Electrospun Nanofiber Composites for Drug Delivery: A Review on Current Progresses.

A medication's approximate release profile should be sustained in order to generate the desired therapeutic effect. The drug's release site, duration, and rate must all be adjusted to the drug's therapeutic aim. However, when designing drug delivery systems, this may be a considerable hurdle. Electrospinning is a promising method of creating a nanofibrous membrane since it enables drugs to be placed in the nanofiber composite and released over time. Nanofiber composites designed through electrospinning for drug release purposes are commonly constructed of simple structures. This nanofiber composite produces matrices with nanoscale fiber structure, large surface area to volume ratio, and a high porosity with small pore size. The nanofiber composite's large surface area to volume ratio can aid with cell binding and multiplication, drug loading, and mass transfer processes. The nanofiber composite acts as a container for drugs that can be customized to a wide range of drug release kinetics. Drugs may be electrospun after being dissolved or dispersed in the polymer solution, or they can be physically or chemically bound to the nanofiber surface. The composition and internal structure of the nanofibers are crucial for medicine release patterns.

CRL4Cdt2 Ubiquitin Ligase, A Genome Caretaker Controlled by Cdt2 Binding to PCNA and DNA.

The ubiquitin ligase CRL4Cdt2 plays a vital role in preserving genomic integrity by regulating essential proteins during S phase and after DNA damage. Deregulation of CRL4Cdt2 during the cell cycle can cause DNA re-replication, which correlates with malignant transformation and tumor growth. CRL4Cdt2 regulates a broad spectrum of cell cycle substrates for ubiquitination and proteolysis, including Cdc10-dependent transcript 1 or Chromatin licensing and DNA replication factor 1 (Cdt1), histone H4K20 mono-methyltransferase (Set8) and cyclin-dependent kinase inhibitor 1 (p21), which regulate DNA replication. However, the mechanism it operates via its substrate receptor, Cdc10-dependent transcript 2 (Cdt2), is not fully understood. This review describes the essential features of the N-terminal and C-terminal parts of Cdt2 that regulate CRL4 ubiquitination activity, including the substrate recognition domain, intrinsically disordered region (IDR), phosphorylation sites, the PCNA-interacting protein-box (PIP) box motif and the DNA binding domain. Drugs targeting these specific domains of Cdt2 could have potential for the treatment of cancer.

A DNA-binding domain in the C-terminal region of Cdt2 enhances the DNA synthesis-coupled CRL4Cdt2 ubiquitin ligase activity for Cdt1.

The Cullin-RING ubiquitin ligase CRL4Cdt2 maintains genome integrity by mediating the cell cycle- and DNA damage-dependent degradation of proteins such as Cdt1, p21 and Set8. Human Cdt2 has two regions, a conserved N-terminal seven WD40 repeat region and a less conserved C-terminal region. Here, we showed that the N-terminal region is sufficient for complex formation with CRL4, but the C-terminal region is required for the full ubiquitin ligase activity. UV irradiation-induced polyubiquitination and degradation of Cdt1 were impaired in Cdt2 (N-terminus only)-expressing cells. Deletion and mutation analysis identified a domain in the C-terminal region that increased ubiquitination activity and displayed DNA-binding activity. The identified domain mediated binding to double-stranded DNA and showed higher affinity binding to single-stranded DNA. As the ligase activity of CRL4Cdt2 depends on proliferating cell nuclear antigen (PCNA) loading onto DNA, the present results suggest that the DNA-binding domain facilitates the CRL4Cdt2-mediated recognition and ubiquitination of substrates bound to PCNA on chromatin.