Inhibitory Effects of Peptide Lunasin in Colorectal Cancer HCT-116 Cells and Their Tumorsphere-Derived Subpopulation

The involvement of cancer stem-like cells (CSC) in the tumor pathogenesis has profound implications for cancer therapy and chemoprevention. Lunasin is a bioactive peptide from soybean and other vegetal sources with proven protective activities against cancer and other chronic diseases. The present study focused on the cytotoxic effect of peptide lunasin in colorectal cancer HCT-116 cells, both the bulk tumor and the CSC subpopulations. Lunasin inhibited the proliferation and the tumorsphere-forming capacity of HCT-116 cells. Flow cytometry results demonstrated that the inhibitory effects were related to apoptosis induction and cell cycle-arrest at G1 phase. Moreover, lunasin caused an increase in the sub-GO/G1 phase of bulk tumor cells, linked to the apoptotic events found. Immunoblotting analysis further showed that lunasin induced apoptosis through activation of caspase-3 and cleavage of PARP, and could modulate cell cycle progress through the cyclin-dependent kinase inhibitor p21. Together, these results provide new evidence on the chemopreventive activity of peptide lunasin on colorectal cancer by modulating both the parental and the tumorsphere-derived subsets of HCT-116 cells

Nonlinear generalized semi-Jordan triple derivable mappings on completely distributive commutative subspace lattice algebras

In this note we proved that each nonlinear generalized semi-Jordan triple derivable mapping on completely distributive commutative subspace lattice algebras is an additive derivation

Thyroid dysfunction and risk of cutaneous malignant melanoma: a bidirectional two-sample Mendelian randomization study

BackgroundEpidemiologic and observational data have found a risk association between thyroid dysfunction and cutaneous malignant melanoma (CMM), however, the cause and direction of these effects are yet unknown. By using a bidirectional two-sample Mendelian randomization (MR) methodology, we hoped to further investigate the causal link between thyroid dysfunction and CMM in this work.MethodsA genome-wide association study (GWAS) of 9,851,867 single nucleotide polymorphisms (SNPs) in a European population was used to develop genetic tools for thyroid dysfunction. Hypothyroidism was linked to 22,687 cases and 440,246 controls. For hyperthyroidism, there were 3545 cases and 459,388 controls. A total of 3751 cases and 372016 controls were included in the genetic data for CMM from UK Biobank (http://www.nealelab.is/uk-biobank) (the Dataset: ieu - b - 4969). Among them, inverse variance weighting (IVW) is the main MR Analysis method for causality assessment. MR-Egger method, MR Pleiotropic residual and outlier test (MR-PRESSO), and simple and weighted median (VM) were used to supplement the IVW method. Sensitivity analyses, mainly Cochran’s Q test, leave-one-out analysis, and MR Egger intercept test were performed to assess the robustness of the outcomes.ResultsThe two-sample MR Analysis results revealed a negative correlation between genetically predicted hypothyroidism and the probability of CMM (OR=0.987, 95%CI =0.075-0.999, p=0.041). The supplemental MR Analysis did not reveal any statistically significant differences, although the direction of the effect sizes for the other approaches was consistent with the IVW effect sizes. The results of the causal analysis were relatively robust, according to a sensitivity analysis. The risk of CMM was unaffected by hyperthyroidism (p>0.05). No correlation between CMM and thyroid dysfunction was seen in the reverse MR analysis.ConclusionAlthough the magnitude of the causal association is weak and further investigation of the mechanism of this putative causal relationship is required, our findings imply that hypothyroidism may be a protective factor for CMM

Wenxin-Keli Regulates the Calcium/Calmodulin-Dependent Protein Kinase II Signal Transduction Pathway and Inhibits Cardiac Arrhythmia in Rats with Myocardial Infarction

