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The monoterpene oxide, Eucalyptol (1,8-Cineole), a primary component of eucalyptus oil, has been evaluated pharmacologically for anti-inflammatory and analgesic activity. Current research aimed to evaluate Eucalyptol's anti-arthritic potential in a Complete Freund's adjuvant induced arthritis that resembles human rheumatoid arthritis. Polyarthritis developed after 0.1 mL CFA injection into the left hind footpad in rats. Oral administration of Eucalyptol at various doses (100, 200 and 400 mg/kg) significantly reduced paw edema, body weight loss, 5-LOX, PGE2 and Anti-CCP levels. Real‐time PCR investigation showed significant downregulation of COX-2, TNF-α, NF-κB, IL-17, IL-6, IL-1β and upregulation of IL-4 and IL-10 in Eucalyptol treated groups. Hemoglobin and RBCs counts significantly increased post-treatment with Eucalyptol while ESR, CRP, WBCs and platelets count significantly decreased. Eucalyptol significantly increased Superoxide Dismutase, Catalase and Glutathione levels compared to CFA-induced arthritic control however, MDA significantly decreased post-treatment. Further, radiographic and histopathological examination of the ankle joints of rodents administered Eucalyptol revealed an improvement in the structure of the joints. Piroxicam was taken as standard. Furthermore, molecular docking findings supported the anti-arthritic efficacy of Eucalyptol exhibited high binding interaction against IL-17, TNF-α, IL-4, IL-10, iNOS NF-κB, 5-LOX, and COX-2. Eucalyptol has reduced the severity of CFA induced arthritis by promoting anti-inflammatory cytokines for example IL-4, IL-10 and by inhibiting pro-inflammatory cytokines such as 5-LOX, COX-2, IL-17, NF-κB, TNF-α, IL-6 and IL-1β. Therefore, Eucalyptol might be as a potential therapeutic agent because of its pronounced anti-oxidant and anti-arthritic activity. [ABSTRACT FROM AUTHOR]

Background and purpose: Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway. Methods: We established an arthritis model by combining chicken type II collagen and complete Freund's adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-β1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1β in combination with TGF-β1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD. Results: Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-β1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD. Conclusion: In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) remains a chronic incurable condition, presenting substantial challenges in treatment. This study explores a novel strategy by investigating the concurrent use of cuminaldehyde, a natural compound, with indomethacin in animal models of MIA-induced OA. Our results demonstrate that the co-administration of cuminaldehyde and indomethacin does indeed produce a superior effect when compared to these compounds individually, significantly enhancing therapeutic outcomes. This effect is evidenced by a marked reduction in pro-inflammatory cytokines IL-6 and IFN-γ, alongside a significant increase in the anti-inflammatory cytokine IL-10, compared to treatments with each compound alone. Radiographic analyses further confirm the preservation of joint integrity and a reduction in osteoarthritic damage, highlighting the association's efficacy in cartilage-reducing damage. These findings suggests that the association of cuminaldehyde and indomethacin not only slows OA progression but also offers enhanced cartilage-reducing damage and fosters the production of protective cytokines. This study underscores the potential benefits of integrating natural products with pharmaceuticals in OA management and stresses the importance of further research to fully understand the mechanisms underlying the observed potentiated effects. [ABSTRACT FROM AUTHOR]

Structure elucidation plays a critical role across the landscape of medicinal chemistry, including medicinal inorganic chemistry. Herein, we discuss the importance of structure elucidation in drug development and then provide three vignettes that capture key instances of its relevance in the development of biologically active inorganic compounds. In the first, we describe the exploration of the biological activity of the trinuclear Ru compound called ruthenium red and the realization that this activity derived from a dinuclear impurity. We next explore the development of Au‐based antitubercular and antiarthritic drugs, which features a key step whereby ligands were discovered to bind to Au through S atoms. The third exposition traces the development of As‐based antiparasitic drugs, a key step of which was the realization that the reaction of arsenic acid and aniline does not produce an anilide of arsenic acid, as originally thought, but rather an amino arsonic acid. These case studies provide the motivation for an outlook in which the development of Sb‐based antiparasitic drugs is described. Although antileishmanial pentavalent antimonial drugs remain in widespread use to this day, their chemical structures remain unknown. [ABSTRACT FROM AUTHOR]

Background: Regulatory T cells (Tregs) are crucial in maintaining immune homeostasis and preventing autoimmunity and inflammation. A proportion of Treg cells can lose Foxp3 expression and become unstable under inflammation conditions. The precise mechanisms underlying this phenomenon remain unclear. Methods: The PI16 gene knockout mice (PI16fl/flFoxp3Cre) in Treg were constructed, and the genotypes were identified. The proportion and phenotypic differences of immune cells in 8-week-old mice were detected by cell counter and flow cytometry. Two groups of mouse Naïve CD4+T cells were induced to differentiate into iTreg cells to observe the effect of PI16 on the differentiation and proliferation of iTreg cells, CD4+CD25+Treg and CD4+CD25− effector T cells (Teff) were selected and co-cultured with antigen presenting cells (APC) to observe the effect of PI16 on the inhibitory ability of Treg cells in vitro. The effects of directed knockout of PI16 in Treg cells on inflammatory symptoms, histopathological changes and immune cell expression in mice with enteritis and autoimmune arthritis were observed by constructing the model of antigen-induced arthritis (AIA) and colitis induced by dextran sulfate sodium salt (DSS). Results: We identified peptidase inhibitor 16 (PI16) as a negative regulator of Treg cells. Our findings demonstrate that conditional knock-out of PI16 in Tregs significantly enhances their differentiation and suppressive functions. The conditional knockout of the PI16 gene resulted in a significantly higher abundance of Foxp3 expression (35.12 ± 5.71% vs. 20.00 ± 1.61%, p = 0.034) in iTreg cells induced in vitro compared to wild-type mice. Mice with Treg cell-specific PI16 ablation are protected from autoimmune arthritis (AIA) and dextran sulfate sodium (DSS)-induced colitis development. The AIA model of PI16CKO is characterized by the reduction of joint structure and the attenuation of synovial inflammation and in DSS-induced colitis model, conditional knockout of the PI16 reduce intestinal structural damage. Additionally, we found that the deletion of the PI16 gene in Treg can increase the proportion of Treg (1.46 ± 0.14% vs. 0.64 ± 0.07%, p < 0.0001) and decrease the proportion of Th17 (1.00 ± 0.12% vs. 3.84 ± 0.64%, p = 0.001). This change will enhance the shift of Th17/Treg toward Treg cells in AIA arthritis model (0.71 ± 0.06% vs. 8.07 ± 1.98%, p = 0.003). In DSS-induced colitis model of PI16CKO, the proportion of Treg in spleen was significantly increased (1.40 ± 0.15% vs. 0.50 ± 0.11%, p = 0.003), Th17 (2.18 ± 0.55% vs. 6.42 ± 1.47%, p = 0.017), Th1 (3.42 ± 0.19% vs. 6.59 ± 1.28%, p = 0.028) and Th2 (1.52 ± 0.27% vs. 2.76 ± 0.38%, p = 0.018) in spleen was significantly decreased and the Th17/Treg balance swift toward Treg cells (1.44 ± 0.50% vs. 24.09 ± 7.18%, p = 0.012). Conclusion: PI16 plays an essential role in inhibiting Treg cell differentiation and function. Conditional knock out PI16 gene in Treg can promote the Treg/Th17 balance towards Treg dominance, thereby alleviating the condition. Targeting PI16 may facilitate Treg cell-based therapies for preventing autoimmune diseases and inflammatory diseases. The research provides us with novel insights and future research avenues for the treatment of autoimmune diseases, particularly arthritis and colitis. [ABSTRACT FROM AUTHOR]

Curcumin is derived from Curcuma longa's dried root rhizomes possessing extensive variety of therapeutic actions such as antifungal, anti-inflammatory, antibacterial, antispasmodic, antioxidant and anti-arthritic. The current study was conducted to fabricate, characterize and optimize curcumin-loaded Eudragit L100 and hydroxy propyl methyl cellulose (HPMC) sustained release and improved bioavailable microparticles for anti-arthritis and anti-inflammatory activities. Curcumin-loaded microparticles made with Eudragit L100 and HPMC via ESE having different polymer and emulsifier concentrations. Optical microscope showed spherical microparticles, and FTIR spectroscopic analysis displayed characteristic peaks at 3519 cm−1, 1366 cm−1, 950 cm−1 and 728 cm−1 due to O–H group, C–OH bending and bending vibration of –CH groups, respectively. SEM analysis showed that mean microparticles diameter was 30.2–76.7 μm having encapsulation efficiency 78.8–96.2%. Curcumin (600 µg/ml) showed 52%HRBC membrane stabilization and 71% protein denaturation inhibition. Curcumin (600 µg/ml) produced microparticles with 30.2 μm-diameter showed highest encapsulation, sustained drug release, significant anti-arthritic potential with good anti-inflammatory activity make it suitable as new therapeutic anti-arthritic agent. From results, it was suggested that this is a promising strategy for the development and treatment of chronic ailments like arthritis and inflammation. [ABSTRACT FROM AUTHOR]

