DREB1 of the AP2/ERF superfamily plays a key role in the regulation of plant response to low temperatures. In this study, a novel DREB1/CBF transcription factor, PnDREB1, was isolated from Iceland poppy (Papaver nudicaule), a plant adaptive to low temperature environments. It is homologous to the known DREB1s of Arabidopsis and other plant species. It also shares similar 3D structure, and conserved and functionally important motifs with DREB1s of Arabidopsis. The phylogenetic analysis indicated that the AP2 domain of PnDREB1 is similar to those of Glycine max, Medicago truncatula, and M. sativa. PnDREB1 is constitutively expressed in diverse tissues and is increased in roots. qPCR analyses indicated that PnDREB1 is significantly induced by freezing treatment as well as by abscissic acid. The expression levels induced by freezing treatment were higher in the variety with higher degree of freezing tolerance. These results suggested that PnDREB1 is a novel and functional DREB1 transcription factor involved in freezing response and possibly in other abiotic stresses. Furthermore, the freezing-induction could be suppressed by exogenous gibberellins acid, indicating that PnDREB1 might play some role in the GA signaling transduction pathway. This study provides a basis for better understanding the roles of DREB1 in adaption of Iceland poppy to low temperatures.

Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-κB (NF-κB) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-κB expression, as well as NF-κB-mediated caspase-3 activation and intestinal cell apoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-κB activation-induced cell apoptosis.

Interleukin 6 (IL6), tumor necrosis factor α (TNFα) and TNF receptor-1(TNFR1) have been shown to involve in oval cell proliferation and hepatocellular carcinoma (HCC) development. However, their role in these processes is still unclear. In the present study, by using hepatocytes-specific DDB1 deletion mouse models, we explored the role and mechanism of IL6, TNFα and TNFR1 in oval cell proliferation and HCC development in the context of inflammation, which is the common features of HCC pathogenesis in humans. Our results showed that IL6 promotes oval cell proliferation and liver regeneration, while TNFα/TNFR1 does not affect this process. Deletion of IL6 accelerates HCC development and increases tumor burden. The number of natural killer(NK) cells is significantly decreased in tumors without IL6, implying that IL6 suppresses HCC by NK cells. In contrast to IL6, TNFR1-mediated signaling pathway promotes HCC development, and deletion of TNFR1 reduced tumor incidence. Increased apoptosis, compensatory proliferation and activation of MAPK/MEK/ERK cascade contribute to the oncogenic function of TNFR1-mediated signaling pathway. Intriguingly, deletion of TNFα accelerates tumor development, which shows divergent roles of TNFα and TNFR1 in hepatocarcinogenesis.

Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations.

The number of percutaneous coronary interventions (PCI) in China has increased more than 20-fold over the last decade. Consequently, there is a need for national-level information to characterize PCI indications and long-term patient outcomes, including health status, to understand and improve evolving practice patterns.

A detailed understanding of the processes controlling adipogenesis is instrumental in the fight against the obesity epidemic. Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. During 3T3-L1 adipocyte differentiation, C/EBPβ is induced early to transactivate the expression of C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ), two master transcription factors for terminal adipocyte differentiation. Studies in recent years have revealed many new target genes of C/EBPβ, implicating its participation in many other processes during adipogenesis, such as mitotic clonal expansion, epigenetic regulation, unfolded protein response, and autophagy. Moreover, the function of C/EBPβ is highly regulated by post-translational modifications, which are crucial for the proper activation of the adipogenic program. Advances toward elucidation of the function and roles of the post-translational modification of C/EBPβ during adipogenesis will greatly improve our understanding of the molecular mechanisms governing adipogenesis.

To investigate whether pretreatment with dexmedetomidine (Dex) has a protective effect against acute lung injury (ALI) in an orthotopic autologous liver transplantation (OALT) rat model and to explore the mechanisms responsible for the protective effect of Dex against lung injury.

