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Previous study demonstrated that Ganoderma meroterpene derivative (GMD) increased the abundance of butyrate-producing bacteria in gut and subsequently delivered anti-metabolic disorder effect of host. To specify the key commensal bacteria associating with the beneficial effects, we tried to isolate and compare the microbiota from the cecal samples of GMD- and vehicle-treated ob/ob mice, and further identified butyrate-producing bacterial strains. It was found that Faeciroseburia intestinalis was enriched and 11 strains affiliated to F. intestinalis were cultivated from the gut of GMD-treated mice. In vitro assay attested butyrate production by representative strain of F. intestinalis. Oral administration with F. intestinalis further demonstrated its benefits on regulating hyperglycemia and hyperlipidemia, on decreasing plasma lipopolysaccharide (LPS) and inflammation, and on improving hepatic injuries. Treatment with F. intestinalis effectively enhanced the level of gut butyrate, which subsequently ameliorated the intestinal barrier function and activated epithelial PPAR-γ signaling pathway to regulate microbiome homeostasis in gut. Our study demonstrated that the causal relationship between the butyrate-producing bacteria and the GMD's therapeutic effects and confirmed the important function of the butyrate-producing F. intestinalis in maintaining host metabolism homeostasis.

A polyphenolic alkaloid-enriched extract (PAE) was prepared from the fruiting bodies of a wild edible mushroom Sarcodon leucopus. Oral administration of PAE reduced hyperglycemia, hyperlipidemia, hepatic steatosis, and LPS-related inflammation in high fat diet-induced obese (DIO) mice. Furthermore, we show that PAE produces taxonomic and predicted functional changes in the gut microbiome of DIO mice. A significant decrease in the family of Ruminococcaceae, especially the secondary bile acid-producing bacteria of Intestinimonas and Anaerotruncus, is detected in the gut microbiome of PAE-treate mice. Accordingly, reductions of deoxycholic acid and lithocholic acid are found in the feces of PAE-treated DIO mice, which benefits for the intestinal integrity and the reduction of inflammation. A gut microbiota related mechanism for the anti-metabolic syndrome effects of the PAE is proposed. We suppose the polyphenolic alkaloid extract from S. leucopus be a new and beneficial prebiotic regulating glucose and lipid metabolisms.

Tcf-1 (encoded by Tcf7) not only plays critical roles in promoting T cell development and differentiation but also has been identified as a tumor suppressor involved in preventing T cell malignancy. However, the comprehensive mechanisms of Tcf-1 involved in T cell transformation remain poorly understood. In this study, Tcf7(fl/fl) mice were crossed with Vav-cre, Lck-cre, or Cd4-cre mice to delete Tcf-1 conditionally at the beginning of the HSC, DN2–DN3, or DP stage, respectively. The defective T cell development phenotypes became gradually less severe as the deletion stage became more advanced in distinct mouse models. Interestingly, consistent with Tcf7(−/−) mice, Tcf7(fl/fl)Vav-cre mice developed aggressive T cell lymphoma within 45 weeks, but no tumors were generated in Tcf7(fl/fl)Lck-cre or Tcf7(fl/fl)Cd4-cre mice. Single-cell RNA-seq (ScRNA-seq) indicated that ablation of Tcf-1 at distinct phases can subdivide DN1 cells into three clusters (C1, C2, and C3) and DN2–DN3 cells into three clusters (C4, C5, and C6). Moreover, Tcf-1 deficiency redirects bifurcation among divergent cell fates, and clusters C1 and C4 exhibit high potential for leukemic transformation. Mechanistically, we found that Tcf-1 directly binds and mediates chromatin accessibility for both typical T cell regulators and proto-oncogenes, including Myb, Mycn, Runx1, and Lyl1 in the DN1 phase and Lef1, Id2, Dtx1, Fyn, Bcl11b, and Zfp36l2 in the DN2–DN3 phase. The aberrant expression of these genes due to Tcf-1 deficiency in very early T cells contributes to subsequent tumorigenesis. Thus, we demonstrated that Tcf-1 plays stage-specific roles in regulating early thymocyte development and transformation, providing new insights and evidence for clinical trials on T-ALL leukemia.

Hericium erinaceus is a very popular edible and medicinal mushroom used for the treatment of enervation and gastrointestinal diseases in Eastern Asia. Chemical investigation on the fruiting body of Hericium erinaceus led to the isolation of 4 new (1 – 4) and 10 known meroterpenoids (5 – 14). The structures of new compounds were determined via analysis of NMR and MS data in combination with chemical derivatization. The inhibitory activities of 1 – 14 against α-glucosidase were evaluated using p-nitrophenyl-α-D-glucopyranoside, sucrose, or maltose as substrate. Compounds 6, 9, 11 – 13 were demonstrated to show the α-glucosidase inhibitory activities. This work confirms the potential of H. erinaceus in the treatment of diabetes.

Background The protein meflin encoded by ISLR contains a C2-type immunoglobulin (Ig)-like domain and five leucine-rich repeat (LRR) domains. ISLR is known to play a role in a small number of tumors, but its role in most tumors is unknown. The purpose of this study was to analyze the expression and prognosis of ISLR in pan-cancer, as well as its correlation with tumor immunity. Methods We used multiple databases and R software to conduct bioinformatics analysis to explore the predictive role of ISLR in pan-cancer, mainly involving expression patterns, prognosis, and immune infiltration. Results Compared with normal tissues, the expression of ISLR was significantly increased or decreased in most tumors. Moreover, the high expression of ISLR may cause the prognosis of some tumors to become better or worse. ISLR also affects immune infiltration in a variety of tumors, which affects the clinical prognosis. ISLR is also significantly related to TMB and MSI in pan-cancer and is related to genes encoding immune regulatory genes. ISLR also affects various cancer-and immune-related pathways. Conclusions ISLR is differentially expressed in tumors, may regulate TME, affect tumor prognosis, and is expected to become a prognostic biomarker.

As part of our search for new cytotoxic and antimicrobial natural products from endolichenic fungi, 19 compounds including 1 new 10-member lactone (2), 1 new polyacetylene glycoside (3), 1 new brasilane-type sesquiterpenoid glycoside (4), and 2 isobenzofuran-1(3H)-one derivatives (5 and 6) were isolated from the solid culture of the endolichenic fungus Hypoxylon fuscum. Their structures were unambiguously elucidated by NMR spectroscopic data, MS, ECD (electronic circular dichroism) calculation, and chemical methods. The cytotoxic effects on K562, SW480, and HEPG2 cell lines and the antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Candida albicans were assessed. Compounds 1, 2, and 5 exhibited moderate cytotoxicity against K562, SW480, and HEPG2 cell lines while compounds 1, 9, and 11 displayed weak antibacterial activity against S. aureus.

