Macrophage-derived hybrid exosome-mimic nanovesicles loaded with black phosphorus for multimodal rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is chronic inflammation characterized by abundant inflammatory cell infiltration and a major cause of joint function disruption. Despite current therapeutic strategies such as non-steroidal drugs or anti-cytokine biologics having shown promise for RA management, their side effects and clinical response rate remain unsatisfactory, attributed largely to the complicated pathomechanisms and multiplicity of the inflammatory cytokines. In this work, novel hybrid exosome-mimic nanovesicles equipped with broad-spectrum anti-inflammatory activity were developed for RA treatment. The hybrid nanovesicles (HNV) were prepared by fusing an M1 macrophage membrane into exosome-mimic nanovesicles extruded from M2 macrophages. The HNV inherit the anti-inflammatory properties of the M2 macrophages and cytokine receptors derived from the M1 membrane. Accordingly, the HNV possess comprehensive anti-inflammation activity via binding proinflammatory factors and releasing anti-inflammatory mediators. Furthermore, black phosphorus nanosheets (BP) were introduced into the HNV (HNV@BP) to eliminate inflammatory cells upon near-infrared (NIR) irradiation, which intrinsically decreases the inflammatory reaction. In a mouse model of collagen-induced arthritis, the HNV loaded with BP targeted and accumulated at the inflammed knee joints, exhibiting multimodal rheumatoid arthritis therapy combined with NIR irradiation through comprehensive inflammation suppression.

[Bioinformatics-based identification of key genes CDC5L and related pathways in osteosarcoma and Ewing's sarcoma].

OBJECTIVE: Osteosarcoma(OS) and Ewing's sarcoma (EWS) are the two most common primary malignant bone tumors in children. The aim of the study was to identify key genes in OS and EWS and investigate their potential pathways. METHODS: Expression profiling (GSE16088 and GSE45544) were obtained from GEO DataSets. Differentially expressed genes were identified using GEO2R and key genes involved in the occurrence of both OS and EWS were selected using venn diagram. Gene ontology and pathway enrichment analyses were performed for the ensembl. Protein-protein interaction (PPI) networks were established by STRING. Further, UCSC was used to predict the transcription factors of the cell division cycke 5-like(CDC5L) gene, and GEPIA was used to analyze the correlation between the transcription factors and the CDC5L gene. RESULTS: The results showed that CDC5L gene was the key gene involved in the pathogenesis of OS and EWS. The gene is mainly involved in mitosis, and is related to RNA metabolism, processing of capped intron-containing pre-mRNA, mRNA and pre-mRNA splicing. CONCLUSION: CDC5L, as a key gene, plays a role in development of OS and EWS, which may be reliable targets for diagnosis and treatment of these primary malignant tumors.

Resistin induces chemokine and matrix metalloproteinase production via CAP1 receptor and activation of p38-MAPK and NF-κB signalling pathways in human chondrocytes.

OBJECTIVES: Adipokine resistin is highly expressed in the serum and synovial uid (SF) of patients with knee osteoarthritis (KOA) but its pathogenic role in KOA remains unclear. We aimed to explore the mechanism of resistin/CAP1 in human KOA chondrocytes. METHODS: We enrolled 103 patients with radiographic KOA and 86 healthy participants as controls. Resistin levels in serum and SF were determined by enzyme-linked immunosorbent assay (ELISA). CAP1 expression was measured in cartilage tissues using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Effects of resistin on chondrocytes and CAP1 were evaluated via qRT-PCR and co-immunoprecipitation. The roles of CAP1, p38-MAPK, and NF-κB signalling pathways in KOA development were evaluated using adenovirus-mediated CAP1 short hairpin RNA, qRT-PCR, western blot, and ELISA. RESULTS: Resistin expression in serum and SF was elevated in severe radiographic KOA. CAP1 levels were higher in KOA cartilage and were positively correlated with resistin expression. Resistin promoted CCL3, CCL4, MMP13, and ADAMTS-4 expression through the CAP1 receptor. Resistin also directly bound to CAP1, as confirmed by co-immunoprecipitation. CAP1 knockdown in chondrocytes attenuated resistin-induced expression of CCL3, CCL4, MMP13, and ADAMTS-4 and activated p38-MAPK and NF-κB signalling pathways. CONCLUSIONS: Resistin binds CAP1 and upregulates the expression of proinflammatory cytokines and matrix-degrading enzymes via p38-MAPK and NF-κB signalling in human chondrocytes.

Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells.

Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 µM, 0.104 µM and 0.916 µM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2 = 0.965) and CoMSIA (q [2] = 0.875, r2 = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.

An Update on the Emerging Role of Resistin on the Pathogenesis of Osteoarthritis.

BACKGROUND: Resistin may be involved in the pathogenesis of osteoarthritis (OA), but a systematic understanding of the role of resistin in OA is lacking. METHODS: We reviewed studies that evaluated the role of resistin in OA. The expression levels of resistin in vitro experiments and OA/rheumatoid arthritis (RA) patients were analyzed. We also studied potential resistin receptors and the signaling pathways that these receptors activate, ultimately leading to cartilage degeneration. RESULTS: Resistin levels in both the serum and synovial fluid were higher in OA and RA patients than in healthy subjects. Overall, resistin levels are much higher in serum than in synovial fluid. In human cartilage, resistin induces the expression of proinflammatory factors such as degradative enzymes, leading to the inhibition of cartilage matrix synthesis, perhaps by binding to Toll-like receptor 4 and the adenylyl cyclase-associated protein 1 receptor, which then activates the p38-mitogen-activated phosphate kinase, protein kinase A-cyclic AMP, nuclear factor-κB, and C/enhancer-binding protein ß signaling pathways. CONCLUSION: Resistin levels are higher in OA patients than in healthy controls; however, the precise role of resistin in the pathogenesis of OA needs to be studied further. Resistin may be a novel therapeutic target in OA in the future.

Collecting duct carcinoma of the kidney: A case report.

Collecting duct carcinoma (CDC) is a rare type of renal tumor, arising from the distal collecting ducts. The prognosis of this disease is extremely poor due to its rapid progression with widespread metastases. The present study reported a case of CDC involving the right renal region of a 62-year-old female patient, presented with right-flank pain that had persisted for one month. A computed tomography scan demonstrated multiple hypoattenuating quasicircular lesions, 0.5-4.3 cm in size, in the upper pole of the right kidney. Following the diagnosis of a right renal tumor, laparoscopic radical resection of the right kidney was performed. Pathological examination demonstrated that the tumor cells were arranged in a glandular or papillary pattern, and marked cytological atypia was observed. Immunohistochemical staining revealed that the tumor cells were positive for epithelial membrane antigen and cytokeratin (CK)7, while they reacted focally with vimentin. However, the tumor cells were negative for CK20, CD10, uroplakin III and p63. Based on these findings, the patient was diagnosed with CDC. In conclusion, immunohistochemical analysis is critical in establishing an accurate diagnosis of CDC and distinguishing this tumor from other subtypes of RCC.