Oxidative stress is the main pathogenesis of diabetic microangiopathy, which can cause microvascular endothelial cell damage and destroy vascular barrier. In this study, it is found that carnosol protects human microvascular endothelial cells (HMVEC) through antioxidative mechanisms. First, we measured the antioxidant activity of carnosol. We showed that carnosol pretreatment suppressed tert-butyl hydroperoxide (t-BHP)-induced cell viability, affected the production of lactate dehydrogenase (LDH) as well as reactive oxygen species (ROS), and increased the produce of nitric oxide (NO). Additionally, carnosol promotes the protein expression of vascular endothelial cadherin (VE-cadherin) to keep the integrity of intercellular junctions, which indicated that it protected microvascular barrier in oxidative stress. Meanwhile, we investigated that carnosol can interrupt Nrf2-Keap1 protein-protein interaction and stimulated antioxidant-responsive element (ARE)-driven luciferase activity in vitro. Mechanistically, we showed that carnosol promotes the expression of heme oxygenase 1(HO-1) and nuclear factor-erythroid 2 related factor 2(Nrf2). It can also promote the expression of endothelial nitric oxide synthase (eNOS). Collectively, our data support the notion that carnosol is a protective agent in HMVECs and has the potential for therapeutic use in the treatments of microvascular endothelial cell injury.

We sought to reveal the key molecular signature in subcutaneous adipose tissue (scAT) following Roux-en-Y gastric bypass (RYGB), through bioinformatics analysis and further verification in vivo.

To assess the association between educational attainment and acute myocardial infarction (AMI) outcomes in China to inform future healthcare interventions.

Documents have reported that long non-coding RNAs (lncRNAs) are involved in tumor progression. Previous study revealed that lncRNA SNHG1 was often elevated in cancer and was linked with poor prognosis in cancer patients. However, its modulatory mechanism has not been fully clarified in gastric cancer (GC). Here, we reported that SNHG1 expression was significantly increased in GC cell lines and tissues. Knockdown of SNHG1 impeded cell growth via disturbing cell cycle distribution and protecting cells from apoptosis. Nevertheless, SNHG1 down-regulation decreased cell invasive ability and reversed epithelial-mesenchymal transition (EMT) phenotype. Mechanismly, it was found that SNHG1 functioned as a competing endogenous RNA to repress miR-140 expression and thereby elevated its down-stream target ADAM10. In summary, SNHG1 promoted GC cell proliferation and invasion via modulating the miR-140/ADAM10 axis. These findings uncovered that lncRNA SNHG1 could be a candidate target for new therapies in GC patients.

Adjuvant chemotherapy has become the frequently adopted standard therapeutic approach for non-small cell lung cancer (NSCLC). However, the development of multidrug resistance (MDR) is a major obstacle contributing to the failure of chemotherapy. This study aimed to identify genes associated with MDR development that predict tumor response to chemotherapy in NSCLC. In the present study, a multidrug-resistant NSCLC cell sub-line, A549/MDR, was established from the A549/DDP cell line and characterized. The resistance index (RI) of this subline was calculated according to the IC50 of A549/MDR relative to the parental A549/DDP cells. The gene expression profiles of A549/DDP and A549/MDR were obtained using an oligonucleotide microarray (Agilent SureHyb microarray chip). The microarray results were validated by qRT-PCR and selected genes were analyzed by in vitro loss-of-function experiments. Gene expression profiling identified 921 differentially expressed genes (DEGs) according to the selection criteria, in which 541 genes were upregulated and 380 genes were downregulated in A549/MDR compared with A549/DDP cells. We found that these DEGs are involved in diverse biological processes, including ribonucleoprotein complex, drug metabolism, the Hippo signaling pathway and transcriptional misregulation. NOLC1, as one of the identified DEGs, was confirmed to be overexpressed in A549/MDR cells and its knockdown significantly enhanced the drug sensitivity of A549/MDR cells in response to multidrug treatment. Furthermore, knockdown of NOLC1 downregulated the expression levels of drug resistance-associated molecules (LRP and MDR1) in A549/MDR cells. These findings provide a new and comprehensive expression profile of MDR in NSCLC cells. Identification and validation of NOLC1 might be a promising therapeutic strategy for the management of MDR of NSCLC patients.