Wenxin-Keli (WXKL) is a Chinese herbal compound reported to be of benefit in the treatment of cardiac arrhythmia, cardiac inflammation, and heart failure. Amiodarone is a noncompetitive inhibitor of the α- and β-adrenergic receptors and prevents calcium influx in the slow-response cells of the sinoatrial and atrioventricular nodes. Overexpression of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in transgenic mice results in heart failure and arrhythmias. We hypothesised that administration of WXKL and amiodarone can reduce the incidence of arrhythmias by regulating CaMKII signal transduction. A total of 100 healthy Sprague Dawley rats were used in the study. The rats were randomly divided into four groups (a sham group, a myocardial infarction (MI) group, a WXKL-treated group, and an amiodarone-treated group). A myocardial infarction model was established in these rats by ligating the left anterior descending coronary artery for 4 weeks. Western blotting was used to assess CaMKII, p-CaMKII (Thr-286), PLB, p-PLB (Thr-17), RYR2, and FK binding protein 12.6 (FKBP12.6) levels. The Ca2+ content in the sarcoplasmic reticulum (SR) and the calcium transient amplitude were studied by confocal imaging using the fluorescent indicator Fura-4. In conclusion, WXKL may inhibit heart failure and cardiac arrhythmias by regulating the CaMKII signal transduction pathway similar to amiodarone

Computational identification of condition-specific miRNA targets based on gene expression profiles and sequence information

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are small and noncoding RNAs that play important roles in various biological processes. They regulate target mRNAs post-transcriptionally through complementary base pairing. Since the changes of miRNAs affect the expression of target genes, the expression levels of target genes in specific biological processes could be different from those of non-target genes. Here we demonstrate that gene expression profiles contain useful information in separating miRNA targets from non-targets.</p> <p>Results</p> <p>The gene expression profiles related to various developmental processes and stresses, as well as the sequences of miRNAs and mRNAs in <it>Arabidopsis</it>, were used to determine whether a given gene is a miRNA target. It is based on the model combining the support vector machine (SVM) classifier and the scoring method based on complementary base pairing between miRNAs and mRNAs. The proposed model yielded low false positive rate and retrieved condition-specific candidate targets through a genome-wide screening.</p> <p>Conclusion</p> <p>Our approach provides a novel framework into screening target genes by considering the gene regulation of miRNAs. It can be broadly applied to identify condition-specific targets computationally by embedding information of gene expression profiles.</p

Self-Assembled Polymeric Micellar Nanoparticles as Nanocarriers for Poorly Soluble Anticancer Drug Ethaselen

A series of monomethoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) diblock copolymers were synthesized, and mPEG-PLA micelle was fabricated and used as a nanocarrier for solubilization and delivery of a promising anticancer drug ethaselen. Ethaselen was efficiently encapsulated into the micelles by the dialysis method, and the solubility of ethaselen in water was remarkably increased up to 82 μg/mL before freeze-drying. The mean diameter of ethaselen-loaded micelles ranged from 51 to 98 nm with a narrow size distribution and depended on the length of PLA block. In vitro hemolysis study indicated that mPEG-PLA copolymers and ethaselen-loaded polymeric micelles had no hemolytic effect on the erythrocyte. The enhanced antitumor efficacy and reduced toxic effect of ethaselen-loaded polymeric micelle when compared with ethaselen-HP-β-CD inclusion were observed at the same dose in H22human liver cancer cell bearing mouse models. These suggested that mPEG-PLA polymeric micelle nanoparticles had great potential as nanocarriers for effective solubilization of poorly soluble ethaselen and further reducing side effects and toxicities of the drug

Tissue-Autonomous Function of Drosophila Seipin in Preventing Ectopic Lipid Droplet Formation

