WM130 preferentially inhibits hepatic cancer stem-like cells by suppressing AKT/GSK3β/β-catenin signaling pathway

OBJECTIVE The eradication of cancer stem cells(CSCs) is signifcant for cancer therapy and prevention.METHODS In this study,we evaluated WM130,a novel derivative of matrine,for its effect on CSCs using human hepatocellular carcinoma(HCC) cell lines,their sphere cells,and sorted EpCAM+cells.RESULTS We revealed that WM130 could not only inhibit proliferation and colony formation of HCC cells,but also suppress the expression of some stemness-related genes and up-regulate some mature hepatocyte marker genes,indicating a promotion of differentiation from CSCs to hepatocytes.WM130 also suppressed the proliferation of doxorubicin-resistant hepatoma cells,and markedly reduced the cells with CSC biomarker EpCAM.Moreover,WM130 suppressed HCC spheres,not only primary spheres but also subsequent spheres,indicating an inhibitory effect on self-renewal capability of CSCs.Interestingly,WM130 exhibiteda remarkable inhibitory preference on HCC spheres and EpCAM+cells rather than their parental HCC cells and EpCAM-cells respectively.In vivo,WM130 inhibited HCC xenograft growth,decreased the number of sphere-forming cells,and remarkably decreased the levels of EpCAM mRNA and protein in tumor xenografts.Better inhibitory effect was achieved by WM130 in combination with doxorubicin.Further mechanism study revealed that WM130 inhibited AKT/GSK3β/β-catenin signaling pathway.CONCLUSION Collectively,our results suggest that WM130 remark.ably inhibits hepatic CSCs,and this effect may via the down-regulation of the AKT/GSK3β/β-catenin pathway.These findings provide a strong rationale for the use of WM130 as a novel drug candidate in HCC therapy.

Mass spectrometry based proteomics profiling of human monocytes

Human monocyte is an important cell type which is involved in various complex human diseases. To better understand the biology of human monocytes and facilitate further studies, we developed the first comprehensive proteome knowledge base specifically for human monocytes by integrating both in vivo and in vitro datasets. The top 2000 expressed genes from in vitro datasets and 779 genes from in vivo experiments were integrated into this study. Altogether, a total of 2237 unique monocyte-expressed genes were cataloged. Biological functions of these monocyte-expressed genes were annotated and classified via Gene Ontology （GO） analysis. Furthermore, by extracting the overlapped genes from in vivo and in vitro datasets, a core gene list including 541 unique genes was generated. Based on the core gene list, further gene-disease associations, pathway and network analyses were performed. Data analyses based on multiple bioinformatics tools produced a large body of biologically meaningful information, and revealed a number of genes such as SAMHDI, G6PD, GPD2 and EN01, which have been reported to be related to immune response, blood biology, bone remodeling, and cancer respectively. As a unique resource, this study can serve as a reference map for future in-depth research on monocytes biology and monocyte-involved human diseases.

Highly reliable and efficient encoding systems for hexadecimal polypeptide-based data storage

Polypeptides consisting of amino acid(AA)sequences are suitable for high-density information storage.However,the lack of suitable encoding systems,which accommodate the characteristics of polypeptide synthesis,storage and sequencing,impedes the application of polypeptides for large-scale digital data storage.To address this,two reliable and highly efficient encoding systems,i.e.RaptorQ-Arithmetic-Base64-Shuffle-RS(RABSR)and RaptorQArithmetic-Huffman-Rotary-Shuffle-RS(RAHRSR)systems,are developed for polypeptide data storage.The two encoding systems realized the advantages of compressing data,correcting errors of AA chain loss,correcting errors within AA chains,eliminating homopolymers,and pseudo-randomized encrypting.The coding efficiency without arithmetic compression and error correction of audios,pictures and texts by the RABSR system was 3.20,3.12 and 3.53 Bits/AA,respectively.While that using the RAHRSR system reached 4.89,4.80 and 6.84 Bits/AA,respectively.When implemented with redundancy for error correction and arithmetic compression to reduce redundancy,the coding efficiency of audios,pictures and texts by the RABSR system was 4.43,4.36 and 5.22 Bits/AA,respectively.This efficiency further increased to 7.24,7.11 and 9.82 Bits/AA by the RAHRSR system,respectively.Therefore,the developed hexadecimal polypeptide-based systems may provide a new scenario for highly reliable and highly efficient data storage.

Different stapling-based peptide drug design:Mimicking α-helix as inhibitors of protein-protein interaction

Peptide stapling strategy has been proven a promising solution in addressing two major pharmacological hurdles, proteolytic stability and membrane permeability, for small peptides as therapeutics. This stapling peptides feature a covalent cross-link of side chains, thus effectively mimicking α-helix as inhibitors of protein-protein interactions. In this review, we category and analyze key examples of various peptide stapling strategies based on different cross-links aligned on the side chain of peptides mainly in the last three years.

A mirror-image protein-based information barcoding and storage technology

A mirror-image protein-based information barcoding and storage technology wherein D-amino acids are used to encode information into mirror-image proteins that are chemically synthesized is described.These mirror-image proteins were then fused into various materials from which information-encoded objects were produced.Subsequently,the mirror-image proteins were extracted from the objects using biotin-streptavidin resin-mediated specific enrichment and cleaved using an Ni(Ⅱ)-mediated selective peptide cleavage.Protein sequencing was accomplished using liquid chromatography/tandem mass spectrometry(LC-MS/MS)and then transcoded into the recorded information.We demonstrated the use of this technology to encode Chinese words into mirror-image proteins,which were then fused onto a poly(ethylene terephthalate)(PET)film and retrieved and decoded by LC-MS/MS sequencing.Compared to information barcoding and storage technologies using natural biopolymers,the mirrorimage biopolymers used in our technology may be more stable and durable.

Generalized Tweakable Even-Mansour Cipher and Its Applications

This paper describes a generalized tweakable blockcipher HPH （Hash-Permutation-Hash）, which is based ona public random permutation P and a family of almost-XOR-universal hash functions H={HK}K∈κ as a tweak and keyschedule, and defined as y = HPHK（（t1, t2）, x） = P（x HK（t1）） HK（t2）, where K is a key randomly chosen from a keyspace/C, （tl, t2） is a tweak chosen from a valid tweak space T, x is a plaintext, and y is a ciphertext. We prove that HPHis a secure strong tweakable pseudorandom permutation （STPRP） by using H-coefficients technique. Then we focus on thesecurity of HPH against multi-key and related-key attacks. We prove that HPH achieves both multi-key STPRP security andrelated-key STPRP security. HPH can be extended to wide applications. It can be directly applied to authentication andauthenticated encryption modes. We apply HPH to PMAC1 and OPP, provide an improved authentication mode HPMACand a new authenticated encryption mode OPH, and prove that the two modes achieve single-key security, multi-key security,and related-key security.

Chemical Synthesis of Structurally Defined Phosphorylated Ubiquitins Suggests Impaired Parkin Activation by Phosphorylated Ubiquitins with a Non-Phosphorylated Distal Unit

Mutations in genes encoding PINK1(PTEN-induced kinase 1)and Parkin(E3 ubiquitin ligase)are identified in familial Parkinson’s disease.However,it remains unclear whether the phosphorylated Ub chains activate wild-type Parkin(w-Parkin)or phosphorylated Parkin(p-Parkin),with the consequent expulsion of the damaged mitochondria.