Summary PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here we report that PTENα, an N-terminally extended form of PTEN, functions in metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation and a CUG-centered palindromic motif is required in this process. PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. We show that PTENα interacts with canonical PTEN to increase PINK1 and promote energy production. These data provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes. Our studies suggest that mammalian cells can use alternate translation initiation mechanisms to generate protein isoforms.

A series of novel 5-[1-aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl] -2-arylamino-1,3,4-oxadiazoles, fungicidally active, were synthesized based on bioisosterism and tested in vivo against wheat leaf rust, Puccinia recondita. These compounds were shown to be fungicidally active, and their activity was influenced by the nature of the substituents. By using the three-dimensional quantitative structure-activity relationships (3D-QSAR) method of comparative molecular field analysis (CoMFA), we have studied the structure and activity relationship of the compounds containing both pyridazinone-substituted 1,3,4-thiadiazoles and pyridazinone-substituted 1,3,4-oxadiazoles. The 3D-QSAR modes gave good correlation between the variations on percent inhibition and the steric-electrostatic properties. The results are consistent with a common mode of action for the pyridazinone-substituted 1,3,4-thiadiazoles and the pyridazinone-substituted 1,3,4-oxadiazoles, which further confirms that the 1,3,4-oxadiazole ring is a bioisosteric analogue of the 1,3,4-thiadiazole ring. These offer important structural insights into designing highly active compounds prior to their synthesis.

Single-walled carbon-nanohorns (SNH) exhibit huge application prospects. Notably, spherical SNH possess different morphology from conventional carbon nanotubes (CNT). However, there is a tremendous lack of studies on the nanotoxicity and mechanism of SNH, and their comparison with nanotubes. Here, the dissimilarity between SNH and CNT is found in many aspects including necrosis, pyroptosis, apoptosis, protein expression, hydrolases leakage, lysosome stress, membrane disturbance and the interaction with membrane proteins. The improved biocompatibility of SNH over four types of established CNT is clearly demonstrated in macrophages. Importantly, a key transmembrane protein, glycoprotein nonmetastatic melanoma protein B (GPNMB) is discovered to initiate the nanotoxicity. Compared to CNT, the weaker nano-GPNMB interaction in SNH group induces lower degree of cascade actions from nano/membrane interplay to final cell hypotoxicity. In conclusion, the geometry of single-construct unit, but not that of dispersive forms or intracellular levels of nanocarbons make the most difference.

Overcoming the epithelial barriers to enhance drug transport is a focused topic for gastrointestinal, intratracheal, intranasal, vaginal, and intrauterine delivery. Nanomedicines with targeting functionization promote such a process owing to specific ligand–receptor interaction. However, compared to the cell uptake of targeting nanotherapies, currently few studies concentrate on their transcytosis including endocytosis for “in” and exocytosis for “out”. In fact, the cellular regulatory mechanism for these pathways as well as the principle of ligand’s effect on the transcytosis are almost ignored. Here, we fabricated transferrin (Tf) functionalized nanogranules (Tf-NG) as the nanomedicine model and confirmed the difference in polar distributions of Tf receptors (TfRs) between two epithelium models (bipolarity for Caco-2 and unipolarity for MDCK cells). Compared to the nonspecific reference, Tf-conjugation boosted the endocytosis by different pathways in two cell models and transformed the intracellular route of Tf-NG in both cells differently, affecting exocytosis, recycling, and degradation but not the secretion pathway. Only bipolar cells could establish a complete transport flow from “in” to “out”, leading to the enhanced transcytosis of Tf-NG. Importantly, epithelia could make responses to Tf-NG transcytosis. Based on the quantitative proteomics, the intracellular trafficking of Tf-NG altered the protein expression profiles, in which the endocytosis- and transcytosis-related proteins were specifically upregulated. Particularly, only bipolar cells could positively feed back to such trafficking via accelerating the subsequent Tf-NG transcytosis. Here, all the cell transport of Tf-NG was polarity associated. In summary, Tf modification elevated the transcytosis of Tf-NG across the epithelium by triggering the polarity-associated transport flow and positive cell feedback loop. These findings provided an insight into the targeting nanodelivery for efficient transport through epithelial barriers.