Composition for the effective management of fibroblastoid synovial cell-mediated rheumatoid arthritis

Abstract

The disclosed invention relates to methods and compositions for use in inhibiting the proliferation and migration of fibroblast-like synoviocytes (FLS) in a subject. The invention also relates to T-helper 17 (T h 17) also discloses a composition and method for regulating imbalances in T cells. The disclosed composition contains 20-50% BDMC, 10-25% DMC by mass, and 30-50% curcumin by mass, and further contains boswellic acid and polysaccharides in the ranges of 35-50% by mass and 35-45% by mass, respectively.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is a PCT application claiming priority to U.S. Provisional Patent Application No. 63126920, filed on 17 December 2020, the contents of which are incorporated herein by reference. The present invention generally relates to methods and compositions for inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in a subject. The present invention also relates to T-Helper 17(T h 17) Compositions and methods for regulating imbalances in T cells are also disclosed. More specifically, the present invention discloses compositions comprising 20-50% BDMC, 10-25% by mass DMC, and 30-50% by mass curcumin, further comprising boswellic acid and polysaccharides from Boswellia serrata. [Background technology]

[0002] Rheumatoid arthritis (RA) is an autoimmune synovial disease caused by a complex interaction of genetic and environmental factors, resulting in synovial inflammation and joint damage. Fibroblast-like synovial cells (FLS) are mesenchymal cells located within the synovial membrane, the soft tissue lining the space of movable joints, tendon sheaths, and synovial bursae (Nygaard, G., Firestein, GS Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat Rev Rheumatol 16, 316-333 (2020)). FLS in the synovial intima lining play a major role in the production of cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. The intima lining layer is composed of two cell types: type A, or macrophage-like synovial cells, and type B, or FLS. The role of FLS, located in the lining layer of the synovial intima, is to regulate the composition of the extracellular matrix (ECM) and synovial fluid, which lubricates and nourishes the cartilage surface. Various studies have shown that in rheumatoid arthritis (RA), type A cells become dominant, generating pro-inflammatory cytokines, chemokines, and growth factors, which in turn activate local FLS, inducing the production of IL-6, prostanoids, and matrix metalloproteinases (MMPs). This process leads to the destruction of the extracellular matrix, triggered by the autocrine / paracrine network, perpetuating synovitis. It has also been documented that RA promotes FLS survival and prevents deletion through apoptosis (Bartok B, Firestein GS: Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010; 233:233-255). Regulatory T cells (Treg) / T-helper 17 (T h17) The balance between cells is linked to the progression of RA. Th17 cells mediate pro-inflammatory responses by secreting IL-17A and TNF-α, which contribute to tissue destruction and articular cartilage damage, while Treg cells mediate anti-inflammatory responses and maintain a state of autoimmune tolerance. This imbalance is thought to be the underlying cause of several autoimmune diseases, including multiple sclerosis, atherosclerosis, and SLE (Li, C. et al. (Arsenic trioxide improves Treg and Th17 balance by modulating STAT3 in treatment-naive rheumatoid arthritis patients. Int. Immunopharmacol. 73, 539-551, 2019)). Furthermore, current treatments for RA using synthetic disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs, either individually or in combination, offer therapeutic strategies but exhibit significant side effects, including hypersensitivity reactions, particularly immune-related ones. Considerable research efforts have been made in this area to discover effective and non-immunomodulatory therapeutic targets (Kohler et al. Current Therapeutic Options in the Treatment of Rheumatoid Arthritis, J. Clin. Med. 8, 1-15 (2019)).

[0003] Rizaldy et al. have shown that extracts of Curcuma longa and Boswellia serrata have therapeutic benefits in osteoarthritis (Rizaldy et al. A randomized Controlled Trial of Curcuma Longa and Boswellia Serrata Extract in Osteoarthritis. Global Journal of Medical Research: H Orthopedic and Musculoskeletal System 19(3)), but this paper does not clarify the pathways and factors that govern this activity. Furthermore, targeting isolated joints in osteoarthritis is entirely different from targeting several joints in rheumatoid arthritis (RA). Svensson et al. reaffirmed that combination therapy, including TNF inhibitors and non-immunomodulatory anti-FLS techniques involving Fc-Ig1 and Ig2, was effective against arthritis with better efficacy and fewer side effects (Svensson et al. Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal. Sci. Adv. 6, eaba4353, Pgs. 1-17 (2020)).

[0004] Shaikh et al. demonstrated that curcumin had a higher anti-inflammatory effect compared to other curcuminoids in the treatment of rheumatoid arthritis. Furthermore, they showed that DMC and BDMC interfered with the effects of curcumin in turmeric (Shaikh et al. Does Curcumin Analogues, Demethoxycurcumin and Bisdemethoxycurcumin (BDMC), Enhance the Therapeutic efficacy of Curcumin in the Treatment of Rheumatoid Arthritis (RA), Nat. Prod. Chem. 8(6), Pgs. 1-9, 2020). Makuch et al. provide a comprehensive review of curcumin for RA, but highlight that its mechanism of action and effects on cell populations require further research (The Immunomodulatory and Anti-Inflammatory Effect of Curcumin on Immune Cell Populations, Cytokines, and In Vivo Models of Rheumatoid Arthritis, Pharmaceuticals, 14, Pgs. 1-18, 2021). Kloesch et al. showed that treatment of FLS with high concentrations of curcumin resulted in a dramatic decrease in cell viability and induced apoptosis. However, the molecular mechanism of curcumin remained unclear (kloesch et al. Anti-Inflammatory and Apoptotic Effects of the Polyphenol Curcumin on Human Fibroblast-like Synoviocytes, 15, Pgs. 400-405 (2013)).

