miR-210-3p protects against osteoarthritis through inhibiting subchondral angiogenesis by targeting the expression of TGFBR1 and ID4.

Excessive subchondral angiogenesis is a key pathological feature of osteoarthritis (OA), as it alters the balance of subchondral bone remodeling and causes progressive cartilage degradation. We previously found that miR-210-3p correlates negatively with angiogenesis, though the specific mechanism of miR-210-3p-related angiogenesis in subchondral bone during OA progression remains unclear. This study was conducted to identify the miR-210-3p-modulating subchondral angiogenesis mechanism in OA and investigate its therapeutic effect. We found that miR-210-3p expression correlated negatively with subchondral endomucin positive (Emcn+) vasculature in the knee joints of OA mice. miR-210-3p overexpression regulated the angiogenic ability of endothelial cells (ECs) under hypoxic conditions in vitro. Mechanistically, miR-210-3p inhibited ECs angiogenesis by suppressing transforming growth factor beta receptor 1 (TGFBR1) mRNA translation and degrading DNA-binding inhibitor 4 (ID4) mRNA. In addition, TGFBR1 downregulated the expression of ID4. Reduced ID4 levels led to a negative feedback regulation of TGFBR1, enhancing the inhibitory effect of miR-210-3p on angiogenesis. In OA mice, miR-210-3p overexpression in ECs via adeno-associated virus (AAV) alleviated cartilage degradation, suppressed the type 17 immune response and relieved symptoms by attenuating subchondral Emcn+ vasculature and subchondral bone remodeling. In conclusion, we identified a miR-210-3p/TGFBR1/ID4 axis in subchondral ECs that modulates OA progression via subchondral angiogenesis, representing a potential OA therapy target.

Epigallocatechin-3-O-gallate ameliorates oxidative stress-induced chondrocyte dysfunction and exerts chondroprotective effects via the Keap1/Nrf2/ARE signaling pathway.

Oxidative stress-induced degeneration and dysfunction of chondrocytes play a key role in the pathological progression of osteoarthritis (OA), a common degenerative joint disease in the elderly. Epigallocatechin-3-O-gallate (EGCG) increases Nrf2-mediated antioxidase expression levels. We aimed to determine the effects of EGCG on C28/I2 human chondrocytes subjected to interleukin-1ß (IL-1ß)-induced oxidative stress. EGCG suppressed IL-1ß-induced oxidative stress, as indicated by decreased malondialdehyde (MDA) and reactive oxygen species (ROS) generation. Additionally, EGCG attenuated the IL-1ß-induced reduction in cartilage matrix generated by chondrocytes by upregulating collagen II, aggrecan, sulfated proteoglycans, and SRY-box transcription factor 9 (SOX9). EGCG reversed the IL-1ß-induced increased cyclooxygenase 2 (COX2), inducible nitric oxide synthase (iNOS), collagen X, and matrix metalloproteinases (MMPs). Furthermore, EGCG inhibited apoptosis and senescence of IL-1ß-treated chondrocytes, as indicated by the decrease in mitochondrial membrane potential and senescence-associated ß-galactosidase-positive cells, respectively. Mechanically, EGCG upregulated nuclear factor erythroid 2-related factor 2 (Nrf2), oxygenase-1 (HO-1), and NADPH quinone oxidoreductase1 (NQO1). The antioxidant and chondroprotective effects of EGCG were blocked by ML385, a Keap1/Nrf2/ARE signaling pathway inhibitor. Thus, EGCG ameliorated oxidative stress-induced chondrocyte dysfunction and exerted chondroprotective effects via Keap1/Nrf2/ARE signaling. This provides a novel perspective on the molecular mechanisms underlying the therapeutic effects of EGCG on OA.

Ellagic acid attenuates interleukin-1ß-induced oxidative stress and exerts protective effects on chondrocytes through the Kelch-like ECH-associated protein 1 (Keap1)/ Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Osteoarthritis (OA) is the most prevalent type of degenerative joint disease, and its pathological progression is highly associated with oxidative stress. Natural antioxidants can attenuate oxidative stress and chondrocyte injury, suggesting that antioxidants have potential applications in the management of OA. Ellagic acid (EA), a natural polyphenol derived from fruits or nuts, exerts antioxidant and anti-inflammatory effects in diseases related to oxidative stress. Herein, we investigated the effects of EA on interleukin-1ß (IL-1ß)-induced oxidative stress and degeneration in C28/I2 human chondrocytes. EA efficiently suppressed IL-1ß-induced oxidative stress and ameliorated oxidative stress-induced dysfunction of chondrocytes, as indicated by the promotion of cartilage matrix secretion. Moreover, EA remarkably suppressed cell apoptosis and senescence, and reduced the expression of proinflammatory factors and metalloproteinases, suggesting that EA could alleviate chondrocyte injury under oxidative stress. Mechanistically, EA upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as well as its downstream targets NADPH quinone oxidoreductase 1 and heme oxygenase-1. ML385, a specific Keap1/Nrf2 pathway inhibitor, blocked the antioxidant and chondroprotective effects of EA. Our findings demonstrated that EA could attenuate oxidative stress and exert protective effects on chondrocytes by upregulating the Keap1/Nrf2 signaling pathway.

