Prediction and validation of common targets in atherosclerosis and non-small cell lung cancer influenced by atorvastatin.

BACKGROUND: Cardiovascular disease and cancer are the main causes of morbidity and mortality worldwide. Studies have shown that these two diseases may have some common risk factors. Atorvastatin is mainly used for the treatment of atherosclerosis in clinic. A large number of studies show that atorvastatin may produce anti-tumor activities. This study aimed to predict the common targets of atorvastatin against atherosclerosis and non-small cell lung cancer (NSCLC) based on network pharmacology. METHODS: The target genes of atherosclerosis and NSCLC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The disease-target-component model map and the core network were obtained using Cytoscape 3.7.1. The MTS and wound healing assay were used to detect the effect of atorvastatin on cell viability and migration of A549 cells. The expression of potential common target genes of atorvastatin against atherosclerosis and NSCLC were confirmed in A549 cells and lung cancer tissues of patients. RESULTS: We identified 15 identical pathogenic genes, and four of which (MMP9, MMP12, CD36, and FABP4) were considered as the key target genes of atorvastatin in anti-atherosclerosis and NSCLC. The MTS and wound healing assays revealed that atorvastatin decreased A549 cells migration significantly. Atorvastatin markedly decreased the expression of MMP9, MMP12, CD36, and FABP4 in A549 cells and patients were treated with atorvastatin. CONCLUSIONS: This study demonstrated 15 common pathogenic genes in both atherosclerosis and NSCLC. And verified that MMP 9, MMP 12, CD 36 and FABP 4 might be the common target genes of atorvastatin in anti-atherosclerosis and NSCLC.

The novel small molecule BH3 mimetic nobiletin synergizes with vorinostat to induce apoptosis and autophagy in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with few therapeutic options; therefore, the identification of new targets and drugs with potent combination therapy is desirable. We previously screened BH3 mimetics from a natural product library, and in this study, we validated nobiletin as a BH3 mimetic. Specifically, we observed its combination potential and mechanism with vorinostat in SCLC in vitro and in vivo. The results showed that combination treatment with nobiletin and vorinostat reduced the proliferation of SCLC H82 cells and increased the levels of apoptotic proteins such as cleaved caspase-9 and cleaved PARP. The combination treatment increased LC3-II expression and induced autophagic cell death. In addition, this treatment significantly inhibited H82 cell xenograft SCLC tumor growth in nude mice. The combination treatment with nobiletin and vorinostat efficiently increased autophagy by inhibiting the PI3K-AKT-mTOR pathway and promoting dissociation of the BCL-2 and Beclin 1 complex, increasing the level of isolated Beclin 1 to stimulate autophagy. Molecular docking and surface plasmon resonance analysis showed that nobiletin stably bound to the BCL-2, BCL-XL and MCL-1 proteins with high affinity in a concentration-dependent manner. These results suggest that nobiletin is a BH3-only protein mimetic. Furthermore, the combination of nobiletin with vorinostat increased histone H3K9 and H3K27 acetylation levels in SCLC mouse tumor tissue and enhanced the expression of the BH3-only proteins BIM and BID. We conclude that nobiletin is a novel natural BH3 mimetic that can cooperate with vorinostat to induce apoptosis and autophagy in SCLC.

Ectopic overexpression of AtHDG11 in tall fescue resulted in enhanced tolerance to drought and salt stress.

Tall fescue (Festuca arundinacea Schreb.) is a cool-season perennial grass, which has been conventionally grown in the temperate area. However, as a major type of cool-season turf grass, its growth has been extended to the sub-tropical climate or even to the transitional climate between the sub-tropical and the tropical, and, in some cases, to heavily salinized lands. The extended growth imposes a serious challenge to its tolerance to the abiotic stress, particularly to drought, salt and high temperature. Here, we report a successful introduction of Arabidopsis AtHDG11 into the tall fescue via Agrobacterium-mediated transformation. The ectopic overexpression of AtHDG11 under the control of CaMV 35S promoter with four enhancers resulted in significantly enhanced tolerance to drought and salt stress. No obvious adverse effects on growth and development were observed in the transgenic plants. The enhanced stress tolerance was associated with a more extensive root system, a lower level of malondialdehyde, a nearly normal Na(+)/K(+) ratio, a higher level of proline and a kinetically accelerated induction of SOD and CAT activities observed in the transgenic plants during drought and/or salt stress, indicating that an enhanced ROS scavenging capability might play a significant role in the acquired tolerance to the abiotic stress.