[0005] WO 2021 / 090154 includes a combination treatment for osteoarthritis encompassing withanolide-enriched ashwagandha, BDMC-enriched curcumin, and AKBA-enriched Boswellia. However, this does not include the non-immunomodulatory FLS pathway. Similarly, AU2010 / 345338 B2 contains a synergistic composition comprising Boswellia extracts and Curcuma species for use in inflammatory conditions, including arthritis, but does not contain any specific pathway. Essentially, there is an unmet need for safer, less toxic, and more effective treatments for RA that can work in conjunction with current methods to improve disease control without suppressing the immune system. Furthermore, if treatments are based on natural herbs, many of the side effects associated with the immunomodulatory effects of RA treatments can be overcome. [Overview of the project]

[0006] Objective of the present invention A primary object of the present invention is to disclose methods and compositions for use in inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in a subject, comprising individual concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid (B), or polysaccharides (PS). Another object is to disclose methods and compositions for use in inhibiting the proliferation and migration of fibroblast-like synovial cells in a subject, comprising compositions of concentrated BDMC curcuminoids and BPS. A further main object of the present invention is to administer compositions comprising individual concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides to T-helper 17(T) in the spleen of mammals. h 17) and methods and compositions for use in regulating imbalances in T cells (Tregs). Another objective is to disclose methods and compositions for use in regulating imbalances in mammals, including T-helper 17 (T) cells, using compositions comprising a combination of concentrated BDMC curcuminoids and BPS. h 17) To disclose methods and compositions for use in alleviating imbalances in T cells (Tregs). Another main object of the present invention is to disclose methods and compositions for use in the therapeutic management of rheumatoid arthritis in mammals, the methods comprising administering a composition comprising individual concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides. Another object is to disclose methods and compositions for use in the therapeutic management of rheumatoid arthritis in mammals, the methods comprising administering a composition comprising a combination of concentrated BDMC curcuminoids and BPS.

[0007] overview This invention relates to the inhibition of FLS proliferation and migration in a target, and to the T-helper 17(T) in mammalian spleen, using BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides individually, or in combination with a concentrated BDMC curcuminoid composition and boswellic acid polysaccharide. h 17) By including methods and compositions for use in regulating imbalances in T cells (Tregs), the aforementioned problems mentioned in the background art are broadly addressed. A first aspect of the present invention relates to compositions for use in inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in a subject, comprising individual concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides. Compositions comprising a combination of concentrated BDMC curcuminoids and BPS are also included.

[0008] A further aspect of the present invention relates to T-helper 17(T) in mammalian spleen, comprising individual concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides. h 17) and includes compositions for use in regulating imbalances in T cells (Treg). It also includes administering a combination of concentrated BDMC curcuminoids and BPS. Another aspect of the present invention encompasses compositions for use in the therapeutic management of rheumatoid arthritis in mammals, comprising individual concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides. It also encompasses the administration of a combination of concentrated BDMC curcuminoids and BPS. Another aspect of the present invention comprises a method for inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in mammals, comprising the step of contacting mammalian FLS with a composition comprising BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides at individual concentrations. The invention also comprises a composition comprising a combination of concentrated BDMC curcuminoids and BPS. A further aspect of the present invention is a) T-Helper 17(T h 17) The process of introducing T-Helper 17(T) into the spleen of mammals comprises the steps of: a) identifying mammals having a Treg imbalance, and b) administering a composition comprising individual concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, and polysaccharides. h 17) This includes methods for regulating T cell (Treg) imbalances. It also includes compositions comprising a combination of concentrated BDMC curcuminoids and BPS.

[0009] Yet another aspect of the present invention encompasses a method for the therapeutic management of rheumatoid arthritis in a subject, comprising: a) identifying a subject having rheumatoid arthritis; and b) administering a composition comprising BDMC, DMC, curcumin, curcuminoid, boswellic acid, or polysaccharide at individual concentrations. Compositions comprising a combination of concentrated BDMC curcuminoid and BPS are also encompassed. The broader scope of the present invention will become apparent from the following detailed description. However, the following detailed description and specific examples, while indicating preferred embodiments of the invention, should not be construed as limitations on the invention, and various changes and modifications, such as varying the concentration range of the samples used, derivatives / analogues of curcuminoids, BPS, experimental conditions, selection of mammals, etc., are within the skill of those in the art and are well within the spirit and scope of the invention from this detailed description.

[0010] The patent or patent application file contains at least one drawing created in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fees.

Brief Description of the Drawings

[0011] [Figure 1] It is a diagram showing immunostaining of vimentin in FLS. [Figure 2] It is a diagram showing immunostaining of vimentin in FLS. [Figure 3] It is a diagram showing concentration-dependent inhibition of FLS proliferation using 10, 20, and 40 μg / mL of AC3. At 20 and 40 μg / ml, P < 0.01 compared to FLS control. [Figure 4] It is a diagram showing the percentage of inhibition of AC3 in a dose-dependent manner at 10, 20, and 40 μg / mL. At 20 and 40 μg / ml, P < 0.01 compared to FLS control. [Figure 5] It is a diagram showing the comparative effect of inhibition of FLS proliferation by any of curcuminoid, AC3, C3, and BPS. Except for BPS, P < 0.01 compared to FLS control. [Figure 6] This figure shows the effects of AC3 and BPS on inhibiting FLS proliferation. For both AC3 combinations and combinations, P<0.01 compared to the FLS control. [Figure 7] This figure shows the cell cycle inhibition by curcuminoids, AC3, C3, and BPS. [Figure 8] This figure shows the percentage of cells in the S phase after treatment with curcuminoids, AC3, C3, or BPS. [Figure 9] This figure shows the percentage of cells treated with AC3, BPS individually, and as a combination. [Figure 10] This figure shows cell cycle inhibition using FACS for untreated cells (Figure 10), curcumin (Figure 11), BDMC (Figure 12), DMC (Figure 13), AC3 (Figure 14), C3 (Figure 15), BPS (Figure 16), each at 40 and 80 μg / mL (Figure 17), and combinations of AC3 and BPS at 10 and 40 μg / mL (Figure 18). [Figure 11] Same as above [Figure 12] Same as above [Figure 13] Same as above [Figure 14] Same as above [Figure 15] Same as above [Figure 16] Same as above [Figure 17] Same as above [Figure 18] Same as above [Figure 19] This figure shows the Bax / Bcl2 ratios suggestive of apoptosis promotion using any of the following combinations: curcuminoids, AC3, C3, BPS, and AC3+BPS. P<0.01 compared to FLS controls with AC3, Cur, and BDMC. P<0.05 with DMC and AC3+BPS. [Figure 20]Figures 20, 21, 22, 23, 24, and 25 show the migration and infiltration of FLS in a migration assay when treated with 15 μg / mL of control, BDMC, curcumin, DMC, AC3, C3, and C3, respectively, as well as BPS (Figure 26), AC3 (10 μg / mL, Figure 27), BPS (40 μg / mL, Figure 28), and a combination of AC3 and BPS (10 + 40 μg / mL, Figure 29). Figures 30 and 31 show the percentage of inhibition of migration. [Figure 21] Same as above [Figure 22] Same as above [Figure 23] Same as above [Figure 24] Same as above [Figure 25] Same as above [Figure 26] Same as above [Figure 27] Same as above [Figure 28] Same as above [Figure 29] Same as above [Figure 30] Same as above [Figure 31] Same as above [Figure 32] This figure shows arthritis scores when treated with a control, an RA control, a celecoxib control, curcuminoids, AC3, C3, BPS, and a combination of AC3+BPS. p<0.05 and **P<0.01. [Figure 33] This figure shows the modulating effects on Th17 (Figure 33), Treg (Figure 34), and the Th17 / Treg ratio (Figure 35) when treated with control, RA, celecoxib, AC3, BPS, and a combination of AC3+BPS. FACS studies of normal (Figure 36), AC3 (50 mg / kg, Figure 37), AC3 (100 mg / kg, Figure 38), BPS (40 mg / kg, Figure 39), AC3+BPS (50+40 mg / kg, Figure 40), AC3+BPS (100+40 mg / kg, Figure 41), and celecoxib (Figure 42). [Figure 34] Same as above [Figure 35] Same as above [Figure 36] Same as above [Figure 37] Same as above [Figure 38] Same as above [Figure 39] Same as above [Figure 40] Same as above [Figure 41] Same as above [Figure 42] Same as above [Modes for carrying out the invention]

