Ubiquitination Regulators Discovered by Virtual Screening for the Treatment of Cancer.

The ubiquitin-proteasome system oversees cellular protein degradation in order to regulate various critical processes, such as cell cycle control and DNA repair. Ubiquitination can serve as a marker for mutation, chemical damage, transcriptional or translational errors, and heat-induced denaturation. However, aberrant ubiquitination and degradation of tumor suppressor proteins may result in the growth and metastasis of cancer. Hence, targeting the ubiquitination cascade reaction has become a potential strategy for treating malignant diseases. Meanwhile, computer-aided methods have become widely accepted as fast and efficient techniques for early stage drug discovery. This review summarizes ubiquitination regulators that have been discovered via virtual screening and their applications for cancer treatment.

Antifungal and eliciting properties of chitosan against Ceratocystis fimbriata in sweet potato.

The inhibitive effects of chitosan on black rot disease caused by Ceratocystis fimbriata in sweet potato tuber root (TR) were evaluated. The results demonstrated that chitosan effectively inhibited the mycelial growth and spore germination of C. fimbriata and directly led to the cell necrosis. Chitosan altered the chitin deposition and influenced the fatty acid composition of C. fimbriata. The application of chitosan effectively controlled the C. fimbriata development in sweet potato TRs 17 days of storage 25 °C. Phenylalanine ammonia lyase (PAL) and superoxide dismutase (SOD) activity were clearly enhanced by the chitosan treatment, while the malondialdehyde (MDA) production was not increased. These findings suggest that chitosan effectively controlled the infection of C. fimbriata in sweet potato TRs owing to its antifungal and eliciting properties, which induced some defense responses during storage.

Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy.

Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.

Detection of Pb²âº at attomole levels by using dynamic light scattering and unmodified gold nanoparticles.

Lead ion (Pb²âº) accumulation in nature can affect the environment and human health severely. Thus, rapid and sensitive detection is of great importance. One-step detection of Pb²âº at attomole levels was realized by using dynamic light scattering (DLS) technique coupled with unmodified gold nanoparticles (AuNPs). Pb²âº-dependent DNAzyme was double-stranded and could not adsorb on the surface of AuNPs, while the substrate strand could be cleaved into ssDNA fragments on addition of Pb²âº. The ssDNA fragments could adsorb on the surface of AuNPs and prevent them from aggregating in the presence of NaCl. Therefore, the disperse state of AuNPs changed on addition of Pb²âº in the presence of DNAzyme and NaCl, which was estimated with an average hydrodynamic diameter by using DLS. Under optimum conditions, the average diameter of the solution decreased linearly with the concentration of Pb²âº over the range from 10 to 300 pM, with a detection limit of 6.2 pM. Moreover, satisfactory results were obtained when the proposed method was applied in the detection of Pb²âº in water samples.

Dynamic-light-scattering-based sequence-specific recognition of double-stranded DNA with oligonucleotide-functionalized gold nanoparticles.

An ultrasensitive and simple dynamic-light-scattering (DLS) assay for the sequence-specific recognition of double-stranded DNA (dsDNA) was developed based on detection of the average diameter change of Au nanoparticle (AuNP) probes modified with oligonucleotides 5'-TTTCTCTTCCTT- CTCTTC-(T)(12)-SH-3' (Oligo 1) and 5'-TTCTTTCTTTTCTTTTTC-(T)(12)- SH-3' (Oligo 2). The target dsDNA was composed of two complementary oligonucleotides: 5'-AAAGAGAAGGAAGAGAAGAAGAAAGAAAAGAAAAAG-3' (Oligo 3) and 3'-TTTCTCTTCCTTCTCTTCTTCTTTCTTTTCTTTTTC-5' (Oligo 4). Hybridization of the two AuNPs-Oligo probes with the target dsDNA induced aggregation of the target dsDNA by forming triplex DNA, which accordingly increased the average diameter. This diameter change could then be detected by DLS. The average diameter was proportional to the target dsDNA concentration over the range from 593 fM to 40 pM, with a detection limit of 593 fM. Moreover, the assay had good sequence specificity for the target dsDNA.