Targeting YAP1-regulated Glycolysis in Fibroblast-Like Synoviocytes Impairs Macrophage Infiltration to Ameliorate Diabetic Osteoarthritis Progression.

The interplay between immune cells/macrophages and fibroblast-like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single-cell RNA sequencing (scRNA-seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients' synovial macrophage infiltration and polarization. In addition, the yes-associated protein 1 (YAP1)/thioredoxin-interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)-dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) which may subsequently fine-tune the infiltration of M1-polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane-camouflaged Verteporfin (Vt)-loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1-polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1.

Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-XL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.

Combination BET Family Protein and HDAC Inhibition Synergistically Elicits Chondrosarcoma Cell Apoptosis Through RAD51-Related DNA Damage Repair.

BACKGROUND: Chondrosarcoma is the second-most common type of bone tumor and has inherent resistance to conventional chemotherapy. Present study aimed to explore the therapeutic effect and specific mechanism(s) of combination BET family protein and HDAC inhibition in chondrosarcoma. METHODS: Two chondrosarcoma cells were treated with BET family protein inhibitor (JQ1) and histone deacetylase inhibitors (HDACIs) (vorinostat/SAHA or panobinostat/PANO) separately or in combination; then, the cell viability was determined by Cell Counting Kit-8 (CCK-8) assay, and the combination index (CI) was calculated by the Chou method; cell proliferation was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) incorporation and colony formation assay; cell apoptosis and reactive oxygen species (ROS) level were determined by flow cytometry; protein expressions of caspase-3, Bcl-XL, Bcl-2, γ-H2AX, and RAD51 were examined by Immunoblotting; DNA damage was determined by comet assay; RAD51 and γ-H2AX foci were observed by immunofluorescence. RESULTS: Combined treatment with JQ1 and SAHA or PANO synergistically suppressed the growth and colony formation ability of the chondrosarcoma cells. Combined BET and HDAC inhibition also significantly elevated the ROS level, followed by the activation of cleaved-caspase-3, and the downregulation of Bcl-2 and Bcl-XL. Mechanistically, combination treatment with JQ1 and SAHA caused numerous DNA double-strand breaks (DSBs), as evidenced by the comet assay. The increase in γ-H2AX expression and foci formation also consistently indicated the accumulation of DNA damage upon cotreatment with JQ1 and SAHA. Furthermore, RAD51, a key protein of homologous recombination (HR) DNA repair, was found to be profoundly suppressed. In contrast, ectopic expression of RAD51 partially rescued SW 1353 cell apoptosis by inhibiting the expression of cleaved-caspase-3. CONCLUSION: Taken together, our results disclose that BET and HDAC inhibition synergistically inhibit cell growth and induce cell apoptosis through a mechanism that involves the suppression of RAD51-related HR DNA repair in chondrosarcoma cells.

Water Stable Heterometallic Zn-Tb Coordination Polymer for Rapid Detection of the Ultraviolet Filter Benzophenone.

Benzophenone (BP) is an ultraviolet filter (UVF) widely used in personal care products such as sunscreens and cosmetics. Excessive exposure to BP-type UVFs is a potential threat to human's health because of their endocrine-disrupting activity. Water stability of lanthanide compounds is crucial when they serve as luminescent sensors because of the practicality and recyclability. In this study, a water-stable luminescent Zn-Tb heterometallic coordination polymer was rationally designed and synthesized for rapid detection of BP. This material showed a high quenching effect, excellent selectivity, and fast response toward BP.

Solvent-induced formation of two gadolinium clusters demonstrating strong magnetocaloric effects and ferroelectric properties.

Two gadolinium clusters, [Gd2(H3L)2(NO3)2](NO3)2 (1) and [Gd3(HL)(H2L)(NO3)4]·C2H5OH (2) (H4L = N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine), were synthesized and characterized with different solvents. The magnetic properties of 1 and 2 were recorded and studied in detail. 1 is a centrosymmetric binuclear Gd2 cluster, adopting a P1[combining macron] space group (point group 1[combining macron]), and exhibits a strong magnetocaloric effect (MCE) entropy with -ΔSm of 27.50 J kg-1 K-1. 2 crystallizes in the Pna21 space group (polar point group mm2) through solvent modulation and contains an asymmetric trinuclear Gd3 cluster. Magnetic and ferroelectric investigations of 2 reveal a large change in the magnetocaloric effect entropy with -ΔSm of 30.22 J kg-1 K-1, ferroelectric hysteresis and dielectric anomalies.

Half-sandwich cycloruthenated complexes from aryloxazolines: synthesis, structures, and catalytic activities.

Seven half-sandwich cycloruthenated complexes [Ru(p-cymene)LCl] (2a-2g) (L = 2-phenyl-2-oxazoline (2a), 2-p-tolyl-4,5-dihydrooxazole (2b), 4,4-dimethyl-2-phenyl-2-oxazoline (2c), 2-(4-chlorophenyl)-4,5-dihydrooxazole (2d), 2-(4-bromophenyl)-4,5-dihydrooxazole (2e), 2-(4-fluorophenyl)-4,5-dihydrooxazole (2f) and 2-(4-nitrophenyl)-4,5-dihydrooxazole (2g)) were synthesized and characterized. All half-sandwich cycloruthenated complexes were fully characterized by (1)H and (13)C NMR spectra, elemental analyses and infrared spectroscopy. The molecular structures of 2a, 2d and 2e were confirmed by single-crystal X-ray diffraction methods. These half-sandwich cycloruthenated complexes were employed in nitroarene reduction using sodium borohydride (NaBH4) as a reducing agent in ethanol at room temperature. The catalytic results indicate that half-sandwich cycloruthenated complexes show promising catalytic activity in nitroarene reduction with a broad substrate and varied functional group compatibility.

[Comprehensive evaluation of improving effects of different organic wastes on a newly reclaimed cultivated land].

There are many problems such as low soil organic matter, available nutrients and microbial activity, compaction, and poor tillage properties for a newly reclaimed cultivated land, and the establishment of a fast, effective measure for improving soil fertility quality is of importance to enhance the quality and production performance of the newly cultivated land. A field experiment was carried out to observe the effect of organic wastes on soil fertility of a newly reclaimed cultivated land, and compared the differences of different types of urban organic wastes. The field experiment included nine treatments, i.e., pig manure, chicken manure, rice straw, vegetable harvest residue, urban sludge, biogas residue, manure+rice straw compost, garbage compost and control without organic fertilizer at annual application rate of 30 t . hm-2, and ran for three consecutive years. The results showed that the application of each type of the eight organic wastes had obvious effects on improving soil fertility. Among them, pig manure, chicken manure, pig manure+rice straw compost, rice straw and biogas residue were the most effective to enhance the carbon pool management index of soil. The addition of pig manure+rice straw compost and biogas residue had the best effect on increasing the soil water stable aggregates and decreasing soil bulk density. Sewage sludge, pig manure+rice straw compost and garbage compost could enhance soil water holding capacity. Pig manure, chicken manure and pig manure+rice straw compost had most obvious effect on increasing soil available nutrients. All kinds of organic wastes increased the number of soil microorganisms and the activity of enzymes. There were some risk of soil heavy metals pollution.for the long-term application of sludge, garbage compost and manure. However, the impact of short-term application of the wastes on soil environmental quality was not obvious. Overall, effects of organic wastes on soil fertility decreased in the order of pig manure+rice straw compost>chicken manure>pig manure>biogas residue >garbage compost>rice straw>urban sludge>vegetable harvest residue, and the effects on soil pollution increased in the sequence of rice straw