[0012] Selected definition All terms used in this application have their ordinary meanings as known in the prior art, unless otherwise specified. Several other specific definitions used in this invention are described below and apply throughout this specification. The claims provide a broader definition unless otherwise specified.

[0013] In this application, any reference to a sample refers to any one or combination of the following agents that produce a therapeutic effect. Agents generally refer to any one of curcumin, bisdemethoxycurcumin, and demethoxycurcumin, i.e., curcuminoids, or their combination when appropriately mentioned. A concentrated BDMC composition refers to a curcuminoid composition containing at least 20% by mass of BDMC. More specifically, AC3 refers to a composition containing 20 - 50% by mass of bisdemethoxycurcumin, 10 - 25% by mass of demethoxycurcumin, and 30 - 50% by mass of curcumin. The C3 complex is enriched in curcumin and consists of 75 - 81% curcumin, 15 - 19% demethoxycurcumin, and 2.2 - 6.5% bisdemethoxycurcumin. Boswellic acid is a natural extract isolated from Boswellia serrata as disclosed in US60 / 268,713, and PS is a polysaccharide from the gum resin of Boswellia serrata. Specifically, whenever reference is made to boswellic acid (B), this refers to a total boswellic acid content of 35 - 50% by mass, standardized to contain 20 - 30% by mass of β-boswellic acid and 12% by mass of 3-acetyl-11-keto-β-boswellic acid (AKBA). Whenever reference is made to polysaccharide (PS), this refers to a polysaccharide (PS) content of 35 - 45% by mass and contains neutral sugars consisting of galactose, arabinose, and D-glucuronic acid. (The Boswellia serrata composition is commercially available as Boswellin® PS from Sami-Sabinsa Group Limited, Bangalore, India)

[0014] To therapeutically manage or manage refers to a state that effectively alleviates the conditions disclosed in the present invention. Any reference to a control in this specification refers to either untreated, RA control, or celecoxib control depending on the experiment, including the examples, and whenever appropriate, the details of the control are mentioned. The present invention generally relates to the inhibition of the proliferation and migration of fibroblast-like synoviocytes, and T-helper 17 (T h17) and methods and compositions for use in regulating imbalances in T cells (Tregs). Compositions comprising a combination of concentrated BDMC curcuminoids and BPS are also included. The present invention also includes methods for the therapeutic management of rheumatoid arthritis in subjects using the aforementioned compositions. In its most preferred embodiment, the present invention discloses a composition for use in inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in a subject, comprising concentrated bisdemethoxycurcumin (BDMC) present in an amount of 20% by mass or more.

[0015] In another preferred embodiment of the present invention, the present invention relates to T-helper 17 (T) in mammalian spleen containing 20% ​​by mass or more of bisdemethoxycurcumin (BDMC). h 17) Disclosed a composition for use in regulating T cell (Treg) imbalance. In a relevant aspect of this embodiment, the imbalance is T compared to the RA control in 3.5. h The ratio of 17 / Treg is preferably 1, or more preferably T h Assuming the ratio of 17 / Treg is between 0 and 1 (Figure 35), T h This was regulated by reducing 17 cells and increasing T cells (Treg) (Figures 33-35, Example 9), resulting in performance nearly equivalent to that of the 0.5 celecoxib control (Figure 35). In yet another preferred embodiment of the present invention, the present invention discloses a composition for use in the therapeutic management of rheumatoid arthritis in mammals, comprising concentrated bisdemethoxycurcumin (BDMC) present in 20% by mass or more. In a relevant aspect of this embodiment, the management of rheumatoid arthritis in mammals involves inhibition of the proliferation and migration of fibroblast-like synovial cells, and T-helper 17 (T) in the mammalian spleen. h This is achieved by regulating imbalances in 17) and T cells (Treg), reducing levels of inflammatory markers, and promoting apoptosis. In relevant aspects of this embodiment, improvement in arthritis score is achieved. This is achieved by inhibition and migration of fibroblast-like synovial cells, and T-helper 17 (T h17) The extent and details of the regulation of imbalances in T cells (Tregs), reduction of inflammatory marker levels, promotion of apoptosis, and improvement of arthritis scores are described in the relevant embodiments.

