Decalin-Containing Tetramic Acids and 4-Hydroxy-2-pyridones with Antimicrobial and Cytotoxic Activity from the Fungus Coniochaeta cephalothecoides Collected in Tibetan Plateau (Medog).

New tetramic acid derivatives, (±)-conipyridoins A-D (1-4), conipyridoins E (5) and F (6), and new 4-hydroxy-2-pyridone alkaloids (±)-didymellamide E (7), (+)-didymellamide B (8), (+)-N-hydroxyapiosporamide (9), and didymellamides F-H (10-12) were isolated and identified from the solid culture of the fungus Coniochaeta cephalothecoides. Chiral resolution of 1, 2, 3, 4, and 7 gave five pairs of enantiomers: 1a/1b, 2a/2b, 3a/3b, 4a/4b, and 7a/7b, respectively. Stereochemistry of 1a and 1b, and 2a and 2b was established and confirmed by the single-crystal X-ray diffraction and electronic circular dichroism (ECD) methods. Absolute configuration in 3a, 3b, 4a, 4b, 7a, and 7b was assigned by ECD calculations. Compounds 1-6 possess an unprecedented chemical skeleton featuring a decalin ring and a tetramic acid moiety. Compound 11 significantly inhibited the growth of Candida albicans and Aspergillus fumigatus with minimum inhibitory concentration (MIC) of 3.13 and 1.56 µM, respectively, and was further confirmed to be a new chitin synthesis inhibitor. Compound 5 exhibited the strongest activity against the growth of both Staphylococcus aureus and MRSA with MIC value of 0.97 µM. In the light of a co-occurrence of 3-acyl tetramic acids and biogenetically related pyridine alkaloids, the biosynthetic pathway for 1-12 was postulated.

Erinacerins C-L, isoindolin-1-ones with α-glucosidase inhibitory activity from cultures of the medicinal mushroom Hericium erinaceus.

The well-known edible and medicinal mushroom Hericium erinaceus produces various bioactive secondary metabolites. Ten new isoindolin-1-ones, named erinacerins C-L (1-10), together with (E)-5-(3,7-dimethylocta-2,6-dien-1-yl)-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one (11) were isolated from the solid culture of H. erinaceus. The structures of new metabolites were established by spectroscopic methods. The absolute configurations of 3, 4, 9, and 10 were assigned by comparing their specific rotations with those of related phthalimidines (13-20). Compounds 5 and 6, 7 and 8, and 9 and 10 are double-bond positional isomers. In a α-glucosidase inhibition assay, compounds 2-11 showed inhibitory activity with IC50 values ranging from 5.3 to 145.1 µM. Preliminary structure-activity analysis indicated that the terpenoid side chain and the phenolic hydroxy groups contributed greatly to the α-glucosidase inhibitory activity of 1-11. In a cytotoxicity assay, compound 11 also presented weak cytotoxicity against two cell lines, A549 and HeLa, with IC50 values of 49.0 and 40.5 µM.

Molecular and morphological description of two new species of Stemphylium from China and France.

Two new species of Stemphylium (anamorphic Pleospora) are described on the basis of morphological characters and molecular phylogenetic analyses. Stemphylium phaseolina and S. variabilis were isolated respectively from diseased leaves of Phaseolus vulgaris L. in Hebei Province, China, and from diseased leaves of Allium sativum L. in Angres, France. The two species exhibit characteristic Stemphylium morphology but are distinct from similar species based on the morphology and development of conidia. The internal transcribed spacer (ITS) nuclear rDNA region and glyceraldehyde-3-phosphate dehydrogenase (gpd) genes were sequenced. The results of maximum parsimony (MP) and maximum likelihood (ML) phylogenetic analyses of the combined DNA sequences of these two gene regions supported S. phaseolina and S. variabilis as two distinct phylogenetic species. The taxonomic descriptions of the new species and their comparison with related species are presented, together with the phylogenetic analysis based on combined DNA sequences of ITS and gpd gene regions.

Ulocladium cantlous sp. nov. isolated from northwestern China: its morphology and molecular phylogenetic position.

A new species of Ulocladium was isolated from diseased leaves from two Cucumis sp. growing in Sinkiang and Gansu provinces of China. Conidia were isolated from necrotic leaves and used to establish single-spore pure cultures. Conidia were harvested from cultures 7 d after incubation for morphological comparisons. The morphology of this species resembles that of U. botrytis and U. consortiale. However it is distinguished from these two species by the sizes of obovoid to broadly ellipsoidal conidia and longer conidiophores. A taxonomic description of U. cantlous, comparison with related species in this genus, and a species phylogeny based on the partial nucleotide sequence of the glyceraldehyde-3-phosphate dehydrogenase (gpd) gene and the Alternaria alternata major allergen (Alt a 1) gene are provided.

Predicting the fate of microRNA target genes based on sequence features.

