Adjuvant-induced Arthritis Research Articles

Effects of Multimodal Therapy, Blinding, and Multi-laboratory Protocol Conduct on the Robustness of the Rat Model of Adjuvant Induced Arthritis.

The aim of this study was to investigate the effects of multimodal therapy comprising buprenorphine (BUP) and indomethacin (IND) on key translational parameters in the rat adjuvant induced arthritis (AIA) model. Furthermore, we investigated the difference between visual assessment scores and histology scores generated by blinded and non-blinded assessors and the robustness and generalizability of results by conducting a multi-laboratory study. The experiment was terminated on day 26 after 11 days (days 15-25) of voluntarily ingested buprenorphine and 7 days of gavage delivered indomethacin treatment (days 19-25). The treatment effects were assessed on the last day of the study, relying on body weight assessment, serum concentrations of α1- acid glycoprotein, and assessment of affected hind paws swelling, in-life and post mortem. Across two laboratories, the combined analgesic treatments had minimal effects on the measured model parameters indicating that multimodal treatment did not affect the translatability of the model. We found an improvement in clinical scores (a negative change in scores) in nearly all medicated animals when scored informed, whereas it was essentially 50:50 for the blinded scorings and no difference between the blinded and informed histological scoring. The present results support the use of more effective analgesic treatment regimens and the good practice recommendations advocating blinding as a mandatory practice in conduct of preclinical in vivo efficacy studies. In spite of minor differences between results obtained at the two sites, there was good agreement between them indicating robustness of the AIA model.

Green chemistry and anti-inflammatory activity of silver nanoparticles using an aqueous curcumin extract

Rat models are sensitive to the induction of arthritis with adjuvants. Therefore, they are beneficial for studying this pathogenesis through the induction of adjuvant arthritis by injection of Complete Freund's Adjuvant (CFA). An eco-friendly green chemistry approach was utilized to synthesize silver nanoparticles (AgNPs) using an aqueous extract of curcumin root as a capping and reducing agent. AgNPs formation was evaluated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and UV–vis spectroscopy analyses. The study aims to assess in vivo inhibitory effect of AgNPs on complete Freund’s adjuvant-induced arthritis in rats. Therefore, male albino rats were divided into four groups: Normal control; arthritic rats untreated; arthritis rats received standard drug (dexamethasone) as a positive control for 14 days; and arthritis rats received 100 mg/kg AgNPs for 14 days. The results showed that the AgNPs exhibit anti‑inflammatory effects in rats arthritis model by reducing the edema and levels of interleukin‑6 (IL-6) and high-sensitive C‑reactive protein (hs-CRP) in the paw tissues compared to the arthritic rats untreated. Overall, these findings evidence that the AgNPs have a potential promising anti‑inflammatory effect against arthritis disease.

Enriched Peripheral Blood-Derived Mononuclear Cells for Treating Knee Osteoarthritis

Osteoarthritis (OA) is a common chronic skeletal disease in the elderly. There is no effective therapy to reverse disease severity and knee OA (KOA) progression, particularly at the late stage. This study aims to examine the effect of peripheral blood-derived mononuclear cells (PBMNCs) on pain and motor function rescue in patients with Kellgren–Lawrence (KL) grade II to IV KOA. Participants received one intra-articular (IA) injection of autologous PBMNCs. The mononuclear cells were isolated from peripheral blood, enriched by a specialized medium (MoFi medium), and separated by Ficoll-Paque solution. The isolated and enriched PBMNCs could differentiate into M1 and M2 macrophages in vitro. The in vivo anti-inflammatory effect of the PBMNCs was similar to that of bone marrow mesenchymal stem cells, evaluated by complete Freund’s adjuvant-induced arthritis in rodents. A single-arm and open-label pilot study showed that patients’ knee pain and motor dysfunction were significantly attenuated after the cell transplantation, assessed by visual analogue scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months post-treatment. Notably, the therapeutic effect of the PBMNCs treatment can be stably maintained for 24 months, as revealed by the KOOS scores. These preclinical and pilot clinical data suggest that IA injection of MoFi-PBMNCs might serve as a novel medical technology to control the pain and the progress of KOA.