[0016] In another most preferred embodiment of the present invention, the present invention discloses a method for inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in mammals, comprising the step of contacting mammalian FLS with a composition comprising concentrated bisdemethoxycurcumin (BDMC) present in 20% by mass or more. In another most preferred embodiment of the present invention, the present invention relates to a) T-Helper 17(T h The method for identifying mammals having an imbalance between 17) and Treg, and a) administering a composition containing concentrated bisdemethoxycurcumin (BDMC) present at 20% by mass or more, is described as a method for distributing T-helper 17 (T) in the spleen of mammals. h 17) A method for regulating imbalances in T cells (Tregs) is disclosed. In relevant aspects of this embodiment, the imbalance is regulated by Tregs compared to RA controls in 3.5. h The ratio of 17 / Treg is preferably 1, or more preferably T h Assuming the ratio of 17 / Treg is between 0 and 1 (Figure 35), T h This is regulated by reducing the number of cells and increasing T cells (Treg) (Figures 33-35, Example 9).

[0017] In yet another most preferred embodiment of the present invention, a method for the therapeutic management of rheumatoid arthritis in a subject is disclosed, comprising the steps of a) identifying a subject having rheumatoid arthritis, and b) administering a composition comprising concentrated bisdemethoxycurcumin (BDMC) present in 20% by mass or more. In a relevant aspect of this embodiment, the management of rheumatoid arthritis in mammals involves inhibition of the proliferation and migration of fibroblast-like synovial cells, and T-helper 17(T) in the mammalian spleen. hThis is achieved by regulating imbalances in 17) and T cells (Treg), reducing levels of inflammatory markers, and promoting apoptosis. In relevant aspects of this embodiment, improvement in arthritis score is achieved. Inhibition and migration of fibroblast-like synovial cells, T-helper 17 (T h 17) The extent and details of the regulation of imbalances in T cells (Tregs), reduction of inflammatory marker levels, promotion of apoptosis, and improvement of arthritis scores are described in the relevant embodiments.

[0018] In embodiments relating to the proliferation and inhibition of FLS, the composition comprises 20-50% by mass of BDMC, 10-25% by mass of demethoxycurcumin (DMC), and 30-50% by mass of curcumin, and the total curcuminoids in the composition are in the range of 20-95% by mass. In a related aspect of this embodiment of the present invention, the composition further comprises boswellic acid (B) and polysaccharide (PS) from Boswellia serrata, with boswellic acid and polysaccharide (BPS) present in the range of 35-50% by mass and 35-45% by mass, respectively. In this embodiment and another related aspect of other embodiments of the present invention, when used individually, the concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, and polysaccharide in the composition are selected from the range of 10-100 μg / mL. In this embodiment and other related embodiments of the present invention, the composition comprises a composition concentrated with BDMC curcuminoids, and BPS is present in combinations of a 1:1 ratio, preferably 1:2, preferably 1:3, preferably 1:4, preferably 4:1, preferably 3:1, or preferably 2:1 ratio. In related embodiments of this embodiment of the present invention, C3 and BPS are used as a combination within the specified range. Finding a combination within the specified range, or finding a suitable range, is common knowledge and known to those skilled in the art. Furthermore, in this embodiment and other embodiments of the present invention, AC3 is more preferably used alone or in combination with BPS. In further embodiments of this embodiment and other embodiments of the present invention, when used individually, the concentrations of BDMC, curcumin, DMC, BPS, AC3, and C3 are in the range of 10 to 100 μg / mL, preferably 20 to 80 μg / mL, or preferably 40 to 60 μg / mL.

[0019] In this embodiment of the present invention and related aspects of other aforementioned embodiments, inhibition of fibroblast-like synovial cells (FLS) is achieved by cell cycle inhibition, reduction in inflammatory marker levels, promotion of apoptosis, and improvement in arthritis scores. In related aspects of this embodiment, after treatment with the sample, inhibition of FLS proliferation is in the range of 10-90%, more preferably 50-90%, or most preferably 60-90%, compared to an untreated control (Figures 3-6, Example 2). In related aspects of this embodiment of the present invention, after treatment with the sample, cell cycle inhibition is in the G0 / G1 phase, and the percentage of cells in the S phase is in the range of 1-20%, more preferably 1-10%, or most preferably 1-5% (Figures 7-9, Example 3). In related aspects of this embodiment of the present invention, the inflammatory marker is selected from the group consisting of TNF-α, IFN-γ, CCL-5, MMP-3, and cathepsin. In a further embodiment of this embodiment, after treatment with each sample, the expression level of inflammatory markers is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% compared to an untreated control (Table 3, Example 4). In a further embodiment of this embodiment, an ELISA study of the inflammatory marker IL6 showed that the combination of AC3 and BPS showed better inhibition compared to the use of AC3 or BPS individually (Example 4). In a further embodiment of this embodiment, after treatment with the sample, apoptosis is promoted by an increase in the Bax / Bcl2 ratio in the range of 1 to 1.5, or preferably in the range of 1.25 to 1.5, compared to an untreated control (Figure 19, Example 5). In a further embodiment of this model, the migration of FLS was inhibited after treatment with the sample (Figures 20-31, Example 6), and the inhibition of migration was in the range of 40-80%, preferably 50-80%, or more preferably 50-70%, compared to an untreated control (Figure 30), and the AC3+BPS combination was effective compared to the individual treatments (Figure 31).In another aspect of this embodiment, after treatment with the sample, the arthritis score is in the range of 1 to 3, more preferably in the range of 1 to 2, compared to an untreated control (Figure 32, Example 8, RA control is 3.5, positive control celecoxib is 1).

[0020] T-helper 17(T) in the spleen of mammals h 17) In embodiments relating to the regulation of imbalances in T cells (Tregs) and the therapeutic management of RA in mammals, when used individually, the concentrations of BDMC, DMC, curcumin, curcuminoids, boswellic acid, or polysaccharides in the compositions are preferably selected from a range of 40 mg / kg (mammalian body weight) to 100 mg / kg (mammalian body weight), or preferably from a range of 50 to 100 mg / kg (mammalian body weight). In the relevant embodiments, the concentrated BDMC curcuminoid composition and BPS are present in combinations of a ratio of 1:1, preferably 1:2, preferably 1:3, preferably 1:4, preferably 4:1, preferably 3:1, or preferably 2:1. In another related embodiment of the present invention, the composition further comprises stabilizers, bioavailability enhancers and antioxidants, pharmaceutically or nutritionally or cosmetically acceptable excipients and enhancers, and is appropriately formulated for oral administration in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies or food products (Example 10). Finding a suitable formulation for administration is well within the scope of the art of those skilled in the art. [Examples]

[0021] (Example 1) Isolation and culture of fibroblast-like synovial cells (FLS): Synovial tissue was obtained from collagen-induced arthritis rats under sterile conditions according to the following method (Jinjun Zhao, Qingqing Ouyang, Ziyou Hu, Qin Huang, Jing Wu, Ran Wang and Min Yang. A protocol for the culture and isolation of murine synovial fibroblasts. Biomedical Reports 5: 171-175, 2016). FLS was isolated from synovial tissue by enzymatic digestion. Briefly, the tissue was cut to 1 mm using microsurgical scissors. 3 The tissue was divided into blocks. Then, for enzymatic digestion, the tissue was incubated at 37°C for 45 minutes in an orbital stirring incubator (200 rpm) using 0.1% collagenase type II enzyme in DMEM supplemented with 10% FBS.