MicroRNAs (miRNAs) are important post-transcriptional regulators that repress gene expression by binding to the 3'UTRs of their target mRNAs. There are two main outcomes for the transcripts targeted by miRNAs: mRNA degradation and translational repression. It is still unclear what factors determine whether a target transcript is degraded or translationally repressed. In this study, we collected two classes of genes that are targeted by miR-1, miR-155, miR-16, miR-30a, and let-7b and built new computational models with machine-learning methods to predict the fates of target genes based on sequence features. The prediction results indicate that the sequence context of the miRNA binding site at the 3'UTR of a target gene plays an important role in determining how an miRNA regulates the expression of its target. Further analysis shows that four out of the five studied miRNAs probably share similar regulatory mechanisms on their target genes.

An overview of hepatocellular carcinoma study by omics-based methods.

Hepatocellular carcinoma (HCC) is one of the most deadly malignancies worldwide. Scientists have been studying the molecular mechanism of HCC for years, but the understanding of it remains incomplete and scattered across the literature at different molecular levels. Chromosomal aberrations, epigenetic abnormality and changes of gene expression have been reported in HCC. High-throughput omics technologies have been widely applied, aiming at the discovery of candidate biomarkers for cancer staging, prediction of recurrence and prognosis, and treatment selection. Large amounts of data on genetic and epigenetic abnormalities, gene expression profiles, microRNA expression profiles and proteomics have been accumulating, and bioinformatics is playing a more and more important role. In this paper, we review the current omics-based studies on HCC at the levels of genomics, transcriptomics and proteomics. Integrating observations from multiple aspects is an essential step toward the systematic understanding of the disease.

Systematic identification of cancer-related long noncoding RNAs and aberrant alternative splicing of quintuple-negative lung adenocarcinoma through RNA-Seq.

OBJECTIVES: Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer prevalent in Asia. There is a dearth of understanding regarding the transcriptome landscape of LUAD without primary known driver mutations. In this study, LUAD samples without well-known driver mutations occurring in EGFR, KRAS, ALK, ROS1 or RET (quintuple-negative) were used for transcriptome study with a focus on long noncoding RNAs (lncRNAs), alternative splicing and gene fusions. MATERIALS AND METHODS: 24 pairs of LUAD and adjacent normal samples and 13 tumor-only samples derived from 37 quintuple-negative patients were used. Differentially expressed lncRNA transcripts were detected by paired t-test and were validated by qPCR. Functions of lncRNAs were predicted by co-expressed mRNAs. Aberrant splicing events in LUAD were identified using MISO. In addition, gene fusions were screened by SOAPfuse. RESULTS AND CONCLUSION: In total, 90 and 153 up- or down-regulated lncRNA transcripts were detected in LUAD samples in comparison with the adjacent normal samples. The most significantly differentially expressed lncRNA transcript was ENST00000598996.1 (FENDRR) down-regulated in LUAD. By lncRNA-mRNA co-expression analysis, functions of 14 lncRNAs were predicted. The predicted functions included vasculature development, immune response, cell cycle and respiratory gaseous exchange. Furthermore, six co-expressed pairs of lncRNAs and their nearby protein coding genes were identified as associated with lung development. This study also identified two highly recurrent (22 in 24) differential exon skipping events occurring in MYH14 and ESYT2 with exon including isoforms of both genes up-regulated in isoform percentage in LUAD samples. On the other hand, two out of 24 LUAD samples possessed the driver mutation exon 14 skipping of MET. The transcriptional alterations of LUAD samples without well-known driver mutations identified in the study can be used as references for future research. The translational values of these transcriptional changes are also worthy of further investigation.

A new sesquiterpene from the entomogenous fungus Phomopsis amygdali.

A new sesquiterpene, (+)-S-1-methyl-abscisic-6-acid (1), together with five known compounds, (+)-S-abscisic acid (2), fusicoccin J (3), 3α-hydroxyfusicoccin J (4), (R)-5-hydroxymethylmellein (5) and 4-hydroxyphenethyl acetate (6) was isolated from the fermentation extract of Phomopsis amygdali, an entomogenous fungus isolated from Call midge. Their structures were determined mainly by analysis of MS and NMR spectroscopic data. Compounds 1-6 were tested for antimicrobial activity against three plant pathogenic fungi: Gibberella zeae, Verticillium albo-atrum, and Fusarium nivale, and two bacteria: Escherichia coli and Pseudomonas aeruginosa 2033E. As a result, compounds 1-4 displayed antibacterial activity against Gram-negative P. aeruginosa 2033E, and the minimum inhibition concentration (MIC value) of 1-4 is 30 µg/mL, 58 µg/mL, 26 µg/mL, and 26 µg/mL, respectively.

A new species of Trichoderma hypoxylon harbours abundant secondary metabolites.

Some species of Trichoderma are fungicolous on fungi and have been extensively studied and commercialized as biocontrol agents. Multigene analyses coupled with morphology, resulted in the discovery of T. hypoxylon sp. nov., which was isolated from surface of the stroma of Hypoxylon anthochroum. The new taxon produces Trichoderma- to Verticillium-like conidiophores and hyaline conidia. Phylogenetic analyses based on combined ITS, TEF1-α and RPB2 sequence data indicated that T. hypoxylon is a well-distinguished species with strong bootstrap support in the polysporum group. Chemical assessment of this species reveals a richness of secondary metabolites with trichothecenes and epipolythiodiketopiperazines as the major compounds. The fungicolous life style of T. hypoxylon and the production of abundant metabolites are indicative of the important ecological roles of this species in nature.