Topical nanogel-based formulations have shown potential in the management of rheumatoid arthritis (RA). The aim of this research work was to explore the synergistic effect of Curcumin (CUR) and Cyclosporine (CYC) in combination via a topical route for the management of RA. The CUR+CYC loaded nanoemulsion was developed using the spontaneous emulsification technique and was subsequently incorporated into Carbopol® Ultrez 30-NF gel. The effect of the developed formulation on levels of proinflammatory cytokines (IL-6, TNF-α) and anti-inflammatory cytokine (IL-10) was evaluated using lipopolysaccharide (LPS) induced RAW 264.7 cell culture model. The anti-arthritic activity was evaluated in a Complete Freund's Adjuvant (CFA) induced arthritic rat model. The optimized nanoemulgel (CUR + CYC NE gel) exhibited average globule size of 15.32 nm ±2.7 nm, poly-dispersity index of 0.181 ± 0.034 and zeta potential of −16.3 mV ± 0.9 mV. The cumulative drug release from ex-vivo diffusion studies on porcine ear skin was 99.189% ± 1.419% at the of 24 h and 99.177% ± 1.234% at the end of 18 h for CUR and CYC, respectively. The cell culture studies revealed that the formulation was able to significantly lower (p <.001) the levels of IL-6 and TNF-α, inhibited prostaglandin E2 (PGE2) while significantly elevating (p <.001) the levels of anti-inflammatory cytokine (IL-10). The gel was found to be non-irritating and showed the inhibition of paw edema and substantial reduction of arthritic symptoms in an arthritic rat model as compared to commercial and other conventional alternatives. This study highlights the potential of the developed nanoemulgel for the management of RA by enhancing the topical permeation of CUR and CYC. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme therapy remains a significant challenge since there is a lack of effective treatment for this cancer. As most of the examined gliomas express or overexpress cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptors γ (PPARγ), we decided to use these proteins as therapeutic targets. Toxicity, antiproliferative, proapoptotic, and antimigratory activity of COX-2 inhibitor (celecoxib—CXB) and/or PPARγ agonist (Fmoc-L-Leucine—FL) was examined in vitro on temozolomide resistant U-118 MG glioma cell line and comparatively on BJ normal fibroblasts and immortalized HaCaT keratinocytes. The in vivo activity of both agents was studied on C. elegans nematode. Both drugs effectively destroyed U-118 MG glioma cells via antiproliferative, pro-apoptotic, and anti-migratory effects in a concentration range 50–100 µM. The mechanism of action of CXB and FL against glioma was COX-2 and PPARγ dependent and resulted in up-regulation of these factors. Unlike reports by other authors, we did not observe the expected synergistic or additive effect of both drugs. Comparative studies on normal BJ fibroblast cells and immortalized HaCaT keratinocytes showed that the tested drugs did not have a selective effect on glioma cells and their mechanism of action differs significantly from that observed in the case of glioma. HaCaTs did not react with concomitant changes in the expression of COX-2 and PPARγ and were resistant to FL. Safety tests of repurposing drugs used in cancer therapy tested on C. elegans nematode indicated that CXB, FL, or their mixture at a concentration of up to 100 µM had no significant effect on the entire nematode organism up to 4th day of incubation. After a 7-day treatment, CXB significantly shortened the lifespan of C. elegans at 25–400 µM concentration and body length at 50–400 µM concentration. [ABSTRACT FROM AUTHOR]

This article examines the role of interleukin-18 (IL-18) in chronic arthritic systemic juvenile idiopathic arthritis (sJIA) compared to polyarticular juvenile idiopathic arthritis (pJIA). The study found that IL-18 had the highest ability to distinguish between chronic arthritic sJIA and pJIA. This research provides valuable insights into the development of more effective treatment strategies for chronic arthritic sJIA. The study also discusses the challenges of differentiating between the two types of arthritis in a clinical setting and suggests the potential use of IL-1 inhibitors as a treatment option for patients with high levels of IL-18. [Extracted from the article]

Objective: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. Methods: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. Results: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1β, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. Conclusion: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA. Key Points • The administration of berberine (BBR) dramatically alleviated the severity of CIA model with a decreased clinic score and joint inflammation. • BBR inhibited the pyroptosis of RA-FLS by downregulating of NLRP3 inflammasomes and activating the Hippo signaling pathway, contributing to the suppression of RA progress. [ABSTRACT FROM AUTHOR]

Background: Mammalian STE20-like kinase 1 (MST1) is involved in the occurrence of cancer and autoimmune diseases by regulating cell proliferation, differentiation, apoptosis and other functions. However, its role and downstream targets in rheumatoid arthritis (RA) remain unclear. Methods: The model of RA fibroblast-like synoviocytes (RA-FLSs) overexpressing MST1 was constructed by lentiviral transfection in vitro and analyzed the effects of MST1 on apoptosis, migration, invasion, and inflammation of RA-FLSs. The effect of MST1 on joint synovial membrane inflammation and bone destruction was observed in vivo by establishing a rat model of arthritis with complete Freund's adjuvant. Results: MST1 is down-regulated in RA-FLSs, and up-regulation of MST1 inhibits the survival, migration, invasion and inflammation of RA-FLSs. Mechanistically, MST1 inhibits SIRT3/mTOR-signaling pathway, inducing decreased mitochondrial autophagy and increased mitochondrial fission, resulting in mitochondrial morphological abnormalities and dysfunction, and ultimately increased apoptosis. We have observed that activation of MST1 alleviates synovial inflammation and bone erosion in vivo. Conclusions: MST1 reduces the survival, migration, invasion and inflammation of FLSs by inhibiting the SIRT3/mTOR axis to reduce mitochondrial autophagy and promote mitochondrial division, thereby achieving the potential role of relieving rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

To investigate the intervention effect of extracorporeal shock wave combined with manual traction on fixation‐induced knee contracture and its influence on PTEN‐PI3K/AKT signaling pathway. Thirty‐six SD male rats were randomly divided into six groups. The left knee joints were not fixed in the control group (C group). Rats in other groups underwent brace fixation in the extended position of the left knee. After 4 weeks of bracing, it is randomly divided into five groups: Model group (M group), natural recovery group (NR group), extracorporeal shock wave treatment group (ET group), manual traction group (MT group), and extracorporeal shock wave combined with manual traction group (CT group). Joint range of motion (ROM) of left knee was carried out to assess joint function. Hematoxylin and eosin (HE) staining and Masson staining were respectively used to assess the cell number and collagen deposition expression. Immunohistochemical staining and Western blot were used to assess protein levels of phosphatase and tensin homolog (PTEN), phosphatidylinositol 3‐kinase (PI3K), and protein kinase B (AKT). The combined therapy was more effective than extracorporeal shock wave therapy or manual traction alone against the joint ROM, cell number and the collagen deposition, low‐expression of PTEN, and overexpression of PI3K/AKT in the anterior joint capsule of rats with knee extension contracture. Extracorporeal shock wave combined with manual traction can promote the histopathological changes of anterior joint capsule fibrosis, upregulate the protein expression of PTEN and downregulate the protein expression of PI3K/AKT in the fibrotic joint capsule in a rat joint contracture model. [ABSTRACT FROM AUTHOR]

Drug repurposing is a strategy for discovering new applications of existing drugs for use in various diseases. Despite the use of structured networks in drug research, it is still unclear how drugs interact with one another or with genes. Prostate adenocarcinoma is the second leading cause of cancer mortality in the United States, with an estimated incidence of 288,300 new cases and 34,700 deaths in 2023. In our study, we used integrative information from genes, pathways, and drugs for machine learning methods such as clustering, feature selection, and enrichment pathway analysis. We investigated how drugs affect drugs and how drugs affect genes in human pancreatic cancer cell lines that were derived from bone metastases of grade IV prostate cancer. Finally, we identified significant drug interactions within or between clusters, such as estradiol-rosiglitazone, estradiol-diclofenac, troglitazone-rosiglitazone, celecoxib-rofecoxib, celecoxib-diclofenac, and sodium phenylbutyrate-valproic acid. [ABSTRACT FROM AUTHOR]

