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The osteoarthritis ( OA) progression is now considered to be related to inflammation. Anemonin ( ANE) is a small natural molecule extracted from various kinds of Chinese traditional herbs and has been shown to inhibiting inflammation response. In this study, we examined whether ANE could attenuate the progression of OA via suppression of IL-1β/ NF-κB pathway activation. Destabilization of the medial meniscus ( DMM) was performed in 10-week-old male C57 BL/6J mice. ANE was then intra-articularly injected into joint capsule for 8 and 12 weeks. Human articular chondrocytes and cartilage explants challenged with interleukin-1β ( IL-1β) were treated with ANE. We found that ANE delayed articular cartilage degeneration in vitro and in vivo. In particular, proteoglycan loss and chondrocyte hypertrophy were significantly decreased in ANE -treated mice compared with vehicle-treated mice. ANE decreased the expressions of matrix metalloproteinase-13 ( MMP13), A disintegrin and metalloproteinase with thrombospondin motifs 5 ( ADAMTS5), collagen X (Col X) while increasing Aggrecan level in murine with DMM surgery. ANE treatment also attenuated proteoglycan loss in human cartilage explants treated with IL-1β ex vivo. ANE is a potent protective molecule for OA; it delays OA progression by suppressing ECM loss and chondrocyte hypertrophy partially by suppressing IL-1β/ NF-κB pathway activation. [ABSTRACT FROM AUTHOR]

Systemic application of glucocorticoids is an essential anti-inflammatory and immune-modulating therapy for severe inflammatory or autoimmunity conditions. However, its long-term effects on articular cartilage of patients' health need to be further investigated. In this study, we studied the effects of dexamethasone (Dex) on the homeostasis of articular cartilage and the progress of destabilization of medial meniscus (DMM)-induced osteoarthritis (OA) in adult mice. Long-term administration of Dex aggravates the proteoglycan loss of articular cartilage and drastically accelerates cartilage degeneration under surgically induced OA conditions. In addition, Dex increases calcium content in calcified cartilage layer of mice and the samples from OA patients with a history of long-term Dex treatment. Moreover, long term usage of Dex results in decrease subchondral bone mass and bone density. Further studies showed that Dex leads to calcification of extracellular matrix of chondrocytes partially through activation of AKT, as well as promotes apoptosis of chondrocytes in calcified cartilage layer. Besides, Dex weakens the stress-response autophagy with the passage of time. Taken together, our data indicate that long-term application of Dex may predispose patients to OA and or even accelerate the OA disease progression development of OA patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Blended organic copolymer (or homopolymer) and inorganic nanoparticles have been widely used (separately or simultaneously) for optimizing membrane pore structure and surface functionality. However, the prepared membranes suffer from degraded stability and insufficient integrity due to the high solubility or incompatibility of the blending additives. In this work, an organic-inorganic nanocomposite (i.e., PLA-TiO 2 ) was designed, and employed for PSF membrane preparation. The Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis confirmed that bidentate chelating dominated the bonding mechanism between PLA and TiO 2 . The resultant PSF/PLA-TiO 2 membranes possessed a highly porous surface with narrowed pore size distribution, demonstrating the strong pore forming ability of PLA-TiO 2 for membrane preparations. Moreover, owing to the distinct inorganic-organic molecular conformation, the PLA-TiO 2 exhibited enhanced stability and dispersibility within the PSF substance, which endowed the membrane with long-acting hydrophilicity and UV responsiveness. Given the UV responsiveness that is introduced by PLA-TiO 2 , UV-assisted strategies (UV-F and UV-C) were designed to further mitigate membrane fouling. The fouling analysis indicated that both reversible fouling and irreversible fouling were reduced in the UV-C process, signifying the synergistic effect between photocatalysis and hydraulics in membrane fouling mitigation. The enhanced membrane performance and the efficient preparation process highlight the potential of PLA-TiO 2 in membrane modifications.

Our recently successful identification of benzoic acid-based DPP-4 inhibitors spurs the further quest for in-depth structure-activity relationships (SAR) study in S 2 ' site DPP-4. Thus novel benzamide fragments were designed to target the S 2 ' site to compromise lipophilicity and improve oral activity. Exploring SAR by introduction of a variety of amide and halogen on benzene ring led to identification of several compounds, exerting moderated to excellent DPP-4 activities, in which 4'-chlorine substituted methyl amide 17g showed most potent DPP-4 activity with the IC 50 value of 1.6 nM. Its activity was superior to reference alogliptin. Docking study ideally verified and interpreted the obtained SAR of designed compounds. As a continuation, DPP-8/9 assays revealed the designed compounds exhibited good selectivity over DPP-8 and DPP-9. Subsequent cell-based test indicated compound 17g displayed low toxicity toward the LO2 cell line up to 100 μM. In vivo evaluation showed compound 17g robustly improved the glucose tolerance in normal mice. Importantly, 17g exhibited reasonable pharmacokinetic (PK) profiles for oral delivery. Overall, compound 17g has the potential to a safe and efficacious DPP-4 inhibitor for T2DM treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis., Methods: Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis., Results: R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice., Conclusions: Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)