Codelivery of CuS and DOX into Deep Tumors with Size and Charge-Switchable PAMAM Dendrimers for Chemo-photothermal Therapy.

Accurate targeting of therapeutic agents to specific tumor tissues, especially via deep tumor penetration, has been an effective strategy in cancer treatments. Here, we described a flexible nanoplatform, pH-responsive zwitterionic acylsulfonamide betaine-functionalized fourth-generation PAMAM dendrimers (G4-AB), which presented multiple advantages for chemo-photothermal therapy, including template synthesis of ultrasmall copper sulfide (CuS) nanoparticles and further encapsulation of doxorubicin (DOX) (G4-AB-DOX/CuS), long-circulating performance by a relatively large size and zwitterionic surface in a physiological environment, combined size shrinkage, and charge conversions via pH-responsive behavior in an acidic tumor microenvironment (TME). Accordingly, high tumor penetration and positive cell uptake for CuS and DOX have been determined, which triggered an excellent combination treatment under near-infrared irradiation in comparison to the monochemotherapy system and irresponsive chemo-photothermal system. Our study represented great promise in constructing multifunctional carriers for the effective delivery of photothermal nanoparticles and drugs in chemo-photothermal therapy.

Genome-Wide Analysis of U-box E3 Ubiquitin Ligase Family in Response to ABA Treatment in Salvia miltiorrhiza.

Plant U-box (PUB) proteins are ubiquitin ligases (E3) involved in multiple biological processes and in response to plant stress. However, the various aspects of the genome and the differences in functions between the U-box E3 (UBE3) ubiquitin ligases remain quite obscure in Salvia miltiorrhiza. The 60 UBE3 genes in the S. miltiorrhiza genome were recognized in the present study. The phylogenetic analysis, gene structure, motifs, promoters, and physical and chemical properties of the genes were also examined. Based on the phylogenetic relationship, the 60 UBE3 genes were categorized under six different groups. The U-box domain was highly conserved across the family of UBE3 genes. Analysis of the cis-acting element revealed that the UBE3 genes might play an important role in a variety of biological processes, including a reaction to the abscisic acid (ABA) treatment. To investigate this hypothesis, an ABA treatment was developed for the hairy roots of S. miltiorrhiza. Thirteen out of the UBE3 genes significantly increased after the ABA treatment. The co-expression network revealed that nine UBE3 genes might be associated with phenolic acids or tanshinone biosynthesis. The findings of the present study brought fresh and new understanding to the participation of the UBE3 gene family in plants, specifically in their biological responses mediated by the ABA. In S. miltiorrhiza, this gene family may be crucial during the ABA treatment. Significantly, the results of this study contribute novel information to the understanding of the ubiquitin ligase gene and its role in plant growth.

A ratiometric fluorescent nanoprobe for signal amplification monitoring of intracellular telomerase activity.

Telomerase is considered a valuable diagnostic and prognostic cancer biomarker. Accurate and reliable detection of telomerase activity is of great value in clinical diagnosis, screening of inhibitors, and therapeutics. Here, we developed a novel amplified fluorescence resonance energy transfer (FRET) nanoprobe for highly sensitive and reliable monitoring of intracellular telomerase activity. The nanoprobe (QDSA@DNA) was composed of a streptavidin-modified quantum dot (QDSA) which was functionalized with a telomerase primer sequence (TP) and Cy5-tagged signal switching sequence (SS) through biotin-streptavidin interaction. When the nanoprobe was assembled, the Cy5 was in close proximity to the QDSA, resulting in high FRET efficiency from the QDSA to Cy5. In the presence of telomerase, the TP could be extended to produce telomeric repeat units, which was complementary to the loop of SS. Thus, the SS could hybridize with elongated sequences to form a rigid double-stranded structure, which forced the Cy5 away from the surface of the QDSA, causing low FRET efficiency. Furthermore, due to the production of multiple repeat units by telomerase, multiple hairpin structures could be opened, yielding significant fluorescence ratio (FQDsa/FCy5) enhancement for sensing of telomerase activity. In this way, the combination of a FRET and target-assisted strategy in a nanoprobe improved the detection accuracy and amplified the detection signal, respectively. The QDSA@DNA nanoprobe also showed high selectivity, excellent nuclease stability, and good biocompatibility. More importantly, this nanoprobe was found to be an excellent platform for efficient monitoring of intracellular telomerase activity, providing a potential platform in tumor diagnosis and screening of telomerase-related inhibitors.

[Research progress on medicinal values of scorpion venom components].

For thousands of years, scorpions and their venoms have been applied in traditional medicine in China to treat a variety of difficult miscellaneous diseases. The venom is a complex mixture of bioactive molecules, such as peptides and proteins (e.g. neurotoxins). Among them, neurotoxins (named scorpion toxins) are the most important bioactive components. Up to now, more and more characterized venom components have been isolated from different scorpions, providing numerous candidate molecules for drug design and development. Many investigations have shown the potent effects of venom or its components against the nervous, immune, infection, cardiovascular and neoplastic diseases. Moreover, the scorpion toxins could be used as molecular backbone to develop new specific drugs based on their unique structures and functions. In this review, we focus on the medicinal values and the possible mechanisms of scorpion toxins with promising medicinal prospect against the relative diseases, providing the data basis for further development of relative drugs.

Baicalein inhibits TNF-α-induced NF-κB activation and expression of NF-κB-regulated target gene products.

The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified baicalein from Scutellaria baicalensis as an inhibitor of NF-κB activation. As examined by the NF-κB luciferase reporter assay, we found that baicalein suppressed TNF-α-induced NF-κB activation in a dose-dependent manner. It also inhibited TNF-α-induced nuclear translocation of p65 through inhibition of phosphorylation and degradation of IκBα. Furthermore, baicalein blocked the TNF-α-induced expression of NF-κB target genes involved in anti-apoptosis (cIAP-1, cIAP-2, FLIP and BCL-2), proliferation (COX-2, cyclin D1 and c-Myc), invasion (MMP­9), angiogenesis (VEGF) and major inflammatory cytokines (IL-8 and MCP1). The flow cytometric analysis indicated that baicalein potentiated TNF-α-induced apoptosis and induced G1 phase arrest in HeLa cells. Moreover, baicalein significantly blocked activation of p38, extracellular signal-regulated kinase 1/2 (ERK1/2). Our results imply that baicalein could be a lead compound for the modulation of inflammatory diseases as well as certain cancers in which inhibition of NF-κB activity may be desirable.