Gastric cancer (GC) is a highly heterogeneous disease with multiple cellular types and poor prognosis. However, the cellular evolution and molecular basis of GC at the individual intra-tumor level has not been well demonstrated. We performed single-cell whole exome sequencing to detect somatic single-nucleotide variants (SNVs) and significantly mutated genes (SMGs) among 34 tumor cells and 9 normal cells from a patient with GC. The Complete Prediction for Protein Conformation (CPPC) approach directly predicting the folding conformation of the protein 3D structure with Protein Folding Shape Code, combined with functional experiments were used to confirm the characterization of mutated SMGs in GC cells. We identified 201 somatic SNVs, including 117 non-synonymous mutations in GC cells. Further analysis identified 24 significant mutated genes (SMGs) in single cells, for which a single amino acid change might affect protein conformation. Among them, two genes (CDC27 and FLG) that were mutated only in single cells but not in the corresponding tumor tissue, were recurrently present in another GC tissue cohort, and may play a potential role to promote carcinogenesis, as confirmed by functional characterization. Our findings showed a mutational landscape of GC at intra-tumor level for the first time and provided opportunities for understanding the heterogeneity and individualized target therapy for this disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic. SARS-CoV-2 is a positive-stranded RNA virus belongs to Coronaviridae family. The viral genome of SARS-CoV-2 contains around 29.8 kilobase with a 5′-cap structure and 3′-poly-A tail, and shows 79.2% nucleotide identity with human SARS-CoV-1, which caused the 2002-2004 SARS outbreak. As the successor to SARS-CoV-1, SARS-CoV-2 now has circulated across the globe. There is a growing understanding of SARS-CoV-2 in virology, epidemiology, and clinical management strategies. In this study, we verified the existence of two 18-22 nt small viral RNAs (svRNAs) derived from the same precursor in human specimens infected with SARS-CoV-2, including nasopharyngeal swabs and formalin-fixed paraffin-embedded (FFPE) explanted lungs from lung transplantation of COVID-19 patients. We then simulated and confirmed the formation of these two SARS-CoV-2-Encoded small RNAs in human lung epithelial cells. And the potential pro-inflammatory effects of the splicing and maturation process of these two svRNAs in human lung epithelial cells were also explored. By screening cytokine storm genes and the characteristic expression profiling of COVID-19 in the explanted lung tissues and the svRNAs precursor transfected human lung epithelial cells, we found that the maturation of these two small viral RNAs contributed significantly to the infection associated lung inflammation, mainly via the activation of the CXCL8, CXCL11 and type I interferon signaling pathway. Taken together, we discovered two SARS-CoV-2-Encoded small RNAs and investigated the pro-inflammatory effects during their maturation in human lung epithelial cells, which might provide new insight into the pathogenesis and possible treatment options for COVID-19.

The beta subunit of F1Fo-ATP synthase (ATP5B) has been demonstrated to play an essential role in tumor progression and metastasis. However, there has been no comprehensive pan-cancer multi-omics analysis of ATP5B, while the clinical relevance of ATP5B and its potential mechanism in regulating breast cancer are still poorly understood. In this study, we demonstrated that ATP5B has a higher frequency of amplification than deletion in most cancer types, and the copy number variation (CNV) of ATP5B was significantly positively correlated with its mRNA expression level. DNA methylation analysis across pan-cancer also revealed a strong correlation between ATP5B expression and epigenetic changes. We identified 6 significant methylation sites involved in the regulation of ATP5B expression. Tissue microarrays (TMA) from 129 breast cancer samples, integrated with multiple additional breast cancer dataset, were used to evaluate the ATP5B expression and its correlation with prognosis. Higher levels of ATP5B expression were consistently associated with a worse OS in all datasets, and Cox regression analysis suggested that ATP5B expression was an independent prognostic factor. Gene enrichment analysis indicated that the gene signatures of DNA damage recognition, the E-cadherin nascent pathway and the PLK1 pathway were enriched in ATP5B-high patients. Moreover, somatic mutation analysis showed that a significant different mutation frequency of CDH1 and ADAMTSL3 could be observed between the ATP5B-high and ATP5B-low groups. In conclusion, this study reveals novel significance regarding the genetic characteristics and clinical value of ATP5B highlighted in predicting the outcome of breast cancer patients.

Historically well-known tumor-promoting gene family plays a key role in cell identity regulation in small cell lung cancer., Comprehensive genomic analyses of small cell lung cancer (SCLC) have revealed frequent mutually exclusive genomic amplification of MYC family members. Hence, it has been long suggested that they are functionally equivalent; however, more recently, their expression has been associated with specific neuroendocrine markers and distinct histopathology. Here, we explored a previously undescribed role of L-Myc and c-Myc as lineage-determining factors contributing to SCLC molecular subtypes and histology. Integrated transcriptomic and epigenomic analyses showed that L-Myc and c-Myc impart neuronal and non-neuroendocrine–associated transcriptional programs, respectively, both associated with distinct SCLC lineage. Genetic replacement of c-Myc with L-Myc in c-Myc–SCLC induced a neuronal state but was insufficient to induce ASCL1-SCLC. In contrast, c-Myc induced transition from ASCL1-SCLC to NEUROD1–SCLC characterized by distinct large-cell neuroendocrine carcinoma–like histopathology. Collectively, we characterize a role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular and histological subtypes.

The Polima system of cytoplasmic male sterility (Pol CMS) was widely used for hybrid seed production, but with high probability of occurrence of maternal false hybrid due to the fertility of Polima CMS (Pol CMS) line greatly affected by the ambient temperature, therefore, the detection of maternal false hybrids is the key to purity identification. In present study, the SSR markers were designed based on the flanking sequences of Pol CMS restorer gene Rfp , and application of SSR markers in hybrid seed purity test of rapeseed. The main results were as follows: the sequences of Rfp were subjected to basic local alignment search tool queries against the Brassica rapa genome to determine chromosome positions, and 32 SSR markers were developed based on the upstream and downstream sequences of Rfp . Among the 32 SSR markers, one codominant marker was polymorphic between Pol CMS sterile and restorer line, the PCR product length was 162 bp in Pol CMS sterile lines, and 184 bp in restorer lines. Based on the PCR sequence, two insert fragments (15 bp and 7 bp) were identified in Pol CMS restorer lines. The SSR marker co-segregated with plant fertility of individuals in the “fengyou737” F 2 population. The purity of “fengyou737”, “fengyou320” and “fengyou958” were identified by means of PCR-SSR markers and field-planting, and the results of two ways were highly consistent, indicated that the codominant SSR marker tightly linked to Rfp , and the marker can detect paternal and maternal false hybrids. The present findings will provide technical assistance for hybrid seed purity test and genetic diversity analysis in rapeseed.

