PI3K before and after baicalin intervention was detected by RT-qPCR.let-7i-3p interference was used to verify whether baicalin mitigated the activation of enhanced NLRP3 inflammasome.[Results]Baicalin(50 and 100 mg/L)significantly reduced the activation of NLRP3 inflammasome,inhibited the protein expressions of p-PI3K,p-Akt,NF-κB p65,NLRP3,ASC and caspase-1,and the secretion of IL-1 and IL-18.let-7i-3p and PIK3CA had a targeted correspondence,and baicalin up-regulated the expression of let-7i-3p and down-regulated the expression of PIK3CA.Baicalin attenuated the activation of NLRP3 inflammasome enhanced by let-7i-3p interference.[Conclusions]Baicalin can up-regulate let-7i-3p expression,inhibit PI3K/Akt/NF-κB signal transduction,and thus reduce the activation of NLRP3 inflammasome in HFLS-RA.

EXPERIMENTAL STUDY ON THE EFFECT OF ACUPUNCTURE ON TROPISM-DISTRIBUTION OF TETRAMETHYLPYRAZINE AND THE CONTENT OF cAMP IN ARTHRITIS RATS

Objective: To verify two hypotheses: 1) Acupuncture can increase the re-distribution of tetramethylpyrazine (ligustrazine) hydrochloride (TMPH) to the target organs in adjuvant arthritic rats. 2) Cyclic Adenosine-3’, 5’-monophosphate (cAMP) is one of the guidance cues involved in this event. Methods: A total of 40 Wistar rats were randomized into blank control (BC), model (MO), medication (ME), Acupuncture (Acu) and Acu+ME groups, with 8 cases in each group. Arthritis model was established by subcutaneous injection of complete Freund’s adjuvant (0.1 mL) into the rat’s foot pad. Electroacupuncture (15 Hz, 0.2-0.3V) was applied to bilateral “Daling”(大陵PC 7), “Taichong” (太冲LR 3) and “Xiguan” (膝关LR 7) for 20 min, and the contents of TMPH in the heart, liver, kidney and the foot (affected focus) tissues and the contents of cAMP in the heart and liver tissues were determined with high performance liquid chromatography and radioimmunoassay techniques respectively. Results: Compared with medication group, the TMPH contents in the heart, liver, kidney and the affected foot tissues in Acu-ME group was obviously higher (P<0.05, P<0.01). In comparison with ME and Acu groups, the cAMP contents in the heart and liver in Acu+ME group was also significantly higher (P<0.05, P<0.01). No significant differences were found between ME and Acu+ME groups in TMPH content of kidney and between Acu+ME and BC groups in cAMP contents in both liver and heart tissues. Conclusion: Acupuncture may promote the target-tropism distribution of ligustrazine, and cAMP may play an important role in it.

Activatable fluorescent probes for imaging and diagnosis of rheumatoid arthritis

Rheumatoid arthritis(RA)is a systemic autoimmune disease that is primarily manifested as synovitis and polyarticular opacity and typically leads to serious joint damage and irreversible disability,thus adversely affecting locomotion ability and life quality.Consequently,good prognosis heavily relies on the early diagnosis and effective therapeutic monitoring of RA.Activatable fluorescent probes play vital roles in the detection and imaging of biomarkers for disease diagnosis and in vivo imaging.Herein,we review the fluorescent probes developed for the detection and imaging of RA biomarkers,namely reactive oxygen/nitrogen species(hypochlorous acid,peroxynitrite,hydroxyl radical,nitroxyl),pH,and cysteine,and address the related challenges and prospects to inspire the design of novel fluorescent probes and the improvement of their performance in RA studies.