IgD enhances the release of neutrophil extracellular traps (NETs) via FcδR in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder affecting primarily the joints. Neutrophils and the release of neutrophil extracellular traps (NETs) contribute to the pathogenesis of RA. However, IgD, which was abnormally higher in RA, has not been studied for its pathological role in neutrophil activation and NETs formation. To investigate the effects of IgD on neutrophil activation and NETs formation via IgD receptor (FcδR), we collect peripheral blood of RA patients and established adjuvant-induced arthritis (AA) rat model. We found that the expression of FcδR on neutrophils was significantly higher in RA patients compared with healthy controls. As a specific marker of NETs, the level of citrullinated histone H3 was positively correlated with sIgD and FcδR in RA patients. IgD enhances the release of NETs and promotes the proliferation of fibroblast-like synoviocytes (FLS) from RA patients by activating neutrophils. As a competitive FcδR blocker, IgD-Fc-Ig fusion protein could significantly reduce NETs formation and FcδR expression on neutrophils in vitro. In vivo, IgD-Fc-Ig could restrain IgD-induced neutrophil activation and NETs formation, thus inhibited FLS proliferation in AA rats. Data presented here demonstrate that neutrophils could be triggered by IgD to release NETs and take part in FLS proliferation in RA patients with excessive IgD. Blocking IgD-FcδR could inhibit neutrophil activation and NETs formation, and represent an additional attractive novel therapeutic strategy for the treatment of RA.

A STUDY OF THE INFLUENCE OF JUVENILE ADJUVANT ARTHRITIS ON DENTAL HARD TISSUES CONDITION IN EXPERIMENTAL ANIMALS.

The aim: To study the intensity and depth of carious tooth lesions in rats with experimental juvenile adjuvant-induced arthritis. Materials and methods: An experimental study on a model of juvenile adjuvant arthritis (JAA) in 10 one-month-old rats induced by method of A.M. Bendele was carried out. 10 rats of the same age were intact. Injection of adjutant in rats of experimental group led to the development of acute local reaction and then caused generalized joint reaction of autoimmune origin. The performed basic therapy of JAA promoted transition of acute autoimmune process to chronic. Rats were withdrawn from the experiment in 58 days and the dental-jaw blocks were made, in which the intensity and depth of carious lesions of the masticatory group of teeth were determined. Results: The course of JAA was accompanied by the development of dental caries in 100% of experimental animals. It was found that the intensity of carious teeth lesions in terms of the number of carious teeth and cavities is probably higher than in intact rats (respectively 4.3 ± 0.3 vs. 2.2 ± 0.6 and 4.5 ± 0.3 vs. 2.3 ± 0.7, p <0.001). In rats with JAA, mostly middle and deep carious cavities were revealed, at the same time in intact rats - superficial and middle carious cavities were observed. Conclusions: It has been established that adjuvant arthritis is accompanied by 100% prevalence of dental caries, high intensity of carious process, presence of middle and deep carious cavities, that confirm the negative influence of autoimmune disease on the condition of the hard tooth tissues.

Surface-decorated nanoliposomal leonurine targets activated fibroblast-like synoviocytes for efficient rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint destruction, leading to impaired life quality, disability, and even premature mortality. However, current medications suffer from limited clinical outcomes and severe side effects due to low bioavailability and non-specific distribution after administration. Herein, a targeting nanosystem (HAP-Lipo@Leo) was constructed for efficient RA treatment, which can precisely deliver a natural anti-arthritic drug leonurine (Leo) to the inflamed joint by HAP-1 peptide-mediated recognition of activated fibroblast-like synoviocytes (FLS). More specifically, HAP-Lipo@Leo was prepared by a combination of thin film hydration and high-pressure microfluidization and surface-decorated with HAP-1 peptide and PEG before encapsulating Leo by the ammonium sulfate gradient method. The as-obtained HAP-Lipo@Leo can be selectively internalized by activated FLS and impairs the lamellipodia formation and overexpression of inflammatory cytokines, both of which play detrimental roles in joint damage. Furthermore, HAP-Lipo@Leo demonstrated arthritic joint-specific distribution, significant inhibition of synovial inflammation, and reversal of cartilage and bone destruction in adjuvant-induced arthritis rats as evidenced by comprehensive investigations including ELISA tests, histopathology examinations, and micro-CT analysis. In addition, HAP-Lipo@Leo exhibited good biocompatibility and safety both in vitro and in vivo. Taken together, HAP-Lipo@Leo holds great potential for clinical RA management by integrating activated FLS targeting, long circulation, multifaceted therapeutic effects, and excellent biocompatibility.