[0022] After incubation, the tubes were vigorously vortexed for 1-2 minutes to release the cells, and the mixture was filtered using a 100 μm mesh strainer. The filtrate was centrifuged at 1200 rpm for 5 minutes, and the cells were resuspended in DMEM supplemented with 10% FBS, 100 μg / ml streptomycin, and 100 U / ml penicillin. The cells were then cultured in a humidified incubator at 37°C and 5% CO2. Following FLS identification based on cytomorphological and immunocytochemical staining using anti-vimentin antibody (PA5-27231, Thermo Fisher Scientific) (Figures 1 and 2), cells from passages 4-7 were used for further study.

[0023] (Example 2) WST-1 Growth Assay: The effect of various samples on FLS growth was measured using the WST-1 assay. FLS were 5 × 10⁶ 3Cells were seeded in 96-well plates at a density of 10 cells / well and incubated overnight at 37°C under 5% CO2. The cells were then treated for 72 hours with various concentrations of samples (AC3, C3, Cur, BDMC, DMC, BPS) as shown in Figures 3–6. After the treatment period, 100 μl of WST-1 reagent (5015944001, Sigma, USA), diluted 1:10 in serum-free DMEM culture medium, was added to each well and incubated for 2 hours at 37°C under 5% CO2. Absorbance was measured at 450 nm using a reference wavelength of 610 nm. AC3 showed better inhibition of FLS proliferation at 20 μg / mL and 40 μg / mL in a dose-dependent manner (Figures 3 and 4). A comparative study of curcuminoid analogs in inhibiting FLS proliferation showed a trend of BDMC > curcumin > DMC at 20 μg / mL (Figure 5), while BPS showed only 10% inhibition. The combination was far more effective than using Boswellin PS (BPS) or AC3 individually (Figure 6).

[0024] (Example 3) Cell cycle analysis: FLS cells (8 × 10 4 Cells (1 per well) were seeded into a 24-well plate and incubated overnight at 37°C under 5% CO2. 。After 24 hours of synchronization in serum-free medium, cells were treated in 10% DMEM FBS for 24 hours, with or without the sample. After the treatment period, cells were collected and suspended in ice-cold PBS. After centrifugation, cells were fixed by dropwise addition of 70% ice-cold ethanol to the pellet while vortex stirring, and stored at 4°C for 30 minutes. Cells were stained with propidium iodide (PI) solution (50 μg / ml) for 30 minutes at 37°C in the dark. DNA content was analyzed by flow cytometry (BD FACS Celesta flow cytometer). Among the curcuminoids, AC3 and BDMC showed maximum inhibition of FLS replication (Figures 7, 8, 12, and 14), and FLS was arrested in the G0 / G1 phase. Boswellin PS (BPS) showed inhibition only at 80 μg / mL (Figures 8 and 16). As illustrated in Figure 9, the combined effect of AC3+BPS on cell cycle inhibition was better than that of the individual samples used (AC3 and BPS).

[0025] (Example 4) Measurement of inflammatory markers: FLS cells (8 × 10) 4 Cells (1 per well) were seeded into a 24-well plate and incubated overnight at 37°C under 5% CO2. 。 Cells were induced in 10% DMEM FBS for 6 and 24 hours with or without recombinant rat TNF-α (catalog number 400-14, Peprotech, New Jersey, USA) at 10 ng / ml to evaluate the anti-inflammatory effects of the samples. Curcumin showed better anti-inflammatory activity by suppressing inflammatory markers (IFNγ, CCL-5, MMP-3, and cathepsin, Table 2), while BDMC was most effective against TNF-α, and most importantly, the combination of AC3 and BPS was the most effective of all (Table 2). ELISA: After a 24-hour incubation period, the culture supernatant was collected and evaluated for the inflammatory marker IL6 using ELISA. At concentrations of 10 μg / mL (AC3) and 40 μg / mL (BPS), inhibition was 20% when used in combination, compared to 3% and 1% when AC3 and BPS were used individually.

[0026] The kit used for testing was the rat IL-6 DuoSet ELISA, R&D Systems, DY506-05. RT-PCR expression study: After 6 hours of incubation, whole cellular RNA from untreated and treated cells was isolated using Trizol Reagent® (Ambion, Life Technologies) according to the manufacturer's instructions, followed by RNase-free DNase I treatment (ThermoFisher Scientific) to remove all genomic DNA. Messenger RNA quality and concentration were analyzed spectrophotometrically (NanoDrop Lite, ThermoFisher Scientific). Using the Revert-aid First Strand cDNA Synthesis Kit (ThermoFisher Scientific), 1 microgram of whole RNA was reverse transcribed to cDNA according to the manufacturer's instructions and stored at -80°C until use.

[0027] Subsequently, 20 μl of the reaction mixture was subjected to PCR using SYBR green qPCR master mix for cDNA amplification using specially designed primers obtained from Eurofins India, with the housekeeping gene β-actin being co-amplified with each reaction as an internal control (Table 2). PCR was performed on a Light cycler 96 (Roche Life Science), and the PCR conditions for the gene consisted of 35 cycles: initial denaturation at 95°C for 10 minutes, followed by denaturation at 95°C for 30 seconds, primer annealing at 60°C for 30 seconds, extension at 72°C for 30 seconds, and final cooling at 72°C for 30 seconds (Table 1).