The objective of this study was to use isobaric tags for relative and absolute quantitation (iTRAQ) proteomic technology to systematically analyze the hepatotoxic mechanism of aflatoxin B1 (AFB1) and its prevention by Se in broilers. Four groups of day-old broilers were allocated into a 2 × 2 factorial design trial that fed a Se-deficient based diet (BD) or the BD + 1.0 mg AFB1/kg, 0.3 mg Se/kg, or 1.0 mg AFB1/kg plus 0.3 mg Se/kg for 3 wk. Dietary AFB1 increased serum ALT and decreased total protein and albumin concentrations, and induced hepatic histopathological lesions in Se adequate groups. Notably, Se deficiency exacerbated these AFB1-induced changes. Furthermore, Se deficiency reduced hepatic glutathione peroxidase but increased thioredoxin reductase and glutathione S-transferase activities and 8-hydroxydeoxyguanosine concentration in AFB1 administrated groups. Moreover, AFB1 dysregulated 261 co-differentially expressed proteins (DEPs) in both Se adequate and deficiency diets, and Se deficiency dysregulated 64 DEPs in AFB1 administrated diets. These DEPs are mainly related to phase I and II metabolizing enzymes, heat shock proteins, DNA repair, fatty acid metabolism and apoptosis. The in vitro study has verified that aldo-keto reductase family1, member10 plays an important role in AFB1-induced hepatotoxicity and Se-mediated detoxification of AFB1 in a chicken leghorn male hepatoma cells. Conclusively, this study has analyzed the hepatic proteome response to dietary AFB1 and Se, and thus shed new light on the mechanisms of hepatotoxicity of AFB1 and its detoxification by Se in broilers.

Summary A beneficial gut Bacteroides-folate-liver pathway regulating lipid metabolism is demonstrated. Oral administration of a Ganoderma meroterpene derivative (GMD) ameliorates nonalcoholic hepatic steatosis in the liver of fa/fa rats by reducing endotoxemia, enhancing lipid oxidation, decreasing de novo lipogenesis, and suppressing lipid export from the liver. An altered gut microbiota with an increase of butyrate and folate plays a causative role in the effects of GMD. The commensal bacteria Bacteroides xylanisolvens, Bacteroides thetaiotaomicron, Bacteroides dorei, and Bacteroides uniformis, which are enriched by GMD, are major contributors to the increased gut folate. Administration of live B. xylanisolvens reduces hepatic steatosis and enhances the folate-mediated signaling pathways in mice. Knockout of the folate biosynthetic folp gene in B. xylanisolvens blocks its folate production and beneficial effects. This work confirms the therapeutic potential of GMD and B. xylanisolvens in alleviating nonalcoholic hepatic steatosis and provides evidence for benefits of the gut Bacteroides-folate-liver pathway.

With the implementation of significant scientific projects such as the Human Genome Project, genomics, transcriptomics, and proteomics have played an important role in the study of human life sciences. At the same time, metabolomics came into being and developed rapidly since mid-1990s. Together with genomics, transcriptomics, and proteomics, it constitutes systems biology. Genomics, transcriptomics, proteomics, and metabolomics have played indispensable roles in the field of life sciences. They are studied from different levels of regulating life processes, so that people can study life phenomena at the molecular level, explore the nature of life, and gradually and systematically understand the law of life development. These methods, together with bioinformatics, have become an important part of systemic biology. Metabolomics studies all metabolic responses of individuals to stimuli, environmental changes, and genetic modifications of exogenous substances (drugs or poisons), and examines the overall picture and dynamic changes of these responses. Metabolomics provides powerful modern experimental techniques for the development of life sciences, as well as new technical support and guarantee for the preclinical safety evaluation and practice of new drugs. The emergence of metabolomics makes up for the shortcomings of microstudies such as genomics and proteomics. With the improvement in analytical methods and data analysis, all the information about the organism obtained by metabolomics will be comprehensively interpreted. Through the analysis of this large amount of information, it was found that the biomarkers related to drugs or clinics were metabolites. It is believed that metabolomics play an increasingly important role in clinical practice and new drug development.

Eight new triterpenoids, ganoleucoins T-Z(1–3, 5–8), and AA (9), together with eleven known triterpenes were isolated and identified from the wild fruiting bodies of the medicinal mushroom Ganoderma leucocontextum. The structures of new compounds were determined on the basis of NMR and MS spectral analysis. The inhibitory effects of 1–9 on HMG-CoA reductase were tested in vitro. Compounds 1, 7 and 8 showed significant HMG-CoA reductase inhibition with IC50 values of 10.2, 9.72 and 8.68 μM, respectively. The other isolated compounds presented relatively weak inhibitory activity with IC50 values >100 μM. Preliminary structure-activity relationship analysis showed that the HMG moiety in 7 and 8 contributed greatly to their inhibitory activity against HMG-CoA reductase. This work further demonstrates the mushroom G. leucocontextum to be valuable herbal medicine that deserves deep investigation.

To understand better the microbial functional populations which are involved in methanogenesis and denitrification in paddy soils with rice straw (RS) and/or nitrogen fertiliser (potassium nitrate, N) application, the dynamics of methanogens and the denitrifying community were monitored simultaneously during the incubation period. The results show that the community structure of methanogens remained relatively stable among treatments based on 16S rDNA analysis, but fluctuated based on 16S rRNA. The Methanocellaceae and Methanosarcinaceae dominated all treatments at 16S rDNA and 16S rRNA level, respectively. RS+N increased the relative abundance of Methanosaetaceae at the 16S rRNA level, while there was an increasing trend in that Methanomicrobiaceae following RS addition at the 16S rDNA level. RS and/or N did not significantly change the diversity of methanogens targeting both 16S rDNA and 16S rRNA. RS and RS+N increased copy numbers of methanogens targeting both 16S rDNA and 16S rRNA analyses. The community structure and abundance of nirS and nosZ-containing denitrifiers, and the diversity of nirS-containing denitrifiers was significantly altered only by the N treatment. These results indicate that the community structure, diversity and abundance of methanogens respond differently to RS addition at the 16S rDNA and 16S rRNA levels.