Thermosensitive smart hydrogel of PEITC ameliorates the therapeutic efficacy in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune condition that accompanies chronic inflammation of joints with limited therapeutic options. Phenethyl isothiocyanate (PEITC), a bioactive phytochemical, exerts its chemopreventive, anti-oxidant, and anti-inflammatory activity via the Nrf-2 pathway. However, limited water solubility, short half-life, and instability are reasons for the low bioavailability of PEITC that hampers clinical application. From studies in healthy rats, the performance of PEITC-loaded chitosan/pluronic F-127 smart hydrogel (PH) as a thermosensitive injectable demonstrated adequate thermosensitivity (gel formation), injectability (ease of administration), biocompatibility (with prolonged contact), pharmacokinetics (sustained drug release), and biosafety (nontoxic to major organs). In the adjuvant-induced arthritis (AIA) rat model, PEITC-hydrogel (PH50) injected into the knee joint lowered RA-related symptoms significantly (paw edema and arthritis score). Further, a marked reduction in bone erosion and inflammation-specific biomarkers was observed. Finally, this study demonstrates a smart injectable hydrogel optimally loaded with PEITC which is safe, biocompatible and exhibits significant therapeutic efficacy in RA conditions.

Quercetin-loaded chitosan nanoparticles ameliorate adjuvant-induced arthritis in rats by regulating anti-oxidant enzymes and downregulating pro- and inflammatory cytokines.

Rheumatoid arthritis (RA) is an inflammatory condition and associated with the symmetrical synovitis of the joints and cause joint pain. The use of anti-rheumatic drugs is associated with many adverse effects. Quercetin, an important polyphenolic flavonoid, possess anti-inflammatory and anti-rheumatic effects. Quercetin use is limited due to poor absorption and bioavailability. Nanomedicines are used for the targeted drug delivery, hence it reduces the adverse effects of the drug. Based upon these factors, quercetin-loaded chitosan nanoparticles (Q-NPs) were prepared by solvent evaporation method, characterized and their better anti-rheumatic effect with mechanistic insights was validated in Freund's complete adjuvant (FCA)-induced arthritic rats along with safety studies. The animals were divided into five groups, each containing 5 animals. Group I was normal control, group II was arthritic control, while groups III, IV and V were administered with quercetin (15mg/Kg) and Q-NPs (10 and 20mg/Kg), respectively. The reduction in ankle diameter, serum oxidative stress markers as well as pro- and inflammatory cytokines, e.g., tumor necrosis factor (TNFα), interleukin (IL-6) were determined. The prepared Q-NPs showed hydrodynamic size of 83.9nm, polydispersity index of 0.687, entrapment efficiency 90.5% as well as no interaction between quercetin and chitosan in Fourier transform infrared spectroscopy (FTIR). A significant reduction (p < 0.001) in ankle diameter was observed after administration of high-dose Q-NPs (4.32 ± 0.14cm to 5.13 ± 0.62cm). There was also reduction (p < 0.001) in levels of TNFα and IL-6 following high-dose Q-NPs (72.56 ± 2.30 and 308.19 ± 11.5pg). The effect on biochemical tests, hematological parameters and oxidative stress parameters was also found to be significant. Histopathological changes of kidney, liver and ankle also confirmed the anti-rheumatic effect of high-dose Q-NPs. The study concludes that administration of Q-NPs (20mg/Kg) may be used for the treatment of FCA-induced RA in rats.

Dissolving microneedle patch-assisted transdermal delivery of methotrexate improve the therapeutic efficacy of rheumatoid arthritis

Methotrexate (MTX) is a first-line treatment for rheumatoid arthritis (RA), but its clinical use is greatly limited by the adverse effects and poor patient compliance caused by traditional oral administration or injection. In recent years, some transdermal drug delivery systems have received considerable attention due to overcoming these shortcomings. In this study, we developed dissolving microneedle patch (DMNP) for transdermal delivery of MTX to treat RA safely and effectively. The morphology, mechanical strength, skin insertion, drug content, in vitro transdermal delivery, and other properties of DMNP were characterized. Meanwhile, the adjuvant-induced arthritis model of rats was established to investigate the therapeutic effect of MTX-loaded DMNP in vivo. The results showed that the microneedles had excellent morphology with neat array and complete needles, good puncture performance and mechanical strength, and rapid intradermal dissolution rate. In vitro transdermal delivery results indicated that microneedles could significantly increase drug transdermal permeation compared with the cream group. The pharmacological study showed that MTX-loaded DMNP significantly alleviated paw swelling, inhibit inflammatory response via downregulating the levels of TNF-α and IL-1β, relieved synovium destruction with less cartilage erosion, and slowed the progression of RA in AIA rats. Besides, DMNP presented better therapeutic performance than cream or intragastric administration at the same dosage of MTX. In conclusion, the MTX-loaded dissolving microneedle patch has advantages of safety, convenience, and high efficacy over conventional administrations, laying a foundation for the transdermal drug delivery system treatment of rheumatoid arthritis.

