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Although stapled peptides offer a powerful solution to overcome the susceptibility of linear peptides to proteolytic degradation and improve their ability to cross membranes, an efficient and durable disease treatment strategy has not yet been developed due to the inevitable elimination of peptide inhibitors and rapid accumulation of target proteins. Herein we developed stapled peptide-based proteolysis-targeting chimeras (SP-PROTACs), that simultaneously exhibited improved cellular uptake and proteolytic stability attributed to the stapled peptides, and efficient target protein degradation promoted by the PROTACs. Based on the PMI peptide with dual specificity for both MDM2 and MDMX, a series of SP-PROTACs were designed. Among them, the optimized SPMI-HIF2-1 exhibited similar binding affinity with MDM2 and MDMX but obviously higher helical contents, improved proteolytic stability, better cellular permeability, and a better pharmacokinetic profile compared with its linear counterpart. Importantly, SPMI-HIF2-1 could effectively kill cancer cells and inhibit tumor progression in subcutaneous and orthotopic colorectal cancer xenograft models through simultaneously promoting the atypical degradation of both MDM2 and MDMX and durable p53 activation. An FP-based binding assay and structural modeling analysis of the ternary complex suggested that SPMI-HIF2-1 simultaneously bound with the target protein and E3 ligase. Our findings not only provide a new class of anticancer drug candidates, but also bridge the gap and reduce the physical distance between peptides and PROTACs.

Aberrant activation of Wnt/β-catenin signaling has been associated with the onset and progression of many types of tumors and thus β-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to β-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/β-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient β-catenin degradation. The obtained xStAx-VHLL sustained β-catenin degradation and manifested strong inhibition of Wnt signaling in cancer cells and in APC −/− organoids. Furthermore, xStAx-VHLL could effectively restrain tumor formation in BALB/C nude mice, and diminish the existing tumors in APC min/+ mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patient-derived organoids. These findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of β-catenin degrader PROTACs as a new class of promising anticancer agent.

Abstract Context Though genome-wide association studies (GWASs) have identified hundreds of genetic variants associated with osteoporosis related traits, such as bone mineral density (BMD) and fracture, it remains a challenge to interpret their biological functions and underlying biological mechanisms. Objective Integrate diverse expression quantitative trait loci and splicing quantitative trait loci data with several powerful GWAS datasets to identify novel candidate genes associated with osteoporosis. Design, Setting, and Participants Here, we conducted a transcriptome-wide association study (TWAS) for total body BMD (TB-BMD) (n = 66 628 for discovery and 7697 for validation) and fracture (53 184 fracture cases and 373 611 controls for discovery and 37 857 cases and 227 116 controls for validation), respectively. We also conducted multi-SNP-based summarized mendelian randomization analysis to further validate our findings. Results In total, we detected 88 genes significantly associated with TB-BMD or fracture through expression or ribonucleic acid splicing. Summarized mendelian randomization analysis revealed that 78 of the significant genes may have potential causal effects on TB-BMD or fracture in at least 1 specific tissue. Among them, 64 genes have been reported in previous GWASs or TWASs for osteoporosis, such as ING3, CPED1, and WNT16, as well as 14 novel genes, such as DBF4B, GRN, TMUB2, and UNC93B1. Conclusions Overall, our findings provide novel insights into the pathogenesis mechanisms of osteoporosis and highlight the power of a TWAS to identify and prioritize potential causal genes.

This paper describes a generalized tweakable blockcipher HPH (Hash-Permutation-Hash), which is based on a public random permutation P and a family of almost-XOR-universal hash functions H = HK K ∈ K as a tweak and key schedule, and defined as y = HPH K (( t 1 , t 2 ) , x ) = P ( x ⊕ H K ( t 1 )) ⊕ H K ( t 2 ), where K is a key randomly chosen from a key space K , ( t 1 , t 2 ) is a tweak chosen from a valid tweak space T , x is a plaintext, and y is a ciphertext. We prove that HPH is a secure strong tweakable pseudorandom permutation (STPRP) by using H-coefficients technique. Then we focus on the security of HPH against multi-key and related-key attacks. We prove that HPH achieves both multi-key STPRP security and related-key STPRP security. HPH can be extended to wide applications. It can be directly applied to authentication and authenticated encryption modes. We apply HPH to PMAC1 and OPP, provide an improved authentication mode HPMAC and a new authenticated encryption mode OPH, and prove that the two modes achieve single-key security, multi-key security, and related-key security.