Arthritis is a major cause of disability. Currently available anti-arthritic drugs, such as disease-modifying anti-rheumatic drugs (DMARDs), have serious side-effects associated with long-term use. Triterpenoids are natural products with known anti-inflammatory properties, and many have revealed efficiency against arthritis both in vitro and in vivo in several animal models, with negligible cytotoxicity. However, poor bioavailability due to low water solubility and extensive metabolism upon oral administration hinder the therapeutic use of anti-arthritic triterpenoids. Therefore, drug delivery systems (DDSs) able to improve the pharmacokinetic profile of triterpenoids and achieve sustained drug release are useful alternatives for targeted delivery in arthritis treatment. Several DDSs have been described in the literature for triterpenoid delivery, including microparticulate and nanoparticulate DDSs, such as polymeric micro and nanoparticles (NPs), polymeric micelles, liposomes, micro and nanoemulsions, and hydrogels. These systems have shown superior therapeutic effects in arthritis compared to the free drugs and are similar to currently available anti-arthritic drugs without significant side-effects. This review focuses on nanocarriers for triterpenoid delivery in arthritis therapy, including osteoarthritis (OA), rheumatoid arthritis (RA) and gout that appeared in the literature in the last ten years. [ABSTRACT FROM AUTHOR]

Background: Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Background: Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Results: Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT2) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. Conclusions: NO/cGMP/KATP, 5HT3 and D2 pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test. [ABSTRACT FROM AUTHOR]

Synovial hypoxia-inducible factor 1α (HIF-1α) is a prospective therapeutic target for rheumatoid arthritis (RA). AMSP-30 m, a novel HIF-1α inhibitor, was reported to have notable anti-arthritic effects in rats with adjuvant-induced arthritis. However, its roles in inhibiting the pathogenic behaviors of fibroblast-like synoviocytes (FLS) and the involved mechanisms remain unknown. Here, AMSP-30 m inhibited proliferation and induced apoptosis in hypoxia-induced RA FLS (MH7A cell line), as evidenced by decreased cell viability, reduced Ki67-positive cells, G0/G1 phase arrest, lowered C-myc and Cyclin D1 protein levels, emergence of apoptotic nuclear fragmentation, raised apoptosis rates, and activation of caspase 3. Furthermore, AMSP-30 m prevented hypoxia-induced increases in pro-inflammatory factor production, MMP-2 activity, migration index, migrated/invasive cells, and actin cytoskeletal rearrangement. In vivo, AMSP-30 m alleviated the severity of rat collagen-induced arthritis (CIA). Mechanically, AMSP-30 m reduced HIF-1α expression and blocked sonic hedgehog (Shh) pathway activation in hypoxia-induced MH7A cells and CIA rat synovium, as shown by declines in pathway-related proteins (Shh, Smo, and Gli-1). Particularly, the combination of Shh pathway inhibitor cyclopamine enhanced AMSP-30 m's inhibitory effects on the pathogenic behaviors of hypoxia-stimulated MH7A cells, whereas the combination of Shh pathway activator SAG canceled AMSP-30 m's therapeutic effects in vitro and in CIA rats, implying a close involvement of Shh pathway inhibition in its anti-arthritic effects. We likewise confirmed AMSP-30 m's anti-proliferative role in hypoxia-induced primary CIA FLS. Totally, AMSP-30 m suppressed hypoxia-induced proliferation, inflammation, migration, and invasion of MH7A cells and ameliorated the severity of rat CIA via inhibiting Shh signaling. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to explore the potential components and mechanisms of Rhodiola rosea–Euonymus alatus drug pair (TY) that ameliorate rheumatoid arthritis (RA). Methods: The main active components, core targets, and important pathways of TY against RA were predicted by network pharmacology analysis. The binding activity between the main active components and the core targets was verified by the molecular docking technique. Collagen‐induced arthritis (CIA) rat model and tumor necrosis factor (TNF)‐α‐induced fibroblast‐like synovial cells in human RA (HFLS‐RA) model were established, respectively. The core targets were verified by cell counting kit‐8 assay, hematoxylin eosin, enzyme‐linked immunosorbent assay, real‐time polymerase chain reaction, and Western blot analysis, and the therapeutic effect of TY was evaluated. Results: A total of 18 possible components and 34 core targets were obtained by network pharmacology, among which inflammatory response, phosphatidylinositide 3‐kinases (PI3K)‐AKT and MAPK pathways were involved in the therapeutic effect of TY on RA. The results of molecular docking showed that kaempferol and quercetin had high binding affinity to interleukin (IL)‐1β, IL‐6, matrix metalloproteinase (MMP)9, and TNF‐α. In vivo and in vitro experiments showed that TY dose‐dependently inhibited the proliferation of HFLS‐RA cells induced by TNF‐α, and significantly reduced the paw swelling and arthritis scores in CIA rats. At the same time, TY inhibited the production of inflammatory factors in CIA rat serum and TNF‐α‐induced HFLS‐RA cells. It also decreased the expression of PI3K, phospho‐protein kinase B, MMP1, MMP3, MMP9, and increased the protein and mRNA levels of tissue inhibitors of MMPs (TIMP)1 in synovial tissue. Conclusion: TY can inhibit the PI3K/AKT signaling pathway and regulate the balance between MMPs and TIMP, thus playing a therapeutic role in RA. [ABSTRACT FROM AUTHOR]

Because of evident role of renin–angiotensin system in the etiology of rheumatoid arthritis, the current study's objective was to assess the anti-arthritic efficacy of ramipril through CFA-instigated arthritic model. The drug has been shown to have anti-inflammatory potential. CFA-instigated arthritic model assessed the anti-arthritic efficacy of ramipril by estimating different parameters, including paw volume, arthritic index scoring, haematological and biochemical attributes, histological and radiographic analyses, and various cytokines level. Ramipril significantly (p < 0.001) reduced paw volume and the arthritic index especially at the dose of 4mg/kg. The biochemical and haematological changes were likewise restored to normal by ramipril administration with an increase in anti-inflammatory cytokines while reducing pro-inflammatory cytokines level. Ramipril's ability to prevent arthritis by preserving the normal architecture of arthritis-induced joints is further supported by radiographic and histological investigation. The study's findings demonstrated ramipril's considerable anti-arthritic activity. To identify the precise mechanism of action, however, thorough mechanistic studies are still needed. [ABSTRACT FROM AUTHOR]

Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by the pathological occurrence of two opposite phenomena—osteoresorption and osteogenesis. Dickkopf-related protein 1 (DKK1) which inhibits the Wingless protein (Wnt) signalling pathway has been shown to be a master regulator of bone remodeling in inflammatory rheumatic diseases. However, the exact relationship between DKK1 serum level and bone remodelling is not clear. The goal of this study is to review state-of-the-art knowledge on the association of serum DKK1 with a bone remodelling in PsA. The MEDLINE-PubMed, EMBASE, Scopus, Web of Science and DOAJ databases were searched for appropriate papers. The English terms: 'DKK1', 'Dickkopf-1' 'Dickkopf related protein 1', 'psoriatic arthritis' and 'PsA' were used for search purposes. Eight original articles and two reviews were identified up to August 2023. In four out of 8 discussed studies DKK1 serum level was higher in PsA patients than in healthy controls [Dalbeth, p < 0.01; Diani, p < 0.001; Chung, p < 0.01; Abd el Hamid, p < 0.001)], it was comparable in another (Daousiss, p = 0.430) and was lower in two (Fassio2017, p < 0.05; Fassio2019, p < 0.05). In one study, the comparative groups included patients with axial spondyloarthritis, where DKK1 serum levels were lower in PsA groups [Jadon, peripheral PsA, p = 0.01]. The true relative serum concentration of DKK1 in PsA, as well as its influence on osteogenesis and osteoresorption, is still equivocal. Further studies on this matter with consistent and stringent methodology are warranted. [ABSTRACT FROM AUTHOR]

Background: Maresin1 (MaR1) is a potent lipid mediator that exhibits significant anti-inflammatory activity in the context of several inflammatory diseases. A previous study reported that MaR1 could suppress MSU crystal-induced peritonitis in mice. To date, the molecular mechanism by which MaR1 inhibits MSU crystal-induced inflammation remains poorly understood. Methods: Mousebone marrow-derived macrophages (BMDMs) were pretreated with MaR1 and then stimulated with FAs (palmitic, C16:0 and stearic, C18:0) plus MSU crystals (FAs + MSUc). In vivo, the effects of MaR1 treatment or Prdx5 deficiency on MSUc induced peritonitis and arthritis mouse models were evaluated. Results: The current study indicated that MaR1 effectively suppressed MSUc induced inflammation in vitro and in vivo. MaR1 reversed the decrease in Prdx5 mRNA and protein levels induced by FAs + MSUc. Further assays demonstrated that MaR1 acceleratedPrdx5 expression by regulating the Keap1-Nrf2 signaling axis. Activation of AMPK by Prdx5 improved homeostasis of the TXNIP and TRX proteins and alleviated mitochondrial fragmentation. In addition, Prdx5 overexpression inhibited the expression of CPT1A, a key enzyme for fatty acid oxidation (FAO). Prdx5 protected against defects in FA + MSUc induced FAO and the urea cycle. Conclusion: MaR1 treatment effectively attenuated MSUc induced inflammation by upregulating Prdx5 expression. Our study provides a new strategy by which Prdx5 may help prevent acute gout attacks. [ABSTRACT FROM AUTHOR]