The objective of this study was to compare the bio-efficacy of 2-hydroxy-4-methylthiobutanoic acid (DL-HMTBA) with that of DL-methionine (DLM) as sources of methionine in terms of the growth performance, carcass traits, feather growth, and redox statuses of Cherry Valley ducks. Six hundred and thirty male ducks were randomly allotted to 9 dietary treatment groups with 7 replicates of 10 birds each. The first group received a basal diet (BD) without methionine addition that was deficient in the total number of sulfur amino acids. In Groups 2 to 5 and Groups 6 to 9, the BD was supplemented with 4 increasing doses of methionine as either DLM or DL-HMTBA. The trial was run from ages 1 to 42 d. Dietary supplementation with DLM and DL-HMTBA improved body weight gain and feed intake as well as weights of carcasses, breast meat, and feathers compared with the BD. No significant difference was observed between the 2 methionine sources on growth performance, carcass traits, and feather growth. Concentrations of some redox markers in the pectoralis major muscle were improved by addition of methionine to the BD. However, a significant difference was observed between DLM and DL-HMTBA in this respect, as the supplementation of DL-HMTBA significantly increased the total antioxidant capacity, the activities of glutathione peroxidase, and the concentration of reduced glutathione in the pectoralis major muscle, compared with DLM. No significant difference between methionine sources was found with regard to the concentrations of oxidized glutathione and malondialdehyde in the pectoralis major muscle. Both DLM and DL-HMTBA increased malondialdehyde concentrations in the pectoralis major muscle compared with the BD. In conclusion, these results indicated that DLM and DL-HMTBA have equal biological value for the growth performance, carcass traits, and feather growth of Cherry Valley duck. Moreover, the improved antioxidant capacity observed with DL-HMTBA makes this a better candidate than DLM for lowering the oxidation process in the meat during post-mortem storage and thereby contributes to a better duck meat quality.

As part of our program to discover new bioactive agents from fungi, 13 new alkaloids accompanying 13 known related alkaloids were isolated from a wild strain of Aspergillus oryzae L1020. Compounds 1 and 2 have unprecedented 6/6/5/7/5 and 6/6/6/5/5 chemical skeletons, representing new members of quinoline alkaloids. Compound 3 is a new macrolactam with an unusual 6/5/6/8 ring system. Compounds 4-13 are new α-cyclopiazonic acid-related alkaloids. The absolute configurations of 1-4, 8, and 9 were assigned by electronic circular dichroism calculations. Compounds 2, 5, 6, 11, 14, 22, and 26 exhibit pronounced neurite outgrowth-promoting effects on PC12 cells in the range of 25-100 μM.

Two new secondary metabolites, kongiilines A and B (1, 7), and two asperphenamate derivatives, asperphenamates B and C (5–6), together with 16 known compounds (2–4, 8–20), were isolated from Tibetan Plateau fungi Penicillium kongii and Penicillium brasilianum. This is the first report on asperphenamates B and C as naturally occurring compounds, and that aspterric acid is isolated from P. brasilianum for the first time. Their structures were elucidated by different spectroscopic techniques including high-resolution electrospray ionisation mass spectrum, 1D nuclear magnetic resonance (NMR), and 2D NMR as well as electronic circular dichroism. Compounds 4, 5, and 10 exhibited cytotoxicity activities against human colon carcinoma HCT116 cell line with IC50 values of 88.16, 77.68, and 36.92 μM, respectively. Fungi from Tibetan Plateau represent important and rich resources for the investigation of new chemicals.

The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure-activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.

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.

Oxidative stress is recognized as one of the most important contributing factors to the development of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) can induce vascular reactive oxygen species (ROS) production, trigger endothelial dysfunction and initiate the progression of atherosclerosis. Previous studies have demonstrated that thioredoxin-1 (Trx) is one of the key regulators of intracellular redox, which is pivotal in atherogenesis. However, the regulation mechanism is still unclear. In this study, we investigated the effects of Trx1 on NADPH oxidase in human umbilical vein endothelial cells (HUVECs), whose ROS level is mainly produced by NADPH oxidase, especially Nox4 isoform. Our data demonstrated that Trx decreased NADPH oxidase activity, ROS production and ICAM-1 expression in ox-LDL treated HUVECs. Genetic gain-of-function and loss-of-function studies showed that Trx1 suppressed ox-LDL-induced Nox4 and p22phox expression. A co-immunoprecipitation assay indicated that Trx1 decreased Nox4-p22phox complex level during ox-LDL stimulation. Transient transfection of Nox4 and p22phox significantly increased intracellular ROS generation, which could be blocked by Trx overexpression. In addition, Trx overexpression also prevented ox-LDL-induced Nox2 and Rac1 protein levels. These results suggest that Trx suppresses NADPH oxidase activity in vascular endothelia under pathological conditions and may prevent the initiation of atherosclerosis by attenuating exceeding ROS production.

Autophagy has been implicated to mediate experimental cerebral ischemia/reperfusion-induced neuronal death; the underlying molecular mechanisms, though, are poorly understood. In this study, we investigated the role of autophagy in regulating the expression of AMPAR subunits (GluR1, GluR2, and GluR3) in oxygen glucose deprivation/reperfusion (OGD/R)-mediated injury of hippocampal neurons. Our results showed that, OGD/R-induced hippocampal neuron injury was accompanied by accumulation of autophagosomes and autolysosomes in cytoplasm alongside a dramatic increase in expression of autophagy-related genes, LC3 and Beclin 1 and increased intracellular Ca2+ levels. Pre-treatment with autophagy inhibitor 3-methyladenine (3-MA) significantly reduced this effect. Moreover, the OGD/R-induced upregulation of mRNA and protein expressions of GluR1, GluR2, and GluR3 were also effectively reversed in cells pretreated with 3-MA. Our findings indicate that OGD/R induced the expression of GluRs by activating autophagy in in vitro cultured hippocampal neurons, which could be effectively reversed by the administration of 3-MA.