Identification of TUL01101: A Novel Potent and Selective JAK1 Inhibitor for the Treatment of Rheumatoid Arthritis.

Janus kinase 1 (JAK1) is a potential target for the treatment of rheumatoid arthritis (RA). In this study, the introduction of a spiro ring with a difluoro-substituted cyclopropionamide resulted in the identification of TUL01101 (compound 36) based on a triazolo[1,5-a]pyridine core of filgotinib. It showed excellent potency on JAK1 with an IC50 value of 3 nM and exhibited more than 12-fold selectivity for JAK2 and TYK2. Whole blood assay also demonstrated the high activity and selectivity (37-fold for JAK2). At the same time, TUL01101 also demonstrated excellent metabolic stability and pharmacokinetics (PK) profiles were assayed in three species (mouse, rat, and dog). Moreover, it has been validated for effective activity in the treatment of RA both in collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models, with low dose and low toxicity. Now, TUL01101 has progressed into phase I clinical trials.

Methotrexate conjugated gold nanoparticles improve rheumatoid vascular dysfunction in rat adjuvant-induced arthritis: gold revival

Endothelial vasomotor dysfunction and accelerated atherosclerosis encompass the features of rheumatoid vascular dysfunction (RVD), increasing cardiovascular morbidity and mortality among rheumatoid arthritis (RA) patients. Methotrexate, among DMARDs, effectively reduces cardiovascular events, but its non-selectivity together with its pharmacokinetic variability often limit drug adherence and contribute to its potential toxicity. Thus, methotrexate was conjugated to gold nanoparticles (MTX/AuNPs) and its effect on RVD in rats’ adjuvant-induced arthritis was evaluated. A comparative study between MTX/AuNPs, free MTX, and AuNPs treatments on joint inflammation, vascular reactivity and architecture, smooth muscle phenotype, systemic inflammation, and atherogenic profile was done. Since MTX/AuNPs effect was superior, it appears that conjugation of MTX to AuNPs demonstrated a synergistic action. MTX immunomodulatory action combined with AuNPs anti-atherogenic potential yielded prompt control of whole features of RVD. These findings highlight the usefulness of nanoparticles-targeted drug-delivery system in refining rheumatoid-induced vascular dysfunction treatment and reviving gold use in RA.

Consumption of Saturated Fatty Acids-Rich Lard Benefits Recovery of Experimental Arthritis by Activating PPAR-γ.

This study investigates the impacts of lard and related fatty acids intake on rheumatoid arthritis (RA) animal models. Collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) are induced in SD rats and C57 BL/6 mice respectively, which are fed by lard-rich diet (LRD) for 42 days with intake restriction or not. AIA SD rats are treated by representative fatty acids for 30 days. Body weight, arthritis score, and metabolic profile are periodically recorded. Monocyte distribution, cytokine/metabolites levels, gene expression, and tissue damages are investigated by flow cytometry, ELISA, colorimetry, PCR, and histological methods. After being treated by fatty acids in vitro, THP-1 monocytes and the corresponding medium are collected for ELISA, PCR, immunoblotting, and reporter gene assays. Irrespective of intake amounts, LRD decreases inflammatory cytokines and inhibits glycolysis in all rheumatic rodents. Furthermore, it alters monocyte distribution and promotes PPAR-γ expression in AIA mice. Overall evidences show that both saturated (SF) and unsaturated fatty acids (USF) from lard can attenuate inflammation by activating PPAR-γ. Silencing PPAR-γ abrogates their anti-inflammatory effects in vitro. Besides, SF can stimulate TLR4/NF-κB pathway. Lard consumption is beneficial for active inflammatory arthritis recovery. Even SF can activate PPAR-γ and consequently attenuate inflammation.

Revealing the Active Constituents and Mechanisms of Semiliquidambar cathayensis Chang Roots against Rheumatoid Arthritis through Network Pharmacology, Molecular Docking, and in Vivo Experiment.

