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The effects of curcumin on selected immune cells involved in the course of rheumatoid arthritis.

The effects of curcumin on selected immune cells involved in the course of rheumatoid arthritis.

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Rheumatoid arthritis (RA) is a widespread chronic autoimmune disorder affecting the joints, causing irreversible cartilage, synovium, and bone degradation. During the course of the disease, many immune and joint cells are activated, causing inflammation. Immune cells including macrophages, lymphocytes, neutrophils, mast cells, natural killer cells,...

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... there is no cure available for rheumatoid arthritis, currently, the research is aimed at minimizing inflammation, pain, and joint damage, enhancing remission of symptoms, and improving the quality of life. Many studies have found that curcumin has a prominent effect on different immune cells and inflammatory mediators (Figure 1). Curcumin is a polyphenolic substance naturally occurring in turmeric, especially in Curcuma Longa, with broad anti-inflammatory properties and proven positive effects in autoimmunological disease therapies, including RA. Curcumin is an antioxidant, which means it can efficiently reduce the level of reactive oxygen species (ROS), weaken redox signaling, and reduce inflammation [22]. ...

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... Curcumin (CUR) (1,7-Bis [4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5,dione) is a natural polyphenolic phytochemical with anti-inflammatory, antioxidant, wound healing and anticancer activities, freely able to cross the BBB and regulate the CNS microenvironment, offering neuroprotective potency in various CNS diseases, with increased glutathione, HO-1, Nrf2 activation and suppressed activation of mediators such as NF-kB, COX-2, iNOS, IL-1, IL-2, IL-6 and C-reactive protein (CRP), by activated macrophages [66,67]. Furthermore, it prevents BBB disruption, induced by Th17 cells, and activates antioxidant heat shock proteins 70, sirtuins and thioredoxin [68,69]. ...
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... The progression of RA is evidently correlated with the serum levels of various cytokines, chemokines, and growth factors [10]. Cytokines are important in RA pathogenesis because they regulate a spectrum of inflammatory processes; the imbalance between pro-and anti-inflammatory cytokines in rheumatoid joints favors the induction of autoimmunity and chronic inflammation, leading to joint destruction [11]. Besides elevated levels of pro-inflammatory cytokines, high oxidative stress has been identified as a major cause of joint damage in RA [12]. ...
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... 54 Similarly, treatment with curcumin effectively downregulates the activation of the proinflammatory mammalian target of rapamycin pathway in synoviocytes and suppresses signal transducer and activator of transcription 1 (STAT1) signaling to reduce B cell activity in mice with collagen-induced arthritis as well as inhibits COX-2 expression and induces apoptosis in primary canine chondrocytes. 55 Furthermore, treatment with curcumin also decreases the expression of interleukin (IL)-1β, IL-6, IL-8, IL-17, IL-18, and TNF-α in animal models of RA. 55 In mouse models of experimental autoimmune encephalomyelitis, curcumin targets inflammatory monocytes and prevents their trans endothelial migration across the blood-brain barrier through inhibition of the NF-κB pathway as well as the expression of the cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and macrophage-1 antigen. 56 Treatment with curcumin reduces the numbers of splenic T and B cells by downregulating the expression of NF-κB, AKT, and extracellular signal-regulated kinase (ERK) 1/2 and Bcl2 in rodents. ...
... 54 Similarly, treatment with curcumin effectively downregulates the activation of the proinflammatory mammalian target of rapamycin pathway in synoviocytes and suppresses signal transducer and activator of transcription 1 (STAT1) signaling to reduce B cell activity in mice with collagen-induced arthritis as well as inhibits COX-2 expression and induces apoptosis in primary canine chondrocytes. 55 Furthermore, treatment with curcumin also decreases the expression of interleukin (IL)-1β, IL-6, IL-8, IL-17, IL-18, and TNF-α in animal models of RA. 55 In mouse models of experimental autoimmune encephalomyelitis, curcumin targets inflammatory monocytes and prevents their trans endothelial migration across the blood-brain barrier through inhibition of the NF-κB pathway as well as the expression of the cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and macrophage-1 antigen. 56 Treatment with curcumin reduces the numbers of splenic T and B cells by downregulating the expression of NF-κB, AKT, and extracellular signal-regulated kinase (ERK) 1/2 and Bcl2 in rodents. ...
... Rheumatoid arthritis is distinguished by persistent systematic inflammation and enlargement of synovium that causes destruction and ablation of articular, cartilage, and bone [5]. FLS cells, via the secretion of different inflammatory mediators, play a main role in initiating and perpetuating rheumatoid arthritis pathogenesis [26]. Furthermore, these cells are resistant to apoptosis, mainly because of overexpression of apoptosis protein inhibitors, and they are responsible for hyperplasia [27]. ...
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This study aimed to evaluate the potential of mesenchymal stem cell–derived exosomes loaded with curcumin (Curc-Exos) as an effective therapeutic strategy for rheumatoid arthritis through modulation of proliferation and inflammatory response in HIG-82 synovial cells. For this purpose, Exos were isolated and characterized with BCA protein assay, DLS, FE-SEM, and TEM. The Curc was embedded by mixing it with Exos in a 1:4 ratio. It was found that the Curc stability has improved after loading on Exos compared to the free Curc. Besides, the in vitro studies using LPS-stimulated HIG-82 synovial cells indicated the efficiency of Curc-Exos in enhancing cytotoxicity and apoptosis compared to the free Curc treatment. It was also revealed that Curc-Exos significantly could reduce the expression levels of anti-apoptotic proteins IAP1 and IAP2 and inflammatory mediators including IL-6, TNF-α, MMP1, and PGE2. This preliminary study confirmed the suitability of Curc-Exos in counteracting the proliferation and inflammatory response of rheumatoid arthritis synovial fibroblasts in vitro.