Acute Lymphoblastic Leukemia Presenting as Systemic Juvenile Idiopathic Arthritis: Experience from Bangladesh

Background: Acute lymphoblastic leukemia (ALL), the most common paediatric malignancy, is a heterogeneous hematologic disease. ALL patients may present with isolated and persistent osteo-articular complaints, lower incidence of hepatomegaly, splenomegaly or lymphadenopathy without clear laboratory features, and misdiagnosed as systemic juvenile idiopathic arthritis (sJIA). Methods: This was a single center cross sectional study over a period of 4 years. Clinic laboratory profiles of 39 ALL children were compared with 39 age and sex-matched sJIA cases. Result: Among 39 ALL patients 89.7% were initially misdiagnosed as sJIA upon clinical presentation. Majority (66.7%) of ALL patients had oligo-articular joint involvement. In sJIA, small joints of the hands were most commonly involved. The total WBC count was significantly higher in ALL patients (p-value 0.0065). CRP and LDH values between the two groups showed significant differences (p-value 0.00006 and 0.00001 respectively). Conclusion: The presentation of leukemia with arthralgia or arthritis makes the diagnosis difficult for the physicians. The diagnosis of sJIA must be made with caution keeping the possibility of haematological malignancy in mind.

Development of biomedical hydrogels for rheumatoid arthritis treatment

Rheumatoid Arthritis(RA)is an autoimmune disorder that hinders the normal functioning of bones and joints and reduces the quality of human life.Every year,millions of people are diagnosed with RA worldwide,particularly among elderly individuals and women.Therefore,there is a global need to develop new biomaterials,medicines and therapeutic methods for treating RA.This will improve the Healthcare Access and Quality Index and also relieve administrative and financial burdens on healthcare service providers at a global scale.Hydrogels are soft and cross-linked polymeric materials that can store a chunk of fluids,drugs and biomolecules for hydration and therapeutic applications.Hydrogels are biocompatible and exhibit excellent mechanical properties,such as providing elastic cushions to articulating joints by mimicking the natural synovial fluid.Hence,hydrogels create a natural biological environment within the synovial cavity to reduce autoimmune reactions and friction.Hydrogels also lubricate the articulating joint surfaces to prevent degradation of synovial surfaces of bones and cartilage,thus exhibiting high potential for treating RA.This work reviews the progress in injectable and implantable hydrogels,synthesis methods,types of drugs,advantages and challenges.Additionally,it discusses the role of hydrogels in targeted drug delivery,mechanistic behaviour and tribological performance for RA treatment.

Synergistic chemotherapy/PTT/oxygen enrichment by multifunctional liposomal polydopamine nanoparticles for rheumatoid arthritis treatment

Amultifunctional liposomal polydopamine nanoparticle(MPM@Lipo)was designed in this study,to combine chemotherapy,photothermal therapy(PTT)and oxygen enrichment to clear hyperproliferating inflammatory cells and improve the hypoxic microenvironment for rheumatoid arthritis(RA)treatment.MPM@Lipo significantly scavenged intracellular reactive oxygen species and relieved joint hypoxia,thus contributing to the repolarization of M1 macrophages into M2 phenotype.Furthermore,MPM@Lipo could accumulate at inflammatory joints,inhibit the production of inflammatory factors,and protect cartilage in vivo,effectively alleviating RA progression in a rat adjuvant-induced arthritis model.Moreover,upon laser irradiation,MPM@Lipo can elevate the temperature to not only significantly obliterate excessively proliferating inflammatory cells but also accelerate the production of methotrexate and oxygen,resulting in excellent RA treatment effects.Overall,the use of synergistic chemotherapy/PTT/oxygen enrichment therapy to treat RA is a powerful potential strategy.