Semiliquidambar cathayensis Chang roots (SC) are traditional Chinese medicine for treating rheumatoid arthritis (RA). However, the effect and potential mechanism of SC remain unclear. This study aims to reveal the anti-RA constituents and mechanisms of SC based on network pharmacology, molecular docking, and adjuvant-induced arthritis (AIA) model rat experiment. In this work, 9 potential active constituents, including kaempferol, quercetin, naringenin, paeoniflorin, catechin, fraxin, gentianin, hesperetin, and ellagic acid 3,3',4-trimethyl ether, in SC crossed 65 target genes of RA. In addition, 28 core targets were enriched in inflammation and others, among which interleukin-17 (IL-17) and tumor necrosis factor (TNF) were the major targets. The binding of bio-constituents with IL-17 and TNF were performed using molecular docking. Rat experiment demonstrated that the extract of SC restored body weight loss, reduced arthritis score and the indices of thymus and spleen, alleviated ankle joint histopathology, decreased the levels of rheumatoid factor (RF), C-reactive protein (CRP), IL-17, TNF-α, IL-1β, IL-6, cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and matrix metalloproteinase-2 (MMP-2), whereas elevated the levels of IL-4 and IL-10. Collectively, it was the first time to comprehensively reveal the anti-RA efficacy and mechanism of SC via suppressing the inflammatory pathway based on network pharmacology, molecular docking, and experimental verification, which provide chemical and pharmacological evidences for the clinical application of SC.

Efficacy of Moxa-burning heat stimulating Zusanli (ST36) and Shenshu (BL23) on expressions of macrophage migration inhibitory factor and macrophage apoptosis in rabbits with adjuvant-induced arthritis.

To evaluate the effects of moxa-burning heat stimulating acupoints Zusanli (ST36) and Shenshu (BL23) on macrophage migration inhibitory factor (MIF) and its related molecules which can provide scientific experimental basis for the clinical application of moxibustion treatment of rheumatoid arthritis (RA). Thirty rabbits were randomly assigned to control group, RA model (established by injecting Freund's Complete Adjuvant) group (RA group) and RA model with moxibustion group [Moxa group, Zusanli (ST36) and Shenshu (BL23), 5 moxa pillars/day, 6 d × 3]. The expressions of MIF mRNA were evaluated with reverse transcription polymerase chain reaction; the apoptosis rates of macrophages were detected by erminal deoxynucleotidyl transferase-mediated dTUP nick end labeling; the expressions of related signal molecules were detected with immunohistochemical S-P method and the levels of IL-2 were detected with enzyme-linked immunosorbent assay. The expressions of MIF mRNA, extracellular regulated protein kinases 2, p38 mitogen-activated protein kinase and nuclear factor-κ-gene binding p65 in synovial tissue of RA group were significantly increased when compared with control group, which were lower remarkably in moxa group than those in RA group. The apoptosis rates of macrophages in RA group were significantly down-regulated as compared with the control group, which were up-regulated in moxa group compared with the RA group. The levels of IL-2 in synovial fluid from the RA group were elevated significantly as compared with that from control group, but those of the moxa group were reduced when compared with those from RA group. Moxibustion may simultaneously regulate the expressions of MIF and its related signaling pathways molecules, the apoptosis rate of macrophages in synovial tissue, as well as the level of inflammatory factors in synovial fluid. The results suggest that the anti-inflammatory effect of moxibustion on RA may be related to inhibit the expression of MIF in synovial tissue, the molecules of some related signaling pathways and promote the apoptosis of macrophage.

Novel tryptanthrin derivatives with benzenesulfonamide substituents: Design, synthesis, and anti-inflammatory evaluation

