Nobiletin suppresses IL-21/IL-21 receptor-mediated inflammatory response in MH7A fibroblast-like synoviocytes (FLS): An implication in rheumatoid arthritis.

The mechanisms driving the development and progression of Rheumatoid arthritis (RA) are complex, novel targeted therapies are gaining traction as potential methods to prevent or slow the progression of RA. Nobiletin is a derivative of citrus fruit that has been shown to attenuate the development of osteoarthritis and inhibit the expression of proinflammatory cytokines. However, the exact mechanisms by which nobiletin exerts these chondroprotective effects remain poorly understood. In the present study, we investigated the impact of nobiletin in mediating the effects of interleukin-21 (IL-21) in MH7A fibroblast-like synoviocytes (FLS), the main cell type found in the articular synovium. Firstly, we demonstrate that nobiletin (25 µM and 50 µM) reduced the expression of the IL-21 receptor by 29% and 51%, respectively, in FLS. Additionally, our findings demonstrate that nobiletin potently ameliorated IL-21-induced increased production of reactive oxygen species and 4-hydroxynonenal, increased expression of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and high-mobility group box 1 (HMGB1), and decreased mitochondrial membrane potential. We also demonstrate the ability of nobiletin to attenuate IL-21-induced expression of matrix metalloproteinases 3 and 13 (MMP-3, MMP-13), key degradative enzymes involved in RA-associated cartilage destruction. Finally, we show that the effects of nobiletin are mediated through the JAK1/STAT3 pathway, as nobiletin significantly reduced the phosphorylation of both JAK1 and STAT3. Taken together, our findings indicate that nobiletin may offer a safe and effective treatment against the development and progression of RA induced by the expression of IL-21 and its receptor.

Preparation and Characterization of the Biological Compound Effervescent Granule of Calcium Acetate.

OBJECTIVE: Calcium acetate (Ca(CH3COO)2) is commonly used in calcium supplement for medicine, which is used as an auxiliary agent to treat osteoporosis. An effervescent granule is widely used in medical industry due to its palatability. The purpose of this study is to develop a new preparation of compound effervescent granule of the biological calcium acetate (Ca(CH3COO)2 effervescent granule), overcoming the disadvantages of the previous other dosage forms of calcium and thus enhancing the therapeutic efficacy. METHODS: The biological Ca(CH3COO)2 effervescent granule was prepared by the wet granulation method. The formulation was optimized by the orthogonal experiment. The effervescent base was comprised of various amounts of citric acid and sodium bicarbonate. Other ingredients were added for optimal performance of effervescent granule. The performed Ca(CH3COO)2 effervescent granule was evaluated for the particle size, repose angle, pH value of solution, calcium acetate content and effervescence time. The in vivo effects of Ca(CH3COO)2 effervescent granule on the bone microarchitecture were investigated via Micro-CT detection, and the serum calcium level was also investigated. RESULTS: The optimized formulation of the biological Ca(CH3COO)2 effervescent granules was composed of calcium acetate, citric acid, sodium bicarbonate, PEG6000, aspartame, PVP ethanol solution, lactose and vitamin D. Our findings reveal that this biological Ca(CH3COO)2 effervescent granule exhibited prominent effect on preventing the bone-mass loss and did better in enhancing the bone microarchitecture compared to the other calcium preparations. CONCLUSION: The biological Ca(CH3COO)2 effervescent granule is a novel dosage form among so many kinds of calcium preparations. It may perform better functions in the dairy calcium supplement.

Bone-targeting drug delivery system of biomineral-binding liposomes loaded with icariin enhances the treatment for osteoporosis.

BACKGROUND: Osteoporosis is a bone-incapacitating malady and it is characterized by obvious bone mass loss and bone microarchitecture deterioration. Current treatments for osteoporosis have many limitations, including the non-obvious therapeutic effect and long-term safety issues. Icariin is a pharmacologically active flavonoid glycoside, which shows potential application in treatment of osteoporosis. But its clinical application is limited by the inherent disadvantages such as poor water solubility, first pass effect after oral administration, and low bioavailability. Moreover, due to lack of targeting ability, icariin cannot accumulate at the local diseased region to provide early protection from fractures. To solve the application problems of icariin and enhance its therapeutic effects on osteoporosis, this work aimed to design a targeting drug delivery system of biomineral-binding liposomes (BBL) mediated by pyrophosphate ions. RESULTS: Biomineral-binding liposomes enhanced the binding ability of liposomes with hydroxyapatite particles. It increased the serum level of alkaline phosphatase and reduced that of tartrate-resistant acid phosphatase 5b. Meanwhile, BBL increased the mechanical strength of femoral midshaft, preserving the trabecular bone microarchitecture. Moreover, BBL could initiate bone turnover/remodeling of rats with osteoporosis. CONCLUSIONS: This drug targeting delivery system of BBL loading with icariin showed more therapeutic advantages than the free icariin for the treatment of osteoporosis, which may be a kind of valid candidate in future osteoporosis therapy.