Cell-derived decellularized extracellular matrix scaffolds for articular cartilage repair.

Articular cartilage repair remains a great clinical challenge. Tissue engineering approaches based on decellularized extracellular matrix (dECM) scaffolds show promise for facilitating articular cartilage repair. Traditional regenerative approaches currently used in clinical practice, such as microfracture, mosaicplasty, and autologous chondrocyte implantation, can improve cartilage repair and show therapeutic effect to some degree; however, the long-term curative effect is suboptimal. As dECM prepared by proper decellularization procedures is a biodegradable material, which provides space for regeneration tissue growth, possesses low immunogenicity, and retains most of its bioactive molecules that maintain tissue homeostasis and facilitate tissue repair, dECM scaffolds may provide a biomimetic microenvironment promoting cell attachment, proliferation, and chondrogenic differentiation. Currently, cell-derived dECM scaffolds have become a research hotspot in the field of cartilage tissue engineering, as ECM derived from cells cultured in vitro has many advantages compared with native cartilage ECM. This review describes cell types used to secrete ECM, methods of inducing cells to secrete cartilage-like ECM and decellularization methods to prepare cell-derived dECM. The potential mechanism of dECM scaffolds on cartilage repair, methods for improving the mechanical strength of cell-derived dECM scaffolds, and future perspectives on cell-derived dECM scaffolds are also discussed in this review.

Organocatalytic enantioselective SN1-type dehydrative nucleophilic substitution: access to bis(indolyl)methanes bearing quaternary carbon stereocenters.

A highly general and straightforward approach to access chiral bis(indolyl)methanes (BIMs) bearing quaternary stereocenters has been realized via enantioconvergent dehydrative nucleophilic substitution. A broad range of 3,3'-, 3,2'- and 3,1'-BIMs were obtained under mild conditions with excellent efficiency and enantioselectivity (80 examples, up to 98% yield and >99 : 1 er). By utilizing racemic 3-indolyl tertiary alcohols as precursors of alkyl electrophiles and indoles as C-H nucleophiles, this organocatalytic strategy avoids pre-activation of substrates and produces water as the only by-product. Mechanistic studies suggest a formal SN1-type pathway enabled by chiral phosphoric acid catalysis. The practicability of the obtained enantioenriched BIMs was further demonstrated by versatile transformation and high antimicrobial activities (3al, MIC: 1 µg mL-1).

Enantioselective Dehydrative γ-Arylation of α-Indolyl Propargylic Alcohols with Phenols: Access to Chiral Tetrasubstituted Allenes and Naphthopyrans.

Herein, we report an enantioselective dehydrative γ-arylation of α-indolyl propargylic alcohols with phenols via organocatalysis, which provides efficient access to chiral tetrasubstituted allenes and naphthopyrans in high yields with excellent regio- and enantioselectivities under mild conditions. This method features the use of cheaply available naphthols/phenols as the C-H aryl source and liberating water as the sole byproduct. Control experiments suggest that the excellent enantioselectivity and remote regioselectivity stem from dual hydrogen-bonding interaction with the chiral phosphoric acid catalyst.

Catalytic Asymmetric Synthesis of Vicinal Tetrasubstituted Diamines via Umpolung Cross-Mannich Reaction of Cyclic Ketimines.

A catalytic asymmetric umpolung cross-Mannich reaction of cyclic ketimines is realized. This protocol provides an efficient methodology for the facile synthesis of chiral vicinal tetrasubstituted diamines in high yields with excellent chemo-, regio-, diastereo-, and enantioselectivities using cinchona-derived bifunctional organocatalysts (85-98% yield, up to >20:1 dr, and >99% ee).

A porous metal-organic framework with a unique hendecahedron-shaped cage: structure and controlled drug release.

A porous MOF constructed from a [Cu2(COO)4] secondary building unit, H3L (H3L = [1,1';3',1'']terphenyl-4,5',4''-tricarboxylic acid), and pyrazine ligands features a unique hendecahedron cage-like cavity with good stability and a high BET surface area of 3235 m(2) g(-1), showing good controlled drug release property of ibuprofen over those of anethole and guaiacol.