We investigated the anti-ulcer activity of ethanol extracts of Polygonum cognatum on indomethacin induced gastric damage in rats. We evaluated the number of ulcer areas, oxidant and antioxidant parameters as well as histopathologic features in rat stomach. We measured the total antioxidant status of P. cognatum in concentrations from 1.56–100 mg/ml. P. cognatum extract inhibited indomethacin induced ulcer formation with an effect similar to a 20 mg/kg dose of the standard anti-ulcer drug, esomeprazole. All doses of P. cognatum extract exhibited positive effects on oxidative stress markers and histopathological features in the stomach tissue of rats. We suggest that the antioxidant activity of P. cognatum extract may be responsible for its gastroprotective effect and that P. cognatum extract may be a useful gastroprotective agent. [ABSTRACT FROM AUTHOR]

Objective: Nanoparticles (NPs) hold a great promise in combating rheumatoid arthritis, but are often compromised by their toxicities because the currently used NPs are usually synthesized by chemical methods. Our group has previously fabricated Ångstrom-scale silver particles (AgÅPs) and demonstrated the anti-tumor and anti-sepsis efficacy of fructose-coated AgÅPs (F-AgÅPs). This study aimed to uncover the efficacy and mechanisms of F-AgÅPs for arthritis therapy. Methods: We evaluated the efficacy of F-AgÅPs in collagen-induced arthritis (CIA) mice. We also compared the capacities of F-AgÅPs, the commercial AgNPs, and the clinical drug methotrexate (MTX) in protecting against K/BxN serum-transfer arthritis (STA) mice. Moreover, we evaluated the effects of F-AgÅPs and AgNPs on inflammation, osteoclast formation, synoviocytes migration, and matrix metalloproteinases (MMPs) production in vitro and in vivo. Meanwhile, the toxicities of F-AgÅPs and AgNPs in vitro and in vivo were also tested. Results: F-AgÅPs significantly prevented bone erosion, synovitis, and cartilage damage, attenuated rheumatic pain, and improved the impaired motor function in mouse models of CIA or STA, the anti-rheumatic effects of which were comparable or stronger than AgNPs and MTX. Further studies revealed that F-AgÅPs exhibited similar or greater inhibitory abilities than AgNPs to suppress inflammation, osteoclast formation, synoviocytes migration, and MMPs production. No obvious toxicities were observed in vitro and in vivo after F-AgÅPs treatment. Conclusions: F-AgÅPs can effectively alleviate arthritis without notable toxicities and their anti-arthritic effects are associated with the inhibition of inflammation, osteoclastogenesis, synoviocytes migration, and MMPs production. Our study suggests the prospect of F-AgÅPs as an efficient and low-toxicity agent for arthritis therapy. [ABSTRACT FROM AUTHOR]

The collagen antibody-induced arthritis (CAIA) model is highly effective in inducing arthritis, making it an attractive model for screening therapeutic compounds such as glucocorticoids (GCs). The severity of discomfort in this model makes it desirable to administer analgesics, but it is a prerequisite that these do not interfere with the model or tested therapeutics. In the present study, we studied the effect of 1 mg/mL tramadol and 3.5 mg/mL paracetamol (TP) on CAIA in male BALB/cAnNCrl mice and the possible interference of TP analgesia with the activity of the GC drug prednisolone (Pred). Our results showed that TP abolished the Pred-induced amelioration of CAIA, as well as several other Pred-induced effects, such as the reduction in thymus weight and the increase in insulin level. This most likely results from the effects of TP on the hepatic metabolism of this drug, since it strongly increased the Cyp3a11 expression in the liver. Altogether, we conclude that TP analgesia is not suitable for the CAIA model in male BALB/cAnNCrl mice, in particular when evaluating the effects of GCs such as Pred. [ABSTRACT FROM AUTHOR]

Background: Ethnopharmacological relevance: Derris brevipes (benth.) Baker is widely used as an anti-arthritic agent in traditional medicine. Aims and Objectives: This study evaluated the anti-inflammatory activity of ethanolic extract of D. brevipes (EEDB) leaves, a member of the Leguminosae family in vitro and ex vivo. Materials and Methods: The EEDB leaves of was screened for anti-inflammatory activities by protein denaturation analysis and proteinase inhibition analysis. Prednisolone was used as the standard. EEDB (at doses of 300 mg/kg and 600 mg/kg) was administered through the oral route. Ex vivo analysis was performed by estimating the expression of tumor necrosis factor-alpha (TNF-a) in collagen (chicken sternal collagen)-induced arthritis (CIA) in Sprague-Dawley rats using the reverse transcription polymerase chain reaction method. The data were analyzed using one-way analysis of variance, followed by Dunnet's multiple comparison tests. Results: Prednisolone (100 mcg/mL) and EEDB (600 mcg/mL) showed percentage inhibition of 80.32% and 80.04%, respectively, in protein denaturation assay. Similarly, prednisolone (600 mcg/mL) and EEDB (600 mcg/mL) showed 66.03% and 56.69% inhibition in the proteinase activity. Synovial tissue TNF-a levels showed a significant decrease in EEDB-treated groups and prednisolone-treated group compared to CIA control rats. Conclusion: From this study, it was concluded that the D. brevipes leaf extract possesses anti-inflammatory activity, which explains its beneficial role in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Endogenous glucocorticoids and commonly used oral glucocorticoids have the property of existing in an inactive and active form in vivo. The inactive form can be converted back to the active form, or ‘recycled’ in cells and tissues that express the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. This recycling provides an important contribution to the action of glucocorticoids. This review examines the literature relating to the importance of 11β-HSD1 activity during glucocorticoid treatment, with an emphasis on studies examining bone and joint disease and the ability of glucocorticoids to suppress inflammatory damage in models of arthritis. Animal models with global or selective deletion of 11β-HSD1 have determined the extent to which this recycling is important in normal physiology and during treatment with oral glucocorticoids. These studies demonstrate that 11β-HSD1-mediated recycling of inactive glucocorticoids has a substantial action and indeed is responsible for the majority of the effects of orally administered glucocorticoids on a range of tissues. Importantly, the anti-inflammatory actions of glucocorticoids appear largely through this mechanism such that mice that lack 11β-HSD1 are resistant to the anti-inflammatory actions of glucocorticoids. The recognition that to a large extent the circulating inactive counterpart of these glucocorticoids is more important to anti-inflammatory effects than the active glucocorticoid presents novel opportunities to more selectively target glucocorticoids to tissues or to reduce the likely side effects. [ABSTRACT FROM AUTHOR]

Background: Derris brevipes is a common medicinal plant used in the traditional system of medicine as an anti-arthritic agent. Aims and Objectives: The present study was to evaluate the anti-arthritic activity of ethanolic extract of D. brevipes (EEDB) leaves, belonging to the family Leguminosae. Materials and Methods: The dried leaves were collected and extracted using 95% ethanol, and the extract was subjected to a preliminary phytochemical screening. In vivo activities were evaluated in collagen (chicken sternal collagen)-induced arthritis (CIA) in Sprague–Dawley rats. Prednisolone was used as the standard, and EEDB (at doses of 300 mg/kg and 600 mg/kg) was administered through the oral route. Body weight measurement, arthritic score, histological score, and radiology score assessments were carried out. Results: Preliminary phytochemical screening of leaf extract from D. brevipes showed the presence of components such as steroids, triterpenoids, and flavonoids. In vivo tests on CIA rats given the extract showed that it could lower the arthritic score, the paw volume, the radiological score, and the histological score. Conclusion: From this study, it is concluded that the D. brevipes leaf extract possesses antiarthritic activity. [ABSTRACT FROM AUTHOR]