Obesity is characterized by accumulation of excess body fat, while lipodystrophy is characterized by loss or absence of body fat. Despite their opposite phenotypes, these two conditions both cause ectopic lipid storage in non-adipose tissues, leading to lipotoxicity, which has health-threatening consequences. The exact mechanisms underlying ectopic lipid storage remain elusive. Here we report the analysis of a Drosophila model of the most severe form of human lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy 2, which is caused by mutations in the BSCL2/Seipin gene. In addition to reduced lipid storage in the fat body, dSeipin mutant flies accumulate ectopic lipid droplets in the salivary gland, a non-adipose tissue. This phenotype was suppressed by expressing dSeipin specifically within the salivary gland. dSeipin mutants display synergistic genetic interactions with lipogenic genes in the formation of ectopic lipid droplets. Our data suggest that dSeipin may participate in phosphatidic acid metabolism and subsequently down-regulate lipogenesis to prevent ectopic lipid droplet formation. In summary, we have demonstrated a tissue-autonomous role of dSeipin in ectopic lipid storage in lipodystrophy

Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9)

The fatality of avian influenza A(H7N9) infection in humans was over 30%. To identify human genetic susceptibility to A(H7N9) infection, we performed a genome-wide association study (GWAS) involving 102 A(H7N9) patients and 106 heavily-exposed healthy poultry workers, a sample size critically restricted by the small number of human A(H7N9) cases. To tackle the stringent significance cutoff of GWAS, we utilized an artificial imputation program SnipSnip to improve the association signals. In single-SNP analysis, one of the top SNPs was rs13057866 of LGALS1. The artificial imputation (AI) identified three non-genotyped causal variants, which can be represented by three anchor/partner SNP pairs rs13057866/rs9622682 (AI P = 1.81 × 10-7), rs4820294/rs2899292 (2.13 × 10-7) and rs62236673/rs2899292 (4.25 × 10-7) respectively. Haplotype analysis of rs4820294 and rs2899292 could simulate the signal of a causal variant. The rs4820294/rs2899292 haplotype GG, in association with protection from A(H7N9) infection (OR = 0.26, P = 5.92 × 10-7) correlated to significantly higher levels of LGALS1 mRNA (P = 0.050) and protein expression (P = 0.025) in lymphoblast cell lines. Additionally, rs4820294 was mapped as an eQTL in human primary monocytes and lung tissues. In conclusion, functional variants of LGALS1 causing the expression variations are contributable to the differential susceptibility to influenza A(H7N9).link_to_OA_fulltex

The water lily genome and the early evolution of flowering plants

Water lilies belong to the angiosperm order Nymphaeales. Amborellales, Nymphaeales and Austrobaileyales together form the so-called ANA-grade of angiosperms, which are extant representatives of lineages that diverged the earliest from the lineage leading to the extant mesangiosperms1–3. Here we report the 409-megabase genome sequence of the blue-petal water lily (Nymphaea colorata). Our phylogenomic analyses support Amborellales and Nymphaeales as successive sister lineages to all other extant angiosperms. The N. colorata genome and 19 other water lily transcriptomes reveal a Nymphaealean whole-genome duplication event, which is shared by Nymphaeaceae and possibly Cabombaceae. Among the genes retained from this whole-genome duplication are homologues of genes that regulate flowering transition and flower development. The broad expression of homologues of floral ABCE genes in N. colorata might support a similarly broadly active ancestral ABCE model of floral organ determination in early angiosperms. Water lilies have evolved attractive floral scents and colours, which are features shared with mesangiosperms, and we identified their putative biosynthetic genes in N. colorata. The chemical compounds and biosynthetic genes behind floral scents suggest that they have evolved in parallel to those in mesangiosperms. Because of its unique phylogenetic position, the N. colorata genome sheds light on the early evolution of angiosperms.Supplementary Tables: This file contains Supplementary Tables 1-21.National Natural Science Foundation of China, the open funds of the State Key Laboratory of Crop Genetics and Germplasm Enhancement (ZW201909) and State Key Laboratory of Tree Genetics and Breeding, the Fujian provincial government in China, the European Union Seventh Framework Programme (FP7/2007-2013) under European Research Council Advanced Grant Agreement and the Special Research Fund of Ghent University.http://www.nature.com/naturecommunicationsam2021BiochemistryGeneticsMicrobiology and Plant Patholog