Metastasis
is a multistep biological process regulated by multiple
signaling pathways. The integrity of the Golgi apparatus plays an
important role in these signaling pathways. Inspired by the mechanism
and our previous finding about accumulation of chondroitin sulfate
in Golgi apparatus in hepatic stellate cells, we developed a Golgi
apparatus-targeting prodrug nanoparticle system by synthesizing retinoic
acid (RA)-conjugated chondroitin sulfate (CS) (CS–RA). The
prodrug nanoparticles appeared to accumulate in the Golgi apparatus
in cancer cells and realized RA release under an acidic environment.
We confirmed that CS–RA exhibited successful inhibition of
multiple metastasis-associated proteins expression in vitro and in vivo by disruption of the Golgi apparatus
structure. Following loading with paclitaxel (PTX), the CS–RA based nanoformulation (PTX–CS–RA)
inhibited migration, invasion, and angiogenesis in vitro and suppressed tumor growth and metastasis in 4T1-Luc bearing mice.
This multistep targeted nanoparticle system potentially enhanced the
effect of antimetastasis combined with chemotherapy.
Background
Osteoarthritis (OA) is the most common chronic degenerative joint disease and is mainly characterized by cartilage degeneration, subcartilage bone hyperplasia, osteophyte formation and joint space stenosis. Recent studies showed that synovitis might also be an important pathological change of OA. However, the molecular mechanisms of synovitis in OA are still not well understood.
Objective
This study was designed to identify key biomarkers and immune infiltration in the synovial tissue of osteoarthritis by bioinformatics analysis.
Materials and Methods
The gene expression profiles of GSE12021, GSE55235 and GSE55457 were downloaded from the GEO database. The differentially expressed genes (DEGs) were identified by the LIMMA package in Bioconductor, and functional enrichment analyses were performed. A protein-protein interaction network (PPI) was constructed, and module analysis was performed using STRING and Cytoscape. The CIBERSORT algorithm was used to analyze the immune infiltration of synovial tissue between OA and normal controls.
Results
A total of 106 differentially expressed genes, including 68 downregulated genes and 38 upregulated genes, were detected. The PPI network was assessed, and the most significant module containing 14 hub genes was identified. Gene Ontology analysis revealed that the hub genes were significantly enriched in immune cell chemotaxis and cytokine activity. KEGG pathway analysis showed that the hub genes were significantly enriched in the rheumatoid arthritis signaling pathway, IL-17 signaling pathway and cytokine-cytokine receptor interaction signaling pathway. The immune infiltration profiles varied significantly between osteoarthritis and normal controls. Compared with normal tissue, OA synovial tissue contained a higher proportion of memory B cells, naive CD4+ T cells, regulatory T cells, resting dendritic cells and resting mast cells, while naive CD4+ T cells, activated NK cells, activated mast cells and eosinophils contributed to a relatively lower portion (P > 0.05). Finally, the expression levels of 11 hub genes were confirmed by RT-PCR.
Conclusion
The hub genes and the difference in immune infiltration in synovial tissue between osteoarthritis and normal controls might provide new insight for understanding OA development.
Biofilm-related bacteria show high resistance to antimicrobial treatments, posing a remarkable challenge to human health. Given bacterial dormancy and high expression of efflux pumps, persistent infections caused by mature biofilms are not easy to treat, thereby driving researchers toward the discovery of many anti-biofilm molecules that can intervene in early stage biofilms formation to inhibit further development and maturity. Compared with mature biofilms, early stage biofilms have fragile structures, vigorous metabolisms, and early attached bacteria are higher susceptibility to antimicrobials. Thus, removing biofilms at the early stage has evident advantages. Many reviews on anti-biofilm compounds that prevent biofilms formation have already been done, but most of them are based on compound classifications to introduce anti-biofilm effects. This review discusses the inhibitory effects of anti-biofilm compounds on early stage biofilms formation from the perspective of the mechanisms of action, including hindering reversible adhesion, reducing extracellular polymeric substances production, interfering in the quorum sensing, and modifying cyclic di-GMP. This information can be exploited further to help researchers in designing new molecules with anti-biofilm activity.
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