Hyperglycemia was proved to cause neuron death in both animal experiments and poor outcome of hemorrhage patients, but the predictive ability of admission blood glucose level for early hematoma growth in patients with intracranial hemorrhage (ICH) is still controversial. Spot sign is a well-established imaging predictor for early hematoma growth, implying active microvascular bleeding. Here, we aim to assess associations between admission serum glucose and early hematoma expansion in ICH patients, as well as spot sign.We retrospectively reviewed all the patients with ICH from January 2017 to March 2018 in West China Hospital, Sichuan University. Admission blood glucose, clinical variables, radiological characteristics, and laboratorial parameters were obtained from medical record. According to computed tomography (CT) and computed tomography angiography (CTA) scan results, hematoma expansion and spot sign were identified by 2 experienced neuroradiologists. Multivariate logistic regression analyses were employed to adjust the associations of hematoma expansion and spot sign with other clinical parameters.Around 42 patients exhibited early hematoma expansions and 26 exhibited spot signs over 138 enrolled patients. The average level of admission blood glucose was 7.55 mmol/L. Multivariate logistic regression analyses revealed that Glasgow Coma Scale (GCS) score on admission, hematoma volume, spot sign, and hyperglycemia were associated with hematoma expansion, whereas admission serum glucose and hematoma size were only associated with spot sign, respectively.Admission blood glucose level is correlated with hematoma growth and incidence of spot sign. These results indicated that hyperglycemia probably plays a critical role in the pathological process of the active bleeding. Further studies should be drawn urgently to understand the potential molecular mechanism of systemic hyperglycemia in affecting prognosis of patients with ICH.

Tetramethylpyrazine (TMP) is an active compound isolated from a Chinese herbal prescription that is widely used in traditional Chinese medicine for the treatment of inflammatory and cardiovascular diseases. We have previously reported that TMP acts as a potent antioxidant protecting endothelial cells against high glucose-induced damages. However, the molecular mechanism responsible for the antioxidant effect of TMP remains to be elucidated. In this study, we show that TMP increases nitric oxide production in endothelial cells and promotes endothelium-dependent relaxation in rate aortic rings. The antioxidant effect of TMP appears attributable to its ability to activate the mitochondrial biogenesis, as reflected in an up-regulation of complex III and amelioration of mitochondrial membrane potential. Furthermore, TMP is able to reverse high glucose-induced suppression of SIRT1 and the biogenesis-related factors, including PGC-1α, NRF1 and TFAM, suggesting a new molecular mechanism underlying the protective effect of TMP on the endothelium.

One of the most striking examples of small RNA regulation of gene expression is the process of RNA editing in the mitochondria of trypanosomes. In these parasites, RNA editing involves extensive uridylate insertions and deletions within most of the mitochondrial messenger RNAs (mRNAs). Over 1200 small guide RNAs (gRNAs) are predicted to be responsible for directing the sequence changes that create start and stop codons, correct frameshifts and for many of the mRNAs generate most of the open reading frame. In addition, alternative editing creates the opportunity for unprecedented protein diversity. In Trypanosoma brucei, the vast majority of gRNAs are transcribed from minicircles, which are approximately one kilobase in size, and encode between three and four gRNAs. The large number (5000-10,000) and their concatenated structure make them difficult to sequence. To identify the complete set of gRNAs necessary for mRNA editing in T. brucei, we used Illumina deep sequencing of purified gRNAs from the procyclic stage. We report a near complete set of gRNAs needed to direct the editing of the mRNAs.

Accumulating evidence indicates that miRNA regulatory circuits play important roles in tumorigenesis. We previously reported that miR-124 is correlated with prognosis of colorectal cancer due to PKM-dependent regulation of glycolysis. However, the mechanism by which miR-124 regulates apoptosis in colorectal cancer remains largely elusive. Here, we show that miR-124 induced significant apoptosis in a panel of colorectal cancer cell lines. The mitochondrial apoptosis pathway was activated by miR-124. Furthermore, the pro-apoptotic role of miR-124 was dependent on the status of PKM1/2 level. PKM1 was required for miR-124-induced apoptosis. Via direct protein-protein interaction, PKM1 promoted HNF4α binding to the promoter region of miR-124 and transcribing miR-124. Moreover, HNF4α or PKM1 had a more dramatic effect on colorectal cancer cell apoptosis in the presence of miR-124. However, inhibition of miR-124 blocked cell apoptosis induced by HNF4α or PKM1. These data indicate that miR-124 not only alters the expression of genes involved in glucose metabolism but also stimulates cancer cell apoptosis. In addition, the positive feedback loop between miR-124 and PKM1/HNF4α plays an important role in colorectal cancer cell apoptosis; it suggests that disrupting this regulatory circuit might be a potential therapeutic tool for colorectal cancer treatment.

