BH3 mimetic ABT-737 sensitizes colorectal cancer cells to ixazomib through MCL-1 downregulation and autophagy inhibition.

The proteasome inhibitor MLN9708 is an orally administered drug that is hydrolyzed into its active form, MLN2238 (ixazomib). Compared with Bortezomib, MLN2238 has a shorter proteasome dissociation half-life and a lower incidence and severity of peripheral neuropathy, which makes it an attractive candidate for colorectal cancer treatment. In the present study, we observed that MLN2238 induced autophagy, as evidenced by conversion of the autophagosomal marker LC3 from LC3I to LC3II, in colorectal cancer cell lines. Mcl-1, an anti-apoptotic Bcl-2 family protein, was markedly elevated after treating a colorectal cancer cell line with MLN2238. We proved that inhibiting Mcl-1 expression enhances MLN2238 induced apoptosis and negatively regulates autophagy. Co-administration of BH3 mimetic ABT-737 with MLN2238 synergistically kills colorectal cancer cells through MCL-1 neutralization and autophagy inhibition. Furthermore, the synergistic killing effect of the combination therapy is correlated with P53 status in colorectal cancer. These data highlight that the combination of ABT-737 with MLN9708 is a promising therapeutic strategy for human colorectal cancer

Complete mitochondrial genome of a predominant parasitoid, Necremnus tutae (Hymenoptera: Eulophidae) of the South American tomato leafminer Tuta absoluta (Lepidoptera: Gelechiidae)

The complete mitochondrial genome of a predominant parasitoid, Necremnus tutae (Hymenoptera: Eulophidae) (GenBank accession number MT916846) is 15,252 bp in length, and contains 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes, and an A + T-rich region. The overall base composition is 38.86% for A, 7.14% for C, 8.57% for G, and 45.43% for T, with a high AT bias of 84.29%. ATA, ATT, ATG were initiation codons and TAA and T were termination codons. All the 22 tRNAs displayed a typical cloverleaf secondary structure, except for trnS1 and trnR which lacked the dihydrouracil (DHU) arm. Phylogenetic analyses were performed using 13 PCGs showed that N. tutae is closely related to Tenthredo tienmushana, which in accordance with the traditional classification.info:eu-repo/semantics/publishedVersio

Linkage disequilibrium blocks, haplotype structure, and htSNPs of human CYP7A1 gene

BACKGROUND: Cholesterol 7-alpha-hydroxylase (CYP7A1) is the rate limiting enzyme for converting cholesterol into bile acids. Genetic variations in the CYP7A1 gene have been associated with metabolic disorders of cholesterol and bile acids, including hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, and gallstone disease. Current genetic studies are focused mainly on analysis of a single nucleotide polymorphism (SNP) at A-278C in the promoter region of the CYP7A1 gene. Here we report a genetic approach for an extensive analysis on linkage disequilibrium (LD) blocks and haplotype structures of the entire CYP7A1 gene and its surrounding sequences in Africans, Caucasians, Asians, Mexican-Americans, and African-Americans. RESULT: The LD patterns and haplotype blocks of CYP7A1 gene were defined in Africans, Caucasians, and Asians using genotyping data downloaded from the HapMap database to select a set of haplotype-tagging SNPs (htSNP). A low cost, microarray-based platform on thin-film biosensor chips was then developed for high-throughput genotyping to study transferability of the HapMap htSNPs to Mexican-American and African-American populations. Comparative LD patterns and haplotype block structure was defined across all test populations. CONCLUSION: A constant genetic structure in CYP7A1 gene and its surrounding sequences was found that may lead to a better design for association studies of genetic variations in CYP7A1 gene with cholesterol and bile acid metabolism

Control of Intestinal Inflammation, Colitis-Associated Tumorigenesis, and Macrophage Polarization by Fibrinogen-Like Protein 2

Fibrinogen-like protein 2 (Fgl2) is critical for immune regulation in the inflammatory state. Elevated Fgl2 levels are observed in patients with inflammatory bowel disease (IBD), but little is known about its functional significance. In this study, we sought to investigate the role of Fgl2 in the development of intestinal inflammation and colitis-associated colorectal cancer (CAC). Here, we report that Fgl2 deficiency increased susceptibility to dextran sodium sulfate-induced colitis and CAC in a mouse model. During colitis development, the expression of the membrane-bound and secreted forms of Fgl2 (mFgl2 and sFgl2, respectively) in the colon were increased and predominantly expressed by colonic macrophages. In addition, using bone marrow chimeric mice, we determined that Fgl2 function in colitis is strictly related to its expression in the hematopoietic cells. Loss of Fgl2 induced the polarization of M1, but suppressed that of M2 both in vivo and in vitro, independent of intestinal inflammation. Thus, Fgl2 suppresses intestinal inflammation and CAC development through its role in macrophage polarization and may serve as a therapeutic target in inflammatory diseases, including IBD