Objective: This experiment explored the function of TTC4 in rheumatoid arthritis inflammation and its possible mechanism. Methods: C57BL/6 mice were immunized intradermally with bovine type II collagen. Lipopolysaccharide induction was performed on RAW264.7 cells. Results: The mRNA expression of TTC4 in articular tissue of mice with rheumatoid arthritis was downregulated. Sh‐TTC4 virus increased arthritis score, morphological change score, paw edema, and spleen index, as well as alkaline phosphatase level in mice with rheumatoid arthritis. Sh‐TTC4 virus increased the levels of inflammatory factors and MDA, and decreased anti‐oxidant factors in articular tissue of mice with rheumatoid arthritis. TTC4 reduced inflammation and oxidative stress in an in vitro model. TTC4 regulated HSP70 in a rheumatoid arthritis model. The inhibition of HSP70 reduced the effects of sh‐TTC4 gene in mice with rheumatoid arthritis. METTL3 reduced the stability of the TTC4 gene. Conclusion: In this study, the TTC4 gene reduced oxidative response and inflammation in the rheumatoid arthritis model through the HSP70/NLRP3 pathway. Therefore, it can be concluded that TTC4 can be used as diagnosis and prognosis evaluation of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

The present study was carried out to determine the phytochemical constituents, physicochemical values, antioxidant activity and in-vitro anti-inflammatory activity of Rheum nobile Hook.f & Thomson according to the standard pharmacopoeial method, which is traditionally used by the indigenous communities of the Sikkim Himalayan region for the treatment of rheumatoid arthritis. The phytochemical investigation revealed the presence of various secondary metabolites such as flavonoids, tannins, phenols, steroids, phlobatannins, saponins, anthraquinones and glycosides. The in-vitro antiinflammatory activity of the plant extract assessed by HRBC membrane stabilisation and protein denaturation methods is found to effectively inhibit HRBC haemolysis and protein denaturation in a dose-dependent manner. The present finding provides evidence for the antioxidant and anti-inflammatory activity of the plant extract, which approves the traditional statements of Rheum nobile as an anti-arthritic agent. [ABSTRACT FROM AUTHOR]

The current study was aimed to investigate the beneficial effect of sumatriptan, a 5‐hydroxytryptamine 1B/1D (5HT1B/1D) receptor agonist, on gastric ulcer in rats via stimulating 5HT1B/1D receptors and suppressing pro‐inflammatory cytokines. Rats were allocated into three models of gastric ulcer: indomethacin (30 mg/kg, PO), water immersion restraint stress (WRS) and ethanol (5 ml/kg PO). Animals were administered with sumatriptan (0.01, 0.1, 0.3 and 1 mg/kg, i.p) 30 min before gastric ulcer induction. GR‐127935 (0.01 mg/kg, i.p, a selective 5HT1B/1D antagonist) was administered 30 min before sumatriptan (0.1 mg/kg) injection. Macroscopic assessments (J‐score), ELISA analysis of tumour necrosis factor‐alpha (TNF‐α) and interleukin‐1beta (IL‐1β) and histopathological changes were performed on the rat's stomach tissues. Gastric ulcer induction in three models caused an increase in J‐score, TNF‐α, IL‐1β and microscopic features. Sumatriptan (0.1 mg/kg) significantly improved gastric injury induced by indomethacin, WRS and ethanol through the reduction in the J‐score, TNF‐α, IL‐1β and microscopic lesions. Concurrent administration of GR‐127935 (0.01 mg/kg) with sumatriptan (0.1 mg/kg) reversed the gastroprotective effect of sumatriptan in three models. Sumatriptan possessed gastroprotective effects on indomethacin‐, WRS‐ and ethanol‐induced gastric damage in rats via the possible involvement of the 5HT1B/1D receptors. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to assess the incidence of hematologic malignancy (HM) among inflammatory arthritis (IA) patients receiving tumor necrosis factor inhibitors (TNFi) compared with the general Turkish population. Methods: HUR-BIO (Hacettepe University Rheumatology Biologic Registry) is a single-center biological disease-modifying anti-rheumatic drug (bDMARD) registry since 2005. Patients with IA, including rheumatoid arthritis, spondyloarthritis, or psoriatic arthritis who had at least one visit after the TNFi were screened from 2005 to November 2021. Standardized incidence rates (SIR) were calculated after adjustment for age and gender and compared with the 2017 Turkish National Cancer Registry (TNCR). Results: Of the 6139 patients registered in the HUR-BIO, 5355 used any TNFi at least once. The median follow-up duration was 2.6 years for patients receiving TNFi. Thirteen patients developed a HM on follow-up. In these patients, the median age at the IA onset was 38 (range, 26–67), and the median age at the HM diagnosis was 55.5 (range, 38–76). Patients using TNFi had an increased HM incidence (SIR 4.23, 95% confidence interval (CI) 2.35–7.05). Ten patients with HM were under 65 years of age. In this group, there was a higher incidence of HM in both men (SIR 5.15, 95% CI 1.88–11.43) and women (SIR 4.76, 95% CI 1.74–10.55). Conclusions: The risk of HMs in inflammatory arthritis patients receiving TNFi was four times higher than in the general Turkish population. [ABSTRACT FROM AUTHOR]

Transdermal route has become a most favorable routes for the delivery of drugs from last few years. It conquered many disadvantages occurred with the oral route of drug delivery system such as major drawbacks is first pass metabolism. To overcome this limitation transdermic delivery system has been developed but the drug which can be delivered through transdermal route are facing barriers because few drugs' particles are unable to penetrate through stratum corneum efficiently. To overcome this challenge our scientist and researchers have developed a new system known as ultra deformable vesicle system (UDV). In this system the drug molecule either synthetic or herbal is incorporated into vesicles which can easily penetrate deeper into skin for targeted drug delivery. Among Transferosomes and Ethosomes Transethosomes is a novel prospect for enhanced transdermal drug delivery through skin. The effective penetrability of nanotransethosomes is due to ethanol, edge activator and phospholipids. There are different methods are there for the preparation of nanotransethosomes like hot method, cold method, transmembrane pH gradient method, ethanol injection method and thin film hydration method. The UDV can be utilized for the delivery of numerous classes of drugs such as anti-arthritic, antibiotic, anticancer, antiviral and analgesic through transdermal route. [ABSTRACT FROM AUTHOR]

Arthritis is an inflammatory disease that affects the joints. Patients suffering from chronic pain are anxious, which contributes to reducing the quality of life. The development of analgesic compounds with anxiolytic properties could prove to be of great interest for the treatment of chronic pain. The objective of the present study was to evaluate the analgesic and anxiolytic properties of the aqueous extract of the bark of the trunk of Diospyros mespiliformis in arthritic mice. Arthritis was induced by injection of 1% formaline into the left hind paw of the animals. Inflammatory pain and comorbid anxiety were tested using a hotplate (55 ± 0.5 °C) and labyrinths (Dark and Light and the open arena), respectively. The aqueous extract of Diospyros mespiliformis reduced the inflammatory process by inhibiting the edema of the legs of animals to a maximum percentage of 63.63 % (minimum of 8.82%) as well as the significant increase (p < 0.001) of the threshold of nociception at the dose of 100 mg/kg. A significant increase (p < 0.001) in the time spent in the lighted compartment alongside the decrease in the time spent in the dark environment was observed with the two-compartment maze. In the open arena the time spent in the central plaza significantly (p < 0.001) increased compared to the time spent on the edge. In addition, a significant decrease (p < 0.01) in the frequency of grooming and training was observed. The aqueous extract of the bark of the trunk of Diospyros mespiliformis displayed beneficial effects on pain and anxiety, justifying it traditional use for the management of arthritis. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to synovial inflammation, pannus formation, cartilage damage, bone destruction, and ultimate disability. Fibroblast-like synoviocytes (FLS) are involved in the pathogenetic mechanism of RA. Cdc37 (cell division cycle protein 37) is regarded as a molecular chaperone involved in various physiological processes such as cell cycle progression, cell proliferation, cell signal transduction, tumorigenesis, and progression. However, the precise role of Cdc37 in the pathogenesis of rheumatoid arthritis (RA) remains uncertain. In our study, we found that Cdc37 expression was upregulated in human rheumatoid synovia in contrast with the normal group. Interestingly, Cdc37 activated the ERK pathway to promote RA-FLS proliferation and migration in vitro. Ultimately, in vivo experiments revealed that silencing of Cdc37 alleviated ankle swelling and cartilage destruction and validated the ERK signaling pathways in vitro findings. Collectively, we demonstrate that Cdc37 promotes the proliferation and migration of RA-FLS by activation of ERK signaling pathways and finally aggravates the progression of RA. These data indicated that Cdc37 may be a novel target for the treatment of RA. [ABSTRACT FROM AUTHOR]