Maternal malnutrition may disrupt ovarian functions in adult offspring. Steroidogenesis and folliculogenesis in the offspring ovary appear to be the major targets of nutritional programming. Nevertheless, the mechanism by which maternal low-protein diet affects the offspring steroidogenesis and folliculogenesis, and the possible pathway linking these two processes remain unclear. In this study, Landrace×Yorkshire crossbred sows were fed either standard (SP) or low-protein (LP, 50% of the SP) diets throughout gestation and lactation. Female offspring were fed the same diet after weaning until 6 months of age. LP offspring had higher serum 17β-estradiol level (P<0.01), which was accompanied by lower mRNA (P<0.05) but higher protein (P<0.05) expression of cytochrome P450 aromatase (CYP19A1) in the ovary. CYP19A1 protein up-regulation was associated with lower ovarian expression of drosha (P<0.05) and miRNAs targeting CYP19A1 (P<0.05). LP offspring had less graafian follicles with more apoptotic granulosa cells (P<0.05), as well as higher caspase 3 activity (P<0.05) and FasL expression (P<0.05) in the ovary. FasL gene up-regulation was associated with higher ERα protein expression (P<0.05) and binding to FasL gene promoter. These results suggest that a maternal LP diet in pregnancy and lactation elevated serum 17β-estradiol level by activating CYP19A1 through miRNA-mediated mechanism, and induced granulosa apoptosis in graafian follicles through ER-activated Fas/FasL-caspase 3 pathway.

Gene assembly, which recovers gene segments from short reads, is an important step in functional analysis of next-generation sequencing data. Lacking quality reference genomes, de novo assembly is commonly used for RNA-Seq data of non-model organisms and metagenomic data. However, heterogeneous sequence coverage caused by heterogeneous expression or species abundance, similarity between isoforms or homologous genes, and large data size all pose challenges to de novo assembly. As a result, existing assembly tools tend to output fragmented contigs or chimeric contigs, or have high memory footprint. In this work, we introduce a targeted gene assembly program SAT-Assembler, which aims to recover gene families of particular interest to biologists. It addresses the above challenges by conducting family-specific homology search, homology-guided overlap graph construction, and careful graph traversal. It can be applied to both RNA-Seq and metagenomic data. Our experimental results on an Arabidopsis RNA-Seq data set and two metagenomic data sets show that SAT-Assembler has smaller memory usage, comparable or better gene coverage, and lower chimera rate for assembling a set of genes from one or multiple pathways compared with other assembly tools. Moreover, the family-specific design and rapid homology search allow SAT-Assembler to be naturally compatible with parallel computing platforms. The source code of SAT-Assembler is available at https://sourceforge.net/projects/sat-assembler/. The data sets and experimental settings can be found in supplementary material.

The novel organic cation transporter 2 (OCTN2) is the physiologically most important carnitine transporter in tissues and is responsible for carnitine absorption in the intestine, carnitine reabsorption in the kidney and distribution of carnitine between tissues. Genetic studies clearly demonstrated that the mouse OCTN2 gene is directly regulated by peroxisome proliferator-activated receptor α (PPARα). Despite its well conserved role as an important regulator of lipid catabolism in general, the specific genes under control of PPARα within each lipid metabolic pathway were shown to differ between species and it is currently unknown whether the OCTN2 gene is also a PPARα target gene in pig, cattle, and human. In the present study we examined the hypothesis that the porcine, bovine, and human OCTN2 gene are also PPARα target genes.

The present study was designed to probe the effects of Huperzine A (HupA) on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model. Diabetic rats were treated with HupA (0.05 and 0.1 mg/kg) for seven weeks. Memory functions were evaluated by the water maze test. Nissl staining was selected for detecting neuronal loss. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA and real-time PCR, respectively. The activities of choline acetylase (ChAT), Acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 were measured using corresponding kits. After seven weeks, diabetic rats exhibited remarkable reductions in: body weight, percentage of time spent in target quadrant, number of times crossing the platform, ChAT and BDNF levels, SOD, GSH-Px and CAT accompanied with increases in neuronal damage, plasma glucose levels, escape latency, mean path length, AChE, MDA level as well as CAT, NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 in cerebral cortex and hippocampus. Supplementation with HupA significantly and dose-dependently reversed the corresponding values in diabetes. It is concluded that HupA ameliorates DACD via modulating BDNF, oxidative stress, inflammation and apoptosis.