Assessing the inhibition of azoxymethane-induced preneoplastic lesions in the rat colon by cooked resistant corn starches and identifying potential genetic targets

Resistant starch (RS) is a complex carbohydrate that reaches the large intestine and is fermented by the colonic microflora. Two types of novel starches were processed: (1) stearic-acid complexed high-amylose cornstarch (SAC) which contains high resistance and (2) Guat from an inbred corn line with a high resistant starch content and ARXGuat from a hybrid of two corn lines AR (digestible starch) and Guat (resistant starch). The inhibition by SAC on colorectal carcinogenesis was compared with high amylose starch (HA) and normal corn starch (CS), and the study for the same purpose on Guat and ARXGuat starches was compared with AR starch. In all of the studies, starch diets were fed to Azoxymethane (AOM) - induced Fisher 344 rats for 8 weeks with 50-55% of the diet replaced with RS. The cooking method of water-boiling was applied to both studies. A bread-baked method was also applied to the SAC study for the comparison of the cooking methods. In the SAC study, the amount and concentration of Short Chain Fatty Acids (SCFAs) were assessed. Global gene expression was also studied in the colon mucosa of rats fed different diets or injected with AOM/saline by Affymatrix Microarray. Target genes differentially expressed after AOM treatment, or by the feeding of SAC were selected and identified by semi-quantitative real-time polymerase chain reaction analysis (semi-qRT-PCR). In our studies, SAC cooked by either the water-boiling or bread-baking method markedly reduced the Aberrant Crypt Foci (ACF) and Mucin Depleted Foci (MDF) numbers, and an enhanced ACF multiplicity was observed compared with cooked HA or CS within their cooking groups. Aberrand crypt foci numbers were dramatically decreased in the rats fed starches cooked by the bread-baking method compared with that in rats fed starch prepared by the water-boiling method. Increased cecal weights and decreased cecal content pH, as well as increased total SCFAs or individual SCFA (butyrate, acetate) amounts were obtained by the same comparison. Microarray screening identified 3368 induced and 3060 repressed genes by AOM treatment and 544 induced and 859 repressed genes by SAC treatment, among which seven genes were confirmed by semi-qRT-PCR. In the Guat and ARXGuat study, Guat was found to cause a slight but significant increase in the ACF multiplicity, but no significant differences were found in total number of ACF, MDF or AC in rats fed either Guat or ARXGuat, relative to those fed AR. Collectively, the studies suggested the inhibitory effect of novel RS SAC on colonic preneoplastic lesions after the starches were cooked. It also revealed that the rats fed starch diets prepared by bread-baked cooking method had decreased preneoplastic lesion numbers compared with those fed water-boiled starch diets

HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine.

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5'-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5'-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism

Baicalin-aluminum alleviates necrotic enteritis in broiler chickens by inhibiting virulence factors expression of Clostridium perfringens

Clostridium perfringens type A is the main cause of necrotic enteritis (NE) in chickens. Since the use of antibiotics in feed is withdrawn, it is imperative to find out suitable alternatives to control NE. Baicalin-aluminum complex is synthesized from baicalin, a flavonoid isolated from Scutellaria baicalensis Georgi. The present study investigated the effects of baicalin-aluminum on the virulence-associated traits and virulence genes expression of C. perfringens CVCC2030, it also evaluated the in vivo therapeutic effect on NE. The results showed that baicalin-aluminum inhibited bacterial hemolytic activity, diminished biofilm formation, attenuated cytotoxicity to Caco-2 cells, downregulated the expression of genes encoding for clostridial toxins and extracellular enzymes such as alpha toxin (CPA), perfringolysin O (PFO), collagenase (ColA), and sialidases (NanI, NanJ). Additionally, baicalin-aluminum was found to negatively regulate the expression of genes involved in quorum sensing (QS) communication, including genes of Agr QS system (agrB, agrD) and genes of VirS/R two-component regulatory system (virS, virR). In vivo experiments, baicalin-aluminum lightened the intestinal lesions and histological damage, it inhibited pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) expression in the jejunal and ileal tissues. Besides, baicalin-aluminum alleviated the upregulation of C. perfringens and Escherichia coli and raised the relative abundance of Lactobacillus in the ileal digesta. This study suggests that baicalin-aluminum may be a potential candidate against C. perfringens infection by inhibiting the virulence-associated traits and virulence genes expression