[0028] [Table 1]

[0029] [Table 2]

[0030] (Example 5) Apoptosis Analysis - FLS apoptosis was evaluated using RT-PCR expression studies. Briefly, FLS cells (8 × 10⁻¹⁴) 4 Cells (1 per well) were seeded into a 24-well plate and incubated overnight at 37°C under 5% CO2. 。 After 24 hours of synchronization in serum-free medium, cells were treated for 24 hours in 10% DMEM FBS with or without the sample. After the treatment period, cells were collected, whole-cellular RNA was isolated, and processed for RT-PCR analysis as previously mentioned (Table 3). The BCl-2 and Bax protein families play a central role in regulating apoptosis. The Bax / Bcl-2 ratio can act as a rheostat determining the susceptibility of cells to apoptosis, with apoptotic cells having a higher Bax / Bcl-2 ratio (Figure 19). Compared to controls, among curcuminoids, BDMC > DMC > curcumin, and the AC3 complex performed better than the C3 complex (Figure 19).

[0031] [Table 3]

[0032] (Example 6) Migration Assay - The migration and infiltration of FLS play a crucial role in synovitis and bone destruction. FLS migrate locally and may also infiltrate distal regions and joints via the bloodstream. RA - FLS secrete MMPs, which further exacerbate cartilage matrix degradation, ultimately leading to bone erosion. The migratory potential of FLS can be studied by evaluating wound closure through a simple scratch assay and FLS migration. Untreated FLS migrate and close the wound, while treated FLS show delayed closure (J Immunol March 1, 2014, 192 (5) 2063-2070). FLS cells (5 × 10⁶) 4Cells (100 / well) were seeded in a 24-well plate and incubated at 37°C under 5% CO2 to achieve a concentration of approximately 80-90%. The cells were then wound by scratching with a 200 μl pipette tip. To ensure complete removal of fragments and suspension cells, the cells were washed with PBS. The cells were then incubated with various concentrations of the sample in DMEM medium containing 2% FBS. The control sample contained cells and culture medium without any sample. Cell migration was assessed by evaluating monolayer gap closure using Magvision software. The percentage of wound closure inhibition was calculated compared to the control well. Compared to the control group (Figure 20), among curcuminoids at 15 μg / mL, BDMC (Figure 21) performed better than DMC (Figure 23) and curcumin (Figure 22), while the AC3 complex (Figure 24) performed better than the C3 complex (Figure 25), and AC3 + Boswellin PS (BPS) (Figure 29) performed better than AC3 (Figure 27) and BPS (Figure 28).

[0033] (Example 7) Arthritis research in rats The mouse model (Table 4) collagen-induced arthritis (CIA) is a widely studied autoimmune model of rheumatoid arthritis. In this model, autoimmune arthritis is induced by immunization using type II collagen (CII) emulsified in a complete Freund's adjuvant. These animals develop autoimmune-mediated polyarthritis, which shares several clinical, histological, and immunological features with the human autoimmune disease rheumatoid arthritis. The immune response to CII is characterized by both stimulation of collagen-specific T cells and the production of high-titer antibodies specific to both the immunogen (xenogenic CII) and the autoantigen (mouse or rat CII).

[0034] [Table 4]

[0035] Arthritis was induced by administering type II collagen (chicken sternal cartilage, Sigma catalog number: C9301) emulsified in a 1:1 ratio with incomplete Freund's adjuvant (FIA). On day 0, rats were intradermally injected with 200 μL (200 μg / animal) of collagen-FIA emulsion into the base of the tail (primary immunization). For the booster injection, the emulsion was prepared in the same manner as above, and 100 μL (100 μg / animal) of collagen-FIA emulsion was injected on day 7. Test samples were administered from day 0 to day 20. (Example 8) Arthritis Score: The degree of swelling and erythema in all four feet was assessed using a standard arthritis scoring method. 0 - No signs, 1 - Redness with no edema, 2 - Redness with mild edema, 3 - Redness with severe edema, 4 - Redness, severe edema, and rigid movement. The combination of AC3 and BPS (Figure 32) was effective at concentrations of 100 and 40 mg / kg, respectively. Celecoxib was used as a positive control along with rheumatoid arthritis controls.

[0036] (Example 9) Analysis of Treg and Th17 cells in spleen isolation: For lymphocyte isolation, spleens were obtained from collagen-induced arthritis rats under sterile conditions. The spleens were washed twice with PBS containing 100 μg / ml streptomycin and 100 U / ml penicillin, cut into small pieces with microsurgical scissors, homogenized using the plunger end of a syringe, and filtered using a 100 μm mesh strainer. The filtrate was centrifuged at 1200 rpm for 5 minutes, washed 1-2 times with PBS, and then filtered to 1 × 10⁶ 6 The cells / ml were suspended in RPMI medium supplemented with 10% FBS. The imbalance was 3.5 compared to the RA control. h The ratio of 17 / Treg is preferably 1, or more preferably T h Assuming the ratio of 17 / Treg is between 0 and 1 (Figure 35), T h This is achieved by reducing the number of cells and increasing the number of T cells (Treg) (Figures 33-35). Flow cytometry (FCM) analysis: To evaluate Th17 and Treg cells, isolated lymphocytes were stimulated for 4 hours with 20 ng / mL phorbol myristate acetate (P8139, Sigma), 500 ng / mL ionomycin, and BD GolgiStop (554724, BD), a protein transport inhibitor containing monensin, at concentrations suggested by the manufacturer.

[0037] After stimulation, cells were collected and 2 × 10⁶ cells were used to evaluate the Th17 and Treg populations. 5 Individual cells were divided into different tubes. The antibody dilutions used for analysis were as recommended by the respective manufacturers. To evaluate the Th17 population, cells were first stained with FITC mouse anti-rat CD3 (559975, BD pharmingen) and APC mouse anti-rat CD4 (550057, BD pharmingen) antibodies. To evaluate the Treg population, cells were first stained with APC mouse anti-rat CD4 (550057, BD pharmingen) and BV421 mouse anti-rat CD25 (565608, BD pharmingen) antibodies. Following the addition of each surface staining antibody, the tubes were incubated for 30 minutes at 4°C in the dark. After surface staining, the cells were fixed and permeabilized using fixation and permeabilization solution (BD Cytofix / Cytoperm, 554722) according to the manufacturer's instructions and resuspended in saponin-containing buffer (BD Perm / Wash, 554723). Following fixation and permeabilization, Th17 and Treg cells were incubated with PE conjugate anti-mouse / rat IL-17A (12-7177-81, eBioscience) and PE conjugate anti-FOXP3 (12-5773-80, eBioscience) antibodies, respectively, for 30 minutes at 4°C in the dark. The cells were then washed twice with saponin-containing buffer, resuspended in staining buffer, and subjected to flow cytometry analysis. FCM was performed using a BD FACSCelesta system (BD Biosciences, Franklin Lakes, New Jersey, USA) and analyzed using FlowJo software.