Crossroads:Pathogenic role and therapeutic targets of neutrophil extracellular traps in rheumatoid arthritis

Rheumatoid arthritis(RA)is a prevalent autoimmune disease whose main features include chronic synovial inflammation,bone destruction,and joint degeneration.Neutrophils are often considered to be the first responders to inflammation and are a key presence in the inflammatory milieu of RA.Neutrophil extracellular traps(NETs),a meshwork of DNA-histone complexes and proteins released by activated neutrophils,are widely involved in the pathophysiology of autoimmune diseases,especially RA,in addition to playing a key role in the neutrophil innate immune response.NETs have been found to be an important source of citrullinated autoantigen antibodies and inflammatory factor release,which can activate RA synovial fibroblasts(FLS)and cause joint damage.This article reviews the role of NETs in the pathophysiology of RA,demonstrating the application of multiple molecules with various therapies,with a view to informing the discovery and development of novel biomarkers and therapeutic targets for RA.

Serum Zinc and Copper Level in Juvenile Idiopathic Arthritis (JIA) Patients and Its Correlation with Disease Duration-A Tertiary Hospital Study

Background: Juvenile Idiopathic Arthritis (JIA) is the most prevalent rheumatic disease in children. It is associated with abnormal levels of serum zinc (Zn) and copper (Cu) as during inflammation serum copper concentration increases and zinc decreases. Objective: To assess the serum Zn and Cu levels in different sub-types of JIA patients and their correlation with the disease duration. Methods: This cross-sectional study was conducted over twelve months at the Pediatric Rheumatology Division, Department of Paediatrics, Bangabandhu Sheikh Mujib Medical University. Sixty-nine JIA cases that fulfilled the International League of Association for Rheumatology (ILAR) criteria were taken as cases and age and sex-matched healthy children were considered as controls. The serum Zn and Cu tests were done using the spectrophotometric method with INDIKO PLUS Drug Analyzer. Data were recorded in a pre-designed questionnaire. Data were checked, verified and analyzed manually where continuous variables were analyzed using unpaired t-test and categorical variables using the ANOVA test. Pearson’s correlation coefficient test was used to see the correlation of serum zinc and copper levels with disease duration. Results: Boys were predominant in both case and control groups, with the majority within the 10 to 16-year-age group. Enthesitis-related arthritis (ERA) was the most common subtype followed by sJIA, Oligo JIA, Poly JIA (RF-) and unclassified subtypes. Disease duration was found less than 12 months in 30.4% of JIA patients. Serum analysis revealed a statistically significant reduction in mean zinc levels and increased copper levels in JIA patients compared to controls. This study observed a negative correlation between serum zinc levels and disease duration, whereas serum copper levels exhibited a positive correlation with disease duration. Conclusion: In conclusion, this study revealed that JIA patients exhibit alterations in serum zinc and copper levels. Serum copper levels showed a positive correlation and serum zinc levels showed a negative correlation with the duration of the disease.

Experimental investigation on the permeability of gap-graded soil due to horizontal suffusion considering boundary effect

The boundary condition is a crucial factor affecting the permeability variation due to suffusion.An experimental investigation on the permeability of gap-graded soil due to horizontal suffusion considering the boundary effect is conducted,where the hydraulic head difference(DH)varies,and the boundary includes non-loss and soil-loss conditions.Soil samples are filled into seven soil storerooms connected in turn.After evaluation,the variation in content of fine sand(ΔR_(f))and the hydraulic conductivity of soils in each storeroom(C_(i))are analyzed.In the non-loss test,the soil sample filling area is divided into runoff,transited,and accumulated areas according to the negative or positive ΔR_(f) values.ΔR_(f) increases from negative to positive along the seepage path,and Ci decreases from runoff area to transited area and then rebounds in accumulated area.In the soil-loss test,all soil sample filling areas belong to the runoff area,where the gentle-loss,strengthened-loss,and alleviated-loss parts are further divided.ΔR_(f) decreases from the gentle-loss part to the strengthened-loss part and then rebounds in the alleviated-loss part,and C_(i) increases and then decreases along the seepage path.The relationship between ΔR_(f) and Ci is different with the boundary condition.Ci exponentially decreases with ΔR_(f) in the non-loss test and increases with ΔR_(f) generally in the soil-loss test.

