The calcineurin B subunit (CNB) has antitumor activity. We showed previously that recombinant human CNB (rhCNB) also had strong anti-tumor activity in vivo, and was thus a promising candidate anti-tumor drug. It appeared to kill tumor cells via immunomodulation. Here, we show that rhCNB inhibits the proliferation of human hepatoma HepG-2 cells, resulting in their apoptosis. Exogenous CNB was found to localize to mitochondria in tumor cells and activate the mitochondrial apoptosis pathway, as indicated by a decrease of mitochondrial transmembrane potential, release of cytochrome C and activation of caspase-9, which then activates caspase-3. At the same time Bcl-2 &Bcl-xL expression decreased, Bim expression increased, and Bax was activated. Interaction between rhCNB and Bcl-xL was detected, which may inhibit the function of Bcl-xL. Long-term tumor targeting was also observed in nude mice. These data deepened our understanding of the anti-tumor mechanism of rhCNB and provided guidance for its drug development.

Cervical spondylotic radiculopathy (CSR) is the most general form of spinal degenerative disease and is characterized by pain and numbness of the neck and arm. Gentongping (GTP) granule, as a classical Chinese patent medicine, has been widely used in curing CSR, whereas the underlying mechanism remains unclear. Therefore, the aim of this study is to explore the pharmacological mechanisms of GTP on CSR. The rat model of CSR was induced by spinal cord injury (SCI). Our results showed that GTP could significantly alleviate spontaneous pain as well as ameliorate gait. The HE staining and Western blot results showed that GTP could increase the quantity of motoneuron and enhance the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) in the spinal cord tissues. Meanwhile, immunofluorescence staining analysis indicated that GTP could reduce the expression of TNF-α in the spinal cord tissues. Furthermore, the protein level of Bax was decreased whereas the protein levels of Bcl-2 and NF200 were increased after the GTP treatment. These findings demonstrated that GTP might modulate the PPAR-γ pathway by inhibiting the inflammatory response and apoptosis as well as by protecting the cytoskeletal integrity of the spinal cord, ultimately play a neuroprotective role in CSR.

PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe-/- mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe-/- mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe-/- mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia.

Improving seed vigor in response to cold stress is an important breeding objective in maize that allows early sowing. Using two cold tolerant inbred lines 220 and P9-10 and two susceptible lines Y1518 and PH4CV, three connected F2:3 populations were generated for detecting quantitative trait locus (QTL) related to seed low-temperature germination ability. At 10°C, two germination traits (emergence rate and germination index) were collected from a sand bed and three seedling traits (seedling root length, shoot length, and total length) were extracted from paper rolls. Significant correlations were found among all traits in all populations. Via single-population analysis, 43 QTL were detected with explained phenotypic variance of 0.62%∼39.44%. Seventeen QTL explained more than 10% phenotypic variance; of them sixteen (94.12%) inherited favorable alleles from the tolerant lines. After constructing a consensus map, three meta-QTL (mQTL) were identified to include at least two initial QTL from different populations. mQTL1-1 included seven initial QTL for both germination and seedling traits; with three explaining more than 30% phenotypic variance. mQTL2-1 and mQTL9-1 covered two to three initial QTL. The favorable alleles of the QTL within these three mQTL regions were all inherited from the tolerant line 220 and P9-10. These results provided a basis for cloning of genes underlying the mQTL regions to uncover the molecular mechanisms of maize cold tolerance during germination.

Ovarian cancer is the most leading cause of death and the third most common gynecologic malignancy in women. Traditional chemotherapy has inevitable drawbacks of nonspecific tumor targeting, high toxicity, and poor therapeutic efficiency. In order to overcome such shortcomings, we prepared a novel nano-carrier drug-delivery system to enhance the anti-tumor efficiency.

AIS is the most common spinal deformity disease, yet its etiology remains uncertain. Significant associations have been found between AIS risk and vitamin D receptor (VDR) gene polymorphisms; however, some of these results are controversial. The aim of this study was to determine whether VDR BsmI rs1544410 and ApaI rs7975232 polymorphisms are correlated with AIS.

Oncogene-induced senescence (OIS), provoked in response to oncogenic activation, is considered an important tumor suppressor mechanism. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt without a protein-coding capacity. Functional studies showed that deregulated lncRNA expression promote tumorigenesis and metastasis and that lncRNAs may exhibit tumor-suppressive and oncogenic function. Here, we first identified lncRNAs that were differentially expressed between senescent and non-senescent human fibroblast cells. Using RNA interference, we performed a loss-function screen targeting the differentially expressed lncRNAs, and identified lncRNA-OIS1 (lncRNA#32, AC008063.3 or ENSG00000233397) as a lncRNA required for OIS. Knockdown of lncRNA-OIS1 triggered bypass of senescence, higher proliferation rate, lower abundance of the cell-cycle inhibitor CDKN1A and high expression of cell-cycle-associated genes. Subcellular inspection of lncRNA-OIS1 indicated nuclear and cytosolic localization in both normal culture conditions as well as following oncogene induction. Interestingly, silencing lncRNA-OIS1 diminished the senescent-associated induction of a nearby gene (Dipeptidyl Peptidase 4, DPP4) with established role in tumor suppression. Intriguingly, similar to lncRNA-OIS1, silencing DPP4 caused senescence bypass, and ectopic expression of DPP4 in lncRNA-OIS1 knockdown cells restored the senescent phenotype. Thus, our data indicate that lncRNA-OIS1 links oncogenic induction and senescence with the activation of the tumor suppressor DPP4.

Previous studies have demonstratedf that heat stress can induce injury of the central nervous system and lead to neuronal cell apoptosis. However, the molecular mechanisms underlying these cellular changes remain unclear. In the present study, flow cytometry was used to investigate heat-stress-induced apoptosis, and caspase-3 activation was also assessed in neurons. The role of reactive oxygen species (ROS) accumulation in the heat-stress-induced apoptosis of neurons was demonstrated using the antioxidant drug manganese (III) tetrakis (4-benzoic acid)porphyrin. The present study presents evidence that heat stress induces mitogen-activated protein kinase (MAPK) activation in rat malignant glioma F98 cells. Following the inhibition of different MAPKs with a range of specific inhibitors, SB203580 (an inhibitor of p38 MAPK), but not PD98059 (an inhibitor of extracellular signal-regulated kinases) or SP600125 (an inhibitor of c-Jun N-terminal kinases), diminished the production of ROS and apoptosis, and prevented activation of the p38-downstream kinase MAPK-activated protein kinase 2 (MK2) in neurons. Inhibiting MK2 with dominant negative adenoviral constructs or a specific inhibitor significantly decreased normal and heat-stress-induced ROS accumulation and cell apoptosis, whereas inhibition of another kinase downstream of p38 MAPK, MAPK-activated protein kinase 5, by transfection with another adenoviral construct did not exert the same effects. Taken together, these findings indicate that heat stress stimulation induces p38-MK2 pathway activation, which exerts a pro-apoptotic effect by regulating ROS accumulation in neurons.

Most studies reported that high plasma endothelin-1 (ET-1), big ET-1, and C-terminal proET-1 (CT-proET-1) were correlated with poor prognosis of heart failure (HF). However, available evidence remains controversial. To help solve the debate, we collected all the available studies and performed a meta-analysis.

To explore the stability of insect resistance during the development of transgenic insect-resistant trees, this study investigated how insect resistance changes as transgenic trees age. We selected 19 transgenic insect-resistant triploid Populus tomentosa lines as plant material. The presence of exogenous genes and Cry1Ac protein expression were verified using polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. The toxicity for Clostera anachoreta and Lymantria dispar was evaluated by feeding fresh leaves to first instar larvae after the trees were planted in the field for 2 years and after the sixth year. Results of PCR showed that the exogenous genes had a long-term presence in the poplar genome. ELISA analyses showed significant differences existed on the 6-year-old transgenic lines. The insect-feeding experiment demonstrated significant differences in the mortality rates of C. anachoreta and L. dispar among different transgenic lines. The average corrected mortality rates of C. anachoreta and L. dispar ranged from 5.6-98.7% to 35.4-7.2% respectively. The larval mortality rates differed significantly between the lines at different ages. Up to 52.6% of 1-year-old transgenic lines and 42.1% of 2-year-old transgenic lines caused C. anachoreta larval mortality rates to exceed 80%, whereas only 26.3% of the 6-year-old transgenic lines. The mortality rates of L. dispar exhibited the same trend: 89.5% of 1-year-old transgenic lines and 84.2% of 2-year-old transgenic lines caused L. dispar larval mortality rates to exceed 80%; this number decreased to 63.2% for the 6-year-old plants. The proportion of 6-year-old trees with over 80% larval mortality rates was clearly lower than that of the younger trees. The death distribution of C. anachoreta in different developmental stages also showed the larvae that fed on the leaves of 1-year-old trees were killed mostly during L1 and L2 stages, whereas the proportion of larvae that died in L3 and L4 stages was significantly increased when fed on leaves of 6-year-old trees. Results of correlation analysis showed there was a significant correlation between the larvae mortality rates of trees at different ages, as well as between Cry1Ac protein contents and larvae mortality rates of 6-year-old trees.

Microwave ablation (MWA), a thermal ablation, is an effective treatment for breast cancer. However, residual breast cancer is still detected. The biological characteristics of residual breast cancer after thermal ablation remain unknown. To mimic insufficient MWA in vitro, breast cancer cells were treated at 37°C, 42°C, 45°C, 47°C and 50°C for 10 mins, the 37°C as control group. Insufficient MWA induced EMT-like changes of residual breast cancer by down-regulation of E-cadherin and up-regulation of vimentin and N-cadherin in vitro and in vivo. For the first time, we reported insufficient MWA promoted distant metastasis of residual breast cancer in vivo. Reduced β-catenin expression by siRNA diminished the EMT-like phenotype and enhanced migration capability induced by heat treatment in breast cancer cells. Moreover, ICG001, a special inhibitor of β-catenin pathway, depressed EMT of residual tumor and distant metastasis in an insufficient MWA nude mice model of breast cancer. In conclusion, our results demonstrate that insufficient MWA promotes EMT of residual breast cancer by activating β-catenin signal pathway, resulting in enhanced distant metastasis of residual breast cancer. In addition, the effectiveness of ICG001 in suppressing enhanced metastasis of residual breast cancer is preliminarily validated.

Whether there is a mechanistic link between FOLR1 and response to cisplatin has not been extensively examined. In this study, we determine the expression of FOLR1 in ovarian cancer and examine if FOLR1 levels influence response to cisplatin.

Public transcriptome databases provide a valuable resource for genome‑wide co‑expression network analysis and investigation of the molecular mechanisms that underlie pathogenesis. To discover genes that may affect patient survival, a large‑scale analysis of human colorectal cancer (CRC) datasets that were retrieved from the NCBI Gene Expression Omnibus was performed. A gene co‑expression network was constructed using weighted gene co‑expression network analysis (WGCNA). A total of 18 co‑expressed gene modules were identified, of which two genes corresponded to cell migration and the cell cycle, two genes were involved in immune responses, two genes corresponded to mitochondrial function, and one gene corresponded to RNA splicing. A total of eight hub genes in the cell migration/extracellular matrix module were associated with poor prognosis in CRC, and the P‑value for collagen type VI α3 chain (COL6A3) was the lowest. In silico analysis of cell type‑specific gene expression and COL6A3 knockout experiments indicated the clinical relevance of COL6A3 in the development of CRC. In summary, the present analysis provides a basis for understanding the molecular characterization of CRC at the transcription level. COL6A3 may be a promising biomarker or target for the prognosis and treatment of CRC.

We searched the PubMed, EMBASE, Cochrane Library and Medline databases for eligible articles. SUVmax, MTV, and TLG on B-PET/CT, DS on I-PET/CT and DS on E-PET/CT were regarded as efficacy data. Combined hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were estimated using RevMan 5.3 software.

Small cell carcinoma of the cervix (SCCC) is a rare primary neuroendocrine cervical carcinoma with a high degree of invasiveness. SCCC is prone to early-stage lymph node and distant metastases and characterized by a poor prognosis. Currently, there is no standard treatment. This study aimed to evaluate the clinicopathological factors and treatment models that influence SCCC prognosis through a systematic review and meta-analysis, to improve the diagnosis and treatment of SCCC. A comprehensive search was performed in multiple medical literature databases to retrieve studies on the clinical prognosis of SCCC published in China and abroad as of March 1, 2017. Twenty cohort studies with 1904 patients were analyzed. Meta-analysis showed statistical significance for the following factors: FIGO staging (hazard ratio [HR] = 2.63, 95% confidence interval [CI]: 2.13-3.24; odds ratio [OR] = 3.72, 95% CI: 2.46-5.62), tumor size (HR = 1.64, 95% CI: 1.25-2.15), parametrial involvement (HR = 2.40, 95% CI: 1.43-4.05), resection margin (HR = 4.09, 95% CI: 2.27-7.39), lymph node metastasis (OR = 2.09, 95% CI: 1.18-3.71), depth of stromal invasion (HR = 1.99, 95% CI: 1.33-2.97), neoadjuvant chemotherapy (HR = 2.06, 95% CI: 1.14-3.73), and adjuvant chemotherapy (HR = 1.63, 95% CI: 1.26-2.12; OR = 1.48, 95% CI: 1.02-2.16). FIGO staging, tumor size, parametrial involvement, resection margin, depth of stromal invasion, and lymph node metastasis can be used as clinicopathological characteristics for the prediction of SCCC prognosis. Neoadjuvant chemotherapy tended to improve prognosis. Our findings suggest that neoadjuvant chemotherapy plus adjuvant chemotherapy may be the preferred strategy. However, adjuvant radiotherapy appeared to cause no significant improvement in prognosis. Therefore, the clinical application of radiotherapy and the relationship between radiotherapy and clinicopathological factors need to be re-examined. The results of this study should be validated and developed in formal, well-designed multicenter clinical trials.

The mesolimbic dopamine system originating in the ventral tegmental area (VTA) is involved in the development of depression, and firing patterns of VTA dopaminergic neurons are key determinants in this process. Here, we describe a crucial role for the M-type Kv 7.4 channels in modulating excitability of VTA dopaminergic neurons and in the development of depressive behaviour in mice.

Pulmonary artery hypertension (PAH) is a fatal disorder. Recent studies suggest that microRNA (miRNA) plays an important role in regulating proliferation of pulmonary artery smooth muscle cells (PASMC), which underlies the pathology of PAH However, the exact mechanism of action of miRNAs remains elusive. In this study, we found that miR-339 was highly expressed in the cardiovascular system and was downregulated by a group of cytokines and growth factors, especially PDGF-BB and FGF2. Functional analyses revealed that miR-339 can inhibit proliferation of PASMC Also, miR-339 inhibited FGF2-induced proliferation, but had no effect on proliferation induced by PDGF-BB The fibroblast growth factor receptor substrate 2 (FRS2) was identified as a potential direct target of miR-339. Consistent with the actions of miR-339, knockdown of FRS2 only inhibited FGF2- but not PDGF-BB-induced proliferation of PASMC In addition, our results showed that inhibition of ERK and PI3K abrogated the downregulation of miR-339 induced by PDGF-BB Finally, miR-339 expression was found to be decreased in the pulmonary arteries of rats with MCT-induced PAH Our study is the first report on the biological role of miR-339 in regulating proliferation of PASMC by targeting FGF signaling, providing new mechanistic insights into PASMC proliferation and pathogenesis of PAH.

Marine molluscs, including oysters, can concentrate high levels of cadmium (Cd) in their soft tissues, but the molecular mechanisms of Cd toxicity remain speculative. In this study, Pacific oysters (Crassostrea gigas) were exposed to Cd for 9 days and their gills were subjected to proteomic analysis, which were further confirmed with transcriptomic analysis. A total of 4,964 proteins was quantified and 515 differentially expressed proteins were identified in response to Cd exposure. Gene Ontology enrichment analysis revealed that excess Cd affected the DNA and protein metabolism. Specifically, Cd toxicity resulted in the inhibition of DNA glycosylase and gap-filling and ligation enzymes expressions in base excision repair pathway, which may have decreased DNA repair capacity. At the protein level, Cd induced the heat shock protein response, initiation of protein refolding as well as degradation by ubiquitin proteasome pathway, among other effects. Excess Cd also induced antioxidant responses, particularly glutathione metabolism, which play important roles in Cd chelation and anti-oxidation. This study provided the first molecular mechanisms of Cd toxicity on DNA and protein metabolism at protein levels, and identified molecular biomarkers for Cd toxicity in oysters.

Cucumis melo is highly diverse for fruit traits providing wide breeding and genetic research opportunities, including genome-wide association (GWA) analysis. We used a collection of 177 accessions representing the two C. melo subspecies and 11 horticultural groups for detailed characterization of fruit traits variation and evaluation of the potential of GWA for trait mapping in melon. Through genotyping-by-sequencing, 23,931 informative SNPs were selected for genome-wide analyses. We found that linkage-disequilibrium decays at ~100 Kb in this collection and that population structure effect on association results varies between traits. We mapped several monogenic traits to narrow intervals overlapping with known causative genes, demonstrating the potential of diverse collections and GWA for mapping Mendelian traits to a candidate-gene level in melon. We further report on mapping of fruit shape quantitative trait loci (QTLs) and comparison with multiple previous QTL studies. Expansion of sample size and a more balanced representation of taxonomic groups might improve efficiency for simple traits dissection. But, as in other plant species, integrated linkage-association multi-allelic approaches are likely to produce better combination of statistical power, diversity capture and mapping resolution in melon. Our data can be utilized for selection of the most appropriate accessions for such approaches.

Quick suberin-based healing after wounding played a protective role for plant to prevent further damage. In this study, the stimulative effect of exogenous abscisic acid (ABA) on wound suberization in postharvest kiwifruit was evaluated through suberin staining with toluidine blue O as well as the determination of suberin phenolics and aliphatics in wound tissue. Furthermore, to reveal the regulatory involvement of ABA in wound suberization, comparative quantitative proteomics and transcriptomics analyses based on iTRAQ and qRT-PCR technique were performed. In proteomics levels, a total of 95 protein species consistently showed differential abundance between ABA and control, including 29 down-regulated and 66 up-regulated protein species. The Kyoto Encyclopedia of Genes and Genomes (KEGG) with protein-protein interaction analyses revealed that ABA mainly affected the antioxidant system, phenylpropanoid metabolism and lipid metabolism associated with wound suberization. Based on the data of proteomics analysis, the differential expressions of genes encoding 11 selected protein species were confirmed by qRT-PCR analyses. GSH-Px, MDHAR, SOD, APX, POD, PAL, CCR, PPO, CYP86B1, DGGT and KCS11 were likely to be the key enzymes that involved the response of ABA to stimulate wound suberization by mediating the antioxidant system, phenylpropanoid metabolism and lipid metabolism.