To evaluate the potential adjuvant effect of Agrocybe aegerita lectin (AAL), which was isolated from mushroom, against a virulent H9N2 strain in vivo and in vitro. In trial 1, 50 BALB/c male mice (8 weeks old) were divided into five groups (n=10 each group) which received a subcutaneous injection of inactivated H9N2 (control), inactivated H9N2+0.2% (w/w) alum, inactivated H9N2+0.5 mg recombinant AAL/kg body weight (BW), inactivated H9N2+1.0 mg AAL/kg BW, and inactivated H9N2+2.5 mg AAL/kg BW, respectively, four times at 7-d intervals. In trial 2, 30 BALB/c male mice (8 weeks old) were divided into three groups (n=10 each group) which received a subcutaneous injection of inactivated H9N2 (control), inactivated H9N2+2.5 mg recombinant wild-type AAL (AAL-wt)/kg BW, and inactivated H9N2+2.5 mg carbohydrate recognition domain (CRD) mutant AAL (AAL-mutR63H)/kg BW, respectively, four times at 7-d intervals. Seven days after the final immunization, serum samples were collected from each group for analysis. Hemagglutination assay, immunogold electron microscope, lectin blotting, and co-immunoprecipitation were used to study the interaction between AAL and H9N2 in vitro. IgG, IgG1, and IgG2a antibody levels were significantly increased in the sera of mice co-immunized with inactivated H9N2 and AAL when compared to mice immunized with inactivated H9N2 alone. No significant increase of the IgG antibody level was detected in the sera of the mice co-immunized with inactivated H9N2 and AAL-mutR63H. Moreover, AAL-wt, but not mutant AAL-mutR63H, adhered to the surface of H9N2 virus. The interaction between AAL and the H9N2 virus was further demonstrated to be associated with the CRD of AAL binding to the surface glycosylated proteins, hemagglutinin and neuraminidase. Our findings indicated that AAL could be a safe and effective adjuvant capable of boosting humoral immunity against H9N2 viruses in mice through its interaction with the viral surface glycosylated proteins, hemagglutinin and neuraminidase.

Medicinal mushroom Ganoderma sp. is considered to be a key source for the production of therapeutic agents. Our current review indicates that a limited number (430) of isolated compounds have been tested and known to be active against several microorganisms and parasites. In this review, we aim to summarise all the antimicrobial and anti-parasitic works on Ganoderma sp. displayed on web of science, google scholar and endnote X7 from 1932 to August 2016. We further present and discuss the structure of active compounds against microorganisms and parasites. In addition, we also discuss the possible further research to identify lead compounds from Ganoderma sp. as a novel strategy to combat the potential global emergence of bad bugs and parasites.

Comprehensive genomic analyses of small cell lung cancer (SCLC), the most aggressive form of lung cancer, have revealed near universal loss of tumor suppressors (RB1 and TP53) and frequent genomic amplification of all three MYC family members. The amplification of each Myc family member is mutually exclusive; hence it had been long suggested that they are functionally equivalent. However, their expression has more recently been associated with specific neuroendocrine markers and distinct histopathology. In this study, we explored a novel role of c-Myc and L-Myc as lineage determining factors contributing to SCLC molecular subtypes and histology. Integrated analyses of a gene regulatory network generated from mRNA expression of primary SCLC tumor and chromatin state profiling of SCLC cell lines showed that Myc family members impart distinct transcriptional programs associated with lineage state; wherein the L-Myc signature was enriched for neuronal pathways while the c-Myc signature was enriched for Notch signaling and epithelial-to-mesenchymal transition. We investigated the functional redundancy and distinction of c-Myc and L-Myc, and noted the insufficiency of L-Myc to induce lineage switch in contrast to the potential of c-Myc to induce trans-differentiation. c-Myc rewires the Myc-accessible landscape and activates neuron al repressor, Rest to mediate transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, our findings reveal a previously undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses.

Sclerotinia sclerotiorum causes a devastating disease in oilseed rape (Brassica napus), resulting in major economic losses. Resistance response of B. napus against S. sclerotiorum exhibits a typical quantitative disease resistance (QDR) characteristic, but the molecular determinants of this QDR are largely unknown. In this study, we isolated a B. napus mitogen-activated protein kinase gene, BnaMPK6, and found that BnaMPK6 expression is highly responsive to infection by S. sclerotiorum and treatment with salicylic acid (SA) or jasmonic acid (JA). Moreover, overexpression (OE) of BnaMPK6 significantly enhances resistance to S. sclerotiorum, whereas RNAi in BnaMPK6 significantly reduces this resistance. These results showed that BnaMPK6 plays an important role in defense to S. sclerotiorum. Furthermore, expression of defense genes associated with SA-, JA- and ethylene (ET)-mediated signaling was investigated in BnaMPK6-RNAi, WT and BnaMPK6-OE plants after S. sclerotiorum infection, and consequently, it was indicated that the activation of ET signaling by BnaMPK6 may play a role in the defense. Further, four BnaMPK6-encoding homologous loci were mapped in the B. napus genome. Using the allele analysis and expression analysis on the four loci, we demonstrated that the locus BnaA03.MPK6 makes an important contribution to QDR against S. sclerotiorum. Our data indicated that BnaMPK6 is a previously unknown determinant of QDR against S. sclerotiorum in B. napus.

Gastric cancer is one of the top five malignant tumors worldwide. At present, the molecular mechanisms of gastric cancer progression are still not completely clear. Cytoplasmic dynein regulates intracellular transport and mitotic spindle localization, and its abnormal function is crucial for tumorigenesis, promotes tumor cell cycle progression, and tumor migration. DYNC1I1 is an important binding subunit of cytoplasmic dynein. However, studies on DYNC1I1 in tumors are currently limited. In the current study, we found that high DYNC1I1 expression in gastric cancer is associated with poor prognosis and is an independent prognostic factor. DYNC1I1 promoted the proliferation and migration of gastric cancer cells both in vitro and in vivo. DYNC1I1 also upregulated IL-6 expression by increasing NF-κB nuclear translocation. Collectively, these data revealed an important role for the DYNC1I1-driven IL-6/STAT pathway in gastric cancer proliferation and migration, suggesting that DYNC1I1 may be a potential therapeutic target for gastric cancer.

Two new arborinane-type triterpenes, myrotheols A (1) and B (2), two new arborinane-type glycosides, myrothesides C (3) and D (4), together with four known diterpenes (5 – 8) were isolated from the ethyl acetate extract of the endolichenic fungus Myrothecium inundatum. The structures of new compounds 1 – 4 were elucidated by NMR and MS analyses. The absolute configuration of 1 was assigned by a single-crystal X-ray diffraction experiment. Compounds 3 and 4 represent the first two natural 4-O-methyl-α-D-mannosides. Compounds 1 – 8 exhibited cytotoxicity against K562 and RKO human cancer cell lines.