The cross-reactivity of the enterovirus 71 to human brain tissue and identification of the cross-reactivity related fragments

<p>Abstract</p> <p>Background</p> <p>EV71 occasionally cause a series of severe neurological symptoms, including aseptic meningitis, encephalitis, and poliomyelitis-like paralysis. However, the neurological destruction mechanism was remained to be clarified. This study described the cross reaction between EV71 induced IgG and human brain tissue.</p> <p>Results</p> <p>Cross reaction of the IgG from 30 EV71 infected patients' sera to human tissues of cerebra was observed, which suggested that some EV71 antigens could induce IgG cross-reactivity to human cerebra. To identify the regions of EV71 virus that containing above antigens, the polypeptide of virus was divided into 19 peptides by expression in prokaryotes cell. Mouse anti-sera of these peptides was prepared and applied in immunohistochemical staining with human adult and fetus brain tissue, respectively. The result indicated the 19 peptides can be classified into three groups: strong cross-reactivity, weak cross-reactivity and no cross-reactivity with human brain tissue according the cross reaction activity. Then, the increased Blood Brain Barrier (BBB) permeability and permits IgG entry in neonatal mice after EV71 infection was determined.</p> <p>Conclusion</p> <p>EV71 induced IgG could enter BBB and cross-reacted with brain tissue in EV71 infected neonatal mice, and then the peptides of EV71 that could induce cross-reactivity with brain tissue were identified, which should be avoided in future vaccine designing.</p

Cyclocarya paliurus Leaves Tea Improves Dyslipidemia in Diabetic Mice: A Lipidomics-Based Network Pharmacology Study

Hyperlipidemia and hepatic steatosis afflict over 75% of patients with type 2 diabetes, causing diabetic dyslipidemia. Cyclocarya paliurus (CP) leaf is a herbal tea which has long been consumed by the Chinese population, particularly people suffering from obesity and diabetes. CP appears to exhibit a hypolipidemic effect in lipid loaded mice (Kurihara et al., 2003), although the detailed mechanisms and active ingredients for this hypolipidemic effect have not yet been answered. In this study, we investigated the beneficial effects of CP and predicted the mechanisms by utilizing lipidomics, serum-pharmacochemistry and network pharmacology approaches. Our results revealed that serum and hepatic levels of total triglyceride (TG), total cholesterol (T-CHO), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), as well as 30 lipids including cholesterol ester (CE), diglyceride (DG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingomyelin (SM) in CP-treated mice were improved in comparison with untreated diabetic mice. In parallel, 14 phytochemical compounds of CP were determined in mice serum after CP administration. Mechanistically, the network pharmacology analysis revealed the predicted targets of CP’s active ingredients ALOX12, APP, BCL2, CYP2C9, PTPN1 and linked lipidome targets PLD2, PLA2G(s), and PI3K(s) families could be responsible for the CP effects on diabetic dyslipidemia. In conclusion, this study revealed the beneficial effects of CP on diabetic dyslipidemia are achieved by reducing accumulation of hepatic lipid droplets and regulating circulatory lipids in diabetic mice, possibly through PI3K signaling and MAPK signaling pathways. GRAPHICAL ABSTRACTWork flow of the evaluation of the effects and mechanisms of Cyclocarya paliurus leaves tea on dyslipidemia in diabetic mice

MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma

ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy., • MST4 kinase regulates the growth, sphere formation, and tumorigenicity of GBM cells • MST4 stimulates autophagy by activating ATG4B through phosphorylation of ATG4B S383 • Radiation increases MST4 expression and ATG4B phosphorylation, inducing autophagy • Inhibiting ATG4B enhances the anti-tumor effects of radiotherapy in GBM PDX models , Huang et al. show that radiation induces MST4 expression and that MST4 phosphorylates ATG4B at serine 383, which increases ATG4B activity and autophagic flux. Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice