Toll-like receptors (TLRs)/NF-κB activation stimulated by lipopolysaccharide (LPS) was associated with diverse biological response in colon cancer, but the underlying mechanism was largely unknown. In the current study, we reported cell proliferation was elevated in adenomatous polyposis coli (APC) mutated- and APC knockdown cell lines, while the proliferation was inhibited in APC wild-type cell lines. Besides, in vivo experiments showed that LPS promoted APC knockdown tumor growth while inhibited proliferation of APC wild type. Further study confirmed that activation of TLRs/NF-κB signaling pathway by LPS cross regulated with APC/GSK-3β/β-catenin pathway, which were depend on APC status of cell lines. Taken together, APC genotypes play a key role in LPS induced different colon cancer biological response by cross-regulating β-catenin and NF-κB, which may provide a novel strategy for carcinogenesis prevention.

PFTK1, also named Cyclin-Dependent Kinase 14 (CDK14), is a member of the cell division cycle 2 (CDC2)-related protein kinase family. It is a serine/threonine-protein kinase involved in the regulation of cell cycle progression and cell proliferation. In this study, we investigated the role of PFTK1 in epithelial ovarian cancer (EOC) development. The expression of PFTK1 was detected by Western blot and immunohistochemistry staining, both of which demonstrated that PFTK1 was overexpressed in EOC tissues and cells. Statistical analysis showed the expression of PFTK1 was associated with multiple clinicopathological factors, including tumor grade, FIGO stage, lymph node metastatis, Ki-67 expression and predicted a poor prognosis of EOC patients. With in vitro studies we found that PFTK1 expression was decreased in serum-starved ovarian cancer cells, and progressively increased after serum-re-feeding. Knocking PFTK1 down by small interfering RNA (siRNA) significantly inhibited ovarian cancer cell proliferation, migration and invasion. Taken together, our study suggested that PFTK1 played an important role in ovarian cancer development.

In this study, NMR-based metabolomics in combination with multivariate pattern recognition technologies were employed to evaluate the physiological variations in the Wistar rats' plasma that are induced by pregnancy on the gestational days (GDs) 11, 14, 17 and 20. Untargeted metabolomics analysis revealed some possible mechanism of physiological effects for healthy pregnancies and showed a metabolic trajectory during pregnancy process. The levels of 24 metabolites were found to change significantly throughout pregnancy in maternal plasma. These metabolite changes involved in varied kinds of metabolic pathways including synthesis of biological substances, microbial metabolism in diverse environments, protein digestion and absorption, carbohydrate metabolism, digestion and absorption, mineral absorption, and ATP (Adenosine Triphosphate)-binding cassette transporters (ABC transporters). The substantial cores of all the metabolic pathways are promoting fetal growth and development and regulating maternal physiological state. This work showed relevant metabolic pathways perturbation in the maternal plasma due to normal pregnancy and provided the physical basis of time-dependent metabolic trajectory against which disease-related maternal physiological responses may be better understood in future studies.

Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been reported by us and others to display potent antitumor effects. However, the molecular target of grifolin has not been identified and the underlying mechanism of action is not fully understood. Here, we report that the ERK1/2 protein kinases are direct molecular targets of grifolin. Molecular modeling, affinity chromatography and fluorescence quenching analyses showed that grifolin directly binds to ERK1/2. And in vitro and ex vivo kinase assay data further demonstrated that grifolin inhibited the kinase activities of ERK1/2. We found that grifolin suppressed adhesion, migration and invasion of high-metastatic cancer cells. The inhibitory effect of grifolin against tumor metastasis was further confirmed in a metastatic mouse model. We found that grifolin decreased phosphorylation of Elk1 at Ser383, and the protein as well as the mRNA level of DNMT1 was also down-regulated. By luciferase reporter and ChIP assay analyses, we confirmed that grifolin inhibited the transcription activity of Elk1 as well as its binding to the dnmt1 promoter region. Moreover, we report that significant increases in the mRNA levels of Timp2 and pten were induced by grifolin. Thus, our data suggest that grifolin exerts its anti-tumor activity by epigenetic reactivation of metastasis inhibitory-related genes through ERK1/2-Elk1-DNMT1 signaling. Grifolin may represent a promising therapeutic lead compound for intervention of cancer metastasis, and it may also be useful as an ERK1/2 kinase inhibitor as well as an epigenetic agent to further our understanding of DNMT1 function.

The -1237T/C polymorphism of the Toll-like receptor 9 (TLR9) gene has been implicated in the susceptibility of inflammatory bowel diseases (IBDs), but the results remain conflicting. We further investigated this association via meta-analysis.

To explore a scientific boundary of WHtR to evaluate central obesity and CVD risk factors in a Chinese adult population. The data are from the Prospective Urban Rural Epidemiology (PURE) China study that was conducted from 2005-2007. The final study sample consisted of 43 841 participants (18 019 men and 25 822 women) aged 35-70 years. According to the group of CVD risk factors proposed by Joint National Committee 7 version and the clustering of risk factors, some diagnosis parameters, such as sensitivity, specificity and receiver operating characteristic (ROC) curve least distance were calculated for hypertension, diabetes, high serum triglyceride (TG), high serum low density lipoprotein cholesterol (LDL-C), low serum high density lipoprotein cholesterol (HDL-C) and clustering of risk factors (number≥2) to evaluate the efficacy at each value of the WHtR cut-off point. The upper boundary value for severity was fixed on the point where the specificity was above 90%. The lower boundary value, which indicated above underweight, was determined by the percentile distribution of WHtR, specifically the 5th percentile (P5) for both males and females population. Then, based on convenience and practical use, the optimal boundary values of WHtR for underweight and obvious central obesity were determined. For the whole study population, the optimal WHtR cut-off point for the CVD risk factor cluster was 0.50. The cut-off points for severe central obesity were 0.57 in the whole population. The upper boundary values of WHtR to detect the risk factor cluster with specificity above 90% were 0.55 and 0.58 for men and women, respectively. Additionally, the cut-off points of WHtR for each of four cardiovascular risk factors with specificity above 90% in males ranged from 0.55 to 0.56, whereas in females, it ranged from 0.57 to 0.58. The P5 of WHtR, which represents the lower boundary values of WHtR that indicates above underweight, was 0.40 in the whole population. WHtR 0.50 was an optimal cut-off point for evaluating CVD risks in Chinese adults of both genders. The optimal boundaries of WHtR were 0.40 and 0.57, indicating low body weight and severe risk for CVD, respectively, in Chinese adults.

We previously isolated islet stellate cells (ISCs) from healthy Wistar rat islets. In the present study, we isolated "already primed by diabetic environment" ISCs from islets of Goto-Kakizaki rats, determined the gene profile of these cells, and assessed the effects of these ISCs on beta-cell function and survival. We detected gene expression of ISCs by digital gene expression. INS-1 cell proliferation, apoptosis, and insulin production were measured after being treated with ISCs supernatant (SN). We observed the similar expression pattern of ISCs and PSCs, but 1067 differentially expressed genes. Insulin production in INS-1 cells cultured with ISC-SN was significantly reduced. The 5-ethynyl-2'-deoxyuridine-positive INS-1 cells treated with ISC-SN were decreased. Propidium iodide- (PI-) positive INS-1 cells were 2.6-fold higher than those in control groups. Caspase-3 activity was increased. In conclusion, ISCs presented in fibrotic islet of GK rats might be special PSCs, which impaired beta-cell function and proliferation and increased beta-cell apoptosis.

Hormesis and adaptive responses are 2 important biological effects of low-dose ionizing radiation (LDR). In normal tissue, LDR induces hormesis as evinced by increased cell proliferation; however, whether LDR also increases tumor cell proliferation needs to be investigated. In this study, cell proliferation was assayed by total cell numbers and the Cell Counting Kit 8 assay. Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3' -kinase(PI3K)-Akt (PI3K/AKT) phosphorylation were determined by Western blot analysis. Human embryonic lung fibroblast 2BS and lung cancer NCI-H446 cell lines were irradiated with LDR at different doses (20-100 mGy). In response to 20 to 75 mGy X-rays, cell proliferation was significantly increased in 2BS but not in NCI-H446 cells. In 2BS cells, LDR at 20 to 75 mGy also stimulated phosphorylation of MAPK/ERK pathway proteins including ERK, MEK, and Raf and of the PI3K/AKT pathway protein AKT. To test whether ERK1/2 and AKT pathway activation was involved in the stimulation of cell proliferation in 2BS cells, the MAPK/ERK and PI3K/AKT pathways were inhibited using their specific inhibitors, U0126 and LY294002. U0126 decreased the phosphorylation of ERK1/2, and LY294002 decreased the phosphorylation of AKT; each could significantly inhibit LDR-induced 2BS cell proliferation. However, LDR did not stimulate these kinases, and kinase inhibitors also did not affect cell proliferation in the NCI-H446 cells. These results suggest that LDR stimulates cell proliferation via the activation of both MAPK/ERK and PI3K/AKT signaling pathways in 2BS but not in NCI-H446 cells. This finding implies the potential for applying LDR to protect normal tissues from radiotherapy without diminishing the efficacy of tumor therapy.

TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity.

Oxytocin has been suggested as a promising new treatment for neurodevelopmental disorders. However, important gaps remain in our understanding of its mode of action, in particular, to what extent oxytocin modulates social and non-social behaviours and whether its effects are generalizable across both sexes. Here we investigated the effects of a range of oxytocin doses on social and non-social behaviours in C57BL/6N mice of both sexes. As the striatum modulates social and non-social behaviours, and is implicated in neurodevelopmental disorders, we also conducted a pilot exploration of changes in striatal protein expression elicited by oxytocin. Oxytocin increased prepulse inhibition of startle but attenuated the recognition memory in male C57BL/6N mice. It increased social interaction time and suppressed the amphetamine locomotor response in both sexes. The striatum proteome following oxytocin exposure could be clearly discriminated from saline controls. With the caveat that these results are preliminary, oxytocin appeared to alter individual protein expression in directions similar to conventional anti-psychotics. The proteins affected by oxytocin could be broadly categorized as those that modulate glutamatergic, GABAergic or dopaminergic signalling and those that mediate cytoskeleton dynamics. Our results here encourage further research into the clinical application of this peptide hormone, which may potentially extend treatment options across a spectrum of neurodevelopmental conditions.

To develop a novel preimplantation genetic screening (PGS) test using next generation sequencing(NGS) as a alternative to current array comparative genomic hybridization (array CGH) method for detection of small segmental translocations in two patients with repeated implantation failure (RIF) and recurrent miscarriage (RM). Inconsistent results were resolved by validation with fluorescence in situ hybridization (FISH).

To evaluate the diagnostic performance of quantitative analysis as an adjunctive diagnostic tool to contrast-enhanced ultrasound (US) for the differentiation of atypical benign focal liver lesions (FLLs) from malignancies in fatty liver. Twenty-seven benign FLLs and fifty-six malignant FLLs that appeared hyper-enhanced during the arterial phase with washout in the portal or late phase in fatty liver were analyzed. Chi-square tests and logistic regression were applied to identify the specific features. Three sets of criteria were assigned: 1) all FLLs subjected to routine contrast-enhanced US; 2) all FLLs subjected to quantification analysis and contrast-enhanced US; and 3) parts of FLLs that could not be diagnosed using contrast-enhanced US (n = 66, 75.9%) but instead were diagnosed using parametric features. The sensitivity, specificity, accuracy and area under the receiver operating characteristic curve (AUC) of the three sets of criteria were analyzed. The AUCs of the criterion set 2 were significantly higher than those of criterion set 1 (0.904 versus 0.792, P = 0.008). Criterion set 3 showed a relatively high sensitivity (90.2%) with a relatively high AUC (0.845). The quantification analysis offers improved diagnostic performance for the differential identification of atypical benign FLLs from malignancies in fatty liver.

Ricin is one of the most toxic and easily produced plant protein toxin extracted from the castor oil plant, and it has been classified as a chemical warfare agent. Here, nanosecond pulsed electric fields (nsPEFs) at 30 kV/cm (pulse durations: 10 ns, 100 ns, and 300 ns) were applied to inactivating ricin up to 4.2 μg/mL. To investigate the efficacy, cells and mice were tested against the ricin treated by the nsPEFs via direct intraperitoneal injection and inhalation exposure. Results showed that nsPEFs treatments can effectively reduce the toxicity of the ricin. Without the nsPEFs treatment, 100% of mice were killed upon the 4 μg ricin injection on the first day, however 40% of the mice survived the ricin treated by the nsPEFs. Compared to injection, inhalation exposure even with higher ricin dose required longer time to observe mice fatality. Pathological observations revealed damages to heart, lung, kidney, and stomach after the ricin exposure, more pronounced for lung and kidney including severe bleeding. Sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE) and circular dichroism (CD) analyses revealed that although the primary structure of ricin was not altered, its secondary structures (beta-sheet and beta-turn) underwent transition upon the nsPEFs treatment.

Fibroblasts are rich in the surrounding microenvironment of hepatocellular carcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role of cancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFs promote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone, brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFs secret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5 increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migration and invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh) pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-β (TGF-β) pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs on HCC metastasis and compromised the activation of Hh and TGF-β pathways in HCC cells. In summary, CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activation of Hh and TGF-β pathways in HCC cells.

From 2014 to 2015, three cases of highly pathogenic avian influenza infection occurred in zoo-housed north-east China tigers (Panthera tigris ssp.altaica) and four tigers died of respiratory distress in succession in Yunnan Province, China. We isolated and characterized three highly pathogenic avian influenza A(H5N1) viruses from these tigers. Phylogenetic analysis indicated that A/tiger /Yunnan /tig1404 /2014(H5N1) belongs to the provisional subclade 2.3.4.4e which were novel reassortant influenza A (H5N1) viruses with six internal genes from avian influenza A (H5N2) viruses. The HA gene of the isolated A/tiger /Yunnan /tig1412 /2014(H5N1) virus belongs to the subclade 2.3.2.1b. The isolated A/tiger /Yunnan /tig1508/2015 (H5N1) virus was a novel reassortant influenza A (H5N1) virus with three internal genes (PB2, PB1 and M) from H9N2 virus and belongs to the subclade 2.3.2.1c.

Mycobacterium smegmatis strain MC² 155 is an attractive model organism for the study of M. tuberculosis and other mycobacterial pathogens, as it can grow well using cholesterol as a carbon resource. However, its global transcriptomic response remains largely unrevealed. In this study, M. smegmatis MC² 155 cultivated in androstenedione, cholesterol and glycerol supplemented media were collected separately for a RNA-Sequencing study. The results showed that 6004, 6681 and 6348 genes were expressed in androstenedione, cholesterol and glycerol supplemented media, and 5891 genes were expressed in all three conditions, with 237 specially expressed in cholesterol added medium. A total of 1852 and 454 genes were significantly up-regulated by cholesterol compared with the other two supplements. Only occasional changes were observed in basic carbon and nitrogen metabolism, while almost all of the genes involved in cholesterol catabolism and mammalian cell entry (MCE) were up-regulated by cholesterol, but not by androstenedione. Eleven and 16 gene clusters were induced by cholesterol when compared with glycerol or androstenedione, respectively. This study provides a comprehensive analysis of the cholesterol responsive transcriptome of M. smegmatis. Our results indicated that cholesterol induced many more genes and increased the expression of the majority of genes involved in cholesterol degradation and MCE in M. smegmatis, while androstenedione did not have the same effect.

Dandruff is an unpleasant scalp disorder common to human populations. In this study, we systematically investigated the intra- and inter-associations among dandruff, physiological conditions such as sebum of the scalp, host demographics such as gender, age and the region of the scalp, and the microorganisms on the scalp. We found that the physiological conditions were highly relevant to the host age and varied in different regions of the same scalp. The sebum quantity and water content were negatively correlated with the formation of dandruff and had significant relationships with the two dominant but reciprocally inhibited bacteria on the scalp (Propionibacterium and Staphylococcus). The dominant fungus (Malassezia species) displayed contrary roles in its contribution to the healthy scalp micro-environment. Bacteria and fungi didn't show a close association with each other, but the intramembers were tightly linked. Bacteria had a stronger relationship with the severity of dandruff than fungi. Our results indicated that the severity of dandruff was closely associated with the interactions between the host and microorganisms. This study suggests that adjusting the balance of the bacteria on the scalp, particularly by enhancing Propionibacterium and suppressing Staphylococcus, might be a potential solution to lessen dandruff.

Sleep deprivation during pregnancy is a serious public health problem as it can affect the health of pregnant women and newborns. However, it is not well studied whether sleep deprivation at different stages of pregnancy has similar effects on emotional and cognitive functions of the offspring, and if so, the potential cellular mechanisms also remain poorly understood.

Human skin is a known target site of inorganic arsenic with effects ranging from hyperkeratosis to dermal malignancies. Tert-butylhydroquinone (tBHQ), approved food-grade phenolic antioxidant, is demonstrated to induce remarkable antioxidant activity in a variety of cells and tissues. The present study aimed at the protective effects of tBHQ on arsenic-induced cytotoxicity and apoptosis in human keratinocytes. Our results demonstrated that tBHQ antagonized arsenic-induced decrease of cell viability, generation of reactive oxygen species (ROS) and lipid peroxidation, as well as reduction of antioxidative enzymes superoxide dismutase (SOD) and catalase (CAT) activities. We also found that tBHQ relieved the G2/M phase arrest by arsenic exposure, which was associated with altering the expression of cell cycle regulators cyclin D1 and CDK4. tBHQ treatment further reduced the numbers of arsenic-induced mitochondrial-mediated apoptotic cells, which occurred concomitantly with the effective recovery of mitochondrial membrane potential (ΔΨm) depolarization, the release of cytochrome c releasing from the mitochondrial as well as the survival signal related factor caspase 3 activation. Our experiments then confirmed that tBHQ activated nuclear factor E2-related factor 2 (NRF2) pathway by increasing NRF2 protein in both nucleus and cytoplasm and upregulating NRF2 downstream targets

Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM's diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients' target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ's cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the "multi-component, multi-target and multi-pathway" combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM's molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.