[0038] (Example 10) Formulation: The composition is formulated with pharmaceutically / nutritionally acceptable excipients, adjuvants, diluents, stabilizers, dispersible gums, bioavailability enhancers, or carriers and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, or food products.

[0039] In a related embodiment, the bioavailability enhancer is selected from the group consisting of piperine (BioPerine®), quercetin, garlic extract, ginger extract, and naringin. In another related embodiment, the stabilizer is selected from the group consisting of rosmarinic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium bisulfite, propyl gallate, cysteine, ascorbic acid, and tocopherol. In yet another related embodiment, the dispersible gum is selected from the group consisting of agar, alginate, carrageenan, gum arabic, guar gum, carob gum, konjac gum, xanthan gum, and pectin. Tables 5-9 provide exemplary examples of nutritional supplement formulations containing bisdemethoxycurcumin.

[0040] [Table 5]

[0041] [Table 6]

[0042] [Table 7]

[0043] [Table 8]

[0044] [Table 9]

[0045] The above-mentioned formulations are merely illustrative examples, and any formulation containing the above-mentioned active ingredients intended for the aforementioned purposes is considered equivalent. Other modifications and variations of the present invention will be apparent to those skilled in the art from the foregoing disclosure and teachings. Therefore, although only specific embodiments of the present invention have been specifically described herein, it will be apparent that numerous modifications may be made thereto without departing from the spirit and scope of the invention and should be interpreted only in conjunction with the appended claims. Another aspect of the present invention may be as follows: [1] A composition for use in inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in a target, comprising concentrated bisdemethoxycurcumin (BDMC) present in an amount of 20% by mass or more. [2] The composition for use according to [1], wherein the composition comprises 20 to 50% by mass of BDMC, 10 to 25% by mass of demethoxycurcumin (DMC), and 30 to 50% by mass of curcumin, and the total curcuminoids in the composition are in the range of 20 to 95% by mass. [3] The composition for use described in [1], wherein, when used individually, the concentration of BDMC, DMC, curcumin, or curcuminoid in the composition is selected from a range of 10 to 100 μg / mL. [4] The composition for use according to [3], further comprising boswellic acid (B) and polysaccharide (PS) from Boswellia serrata, wherein the boswellic acid comprises 35-50% by mass of boswellic acid, 20-30% by mass of β-boswellic acid, 12% by mass of 3-acetyl-11-keto-β-boswellic acid (AKBA), and 35-45% by mass of polysaccharide. [5] The composition for use described in [4] above, wherein, when used individually, the concentrations of boswellic acid and polysaccharide are selected from a range of 10 to 100 μg / mL. [6] The composition for use described in [1], wherein the concentrated BDMC curcuminoid composition and BPS are present in a combination of a ratio of 1 to 4:4 to 1. [7] The composition for use according to [1], wherein inhibition of fibroblast-like synovial cells (FLS) is brought about by cell cycle inhibition, reduction of inflammatory marker levels, and promotion of apoptosis. [8] The composition for use described in [7] above, wherein the cell cycle inhibition occurs during the G0 / G1 phase. [9] The composition for use described in [7], wherein apoptosis is measured as a ratio of Bax to Bcl-2.

[10] The composition for use according to [7], wherein the inflammatory marker is selected from the group consisting of TNF-α, IFN-γ, CCL-5, MMP-3, and cathepsin.

[11] The composition for use according to [1], wherein inhibition of fibroblast-like synovial cells results in improvement of the arthritis score.

[12] The composition for use described in [1] above, wherein the target is a mammal.

[13] T-helper 17(T) in mammalian spleen containing concentrated BDMC present at 20% by mass or more h 17) Compositions for use in regulating imbalances in T cells (Tregs).

[14] The composition for use according to

[13] , wherein the composition comprises 20 to 50% by mass of BDMC, 10 to 25% by mass of DMC, and 30 to 50% by mass of curcumin, and the total curcuminoids in the composition are in the range of 20 to 95% by mass.

[15] The composition for use according to

[13] , wherein, when used individually, the concentration of BDMC, DMC, curcumin, or curcuminoid in the composition is selected from a range of 40 mg / kg (mass body weight) to 100 mg / kg (mass body weight).

[16] The composition for use according to

[13] , further comprising boswellic acid (B) and polysaccharide (PS) from Boswellia serrata, wherein the boswellic acid comprises 35-50% by mass of boswellic acid, 20-30% by mass of β-boswellic acid, 12% by mass of 3-acetyl-11-keto-β-boswellic acid (AKBA), and 35-45% by mass of polysaccharide.

[17] The composition for use described in

[16] , wherein, when used individually, the concentration of boswellic acid and polysaccharide is selected from a range of 40 mg / kg (mammalian body weight) to 100 mg / kg (mammalian body weight).

[18] The composition for use described in

[13] , wherein the concentrated BDMC curcuminoid composition and BPS are present in a combination of a ratio of 1 to 4:4 to 1.

[19] Disequilibrium, T h It regulates by decreasing 17 cells and increasing T cells (Treg), thereby T h A composition for use according to

[13] that reduces the 17 / Treg ratio.

[20] A composition for use as described in

[13] , further comprising a stabilizer, a bioavailability enhancer and an antioxidant, a pharmaceutically or nutritionally or cosmetically acceptable excipient and enhancer, for oral administration in the form of a tablet, capsule, syrup, gummy, powder, suspension, emulsion, chewable, candy or food product.

[21] A composition for use in the treatment and management of rheumatoid arthritis in mammals, comprising concentrated bisdemethoxycurcumin (BDMC) present in an amount of 20% by mass or more.

