Quality,bioactivity study,and preclinical acute toxicity,safety pharmacology evaluation of PEGylated recombinant human endostatin (M2ES)

Endostar, a potent endogenous antiangiogenic factor, is wildly used in clinics. However, it was easily degraded by enzymes and rapidly cleared by the kidneys. To overcome these shortcomings, PEGylated recombinant human endostatin was developed. In this study, the purity of M₂ES was evaluated by silver stain and reversed‐phase high‐performance liquid chromatography. Ultraviolet spectrum was used to examine the structural of M₂ES and endostar. The bioactivity and antitumor efficacy of M₂ES were evaluated using an in vitro endothelial cell migration model and athymic nude mouse xenograft model of a heterogeneous lung adenocarcinoma, respectively. A preclinical study was performed to evaluate the acute toxicity and safety pharmacology in rhesus monkeys. The purity of M₂ES was more than 98%; PEG modification has no effect on endostatin structure. Compared with the control group, M₂ES dramatically retards endothelial cell migration and tumor growth. After intravenous (IV) infusions of M₂ES at a dose level of three and 75 mg/kg in rhesus monkeys, there was no observable serious adverse event in both acute toxicity and safety pharmacology study. On the basis of the quality and bioactivity study data of M₂ES and the absence of serious side effect in rhesus monkeys, M₂ES was authorized to initiate a phase I clinical trial.     

Overexpression of RYBP inhibits proliferation,invasion, and chemoresistance to cisplatin in anaplastic thyroid cancer cells via the EGFR pathway

Ring1 and YY1 binding protein (RYBP), a new member of the polycomb group protein family, has been reported to play an important role in various biological processes. Recently, more and more studies have demonstrated an implication of RYBP in cancer development. However, the specific role of RYBP in anaplastic thyroid cancer (ATC) remains unknown. In this study, we investigated for the first time the expression pattern and biological functions of RYBP in ATC. We showed that RYBP was lowly expressed in ATC tissues and cell lines. We also found that overexpression of RYBP inhibited ATC cell proliferation, invasion, and cisplatin resistance. Furthermore, we observed that upregulation of RYBP decreased the phosphorylation of EGFR and ERK1/2 in ATC cells. Taken together, our data indicated that RYBP might be considered as a promising therapeutic target for the treatment of ATC.     

Condensin-Dependent Chromatin Compaction Represses Transcription Globally during Quiescence

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Assembly of rhizosphere microbial communities in Artemisia annua: recruitment of plant growth‐promoting microorganisms and inter‐kingdom interactions between bacteria and fungi

Plant and Soil - Plant roots assemble unique microbial communities in rhizosphere, which are critical for plant adapting to natural environment. Given the pivotal importance of plant-microbe...     

Bak interacts with AKT and is involved in TNFα/CHX-induced apoptosis

Molecular and Cellular Biochemistry - Bak is important for TNFα/CHX-induced neuronal death, but the precise molecular mechanism remains unclear. At the same time, TNFα/CHX concomitantly...     

PIK3CA hotspot mutations p. H1047R and p. H1047L sensitize breast cancer cells to thymoquinone treatment by regulating the PI3K/Akt1 pathway

Background

Nigella sativa (N. sativa) exhibits anti-inflammatory, antioxidant, antidiabetic, antimetastatic and antinociceptive effects and has been used to treat dozens of diseases. Thymoquinone (TQ) is an important and active component isolated from N. sativa seeds. Inhibition of cancer-associated activating PIK3CA mutations is a new prospective targeted therapy in personalized metastatic breast cancer (MBC). TQ is reported to be an effective inhibitor of the PI3K/Akt1 pathway in MBC. This study aimed to evaluate the in vitro antitumor effect of TQ in the context of two PIK3CA hotspot mutations, p. H1047R and p. H1047L.

Methods and results

Molecular dynamics, free energy landscapes and principal component analyses were also used to survey the mechanistic effects of the p. H1047R and p. H1047L mutations on the PI3K/Akt1 pathway. Our findings clearly confirmed that the p. H1047R and p. H1047L mutants could reduce the inhibitory effect of ΔNp63α on the kinase domain of PIK3CA, resulting in increased activity of PI3K downstream signals. Structurally, the partial disruption of the interaction between the ΔNp63α DNA binding domain and the PIK3CA kinase domain at residues 114–359 and 797–1068 destabilizes the conformation of the activation loop and modifies the PIK3CA/ΔNp63α complex. Alongside these structural changes, we found that TQ treatment resulted in high PI3K/Akt1 pathway inhibition in p. H1047R and p. H1047L-expressing cells versus wild-type cells.

Conclusions

These two PIK3CA hotspot mutations therefore not only contribute to tumor progression in patients with MBC but may also serve as targets for the development of novel small molecule therapeutic strategies.

     

EphA4 Obstructs Spinal Cord Neuron Regeneration by Promoting Excessive Activation of Astrocytes

Cellular and Molecular Neurobiology - Studies have found that molecular targets that regulate tissue development are also involved in regulating tissue regeneration. Erythropoietin-producing...