... Similarly, in rheumatoid arthritis (RA), an osteo-autoimmune disease caused by cartilage depletion in inflamed joints, osteoclast stimulation of bone resorption is CD4+ cell-mediated [15]. Consistently, accumulation of T cells in the synovial fluid promotes osteoclastogenesis secreting interleukin-17 (IL-17), which induces the expression of Receptor activator of nuclear factor kappa-Β ligand (RANKL) in synovial fibroblasts and increases local inflammation [16]. ...
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... Interestingly, curcumin was used in LPS-activated RAW 264.7 macrophages model to observe the anti-inflammatory activity. However, it was observed that curcumin promoted macrophage apoptosis and inhibited NF-κB activation [78][79][80]. In one study, anti-inflammatory activity on synovial fibroblasts was demonstrated based on CIA-induced rheumatoid arthritis model in rat, where curcumin inhibited COX-2 and subsequently blocked prostaglandin E2 synthesis, and it also inhibited synovial cell proliferation and other inflammatory mediators, like IL-1β, NF-κB, and TNF-α [81,82]. ...
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... Rheumatoid arthritis (RA) is one of the most widespread diseases in the form of chronic inflammation, affecting about 1% of the total global population, with yet not fully understood pathogenesis [1][2][3][4]. This autoimmune condition is characterized by various burdensome symptoms including pain, swelling, and stiffness in joints of hands, wrists, knees and feet, greatly reducing the comfort of life. ...
... RA seems to be more of a set of different, case-dependent pathological conditions, leading to common symptoms varying in course and severity between patients [9], thus making the development of personalized therapy even more tedious. The development of this disorder would not be possible without communication of immune cells with those localized within the joint, of which synoviocytes seem to play a crucial role [4]. ...
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Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases, affecting approximately 1% of the total global population. Curcumin, a natural polyphenol is a substance that could potentially mitigate the course of this disease. To evaluate curcumin’s anti-inflammatory impact on synoviocytes in the RA model, a set of experiments was conducted on SW982 cells, stimulated by IL-1β, IL-6, or TNF-α to emulate inflammation. During the research, the curcumin effect was evaluated by measuring cell survivability, expression of MMP1 gene, subcellular localization of P70S6K1 protein, and its phosphorylated form and amount of produced IL-6 and TNF-α. Results of conducted experiments presented a positive impact of curcumin on synoviocytes in the RA model, by reducing SW982 cells’ survivability, decreasing levels of MMP1 gene expression and TNF-α protein production, which altogether confirm beneficial effects of the curcumin therapy in a RA in vitro model.
... Interestingly, curcumin was used in LPS-activated RAW 264.7 macrophages model to observe the anti-inflammatory activity. However, it was observed that curcumin promoted macrophage apoptosis and inhibited NF-κB activation [78][79][80]. In one study, anti-inflammatory activity on synovial fibroblasts was demonstrated based on CIA-induced rheumatoid arthritis model in rat, where curcumin inhibited COX-2 and subsequently blocked prostaglandin E2 synthesis, and it also inhibited synovial cell proliferation and other inflammatory mediators, like IL-1β, NF-κB, and TNF-α [81,82]. ...
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Chronic inflammation and oxidative damage have been proven as fundamental factors associated with many systemic diseases, leading to increased morbidity. To deal with this, formulation of new functional foods, dietary polyphenols, and supplements containing multiple natural antioxidants and/or anti-inflammatory agents is required to reduce oxidative stress and inflammatory cascade. Several studies have shown a positive association between increased intake of dietary antioxidants and reduced risk for chronic inflammatory diseases and oxidative stress. This chapter concentrates on the underlying mechanisms of how different groups of dietary antioxidants, like vitamin C, vitamin E, flavonoids, carotenoids, and plant polyphenols, prevent the processes of inflammation and oxidative stress responses. Oxidative stress and inflammation mechanisms are discussed in the light of critical balance of pro- and anti-inflammatory cytokines. Also, roles of dietary antioxidants were discussed as an adjunctive treatment strategy to COVID-19 patients. Given the convincing evidence for protective as well as curative role of dietary antioxidants in inflammatory processes, more detailed understanding on the effects of nutrients on multiple aspects and development of novel anti-inflammatory agents is required to optimize approaches. To improve the bioavailability and targeted delivery of external antioxidants, nonreactive carriers or vehicles are needed to be designed with more precision and accuracy.
... It was demonstrated that administration of recombinant human IL-2 (rhIL-2) at or just before disease onset exacerbated the disease (days 21-28 after the first immunization), whereas rhIL-2 administered before disease onset (days 14-21 after the first immunization) inhibited the CIA. It was concluded that the indirect suppressive effect was mediated by IFN-γ because in mice treated with an anti-IFN-γ Ab, both early and late IL-2 administration exacerbated the CIA [198]. In addition, IL-2/anti-IL-2 monoclonal antibody immune complexes have been reported to inhibit murine CIA. ...
... As for IFN-γ, according to a recent study, CD8+ T cells are the dominant source of IFN-γ, which activates CD4 + T cells, synovial fibroblasts, and monocytes/macrophages. Monocytes/macrophages produce INF-γ, which enhances osteoclastogenesis leading to joint damage in RA [12,198] Histopathological examination of joints has revealed inhibition of synovial cell proliferation and lower levels of IL-17, IL-6, and TNF-α [11]. Although these data may reflect the usage of different types of IL-2, they may also reflect a change in the cytokine cascade in the mouse CIA model between the onset stage and the later stage. ...
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Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-7, IL-17, IL-21, IL-23, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1β, IL-18, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.