A robust, microwave‐assisted, highly efficient, solid‐phase peptide synthesis method for preparing isopeptide‐linked 62‐mer and 76‐mer isoubiquitins and polyubiquitin is developed. The strategy avoids the use of costly resins and pseudoprolines, and the isopeptide‐linked building blocks can be assembled with high initial purity within 1 day. All seven diubiquitins are successfully synthesized on a multi‐milligram scale; a four‐segment, three‐ligation method is used to obtain a K33‐/K11‐linked mixed triubiquitin in excellent yield. Circular dichroism and crystallographic analyses are used to verify the structures of the well‐folded, synthetic polyubiquitin chains. The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of isopeptide‐linked isoUbs and to pave the way for the study of longer polyubiquitin chains. A robust and highly efficient, high‐efficiency solid phase peptide synthesis–based strategy for the synthesis of isopeptide‐linked 62‐mer and 76‐mer isoubiquitins, various diubiquitins, and K33‐/K11 mixed triubiquitin is developed. The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of isopeptide‐linked isoubiquitins and to pave the way for the study of longer polyubiquitin chains.

Matrine is an alkaloid extracted from a Chinese herb Sophora flavescens Ait, which has shown chemopreventive potential against various cancers. In this study, we evaluated the anticancer efficacy of a novel derivative of matrine, （6aS, 10S, 11aR, 11bR, 11cS）- lO-methylamino-dodecahydro-3a,7a-diazabenzo （de） anthracene-8-thione （MASM）, against human hepatocellular carcinoma （HCC） ceils and their corresponding sphere cells in vitro and in vivo. Human HCC cell lines （Hep3B and Huh7） were treated with MASM. Cell proliferation was assessed using CCK8 and colony assays; cell apoptosis and cel{ cycle distributions were examined with flow cytometry. The expression of cell markers and signaling molecules was detected using Western blot and qRT-PCR analyses. A sphere culture technique was used to enrich cancer stem cells （CSC） in Hep3B and Huh7 cells. The in vivo antitumor efficacy of MASM was evaluated in Huh7 cell xenograft model in BALB/c nude mice, which were administered MASM （10 mg.kg-~-d~, ig） for 3 weeks. After the treatment was completed, tumor were excised and weighed. A portion of tumor tissue was enzymatically dissociated to obtain a single cell suspension for the spheroid formation assays. MASM （2, 10, 20 pmol/L） dose-dependently iahibited the proliferation of HCC cells, and induced apoptosis, which correlated with a reduction in Bcl-2 expression and an increase in PARP cleavage. MASM also induced cell cycle arrest in Go/G~ phase, which was accompanied by increased p27 and decreased Cyclin D1 expression, interestingly, MASM （2, 10, and 20 pmoVL） drastically reduced the EpCAM＋/CD133＊ cell numbers, suppressed the sphere formation, inhibited the expression of stem cell marker genes and promoted the expression of mature hepatocyte markers in the Hep3B and Huh7 spheroids. Additionally, MASM dose-dependently suppressed the PI3K/AKT/mTOR and AKT/GSK313/13-catenin signaling pathways in Hep3B and Huh7 cells. In Huh7 xenograft bearing nude mice, MASM administration significantly inhibited Huh7 xenograft tumor growth and markedly reduced the number of surviving cancer stem-like cells in the tumors. MASM administration also reduced the expression of stem cell markers while increasing the expression of mature hepatocyte markers in the tumor tissues. The novel derivative of matrine, MASM, markedly suppresses HCC tumor growth through multiple mechanisms, and it may be a promising candidate drug for the treatment of hepatocellular carcinoma.