Review article: Inferring permafrost and permafrost thaw in the mountains of the Hindu Kush Himalaya region

The cryosphere reacts sensitively to climate change, as evidenced by the widespread retreat of mountain glaciers. Subsurface ice contained in permafrost is similarly affected by climate change, causing persistent impacts on natural and human systems. In contrast to glaciers, permafrost is not observable spatially and therefore its presence and possible changes are frequently overlooked. Correspondingly, little is known about permafrost in the mountains of the Hindu Kush Himalaya (HKH) region, despite permafrost area exceeding that of glaciers in nearly all countries. Based on evidence and insight gained mostly in other permafrost areas globally, this review provides a synopsis on what is known or can be inferred about permafrost in the mountains of the HKH region. Given the extreme nature of the environment concerned, it is to be expected that the diversity of conditions and phenomena encountered in permafrost exceed what has previously been described and investigated. We further argue that climate change in concert with increasing development will bring about diverse permafrost-related impacts on vegetation, water quality, geohazards, and livelihoods. To better anticipate and mitigate these effects, a deepened understanding of high-elevation permafrost in subtropical latitudes as well as the pathways interconnecting environmental changes and human livelihoods are needed

Growth Inhibition and Apoptosis Induced by Osthole, A Natural Coumarin, in Hepatocellular Carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported. METHODS AND FINDINGS: HCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array) assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment. CONCLUSION: Osthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of apoptosis-related genes

Statin Treatment Increases Lifespan and Improves Cardiac Health in Drosophila by Decreasing Specific Protein Prenylation

Statins such as simvastatin are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and standard therapy for the prevention and treatment of cardiovascular diseases in mammals. Here we show that simvastatin significantly increased the mean and maximum lifespan of Drosophila melanogaster (Drosophila) and enhanced cardiac function in aging flies by significantly reducing heart arrhythmias and increasing the contraction proportion of the contraction/relaxation cycle. These results appeared independent of internal changes in ubiquinone or juvenile hormone levels. Rather, they appeared to involve decreased protein prenylation. Simvastatin decreased the membrane association (prenylation) of specific small Ras GTPases in mice. Both farnesyl (L744832) and type 1 geranylgeranyl transferase (GGTI-298) inhibitors increased Drosophila lifespan. These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan species, and may explain the pleiotropic (non-cholesterol related) health effects of statins

PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications

Although high-throughput RNA sequencing (RNA-seq) has greatly advanced small non-coding RNA (sncRNA) discovery, the currently widely used complementary DNA library construction protocol generates biased sequencing results. This is partially due to RNA modifications that interfere with adapter ligation and reverse transcription processes, which prevent the detection of sncRNAs bearing these modifications. Here, we present PANDORA-seq (panoramic RNA display by overcoming RNA modification aborted sequencing), employing a combinatorial enzymatic treatment to remove key RNA modifications that block adapter ligation and reverse transcription. PANDORA-seq identified abundant modified sncRNAs—mostly transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs)—that were previously undetected, exhibiting tissue-specific expression across mouse brain, liver, spleen and sperm, as well as cell-specific expression across embryonic stem cells (ESCs) and HeLa cells. Using PANDORA-seq, we revealed unprecedented landscapes of microRNA, tsRNA and rsRNA dynamics during the generation of induced pluripotent stem cells. Importantly, tsRNAs and rsRNAs that are downregulated during somatic cell reprogramming impact cellular translation in ESCs, suggesting a role in lineage differentiation