Herein, two series of tryptanthrin derivatives with benzenesulfonamide substituents were designed and synthesized to discover novel anti-inflammatory agents. The anti-inflammatory activities of all derivatives were screened by evaluating their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. Among them, compound 8j exhibited the best NO inhibitory activity (IC50 = 1.25 ± 0.21 μM), with no obvious toxicity. Further evaluation showed that 8j could also significantly reduce the levels of pro-inflammatory cytokines interleukin-1β (IL-1β, IC50 = 8.48 ± 0.23 μM) and tumor necrosis factor-α (TNF-α, IC50 = 11.53 ± 0.35 μM) and downregulate the LPS-induced expression of iNOS and COX-2. Reverse docking of 8j suggested p38α as the molecular target, which is a well-known crucial player in the p38 MAPK signaling pathway that controls the transcription of pro-inflammatory mediators. Cellular thermal shift assay showed that 8j efficiently stabilized p38α in LPS-treated RAW264.7 cells. Western blot showed that inflammatory response was inhibited by 8j through inhibiting the phosphorylation of p38α and MK2 in the p38 MAPK signaling pathway. Finally, In vivo studies showed that 8j could significantly ameliorate the degree of foot swelling and knee joint pathology in adjuvant-induced arthritis (AIA) rats and reduce levels of TNF-α and IL-1β in serum, achieving the effect of protecting synovial tissue and ameliorating arthritis. These findings suggested that 8j may be a promising compound for further development of anti-inflammatory agents.

Validation of traditional claims of anti-arthritic efficacy of trans-Himalayan snow mountain garlic (Allium ampeloprasum L.) extract using adjuvant-induced arthritis rat model: A comparative evaluation with normal garlic (Allium sativum L.) and dexamethasone

Ethnopharmacological relevanceSnow Mountain Garlic (SMG) (Allium ampeloprasum L.) is a wild trans-Himalayan member of the genus Allium, valued for its anti-inflammatory and anti-arthritic properties in the mountain folk medicinal system (Sowa-Rigpa). Despite its age-old medicinal usage by traditional therapists and the native population for various ailments including rheumatism, there is no scientific validation of its phyto-pharmaceutical merits. Aim of the studyThe present pre-clinical study compared the in-vivo anti-arthritic effects of SMG with reported efficacy doses of normal garlic (Allium sativum L.) extract and dexamethasone in a complete Freund's adjuvant (CFA)-induced arthritis rat model. Materials and methodsThe female Wistar rats were immunized by the subplannter injection of CFA into the right hind footpad. Aqueous extracts of SMG and normal garlic were administered orally at a dose of 250 mg/kg and 500 mg/kg for 28 days. Dexamethasone was used as positive control drug. Behavioral parameters including paw markers, arthritis index, joint stiffness, body weight change, etc. were measured. Also, the changes in histopathological indices, hematological profile, inflammatory mediators, and serum cytokines level was determined. ResultsTreatment of rats with SMG extracts significantly (p < 0.001) prevented the reduction in body weight and hematological changes as well as ameliorated clinical symptoms such as arthritic index, joint stiffness, arthritis score, edema, hyperalgesia, and histopathological indices. This was associated with a significant reduction in the serum levels of RF, CRP, anti-CCP, and proinflammatory cytokines exhibiting strong anti-arthritic potential. SMG extracts could also significantly down regulate the NF-κB, COX-2, and iNOS expression in the ankle joint tissues. ConclusionsThe present study is the first attempt to validate the phyto-pharmaceutical efficacy of this folk garlic variety from the trans-Himalayan region. Overall, SMG extract showed remarkable preventive anti-inflammatory and anti-arthritic activities which were closely comparable to therapeutic effects of dexamethasone and at par or even better than normal garlic w.r.t. several study parameters.

Evaluation of Curcumin, Piperine, and Ferrous Sulphate Combination Potential in the Adjuvant-induced Arthritis Model in Male Wistar Rats

Evaluation of Curcumin, Piperine, and Ferrous Sulphate Combination Potential in the Adjuvant-induced Arthritis Model in Male Wistar Rats

Biosynthesis of Silver Nanoparticles Using Commiphora mukul Extract: Evaluation of Anti-Arthritic Activity in Adjuvant-Induced Arthritis Rat Model.