Bone and muscle, two major tissue types of musculoskeletal system, have strong genetic determination. Abnormality in bone and/or muscle may cause musculoskeletal diseases such as osteoporosis and sarcopenia. Bone size phenotypes (BSPs), such as hip bone size (HBS), appendicular bone size (ABS), are genetically correlated with body lean mass (mainly muscle mass). However, the specific genes shared by these phenotypes are largely unknown. In this study, we aimed to identify the specific genes with pleiotropic effects on BSPs and appendicular lean mass (ALM). We performed a bivariate genome-wide association study (GWAS) by analyzing ~690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) followed by a replication study in 2,286 unrelated US Caucasians (558 males and 1,728 females). We identified 14 interesting single nucleotide polymorphisms (SNPs) that may contribute to variation of both BSPs and ALM, with p values <10 −6 in discovery stage. Among them, the association of three SNPs ( rs2507838 , rs7116722 , and rs11826261 ) in/near GLYAT (glycine- N -acyltransferase) gene was replicated in US Caucasians, with p values ranging from 1.89 × 10 −3 to 3.71 × 10 −4 for ALM–ABS, from 5.14 × 10 −3 to 1.11 × 10 −2 for ALM–HBS, respectively. Meta-analyses yielded stronger association signals for rs2507838 , rs7116722 , and rs11826261 , with pooled p values of 1.68 × 10 −8 , 7.94 × 10 −8 , 6.80 × 10 −8 for ALB–ABS and 1.22 × 10 −4 , 9.85 × 10 −5 , 3.96 × 10 −4 for ALM–HBS, respectively. Haplotype allele ATA based on these three SNPs was also associated with ALM–HBS and ALM–ABS in both discovery and replication samples. Interestingly, GLYAT was previously found to be essential to glucose metabolism and energy metabolism, suggesting the gene’s dual role in both bone development and muscle growth. Our findings, together with the prior biological evidence, suggest the importance of GLYAT gene in co-regulation of bone phenotypes and body lean mass.

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.

DEK is a protein ubiquitously expressed in multicellular organisms as well as certain unicellular organisms. It is associated with the regulation of cell proliferation, differentiation, migration, apoptosis, senescence, self-renewal and DNA repairing. In tumor cells it is associated with the carcinogenesis process, however there have been few previous studies into the expression of DEK in lung cancer. In the present study the expression level of DEK mRNA and protein was detected in lung cancer tissues and non-cancerous counterparts by performing reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining. It was revealed that the expression of DEK was increased in lung cancer tissues compared with normal tissue. Knock-down and over-expression of DEK in A549 cells were performed to determine the role of DEK in tumor formation. An MTT assay, colony formation assay and Matrigel invasion assay demonstrated that DEK positively regulated cell proliferation and invasion. These results suggest that DEK is highly expressed in lung cancer tissues and positively regulates cell proliferation and invasion.

A total of 484 rice samples were collected from five polluted areas in China to investigate the cadmium (Cd) contamination of rice and its potential health risks. The mean Cd contents of analyzed rice samples obtained from different areas ranged from 0.149 to 0.189 mg·kg −1 . Cd concentrations in more than 18 % of rice samples exceeded the maximum allowable Cd concentration, and the highest level of 41.1 % was observed in samples from Hezhang, Guizhou, which was characterized by serious Cd pollution. Target hazard quotient (THQ) values of 1.5 to 7.8 from rice intake indicated a significant non-carcinogenic health risk for humans, particularly for highly exposed consumers. Children are more at risk than adults, as indicated by the higher THQs. Moreover, carcinogenic risks of Cd from rice intake for average and high consumers in the selected areas were two to three and four to eight greater, respectively, than the threshold value recommended by the International Commission on Radiological Protection.