[22] The composition for use according to

[21] , wherein the composition comprises 20 to 50% by mass of bisdemethoxycurcumin, 10 to 25% by mass of demethoxycurcumin, and 30 to 50% by mass of curcumin, and the total curcuminoids in the composition are in the range of 20 to 95% by mass.

[23] The composition for use according to

[21] , wherein, when used individually, the concentration of BDMC, DMC, curcumin, or curcuminoid in the composition is selected from 40 mg / kg (mammalian body weight) to 100 mg / kg (mammalian body weight).

[24] The composition for use according to

[21] , further comprising boswellic acid (B) and polysaccharide (PS) from Boswellia serrata, wherein the boswellic acid and polysaccharide (BPS) are present in amounts of 35-50% by mass and 35-45% by mass, respectively.

[25] The composition for use described in

[24] , wherein, when used individually, the concentration of boswellic acid and polysaccharide is selected from the range of 40 mg / kg (mammalian body weight) to 100 mg / kg (mammalian body weight).

[26] The composition for use according to

[21] , wherein the concentrated BDMC curcuminoid composition and BPS are present in a combination of a ratio of 1 to 4:4 to 1.

[27] Management of rheumatoid arthritis in mammals involves inhibiting the proliferation and migration of fibroblast-like synovial cells, and T-helper 17(T h 17) A composition for use as described in

[21] above, which is brought about by the regulation of imbalances in T cells (Tregs), a reduction in the levels of inflammatory markers, promotion of apoptosis, and improvement of arthritis scores.

[28] The composition for use according to

[21] , further comprising a stabilizer, a bioavailability enhancer and an antioxidant, a pharmaceutically or nutritionally or cosmetically acceptable excipient and enhancer, and administered orally in the form of a tablet, capsule, syrup, gummy, powder, suspension, emulsion, chewable, candy or food product.

Claims

1. A composition for use in inhibiting the proliferation and migration of fibroblast-like synovial cells (FLS) in mammals, wherein the composition comprises 20 to 95% by mass of total curcuminoids, and the composition comprises 20% by mass or more of BDMC, wherein the total curcuminoids comprise 20 to 50% by mass of bisdemethoxycurcumin, 10 to 25% by mass of demethoxycurcumin, and 30 to 50% by mass of curcumin, relative to the total mass of the total curcuminoids.

2. The composition for use according to claim 1, wherein, when used, the concentration of the total curcuminoids in the composition is selected from a range of 10 to 100 μg / mL.

3. The composition for use according to claim 1, further comprising boswellic acid (B) and polysaccharide (PS) from Boswellia serrata, wherein the boswellic acid and polysaccharide (hereinafter, "BPS") comprises 35 to 50% by mass of boswellic acid (B) standardized to contain 20 to 30% by mass of β-boswellic acid, 12% by mass of 3-acetyl-11-keto-β-boswellic acid (AKBA), and 35 to 45% by mass of polysaccharide (PS).

4. The composition for use according to claim 3, wherein, when used, the concentration of boswellic acid and polysaccharide is selected from a range of 10 to 100 μg / mL.

5. The composition for use according to claim 1, wherein inhibition of fibroblast-like synovial cells (FLS) is brought about by cell cycle inhibition, reduction of inflammatory marker levels, and promotion of apoptosis.

6. The composition for use according to claim 5, wherein the cell cycle inhibition occurs during the G0 / G1 phase.

7. The composition for use according to claim 5, wherein the inflammatory marker is selected from the group consisting of TNF-α, IFN-γ, CCL-5, MMP-3, and cathepsin.

8. The composition for use according to claim 1, wherein inhibition of fibroblast-like synovial cells results in an improvement in the arthritis score.

9. T-helper 17 (T) in the spleen of mammals h A composition for use in adjusting the ratio of 17) / T cells (Treg), wherein the composition comprises 20 to 95% by mass of total curcuminoids, the composition comprises 20% by mass or more of BDMC, and the total curcuminoids comprises 20 to 50% by mass of bisdemethoxycurcumin, 10 to 25% by mass of demethoxycurcumin, and 30 to 50% by mass of curcumin, relative to the total mass of the total curcuminoids.

10. T-Helper 17 (T h 17) Regulation of the ratio of T cells (Treg) h This involves reducing the number of cells and increasing the number of T cells (Treg), thereby T h The composition for use according to claim 9, wherein the 17 / Treg ratio is reduced.

11. A composition for use in the treatment and management of rheumatoid arthritis in mammals, wherein the composition comprises 20 to 95% by mass of total curcuminoids, the composition comprises 20% by mass or more of BDMC, and the total curcuminoids comprises 20 to 50% by mass of bisdemethoxycurcumin, 10 to 25% by mass of demethoxycurcumin, and 30 to 50% by mass of curcumin, relative to the total mass of the total curcuminoids.

12. The composition for use according to claim 9 or 11, wherein, when used, the concentration of total curcuminoids in the composition is selected from 40 mg / kg (mammalian body weight) to 100 mg / kg (mammalian body weight).

13. The composition for use according to claim 9 or 11, further comprising boswellic acid (B) and polysaccharide (PS) from Boswellia serrata, wherein the boswellic acid (B) and polysaccharide (PS) are present in amounts of 35 to 50% by mass and 35 to 45% by mass, respectively.

14. The composition for use according to claim 13, wherein, when used, the concentration of boswellic acid (B) and polysaccharide (PS) is selected from the range of 40 mg / kg (mammalian body weight) to 100 mg / kg (mammalian body weight).

15. The composition for use according to any one of claims 1, 9, or 11, wherein the total curcuminoids and BPS are present in a combination of concentrations from 1 to 4:4 to 1.

16. The management of rheumatoid arthritis in mammals involves inhibiting the proliferation and migration of fibroblast-like synovial cells, and T-helper 17 (T h A composition for use according to claim 9 or 11, which is brought about by regulating the ratio of 17 / T cells (Treg), reducing the levels of inflammatory markers, promoting apoptosis, and improving arthritis scores.

17. The composition for use according to claim 9 or 11, further comprising a stabilizer, a bioavailability enhancer and an antioxidant, a pharmaceutically or nutritionally or cosmetically acceptable excipient and enhancer, and administered orally in the form of a tablet, capsule, syrup, gummy, powder, suspension, emulsion, chewable, candy or food product.

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