The disease caused by Sclerotinia sclerotiorum has traditionally been difficult to control, resulting in tremendous economic losses in oilseed rape (Brassica napus). Identification of important genes in the defense responses is critical for molecular breeding, an important strategy for controlling the disease. Here, we report that a B. napus mitogen-activated protein kinase gene, BnaMPK3, plays an important role in the defense against S. sclerotiorum in oilseed rape. BnaMPK3 is highly expressed in the stems, flowers and leaves, and its product is localized in the nucleus. Furthermore, BnaMPK3 is highly responsive to infection by S. sclerotiorum and treatment with jasmonic acid (JA) or the biosynthesis precursor of ethylene (ET), but not to treatment with salicylic acid (SA) or abscisic acid. Moreover, overexpression (OE) of BnaMPK3 in B. napus and Nicotiana benthamiana results in significantly enhanced resistance to S. sclerotiorum, whereas resistance is diminished in RNAi transgenic plants. After S. sclerotiorum infection, defense responses associated with ET, JA, and SA signaling are intensified in the BnaMPK3-OE plants but weakened in the BnaMPK3-RNAi plants when compared to those in the wild type plants; by contrast the level of both H2O2 accumulation and cell death exhibits a reverse pattern. The candidate gene association analyses show that the BnaMPK3-encoding BnaA06g18440D locus is a cause of variation in the resistance to S. sclerotiorum in natural B. napus population. These results suggest that BnaMPK3 is a key regulator of multiple defense responses to S. sclerotiorum, which may guide the resistance improvement of oilseed rape and related economic crops.

Germline variants of PIP4K2A impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of PIP4K2A in cancers, regulatory network and prognostic effect of this gene remains poorly understood in tumorigenesis and leukemogenesis. In this study, we conducted genome-wide gene expression association analyses in pediatric B-ALL cohorts to discover expression associated genes and pathways, which is followed by the bioinformatics analyses to investigate the prognostic role of PIP4K2A and its related genes in multiple cancer types. 214 candidates were identified to be significantly associated with PIP4K2A expression in ALL patients, with known cancer-related genes rankings the top (e.g., RAC2, RBL2, and TFDP1). These candidates do not only tend to be clustered in the same types of leukemia, but can also separate the patients into novel molecular subtypes. PIP4K2A is noticed to be frequently overexpressed in multiple other types of leukemia and solid cancers from cancer cohorts including TCGA, and associated with its candidates in subtype-specific and cancer-specific manners. Interestingly, the association status varied in tumors compared to their matched normal tissues. Moreover, PIP4K2A and its related candidates exhibit stage-independent prognostic effects in multiple cancers, mostly with its lower expression significantly associated with longer overall survival (p < 0.05). Our findings reveal the transcriptional regulatory network of PIP4K2A in leukemia, and suggest its potentially important role on molecular subtypes of multiple cancers and subsequent treatment outcomes.

Single-cell omics has great value in basic biological research and medical science, possessing the power to reveal genetic, transcriptomic, epigenetic, proteomic, and metabolomic features at cell-level resolution. As the basic unit of organisms, single cells have diversity, heterogeneity, and dynamics that can be delineated only by obtaining the omics information from each cell, as opposed to assessing the average signal from a complex cell population. Single-cell omics technologies have been applied to studying cell heterogeneity in a broad range of complex biological systems, including microbial ecosystems, tumors, the nervous system, and embryos, to provide detailed insights into cellular heterogeneity that were not available through conventional techniques. Single-cell omics has brought about revolutions in multiple fields of biological studies. Recent single-cell omics studies on cancers have provided extensive details of cell heterogeneity in individual tumors, opening a view to initial basis of the molecular mechanism of tumor initiation, intratumoral heterogeneity, cancer invasion, drug resistance, and tumor metastasis, as well as cancer microenvironment. Dissecting the composition of different cell types and cell states throughout a biological system, known as distinguishing distinct “identities” of cells, is another important new area of single-cell omics—as seen in the Human Cell Atlas Project, which ambitiously is aiming to classify cells into types and create a comprehensive spectrum of all human cells. Moreover, interrogating cell heterogeneity by single-cell omics has further paved the way for investigating a variety of complex diseases and biological processes, including neurological disorders, immune diseases, and even aging. Such research will impact treatment strategies and improve the management of disease.

Five new spirobisnaphthalenes (1–5), one new tetralone derivative (6), and six new lactones (7–12) together with the known compound urnucratin C (13) have been isolated from the solid culture of the cup fungus Plectania sp. The structures of the new compounds were unambiguously elucidated on the basis of one- and two-dimensional NMR spectroscopy, high-resolution mass spectrometry, and circular dichroism (CD) spectroscopy. Compounds 1–6 were found to be active against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Bacillus subtilis, and Pseudomonas aeruginosa. In addition, the cytotoxicities of 1–13 were evaluated against the HepG2 and K562 cell lines by using the CCK8 assay. Compounds 1–3 and 13 showed moderate cytotoxicity against HepG2 and K562 with IC50 values in the range 10.7–38.5 µm. This is the first report of secondary metabolites from this cup fungus.

Background & Aims: BCAT1 initiates the catabolism of branched-chain amino acids. Here, we investigated the function of BCAT1 and its transcriptional regulatory mechanism in hepatocellular carcinoma (HCC). Methods: RNASeq was used to evaluate BCAT1 mRNA levels in HCC and normal matched specimens. After the exogenous expression of BCAT1 in BEL-7404 cells and the suppression of endogenous BCAT1 expression with shRNA in HepG2 cells, the cell proliferation, clone-forming ability and cell-cycle changes were measured with MTT assay, colony-forming assay and flow cytometry respectively. A xenograft model was used to investigate the effect of BCAT1 on cancer growth in vivo. Chromatin immunoprecipitation and luciferase reporter technologies were used to confirm the transcriptional regulation of the BCAT1 gene by MYC. The expression of the BCAT1 and MYC proteins in 122 HCC tissues was determined with an immunohistochemical analysis. Results: BCAT1 mRNA was clearly increased in HCC tissues and hepatomas. The ectopic expression of BCAT1 in BEL-7404 cells enhanced their proliferation, clone formation, tumourigenic properties, S-G2/M phase transition and chemoresistance to cisplatin. The suppression of BCAT1 expression in HepG2 cells significantly inhibited their proliferation, clone formation, and S-G2/M phase transition and caused their chemosensitization to cisplatin. MYC affected the transcriptional regulation of BCAT1. Clinical data showed that BCAT1 expression correlated with a significantly poorer prognosis. Conclusion: BCAT1 plays a pathogenic role in HCC by causing cell proliferation and chemoresistance. The MYC transcription factor is involved in regulating the transcriptional activity of BCAT1. BCAT1 expression has prognostic significance for the survival of patients with HCC. (Less)

Five new cyclohexadepsipeptides termed as enniatins R - V (1 - 5) and seven known cyclohexadepsipeptides (6 - 12) were isolated from the solid culture of Fusarium proliferatum, a fungus isolated from the cadaver of an unidentified insect collected in Tibet. Their structures were elucidated by NMR and MS spectroscopic analysis. The X-ray single-crystal structure of 6 was reported for the first time. Enniatins R and S represented the first enniatins incorporating with an unusual 2,3-dihydroxy-isovaleric acid (Div) residue. The cytotoxicity and autophagy-inducing activities of 1 - 12 were evaluated in vitro. Beauvenniatin F (11) exhibited strong cytotoxicity against K562/A (adriamycin-resistant K562) with IC50 value of 3.78 μm, and also autophagy-inducing activity at the concentration of 20 μm in GFP-LC3 stable HeLa cells.