We aimed to compare a transient receptor potential vanilloid 2 (TRPV2) agonist with a TNF inhibitor, and to test the potential of their combination in collagen-induced arthritis (CIA) as a potential future strategy for rheumatoid arthritis (RA). Following the onset of CIA DBA1/j mice were started on treatment with either vehicle, etanercept (8 mg/kg three times a week), the TRPV2 agonist O1821 (20–30 mg/kg/day), or a combination of both. Mice were scored over a 61-day period. Synovial tissues were obtained for RNA sequencing. Mice on monotherapy with either O1821 or etanercept developed milder clinical disease. The O1821 protection was observed at an earlier time-point than in the etanercept group. The combination therapy group achieved a more robust and sustained reduction in disease severity than either monotherapy group. All treatment groups had reduced scores for synovial inflammation, synovial hyperplasia, and erosive changes, compared with controls, with the combination group achieving the most significant protection. RNA sequencing and pathway analyses of synovial tissues identified pathways and processes regulated by the TRPV2 agonist, such as chemotaxis and cytokine receptor signaling, including IL6R. The combination therapy affected additional pathways not seen in the monotherapy groups. In conclusion, the TRPV2 agonist achieved an overall similar reduction in arthritis severity and histology scores as etanercept, but the combination therapy achieved a more sustained disease control and more pronounced reduction in joint damage, suggesting a potential future option for improving disease control in RA. RNA sequencing analyses identified new pathways regulated by TRPV2, and also by the combination treatment. [ABSTRACT FROM AUTHOR]

Background: The ongoing epidemic of prescription opiate abuse is one of the most pressing health issues in the United States today. Consequently, analgesic adjuncts, such as multimodal drug regimens and regional anesthetic blocks (like transversus abdominis plane (TAP) block), have been introduced to the perioperative period in hopes of decreasing postoperative opiate use. However, the effect of these interventions on intraoperative opiate use has not been examined. We hypothesized that preoperative TAP block would be associated with decreased intraoperative opiate use during minimally invasive cholecystectomy. Methods: This was a retrospective review of patients undergoing minimally invasive cholecystectomy between June 2018 and January 2021. Perioperative data, operative times, and medication administration data were collected. Intraoperative opiate use was calculated in total morphine equivalent doses (MED) for each patient and adjusted for operative time. Univariate analysis and multivariate linear regression were performed to determine factors affecting intraoperative opiate requirements. Results: 261 patients were included in this study, of which 62 (23.8%) received preoperative TAP block and 199 (76.2%) did not. Preoperative TAP block was associated with decreased intraoperative opiate use (0.199 vs 0.312, p < 0.001), while there were no statistically significant differences associated with other analgesic adjuncts including preoperative acetaminophen (p = 0.485), celecoxib (p = 0.112), gabapentin (p = 0.165), or intraoperative ketorolac (p = 0.200). On multivariate analysis, preoperative TAP block was independently associated with decreased intraoperative opiate use (< 0.001), while chronic cholecystitis on final pathology was associated with increased intraoperative opiate use (p = 0.002). Conclusion: The use of preoperative TAP block was associated with decreased intraoperative opiate use during minimally invasive cholecystectomy and should be considered for routine use. Future research should investigate whether preoperative TAP blocks and a subsequent decrease of intraoperative opiates, also result in a decrease in postoperative opiate use and improvements in postoperative outcomes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of levofolinic acid (LVF) administered 48 h before methotrexate (MTX) in reducing gastrointestinal side effects without interference with drug efficacy. Methods: A prospective observational study was performed including patients with Juvenile Idiopathic Arthritis (JIA) reporting significant gastrointestinal discomfort after MTX despite taking a dose of LVF 48 h after MTX. Patients with anticipatory symptoms were excluded. A LVF supplemental dose was added 48 h before MTX and patients were followed every 3–4 months. At each visit data on gastrointestinal symptoms, disease activity (JADAS, ESR, CRP values) and treatment changes were collected. Friedman test for repeated measures analyzed differences between these variables over time. Results: Twenty-one patients were recruited and followed for at least 12 months. All patients received MTX subcutaneously (mean 9.54 mg/m2) and LVF 48 h before and after MTX (mean 6.5 mg/dose), 7 received a biological agent too. Complete remission of gastrointestinal side effects was reported in 61.9% of study patients at first visit (T1) and increased over time (85.7%, 95.2%, 85.7% and 100% at T2, T3, T4, T5, respectively). MTX efficacy was maintained as showed by significant reduction of JADAS and CRP (p = 0.006 and 0.008) from T1 to T4 and it was withdrawn for remission in 7/21. Conclusions: LVF given 48 h before MTX significantly reduced gastrointestinal side effects and did not reduce drug's efficacy. Our results suggest that this strategy may improve compliance and quality of life in patients with JIA and other rheumatic diseases treated with MTX. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) displays very similar characteristics to those of tumor cells, platycodin D (PD) is a triterpenoid saponin abundant in Platycodon grandiflorum (PG), plays an important role in the inhibition of tumor growth. Our previous experiments confirmed that PD inhibited MH7A cell proliferation and migration, but it's possible mechanism remain unclear. This study aimed to reveal the mechanism of PD on RA, based on network pharmacology analysis. Rat of CIA was treated with the different doses PD. The arthritis score and paw volume were evaluated, ankle imaging changes were observed via myosseous ultrasound, all rats were anaesthetized by intraperitoneal injection of 25% urethane (1 mL/100 g), and ankle histopathology was observed using hematoxylin and eosin (HE) staining. Cell (MH7A) Counting Kit 8 (CCK8) was used to measure cell activity, and JC-1 assay kit and flow cytometry were employed to examine the cell mitochondrial membrane potential and apoptosis. The expression levels of Sonic hedgehog (Shh) signaling pathway-related proteins were observed by Western blotting. Cell inflammation levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 being determined via enzyme-linked immunoassay ELISA and q-PCR. In total, the saponin PD significantly improves joint synovium inflammation and apoptosis in CIA rats. The activity of administered MH7A was significantly inhibited, the mitochondrial membrane potential decreased, the expression level of the Shh signaling pathway-related protein SuFu increased, the expression levels of SHh and Gli decreased, and cell serum levels of TNF-a and IL-6 decreased significantly. Therefore, PD exhibits therapeutic potential for synovial hyperplasia in RA. [ABSTRACT FROM AUTHOR]

Nanomedicine has emerged as an important approach for targeting RA medication. Rheumatoid arthritis (RA) is a widespread autoimmune disorder marked by multiple inflamed joints. Gold nanoparticles (GNPs) have been demonstrated as efficacious nanocarriers due to their unique characteristics and the relative simplicity of their synthesis in varied sizes; moreover, they have the capability to alleviate several inflammatory markers. The current objective was to combine methotrexate (MTX) with GNPs to overcome MTX restrictions. GNPs were fabricated by a chemical reduction technique, utilizing sodium citrate and tween 20. The MTX-GNPs formulations were characterized in vitro by % entrapment efficiency (%EE), particle size, polydispersity index (PDI) zeta potential, and % release. The MTX-GNPs formulation was administrated as an intra-articular solution, and additionally, incorporated into a Carbopol gel to investigate its anti-arthritic effectiveness and bioavailability in vivo. The results indicated that a %EE of 87.53 ± 1.10%, and a particle size of 60.62 ± 2.41 nm with a PDI of 0.31 ± 0.03, and a zeta potential of −27.80 ± 0.36 mV were optimal. The in vitro release of MTX from the MTX-GNPs formulation demonstrated that the MTX-GNPs formulation's release was 34.91 ± 1.96% and considerably (p < 0.05) lower than that of free MTX, showing a significant difference in dissolution patterns (p < 0.05). In vivo, MTX-GNPs formulations inhibited IL-6 by 36.52%, ACCP (63.25 %), COMP (28.16%), and RANKL (63.67%), as well as elevated IL-10 by 190.18%. Transdermal MTX-GNPs decreased IL-6 by 22.52%, ACCP (56.63%), COMP (52.64%), and RANKL (79.5%), as well as increased IL-10 by 168.37%. Histological investigation supported these recent findings. Conclusions: Marked improvements in MTX anti-arthritic effects are seen when it is conjugated to GNPs. [ABSTRACT FROM AUTHOR]

