Uncariitannin, a polyphenolic polymer from Uncaria gambier, attenuates Staphylococcus aureus virulence through an MgrA-mediated regulation of α-hemolysin.

A global transcriptional regulator, MgrA, was previously identified as a key determinant of virulence in Staphylococcus aureus. An 80% EtOH extract of Uncaria gambier was found to attenuate the virulence of S. aureus via its effects on MgrA. Using bioassay-guided fractionation, a polyphenolic polymer, uncariitannin, was found to be the main bioactive constituent of the extract, and its structure was characterized using spectral and chemical analysis. The molecular weight and polydispersity of uncariitannin were determined by gel permeation chromatography-refractive index-light scattering analysis. An electrophoretic mobility shift assay showed that uncariitannin could effectively inhibit the interaction of MgrA with DNA in a dose-dependent manner. Treatment with uncariitannin could decrease the mRNA and protein levels of Hla in both the S. aureus Newman and USA300 LAC strains. Further analysis of Hla expression levels in the Newman ΔmgrA and Newman ΔmgrA/pYJ335-mgrA strains indicated that uncariitannin altered Hla expression primarily in an MgrA-dependent manner. A mouse model of infection indicated that uncariitannin could attenuate MRSA virulence. In conclusion, uncariitannin may be a potential candidate for further development as an antivirulence agent for the treatment of S. aureus infection.

Erratum: In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell: Erratum.

[This corrects the article DOI: 10.7150/thno.19840.].

Protective Effect of Quercetin in LPS-Induced Murine Acute Lung Injury Mediated by cAMP-Epac Pathway.

Quercetin (Que) as an abundant flavonol element possesses potent antioxidative properties and has protective effect in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the specific mechanism is still unclear, so we investigated the effect of Que from in vivo and in vitro studies and the related mechanism of cAMP-PKA/Epac pathway. The results in mice suggested that Que can inhibit the release of inflammatory cytokine, block neutrophil recruitment, and decrease the albumin leakage in dose-dependent manners. At the same time, Que can increase the cAMP content of lung tissue, and Epac content, except PKA. The results in epithelial cell (MLE-12) suggested that Que also can inhibit the inflammatory mediators keratinocyte-derived chemokines release after LPS stimulation; Epac inhibitor ESI-09 functionally antagonizes the inhibitory effect of Que; meanwhile, PKA inhibitor H89 functionally enhances the inhibitory effect of Que. Overexpression of Epac1 in MLE-12 suggested that Epac1 enhance the effect of Que. All those results suggested that the protective effect of quercetin in ALI is involved in cAMP-Epac pathway.

In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell.

Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations. The in vivo bioactivity study of the peptide in the ovarian teratocarcinoma (PA-1) xenograft model showed a tumor growth rate inhibition of 70% with a dosage of 10 mg/kg (one injection every other day). This is the first application of a stabilized peptide modulator targeting stem-like cancer cell both in vitro and in vivo and provides references to cancer stem cell therapy.

Black phosphorus quantum dot based novel siRNA delivery systems in human pluripotent teratoma PA-1 cells.

As a novel semiconducting material, the inherent, direct, and appreciable band gap endows BP with preferable optical and electronic properties other than graphene and transition metal dichalcogenides. In addition, bio-related applications with equal importance also attract great attention thanks to several inherited advantages of BP including large drug loading capacity, high PDT efficiency, high biocompatibility and degradability. However, to date there is limited research about the biomedical applications of BP. In this study, we reported the engineering of polyelectrolyte polymers coated BP quantum dots (BP-QDs)-based nanocarriers to deliver small interfering RNA (siRNA) into human ovarian teratocarcinoma PA-1 cells. Compared to the commercial delivery reagents, superior transfection efficiency of BP-QD was detected. The expression of the LSD1 (lysine-specific demethylase 1) mRNA in PA-1 cells was significantly suppressed by BP-QDs-LSD1 siRNA complex. Notably, BP-QDs possess excellent biocompatibility and low cytotoxicity even at concentrations as high as 5 mg mL-1. The combination treatment of BP nanodots-LSD1 siRNA complex with NIR light could inhibit the cell growth rate by more than 80%. In conclusion, this is the first application of BP-QDs as gene delivery systems, which shows promising potential for siRNA delivery and photothermal effects in cancer therapy.

Crosslinked Aspartic Acids as Helix-Nucleating Templates.

Described is a facile helix-nucleating template based on a tethered aspartic acid at the N-terminus [terminal aspartic acid (TD)]. The nucleating effect of the template is subtly influenced by the substituent at the end of the side-chain-end tether as indicated by circular dichroism, nuclear magnetic resonance, and molecular dynamics simulations. Unlike most nucleating strategies, the N-terminal amine is preserved, thus enabling further modification. Peptidomimetic estrogen receptor modulators (PERMs) constructed using this strategy show improved therapeutic properties. The current strategy can be regarded as a good complement to existing helix-stabilizing methods.

Disulfide Bridges in Defensins.

Defensins are small cationic cysteine rich peptides, which usually contain 18-45 amino acids and possess amphiphilic properties. The term "defensin" was coined as the sequences of rabbit and human leukin/phagocytin molecules were first reported in 1985. Since then, various defensins were isolated and characterized from insects, plants and vertebrates. Using vertebrate defensins as examples, defensins are categorized into three sub-families based on their different patterns of intramolecular disulfide linkages: α defensins, ß defensins, and θ defensins. During the past decades, continuous attentions were casted on various defensins for their broad activity against bacteria, fungi and viruses. In this review, we focus on the effect of characteristic intramolecular disulfide bonds on the antimicrobial activity of defensins. The disulfide bonds are important for holding the defensins in their three dimensional structures, while also contribute to their antimicrobial activity and chemotactic activity. This review summarizes the effects of disulfide bonds, their synthetic formation pathways and potential pharmaceutical applications.