Nine new sesquiterpenoids, clitocybulol derivatives, clitocybulols G-O (1-9) and three known sesquiterpenoids, clitocybulols C-E (10-12), were isolated from the solid culture of the edible fungus Pleurotus cystidiosus. The structures of compounds 1-12 were determined by spectroscopic methods. The absolute configurations of compounds 1-9 were assigned via the circular dichroism (CD) data analysis. Compounds 1, 6 and 10 showed moderate inhibitory activity against protein tyrosine phosphatase-1B (PTP1B) with IC50 values of 49.5, 38.1 and 36.0μM, respectively.

The primary effect of the endoplasmic reticulum (ER) stress response or unfolded protein response (UPR) is to reduce the load of unfolded protein and promote survival. However, prolonged and severe ER stress leads to tissue injury and serious diseases. Thus, it is important to identify drugs that can attenuate ER stress for the treatment of diseases. Natural products continue to provide lead compounds for drug discovery and front‑line pharmacotherapy for people worldwide. Previous studies have indicated that selenoprotein S (SelS) is a sensitive and ideal maker of ER stress. In the present study, a firefly luciferase reporter driven by the SelS gene promoter was used to screen for natural compounds capable of attenuating ER stress. From this, paclitaxel (PTX) was identified to efficiently inhibit the promoter activity of the SelS gene, and further results revealed that PTX significantly inhibited the tunicamycin‑induced upregulation of SelS at the mRNA and protein levels in HepG2 and HEK293T cells. In addition, PTX was able to efficiently inhibit the expression of the ER stress marker, glucose‑regulated protein 78, in ER stress, indicating that PTX may reverse ER stress. Taken together, these results suggest that PTX is able to inhibit SelS expression during ER stress and attenuate ER stress.

Diterpenes has been reported to possess multiple bioactivities consisting of anti-microbial and anti-inflammatory properties. This study reveals a new cyathane-type diterpene (cyathin Q) from the culture of the fungus Cyathus africanus by bioactivity-guided separation. The structure of cyathin Q was determined based on spectroscopic measurements (NMR and MS). The bioactivity evaluation shows that cyathin Q has a strong anticancer activity against HCT116 cells and Bax-deficient HCT116 in vitro and in vivo. This compound induced hallmarks of apoptotic events in HCT116 cells, including caspase activation, cytochrome c release, poly (ADP-ribose) polymerase (PARP) cleavage, and depolarization of the mitochondrial inner transmembrane potential. This process is accompanied with the increased mitochondrial ROS, down-regulation of Bcl-2 protein, and up-regulation of Bim protein. We also observed the cleavage of autophagy-related protein ATG5 in cyathin Q-induced apoptosis. Taken together, our study identified a new fungal diterpene that exhibited anticancer activity via induction of mitochondria and autophagy-dependent apoptosis in HCT116 cells.

International audience; Nitrogen fertilization and returning straw to paddy soil are important factors that regulate CH4 production. To evaluate the effect of rice straw and/or nitrate amendment on methanogens, a paddy soil was anaerobically incubated for 40 days. The results indicated that while straw addition increased CH4 production and the abundances of mcrA genes and their transcripts, nitrate amendment showed inhibitory effects on them. The terminal restriction fragment length polymorphism (T-RFLP) analysis based on mcrA gene revealed that straw addition obviously changed methanogenic community structure. Based on mcrA gene level, straw-alone addition stimulated Methanosarcinaceaes at the early stage of incubation (first 11 days), but nitrate showed inhibitory effect. The relative abundance of Methanobacteriaceae was also stimulated by straw addition during the first 11 days. Furthermore, Methanosaetaceae were enriched by nitrate-alone addition after 11 days, while Methanocellaceae were enriched by nitrate addition especially within the first 5 days. The transcriptional methanogenic community indicated more dynamic and complicated responses to straw and/or nitrate addition. Based on mcrA transcript level, nitrate addition alone resulted in the increase of Methanocellaceae and the shift from Methanosarcinaceae to Methanosaetaceae during the first 5 days of incubation. Straw treatments increased the relative abundance of Methanobacteriaceae after 11 days. These results demonstrate that nitrate addition influences methanogens which are transcriptionally and functionally active and can alleviate CH4 production associated with straw amendment in paddy soil incubations, presumably through competition for common substrates between nitrate-utilizing organisms and methanogens.

One new perhydrobenzannulated 5,5-spiroketal sesquiterpene, pleurospiroketal F (1), as well as six new modified bisabolene sesquiterpenes pleurotins A–F (2–7) were isolated from solid-state fermentation of Pleurotus citrinopileatus. The structures of compounds 1–7 were determined by NMR and MS spectroscopic analysis. The absolute configuration of 1 was determined by X-ray diffraction analysis, while the absolute configurations of 3–7 were assigned using the in situ dimolybdenum circular dichroism method and circular dichroism data comparison. Protein tyrosine phosphatase 1B plays a crucial role as a negative regulator of the insulin-dependent signal cascades. Therefore, the protein tyrosine phosphatase 1B inhibitor can be used for treating type 2 diabetes mellitus and obesity. Compounds 2 and 6 showed moderate inhibitory effects on protein tyrosine phosphatase 1B with IC50 s of 32.1 µM and 30.5 µM, respectively. The kinetic study confirmed compound 2 to be a noncompetitive inhibitor. Compounds 1–7 did not show cytotoxic activity against cancer cell lines (IC50 > 50 µM).

Trichodermates A – F (1–6, resp.), six new trichothecene polyunsaturated octadioic acid esters, and (−)-harzianum B (7) were isolated from the fermentation extract of Trichoderma sp., a plant pathogenic fungus isolated from stem rot of an unidentified tree in Thailand. The structures of 1–7 were elucidated by NMR experiments. The absolute configuration at C(12) in 3 was assigned by in situ dimolybdenum circular dichroism method, whereas that in 7 was deduced after hydrolysis of 7 to 8 via modified Mosher's method. Compounds 1 and 2 showed modest cytotoxic activities against the K562 (human myelogenous leukemia) cell line with IC50 values of 12.12 and 13.08 μM, respectively.