Case Report: Rhupus (The Association of Systemic Lupus Erythematosus and Rheumatoid Arthritis): About 2 Cases

Introduction: The association of systemic lupus erythematosus and rheumatoid arthritis (rhupus) is a rare clinical condition. Throughout the world, 287 cases of Rhupus have been described. We report two new observations of two patients who presented predominantly distal erosive polyarthritis with positive anti-Sm antibodies in one case and SmRNP in the other case. Observations: Case 1: 37 years old patient, with a recent diagnosis of pulmonary tuberculosis. She has since 8 months an inflammatory, bilaterally and symmetrical polyarthralgia without deformation or ankylosing synovitis, associated with malar erythema without other abnormalities. Immunological tests showed: positive Rheumatoid factor at 158 IU/ml, positive Anti-CCP at 550 IU/ml, and positivity of antinuclear at 1/1280 nuclear fluorescence with a strong presence of anti-Sm >8 IU/ml. The diagnosis of rhupus was concluded, without serious visceral involvement. Case 2: A 28-year-old patient, married with 3 children, with bilateral, symmetrical, deforming and chronic polyarthritis affecting large and small joints, which had been evolving for over 5 years without cutaneous abnormality associated. Paraclinical investigations showed: a biological inflammatory syndrome. Immunology was positive, with rheumatoid factors at 78 IU/ml, anti-CCP at 561 IU/ml, antinuclear antibodies at 1/1280 with positive anti-SmRNP and anti-SSA/Ro52, and a positive direct Coombs test. Joint ultrasound revealed tenosynovitis of the extensors and common flexors of the fingers, erosions and synovitis of multiple PPIs. The diagnosis of rhupus was based on the presence of 10 ACR criteria for RA and 8 ACR/EULAR 2019 criteria for SLE. Conclusion: Rheumatoid arthritis is a rare autoimmune disease combining features of both systemic lupus erythematosus and rheumatoid arthritis in the same patient, often sequentially. Despite a growing number of case reports and series, a consensus on the classification of SLE arthritis is still lacking, and diagnostic criteria for rhupus do not exist. These cases of rhupus must be recognized, as the vital and/or functional prognosis may be different from SLE alone or isolated RA.

Interleukin 6 and Bone Erosions in Rheumatoid Arthritis in an African Hospital

Introduction: Rheumatoid arthritis (RA) is a chronic, erosive and deforming inflammatory rheumatic disease. In the era of biotherapies and the arrival of biosimilars in sub-Saharan Africa, the objective of this study was to describe plasma IL-6 variations in RA patients at Cité Verte District Hospital (Cameroon). Material and Methods: Descriptive and analytical cross-sectional study from December 1, 2021 to May 31, 2022. We included patients over 18 years old suffering from RA (ACR/EULAR 2010). Patients with an infection were not included. The data collected were age, sex, smoking status, family history, disease duration, disease activity by DAS28, CRP, rheumatoid factor, and plasma level of IL-6. Bone erosion was sought on radiography and ultrasound. Result: We included 31 patients, 25 of whom were women (80.6%). The mean age was 47.27 ± 17.97 years. Disease activity was predominantly moderate (32.3%) and severe (32.3%). Mean IL-6 level was 15.29 ± 2.36 pg/ml (extremes: 11.26 pg/ml and 20.15 pg/ml). IL-6 levels were higher in patients with a history of smoking. Similarly, IL-6 levels were higher in patients with mildly active RA in remission than in moderately and severely active RA. Mean IL-6 levels were significantly higher in patients with erosive RA (16.3 pg/ml VS 14.6 pg/ml). Conclusion: IL-6 levels were significantly elevated in men, weaned smokers and patients with bone erosions.

Fasudil-modified macrophages reduce inflammation and regulate the immune response in experimental autoimmune encephalomyelitis

Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.

Aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders:progress of experimental models based on disease pathogenesis

Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.