Rheumatoid arthritis (RA) is a major global public health challenge, and novel therapies are required to combat it. Silver nanoparticles (AgNPs) have been employed as delivery vehicles of anti-inflammatory drugs for RA therapy, and it has been recently realized that AgNPs have anti-inflammatory action on their own. However, their conventional synthesis processes might result in cytotoxicity and environmental hazards. Instead, the use of natural products as a reducing and stabilizing agent in the biosynthesis of silver nanoparticles has arisen as an option to decrease the cytotoxic and environmental concerns associated with chemical synthesis of AgNPs. In this study, we challenged the efficacy of Commiphora mukul (guggul) aqueous extract as a reducing and/or capping agent for the biosynthesis of AgNPs. Guggul-mediated biosynthesized silver nanoparticles (G-AgNPs) were characterized via UV-vis spectroscopy, dynamic light scattering, and scanning electron microscopy. In addition, their anti-arthritic potential was evaluated in an adjuvant-induced arthritis (AIA) model. The fabricated NPs showed an absorption peak at 412 nm, corresponding to the typical surface plasmon resonance band of AgNPs. The synthesized G-AgNPs were nearly spherical, with a particle size of 337.6 ± 12.1 nm and a negative surface charge (-18.9 ± 1.8 mV). In AIA rat model, synthesized G-AgNPs exerted a potent anti-inflammatory action, as manifested by a remarkable reduction in paw volume (&gt;40%) along with elicitation of a minimal arthritic score, compared to control rats. In addition, when compared to arthritic rats, treatment with G-AgNPs efficiently restored the activity of antioxidant enzyme, superoxide dismutase, and catalase, indicating the efficiency of synthesized G-AgNPs in alleviating the oxidative stress associated with RA. Finally, histological examination revealed comparatively lower inflammatory cells infiltration in ankle joint tissue upon treatment with G-AgNPs. Collectively, biosynthesized G-AgNPs might represent a plausible therapeutic option for the management of RA.

High-Throughput Metabolomics Integrated Network Pharmacology Reveals the Underlying Mechanism of Paeoniae Radix Alba Treating Rheumatoid Arthritis.

Objective: The mechanism of action and potential targets of Paeoniae Radix Alba (Baishao, B) in the treatment of adjuvant-induced arthritis (AIA) rats are explained using metabolomics and network pharmacology techniques, and the research evidence for the development of anti-rheumatoid arthritis (RA) drugs is enriched. Methods: The rats were injected with Freund’s complete adjuvant (CFA) to induce arthritis. We then measured the general physical characteristics, examined their X-rays and histopathology to evaluate the pathological condition of the inflammation models, and conducted metabolomics studies on the change in urine metabolism caused by CFA. The lyophilized powder of B at a dose of 2.16 g/kg was orally administered to the rats continuously for 28 days, and the therapeutic effect was evaluated. Network pharmacology prediction shows that B contains the target action of the ingredient, and the simulation of the target molecular docking, in combination with the metabolomics analysis results, shows that B has a potential role in the treatment of AIA rats. Results: B can reduce the paw swelling and pathological changes in rats caused by CFA, reverse the levels of 12 urine biomarkers, and regulate histidine metabolism, phenylalanine metabolism, arginine, proline metabolism, pyrimidine metabolism, etc. The prediction of the active ingredient target in B indicates that it may act as an inflammatory signaling pathway in anti-RA, among them being paeoniflorin, palbinone, beta-sitosterol, kaempferol, and catechin, which are the significant active ingredients. Conclusion: The metabolomics results revealed the markers and metabolic mechanisms of urinary metabolic disorders in rats with AIA, demonstrated the efficacy of the therapeutic effect of B, and identified the key ingredients in B, providing theoretical support for the subsequent development and utilization of B.

A liquid chromatography-mass spectrometry untargeted urinary metabonomics combined with quantitative analysis of seven amino acids biomarkers on yaobitong capsule in the intervention of rheumatoid arthritis rats.

Yaobitong capsule is a compound preparation of traditional Chinese medicine that has been widely applied in disease treatment. To insight into the therapeutic effects of the yaobitong capsule on rheumatoid arthritis and its mechanisms, a liquid chromatography-mass spectrometry untargeted urine metabolomics method was established and validated, combined with the quantitative analysis of seven potential amino acid biomarkers in rat urine. The results showed that 35 potential biomarkers were found in untargeted metabonomics, which was related to amino acid metabolism, lipid metabolism, energy metabolism, and purine metabolism. Moreover, seven amino acid biomarkers, including proline, methionine, glutamic acid, histidine, lysine, cysteine, and glutamine, were further separated and quantified in multiple-reaction monitoring with a positive ionization mode. Then the linearity, standard curves, accuracy, precision, limit of quantitation, recovery, stability, carryover, and matrix effect of the quantitative method were examined. Finally, the validated method was successfully applied to investigate the urine samples of the control group, adjuvant-induced rheumatoid arthritis model group, yaobitong capsule-treatment group, and positive control group in rats. The contents of seven amino acids in different groups showed significant differences. Consequently, our findings revealed that the yaobitong capsule exerted therapeutic effects on rheumatoid arthritis rats by maintaining amino acid homeostasis.