Metabolic syndrome characterized by obesity, hyperglycemia and liver steatosis is becoming prevalent all over the world. Herein, a water insoluble polysaccharide (WIP) was isolated and identified from the sclerotium of Poria cocos, a widely used Traditional Chinese Medicine. WIP was confirmed to be a (1-3)-β-D-glucan with an average Mw of 4.486 × 106 Da by NMR and SEC-RI-MALLS analyses. Furthermore, oral treatment with WIP from P. cocos significantly improved glucose and lipid metabolism and alleviated hepatic steatosis in ob/ob mice. 16S DNA sequencing analysis of cecum content from WIP-treated mice indicated the increase of butyrate-producing bacteria Lachnospiracea, Clostridium. It was also observed that WIP treatment elevated the level of butyrate in gut, improved the gut mucosal integrity and activated the intestinal PPAR-γ pathway. Fecal transplantation experiments definitely confirmed the causative role of gut microbiota in mediating the benefits of WIP. It is the first report that the water insoluble polysaccharide from the sclerotium of P. cocos modulates gut microbiota to improve hyperglycemia and hyperlipidemia. Thereby, WIP from P. cocos, as a prebiotic, has the potential for the prevention or cure of metabolic diseases and may elucidate new mechanism for the efficacies of this traditional herbal medicine on the regulation of lipid and glucose metabolism.

Single cancer cell-sequencing studies currently use randomly selected cells, limiting correlations among genomic aberrations, morphology, and spatial localization. We laser-captured microdissected single cells from morphologically distinct areas of primary breast cancer and corresponding lymph node metastasis and performed whole-exome or deep-target sequencing of more than 100 such cells. Two major subclones coexisted in different areas of the primary tumor, and the lymph node metastasis originated from a minor subclone in the invasive front of the primary tumor, with additional copy number changes, including chr8q gain, but no additional point mutations in driver genes. Lack of metastasis-specific driver events led us to assess whether other clonal and subclonal genomic aberrations preexisting in primary tumors contribute to lymph node metastasis. Gene mutations and copy number variations analyzed in 5 breast cancer tissue sample sets revealed that copy number variations in several genomic regions, including areas within chr1p, chr8q, chr9p, chr12q, and chr20q, harboring several metastasis-associated genes, were consistently associated with lymph node metastasis. Moreover, clonal expansion was observed in an area of morphologically normal breast epithelia, likely driven by a driver mutation and a subsequent amplification in chr1q. Our study illuminates the molecular evolution of breast cancer and genomic aberrations contributing to metastases.

It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.

Sesterterpenes are usually found in plants and fungi, but are rare in bacteria. Here, we present the identification of StsC from Streptomyces somaliensis, a member of the UbiA superfamily, as a membrane-bound sesterterpene cyclase in bacteria. The cyclized products for StsC, somaliensenes A (1) and B (2), were identified by expressing the corresponding gene in an engineered Escherichia coli strain. The structures of 1 and 2 were determined by analysis of the NMR and MS spectroscopic data.

Three new cyathane diterpenes erinacines T–V (1–3), and two known cyathane diterpenes erinacine A (4) and erinacine P (5) were isolated from the liquid cultures of Hericium erinaceus. The structures of 1–3 were determined by extensive spectroscopic analysis. All isolated compounds were evaluated for the cytotoxicity, and neurite-promoting activities using PC12 cell line. Compounds 1–3, and 5 exhibited pronounced neurite outgrowth-promoting effects on PC12 cells in the range of 2.5−10 μM. Compound 4 showed weak cytotoxicity against PC12 cells with IC50 of 73.7 μM.

Eight new alkaloids (1–8), were isolated from the solid culture of Hericium erinaceus. The structures of new metabolites were established by spectroscopic methods. The absolute configuration of 1 was determined by electronic circular dichroism (ECD) calculation. Compounds 5–8 showed inhibitory activities against both protein tyrosine phosphatase-1B (PTP1B) and α-glucosidase. In the cytotoxicity assay, compounds 1–4 showed moderate cytotoxicity against K562 cells with IC50 values in the range of 11.4–18.2 μM, and also weak cytotoxicity against doxorubicin resistant K562 cells.

Aim. To investigate the effect of ginkgolide B on junction proteins and the reduction of monocyte migration in oxidized low-density lipoprotein- (ox-LDL-) treated endothelial cells.Methods. Human umbilical vein endothelial cells (HUVECs) were used in the present study. Immunofluorescence and Western blot were performed to determine the expression of junctional adhesion molecule-A (JAM-A), connexin 43 (Cx43), and vascular endothelial cadherin (VE-cadherin). Monocyte migration was detected by the Transwell assay.Results. ox-LDL stimulation increased JAM-A expression by 35%, Cx43 expression by 24%, and VE-cadherin expression by 37% in HUVECs. Ginkgolide B (0.2, 0.4, and 0.6 mg/mL) dose-dependently abolished the expression of these junction proteins. The monocyte transmigration experiments showed that the level of monocyte migration was sixfold higher in the ox-LDL-treated group than in the control group. Ginkgolide B (0.6 mg/mL) nearly completely abolished monocyte migration. Both ginkgolide B and LY294002 suppressed Akt phosphorylation and the expression of these junction proteins in ox-LDL-treated endothelial cells. These results suggest that the ginkgolide B-induced inhibition of junction protein expression is associated with blockade of the PI3K/Akt pathway.Conclusion. Ginkgolide B suppressed junction protein expression and reduced monocyte transmigration that was induced by ox-LDL. Ginkgolide B may improve vascular permeability in atherosclerosis.

Cluster of ddifferentiation 24 (CD24) is a widely used cancer stem cell (CSC) marker in numerous cancer types. However, a number of studies have shown that CD24 is a prognostic marker, but not a CSC marker for lung adenocarcinoma. In the present study, firstly, bioinformatic analyses were used to identify the CD24 mRNA levels in the subtypes of lung cancer. Secondly, CD24high and CD24low cells were isolated from the side population of Lewis lung carcinoma (LLC) cells using flow cytometry. Furthermore, the stemness of CD24high and CD24low cells were determined in vivo and in vitro. Lastly, the mechanism(s) of nicotine-inhibited CD24 expression in LLC cells were assessed. The main findings of this study are that: i) CD24 could be used as a prognostic marker for human lung adenocarcinoma; ii) the in vitro and in vivo experiments did not determine a significant influence of CD24 on the tumorgenicity of LLC cells; and iii) nicotine inhibited CD24 expression in LLC cells by upregulation of RAS. However, the detailed mechanism(s) of these results require further analysis.