[Screening for lifespan-extension mutants with paraquat in Arabidopsis].

Genetic analyses of lifespan in model animals have revealed that extended lifespans are closely associated to increased resistance to oxidative stress. In the model plant Arabidopsis, late-flowering mutants are also found to be more tolerant to oxidative stress. However, Arabidopsis mutants with extended lifespans are poorly studied so far. In this study, a screening system for mutants with extended lifespans in Arabidopsis was established using paraquat, a potent herbicide that exacerbates O2-. radical production. The relationship between lifespan and resistance to oxidative stress was examined with one of the mutants, SFNA-9-4. Compared to that of wild type, the lifespan of SFNA-9-4 is significantly extended, and its resistance to oxidative stress is also significantly elevated. These results suggest that, as in Drosophila, paraquat can also be used to screen for mutants with extended lifespans in Arabidopsis.

[Detection and analysis of QTL for seed dormancy in rice (Oryza sativa L.) using RIL and CSSL population].

A recombinant inbred line (RIL) population and two chromosome segment substitution line (CSSL) population derived from the cross of Asominori (japonica) and IR24 (indica) were used to detect QTL controlling seed dormancy. CSSL1 were a series of IR24 chromosome segment substitution lines in Asominori background, and CSSL2 were a series of introgression lines of Asominori in the background of IR24. Three QTL were detected on chromosome 3, 6 and 9 in RIL population, and individual QTL accounted for between 12.3% and 13%. Three QTL were detected on chromosome 1, 3 and 7 in CSSL1, and individual QTL accounted for between 11.5% and 18.9%. Three QTL were detected on chromosome 1, 2 and 7 in CSSL2, and individual QTL accounted for between 11% and 16%. The QTLs on chromosome 1 and 7 were detected in CSSL1 and CSSL2 populations simultaneously, QTL came from Asomonori, the moderate dormant cultivar, increased seed dormancy, and QTL from IR24, the weakly dormant cultivar, decreased seed dormancy. It can be deduced that there exist genes controlling seed dormancy at this region.

[Serial analysis of gene expression].

Serial analysis of gene expression (SAGE) is recently developed, a sequenced-based technique, which permits comprehensive and quantitative gene expression profiles from specific tissues or cells. SAGE has been successfully applied for transcriptome research and identification of differentially expressed genes between mRNA populations. This article mainly reviews the principle,development and application of SAGE.

[In silico cloning of glucose-6-phosphate dehydrogenase cDNA from rice (Oryza sativa L.)].

In silico cloning was a new strategy of gene cloning developed with the development of genome, EST projects and bioinformatics. Using wheat glucose-6-phosphate dehydrogenase cDNA (clone: Tagpdl) sequence as a querying probe, one highly homologous BAC clone sequence was obtained from rice sequence database of GenBank and the putative cDNA sequence of rice glucose-6-phosphate dehydrogenase was assembled according to the wheat clone. Furthermore, the full-length cDNA of rice glucose-6-phosphate dehydrogenase was cloned by RT-PCR with two primers designed based on this assembled cDNA sequence. Since this fragment contained a complete ORF of 1515 bp with a stop codon in its upstream and poly(A) signal in its downstream, it could be concluded that a full-length gene (GenBank accession number AY078072), which was named as OsG6PDH. Homology analysis of OsG6PDH showed a 88% identity with wheat and the deduced amino acid showed 89%, 79% and 80% homology with G6PDH from wheat, tomato and tobacco respectively. OsG6PDH was expressed in inflorescence, embryo, root and leaf of rice, with a slightly higher in inflorescence and root. It was also discussed in this paper that the application of in silico cloning in the isolation of functional genes from rice.