Glucose 6-phosphate isomerase (G6PI) is an indicator to assist in diagnosis of rheumatoid arthritis (RA) and monitor the disease. It also plays a key role in proliferating RA synovial tissues, pannus formation, and invasion and destruction of articular cartilage. In this study, we synthesized nanoparticles targeting G6PI (siG6PI-MSN) using mesoporous silica nanocarriers (MSN) and small interfering RNA (siRNA), followed by identifying the characteristics and functions, and preliminarily exploring their application in the treatment of RA in vivo with a type II collagen-induced arthritis (CIA) rat model. It showed that the synthetic functionalized carrier had a regular pore structure and a specific volume and surface area. No obvious hemolysis or toxicity of the carrier was found when its concentration was below 100 µg/ml. Cytological results in vitro suggested that siG6PI-MSN significantly inhibited G6PI expression and reduced the ability of proliferation, migration, and invasion of FLSs, compared with the siNC-MSN group. In vivo results in the CIA rat model showed that the arthritis index and degree of joint swelling among rats in the siG6PI-MSN-treatment group were significantly lower than those in the control group. Moreover, the number of FLSs in Synovium and the levels of TNF α and IL-1 β were also significantly decreased in the siG6PI-MSN group. Histopathology of the synovial tissue and cartilage revealed siG6PI-MSN treatment significantly reduced the pathological manifestations of arthritis. In conclusion, siG6PI-MSN effectively suppresses the proliferation and invasive growth of synovial tissue and improve joint swelling and inflammatory infiltration, thereby preventing joint damage in RA. This carrier may be a new therapeutic measure for RA, with potential social and economic benefits. Mesoporous silica nanocarriers were used as the carriers, and small interfering RNA (siRNA) to synthesize nanoparticles targeting G6PI (siG6PI-MSNs). siG6PI-MSNs effectively suppress the proliferation and invasive growth of synovial tissue and improve joint swelling and inflammatory infiltration, thereby preventing joint damage in RA. Mesoporous silica nanocarriers were used as the carriers, and small interfering RNA (siRNA) to synthesize nanoparticles targeting G6PI(siG6PI-MSN). siG6PI-MSN effectively suppresses the proliferation and invasive growth of synovial tissue and improve joint swelling and inflammatory infiltration, thereby preventing joint damage in RA. [ABSTRACT FROM AUTHOR]

Ornamental plants often gain relevance not only for their decorative use, but also as a source of phytochemicals with interesting healing properties. Herein, spontaneous Centranthus ruber (L.) DC. and Tropaeolum majus L., mainly used as ornamental species but also traditionally consumed and used in popular medicine, were investigated. The aerial parts were extracted with methanol trough maceration, and resultant crude extracts were partitioned using solvents with increasing polarity. As previous studies mostly dealt with the phenolic content of these species, the phytochemical investigation mainly focused on nonpolar constituents, detected with GC-MS. The total phenolic and flavonoid content was also verified, and HPTLC analyses were performed. In order to explore the potential antiarthritic and anti-obesity properties, extracts and their fractions were evaluated for their anti-denaturation effects, with the use of the BSA assay, and for their ability to inhibit pancreatic lipase. The antioxidant properties and the inhibitory activity on the NO production were verified, as well. Almost all the extracts and fractions demonstrated good inhibitory effects on NO production. The n-hexane and dichloromethane fractions from T. majus, as well as the n-hexane fraction from C. ruber, were effective in protecting the protein from heat-induced denaturation (IC50 = 154.0 ± 1.9, 270.8 ± 2.3 and 450.1 ± 15.5 μg/mL, respectively). The dichloromethane fractions from both raw extracts were also effective in inhibiting pancreatic lipase, with IC50 values equal to 2.23 ± 0.02 mg/mL (for C. ruber sample), and 2.05 ± 0.02 mg/mL (T. majus). Obtained results support the traditional use of these species for their beneficial health properties and suggest that investigated plant species could be potential sources of novel antiarthritic and anti-obesity agents. [ABSTRACT FROM AUTHOR]

Background: To treat the joint pain arial part of Asparagus officinalis (asparagus) has historically been used. However, its efficacy for rheumatoid arthritis has not been pharmaceutically evaluated. We explore the phytochemical analysis anti-inflammatory, analgesic and anti-arthritic activity of petroleum ether, ethanol and aqueous extracts of Asparagus officinalis aerial part. Materials and Methods: Tail- flick method was used to evaluate the analgesic activity anti-inflammatory activity was carried out using paw oedema induced with carrageenan and CFA induced arthritic model was used to evaluate the potential in anti- arthritic activity in rats. The Petroleum ether, ethanolic and aqueous extracts were dosed orally in three divided doses (75, 150 and 300 mg/ kg). For anti- inflammatory and analgesic activity diclofenac sodium at 10 mg/kg was used as standard, whereas in anti-arthritic model prednisolone at 5 mg/kg and methotrexate at 0.5 mg/ kg were used as standard. One-way ANOVA followed by Dunnett’s multiple range test were used to analyse statistical significance between means. Results: The results revealed a dosecontrolled anti-inflammatory, anti-arthritic effect with different extracts whereas at some extent analgesic activity was observed. Four compounds were present and confirmed by LCMS/MS. The CFA model's findings showed improved defence against arthritic lesions and changes in body weight. Additionally, Asparagus officinalis significantly improved rheumatoid factor, changed WBCs, and favourably altered radiographic and histological alterations. Conclusion: The findings indicate that Asparagus officinalis is a strong anti-arthritic and anti-inflammatory compound that may be suggested for the treatment of both chronic and acute inflammation. [ABSTRACT FROM AUTHOR]

Arthritis comes under the bandwagon of one of the most menacing diseases that are known to mankind and the more concerning matter is unavailability of permanent cure for this condition. The conditions of severe joint inflammation are being treated with conventional therapeutics that imparts a range of adverse effects, which prompted the researchers to look for safer options in the form of herbal medicines. Numerous plants, their parts, extracts, and their phyto-isolates have been explored till date for their anti-arthritic potential. However, there are risks of stability and delivery issues with these plant products, hence limiting their utility for effective therapy in the management of inflammatory diseases. Nanotechnology based herbal medicines may overcome the delivery limitation of various natural products utilizing the multi and versatile properties of various nanoparticles. This review reports the herbal anti-arthritic drugs, challenges associated with them, and pharmacodynamics/ pharmacokinetics of anti-arthritic herbal nanomedicines. [ABSTRACT FROM AUTHOR]

Objectives: National health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies' evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences.Methods: Interviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted.Results: Acceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements.Conclusions: Differences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed. [ABSTRACT FROM AUTHOR]

Pterostilbene is a stilbene flavonoid that occurs naturally in various plants as well as produced by genetic engineering. It exhibits anti-inflammatory, analgesic, anti-oxidant and neuroprotective activities. This research was aimed to determine the potential of pterostilbene against arthritis and peripheral neuropathy in Complete Freund's Adjuvant (CFA) induced arthritis. Rat hind paw was injected with 0.1 ml CFA to induce arthritis. Standard control animals received oral methotrexate (3 mg/kg/week). Pterostilbene at 12.5, 25 and 50 mg/kg was given orally to different groups of arthritic rats from day 7–28 for 21 days. Pterostilbene significantly reduced paw diameter and retarded the decrease in body weight of arthritic rats. It profoundly (p < 0.05–0.0001) reduced lipid peroxidation and nitrites, while increased superoxide dismutase (SOD) in the liver tissue. Pterostilbene treatment significantly (p < 0.0001) reduced TNF-α and IL-6 levels. Pterostilbene markedly improved (p < 0.05–0.001) motor activity and showed analgesic effect in arthritic rats at 25 and 50 mg/kg as compared to disease control rats. Furthermore, it notably (p < 0.05–0.0001) increased SOD activity, nitrites, noradrenaline and serotonin levels in the sciatic nerve of arthritic rats. Treatment with pterostilbene also ameliorated the CFA-induced pannus formation, cartilage damage and synovial hyperplasia in the arthritic rat paws. It is determined from the current study that pterostilbene was effective in reducing CFA-induced arthritis in rats through amelioration of oxidative stress and inflammatory mediators. It was also effective to treat peripheral neuropathy through modulation of oxidative stress and neurotransmitters in sciatic nerves. [ABSTRACT FROM AUTHOR]

Background: Diclofenac etalhyaluronate (DF-HA) is a recently developed analgesic conjugate of diclofenac and hyaluronic acid that has analgesic and anti-inflammatory effects on acute arthritis. In this study, we investigated its analgesic effect on osteoarthritis, using a rat model of monoiodoacetate (MIA).Methods: We injected MIA into the right knees of eight 6-weeks-old male Sprague-Dawley rats. Four weeks later, rats were randomly injected with DF-HA or vehicle into the right knee. Seven weeks after the MIA injection, fluorogold (FG) and sterile saline were injected into the right knees of all the rats. We assessed hyperalgesia with weekly von Frey tests for 8 weeks after MIA administration. We took the right knee computed tomography (CT) as radiographical evaluation every 2 weeks. All rats were sacrificed 8 weeks after administration of MIA for histological evaluation of the right knee and immunohistochemical evaluation of the DRG and spinal cord. We also evaluated the number of FG-labeled calcitonin gene-related peptide (CGRP)-immunoreactive(ir) neurons in the dorsal root ganglion (DRG) and ionized calcium-binding adapter molecule 1 (Iba1)-ir microglia in the spinal cord.Results: Administration of DF-HA significantly improved pain sensitivity and reduced CGRP and Iba1 expression in the DRG and spinal cord, respectively. However, computed tomography and histological evaluation of the right knee showed similar levels of joint deformity, despite DF-HA administration.Conclusion: DF-HA exerted analgesic effects on osteoarthritic pain, but did not affect joint deformity. [ABSTRACT FROM AUTHOR]

Objective: To discover a novel peptoid antagonist that targets the interleukin‐15 (IL‐15) receptor and to evaluate its therapeutic efficacy in the treatment of inflammation and arthritis. Methods: A new compound (IFRA3, interleukin‐15 receptor antagonist 3) was discovered using a unique on‐bead two‐colour combinatorial cell screening of a peptoid library. The interaction of IFRA3 with IL‐15 receptor was assessed by in vitro pull‐down and thermal shift assays. The efficacy of IFRA3 in treating inflammation and arthritis was evaluated in mouse models. Results: IFRA3Q1 (a tetrameric derivative of IFRA3) inhibited the activity of IL‐15 and suppressed CTLL‐2 cell proliferation (which depends on IL‐15 activity). IFRA3Q1 exhibited strong in vivo anti‐inflammatory activity in carrageenan‐induced inflammation in mice. Furthermore, IFRA3Q1 inhibited collagen‐induced arthritis in DBA/1J mice. Conclusion: By binding to and inhibiting the function of IL‐15 receptor, IFRA3Q1 exhibited significant anti‐arthritis activity. Our findings suggest that IFRA3Q1 represents a new paradigm for arthritis therapy by targeting IL‐15 signalling. [ABSTRACT FROM AUTHOR]

Objective: The excessive proliferation of fibroblast-like synoviocytes (FLSs) is a key inducement for the occurrence and development of rheumatoid arthritis (RA). Hypoxia inducible factor-α (HIF-α) accumulation is involved in the regulation of cell biological functions in the hypoxic microenvironment of synovium. This study aimed to investigate the roles of HIF-α and its level regulator prolyl hydroxylases (PHDs) in FLSs proliferation and to explore the regulatory effect of geniposide (GE). Materials and methods: Adjuvant arthritis rats and RA-FLSs cell line MH7A were taken as the research objects. MH7A cells were incubated in a hypoxic chamber with 2% O2 for hypoxia treatment. CCK-8, FACS, EdU and Western blot assays were performed to evaluate MH7A cells proliferation. Iron assay was conducted to determine intracellular Fe2+ level. Results: MH7A cells proliferation was significantly enhanced under hypoxia, accompanied by an increase of HIF-1α level. Decreased HIF-1α level by PX-478 inhibited MH7A cells proliferation. Furthermore, PHD2 was highly expressed in vivo and in vitro, and played a key role in modulation of HIF-1α protein level, which was confirmed by PHD2 inhibitor IOX4 and proteasome inhibitor MG132. GE treatment alleviated synovial hyperplasia in AA rats and inhibited MH7A cells proliferation with a reduction in HIF-1α level. Fe2+ acts as an enzymatic cofactor to control PHD2 activity. Iron assay showed that GE reversed the decline of Fe2+ level in MH7A cells under hypoxia. Conclusion: GE attenuates abnormal proliferation of RA-FLSs via inhibiting HIF-1α accumulation through enhancement of PHD2 activity. [ABSTRACT FROM AUTHOR]

Indomethacin is a widely used nonsteroidal anti-inflammatory drug; however, its clinical utility is accompanied by serious adverse reactions including peptic ulcers. The current study aims to investigate the protective potential of perindopril against indomethacin-induced gastric injury in rats. Perindopril (4 mg/kg) was administered orally for 7 days and indomethacin (60 mg/kg, single oral dose) was administered on the 7th day, 1 h after perindopril administration. Pantoprazole was used as a standard agent. Ulcer index (UI), preventive index ratio (PI), histopathological examination, oxidative stress, and inflammatory biomarkers were investigated. Perindopril significantly decreased UI while increased PI and counteracted histopathological aberrations induced by indomethacin. It alleviated indomethacin-induced oxidative stress by lowering NO while increasing GSH content and superoxide dismutase activity. Perindopril significantly downregulated TNF-α and asymmetric dimethylarginine (ADMA), while significantly upregulated COX-2, PGE-2, dimethylarginine dimethylaminohydrolase-1 (DDAH-1), ANG-(1-7), and ACE-2 expression. Together, these findings suggest the gastroprotective effects of perindopril through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling. Perindopril attenuated gastric histopathological damage. It increased GSH content and SOD activity while decreased NO content. It modulated gastric ADMA and DDAH-1 activity. It reduced TNF-α, while increased COX-2 and PGE-2 expression. It upregulated ACE-2 activity and ANG-(1-7) protein expression. [ABSTRACT FROM AUTHOR]

Fibrotic changes in the infrapatellar fat pad (IFP) are involved in the pathogenesis of knee osteoarthritis (KOA). HIF-1α is a transcription factor that is activated during hypoxia and is suggested to play a role in fibrosis in various organs. However, its participation in the fibrotic changes in IFP remains unclear. Therefore, we investigated the role of HIF-1α in IFP fibrosis using a carrageenan-induced KOA rat model and evaluated the potential of low-intensity pulsed ultrasound (LIPUS) as a novel treatment for KOA. A rat model was prepared by intra-articular injection of 0.5% carrageenan (50 µl) using 8-week-old male Wistar rats. Fibrosis of the IFP was evaluated histologically by hematoxylin and eosin and Sirius Red staining at 1 and 2 weeks after intra-articular injection. The mRNA expression levels of HIF-1α and fibrosis-related molecules, CTGF and VEGF, were analyzed using reverse transcription-quantitative PCR, and the DNA binding activity of HIF-1α was assessed using a binding assay. In addition, the effect of irradiation with LIPUS on the fibrosis of IFP was verified. Histological studies demonstrated a significant increase in the fibrosis of IFP 1 and 2 weeks after intra-articular injection of carrageenan, accompanied by overexpression of CTGF and VEGF, which was followed by upregulation of transcriptional activation of HIF-1α. Moreover, intervention with LIPUS for 2 weeks after injection of carrageenan attenuated fibrosis of IFP, accompanied by a significant reduction in the transcriptional activation of HIF-1α and decreased the gene expression levels of HIF-1α, CTGF, and VEGF. The present study demonstrated that activation of HIF-1α promoted fibrosis of IFP in carrageenan-induced arthritis in rats and that intervention with LIPUS decreased the activity of HIF-1α and inhibited fibrosis. These results suggest that LIPUS may serve as a novel approach for the treatment of KOA, through its modulation of HIF-1α. [ABSTRACT FROM AUTHOR]

Snail slime is used widely in African traditional medicine, specifically in Nsukka Enugu, Nigeria, for wound management; however, this claim lacks scientific validation. Herein, we investigated the gastroprotective effect of aqueous Achatina achatina L. (snail) slime extract (ASSE) on indomethacin- and ethanol-induced ulceration in Wistar albino rat models. Biochemical analysis of ASSE showed appreciable levels of manganese, iron, zinc, copper, molybdenum, selenium, Vitamin C, B1, B2, and B3 and a basic pH. The experimental design consists of two Phases (five groups of five rats each). In both Phases, group I (positive control) received 3ml of distilled water, while groups II-V received 20 mg/kg body weight omeprazole (standard drug), 50, 100, and 200 mg/kg bw ASSE, respectively, via oral intubation. The various treatments lasted for 21-days. Following 24-hours fasting with access to only water (which spanned between the 22nd -23rd day), ulceration was induced separately on the experimental animals in Phase I with a single oral dose of indomethacin (30 mg/kg bw) and in Phase II with a single oral dose of acidified ethanol (1.5 ml/kg bw), via the gastric gavage. The LD50 study showed safety up to 5000 mg/kg bw ASSE. After induction, a significant (P<0.05) increase in the number of ulcers and mean ulcer index were recorded in group 1 of both Phases; however, rats administered various concentrations of ASSE showed significant (P<0.05) amelioration of the ulceration in both Phases, and these were on par with the standard control. These results suggest that aqueous snail slime extract possesses gastroprotective potential. [ABSTRACT FROM AUTHOR]