Comprehensive Characterization of Oncogenic Drivers in Asian Lung Adenocarcinoma.

INTRODUCTION: The incidence rate of lung adenocarcinoma (LUAD), the predominant histological subtype of lung cancer, is elevated in Asians, particularly in female nonsmokers. The mutation patterns in LUAD in Asians might be distinct from those in LUAD in whites. METHODS: We profiled 271 resected LUAD tumors (mainly stage I) to characterize the genomic landscape of LUAD in Asians with a focus on female nonsmokers. RESULTS: Mutations in EGFR, KRAS, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), and BRAF; gene fusions involving anaplastic lymphoma receptor tyrosine kinase gene (ALK), ROS1, and ret proto-oncogene (RET); and Met Proto-Oncogene Tyrosine Kinase (MET) exon 14 skipping were the major drivers in LUAD in Asians, exhibiting mutually exclusive and differing prevalence from those reported in studies of LUAD in non-Asians. In addition, we identified a novel mutational signature of XNX (the mutated base N in the middle flanked by two identical bases at the 5' and 3' positions) that was overrepresented in LUAD tumors in nonsmokers and negatively correlated with the overall mutational frequency. CONCLUSIONS: In this cohort, approximately 85% of individuals have known driver mutations (EGFR 59.4%, KRAS 7.4%, ALK 7.4%, ERBB2 2.6%, ROS1 2.2%, RET 2.2%, MET 1.8%, BRAF 1.1%, and NRAS 0.4%). Seventy percent of smokers and 90% of nonsmokers had defined oncogenic drivers matching the U.S. Food and Drug Administration-approved targeted therapies.

New ambuic acid derivatives from the solid culture of Pestalotiopsis neglecta and their nitric oxide inhibitory activity.

Four new ambuic acid derivatives (1-4), and four known derivatives (5-8), were isolated from the solid culture of a plant pathogenic fungus Pestalotiopsis neglecta. Their structures were elucidated by extensive NMR experiments. The absolute configuration of the C-16 secondary alcohol in 1 was deduced via the CD data of the in situ formed [Rh2(OCOCF3)4] complex with the acetonide derivative of 1. The absolute configuration in 3 was assigned by comparison of the experimental and simulated electronic circular dichroism (ECD) spectrum. The NMR data of compound 5 was reported for the first time. In the nitric oxide (NO) inhibition assay, compounds 4, 6 and 7 showed inhibitory activity against the NO production in the lipopolysaccharide (LPS)-induced macrophage with IC50 values of 88.66, 11.20, and 20.80 µM, respectively.

New α-glucosidase inhibitors with p-terphenyl skeleton from the mushroom Hydnellum concrescens.

The purpose of this study is to elucidate the bioactive components responsible for the the α-glucosidase inhibitory activity detected in the EtOAc extract of the mushroom Hydnellum concrescens. Two new p-terphenyl derivatives, concrescenins A (1) and B (2), in along with six known compounds thelephantins L (3), I (4), J (5), K (6), dihydroauran-tiacin dibenzoate (7), and curtisian A (8) were isolated from the fruiting bodies of H. concrescens. Their chemical structures were elucidated by NMR experiments. Compounds 1-4 and 6-8 showed the inhibitory activity against α-glucosidase with the IC50 of 0.99, 3.11, 4.53, 18.77, 2.98, 5.16, and 8.34 µM, respectively. Kinetic analysis of α-glucosidase indicated that compounds 1 and 2 inhibited the activity of α-glucosidase in a noncompetitive fashion with a Ki value of 0.02 and 0.21 µM, respectively. In antioxidant evaluation, compounds 1 and 4 showed weak DPPH scavenging activity (EC50=82.50 and 161.75 µM) and weak reducing ability (EC50=193.57 and 152.94 µM). The current research supports the potential use of mushroom-derived p-terphenyl derivatives for the treatment of diabetes.

Primary transcripts and expressions of mammal intergenic microRNAs detected by mapping ESTs to their flanking sequences.

MicroRNAs (miRNAs) are a class of approximately 22-nt small RNAs that regulate posttranscriptional gene expression. Thousands of expressed sequence tags (ESTs) have been identified by using upstream 2500-nt and downstream 4000-nt flanking sequences to BLAST in the dbEST database. The cotranscription of the miRNAs and their flanking sequences covered by the matched ESTs is verified by RT-PCR. It directly reveals that a large portion of mammalian intergenic miRNAs are first transcribed as long primary transcripts (pri-miRNAs). Also, the transcripts' ranges of tens of pri-miRNAs are predicted by the EST-extension method. We then extracted the tissue-specific expression information from the annotations of the matched ESTs and established the expression profile of the studied miRNAs for tens of tissues. This provided a new way to establish the expression profiles of miRNAs. Results show that the human brain, lung, liver, and eye and the mouse brain, eye, and mammary gland are tissues in which enriched numbers of miRNAs are expressed.