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SummaryResistance to apoptosis due to caspase deregulation is considered one of the main hallmarks of cancer. However, the discovery of novel non-apoptotic caspase functions has revealed unknown intricacies about the interplay between these enzymes and tumor progression. To investigate this biological problem, we capitalized on a Drosophila tumor model highly relevant for humans that relies on the concomitant upregulation of EGFR and the JAK/STAT signaling pathway. Our results indicate that widespread non-apoptotic activation of initiator caspases limits JNK signaling and facilitates cell fate commitment in these tumors, thus preventing the overgrowth and exacerbation of malignant features. Intriguingly, these caspase functions are strongly linked to the ability of these enzymes to control the recruitment and subsequent proliferation in situ of macrophage-like cells on the tumor. These findings assign novel tumor-suppressor activities to caspases independent of apoptosis, while providing highly relevant molecular details to understanding their diverse contribution during tumor progression.

Background Abnormal microRNAs (miRNAs) expression is closely related to the development and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). We aimed to elucidate the invasive mechanism and clinical significance of miR‐10b in PDAC. Methods The RNA sequence data of pancreatic cancer were extracted from the TCGA database. R packages were performed to analyze the differential expression of RNAs. TargetScan, picTar, and miRanda were used to predict the target gene of miRNA. The expression level of the selected candidate was tested by western blot and RT‐PCR in PDAC cells and tissues. Scrape and Transwell assays were determined the effect of candidate molecules on cell migration and invasion. The gain of function and loss of function was achieved by co‐culture with mimics and vector. Luciferase reporters were generated based on the psiCHECK2 vector. The relative luciferase activity was measured with the Dual‐Luciferase Reporter Assay System and Infinate M200 PRO microplate reader. Results Based on the TCGA data and bioinformatics analysis, we obtained seven differentially expressed miRNAs. Both TCGA data and our center clinical date indicated that miR‐10b was contributed to the poor survival of PDAC. Based on the target gene prediction database, we found that E2F7 was a target mRNA of miR‐10b. In subsequent experiments in molecular biology, miR‐10b expression was downregulated in PDAC cells and tissues, while E2F7 was upregulated. Scrape and Transwell assay indicated that miR‐10b could inhibit the invasion and migration of PDAC. MiR‐10b was confirmed to be by the E2F7 targeting site by dual‐luciferase report. Moreover, rescue experiments prove that miR‐10b could inhibit the invasion and migration of PDAC cells by regulating E2F7 expression. Conclusion Our results suggest that miR‐10b could inhibit the progression of PDAC by regulating E2F7 expression and acts as an independent prognostic risk factor for PDAC., Acquired the miRNA sequencing dataset and corresponding clinical records of PDAC from TCGA. Differentially expressed miRNA analysis and survival analysis indicated miR‐10b was PDAC progression associated miRNA. And E2F7 was a potential target of miR‐10b. And miR‐10b may inhibit PDAC cell migration and invasion by targeting E2F7.

Amyloid beta (Aβ) is the main component of the amyloid plaques that accumulate in the brains of Alzheimer patients. The present study was conducted to investigate whether the combined treatment with selenium (Se) and zinc (Zn) offers more beneficial effects than that provided by either of them alone in reversing Aβ25–35-induced neurotoxicity in PC12 cells. Cells were pretreated with 0.1 μmol/L of Se and Zn for 4 h, after treated with 10 mmol/L Aβ25–35 for 24 h. Cells were divided into control and five treated groups, and received either 10 mmol/L Aβ25–35,10 mmol/L Aβ25–35 + 0.1 μmol/L Se, 10 mmol/L Aβ25–35 + 0.1 μmol/L Zn, 10 mmol/LAβ25–35 + 0.1 μmol/L Se + 0.1 μmol/L Zn, or 0.1 μmol/L Se + 0.1 μmol/L Zn. The result showed that cell viability was decreased in MTT metabolic rate; LDH release and MDA, H2O2, and NO levels were increased and the GSK-3β and phosphorylated tau protein level were increased in Aβ25–35-treated group (P

Malignant melanoma is a highly aggressive neoplasia of melanocytic origin. In part because of the lack of effective treatment methods, the incidence and mortality rates of this disease continue to increase. Rapidly accumulating evidence suggests that dysregulation of epigenetic mechanisms, including DNA methylation/demethylation, chromatin modification, and remodeling, and diverse activities of noncoding RNAs, play a central role in the pathogenesis of melanoma. The epigenetic mark 5-hydroxymethylcytosine (5-hmC) has attracted interest since 2009, when it was shown that ten-eleven translocation proteins can enzymatically convert 5-methylcytosine into 5-hmC, a key intermediate of DNA demethylation. Factors that regulate DNA hydroxymethylation are frequently altered in cancer, leading to deregulation of 5-hmC levels. In this review, we will discuss the relationship between melanoma and DNA hydroxymethylation, the regulation of DNA hydroxymethylation, and defects in this pathway in melanoma.

Schisandrin A (Sch A) is a lignin extracted from the fruit of Schisandra chinensis, which has potential anti-inflammatory properties and is used for treating various inflammatory diseases. In this study, we aimed to evaluate the anti-inflammatory effects of Sch A and the underlying mechanisms in animal models of acute inflammation. First, the anti-inflammatory effects of Sch A were evaluated preliminarily in an animal model of xylene-induced ear edema. Sch A pretreatment significantly decreased the degree of edema and inhibited telangiectasia in the ear. Second, a mouse model of paw edema was used to investigate the anti-inflammatory effects and mechanisms of Sch A. Pretreatment with Sch A significantly inhibited carrageenan-induced paw edema in mice. Hematoxylin-eosin (HE) staining of paw tissues demonstrated that Sch A inhibited the infiltration of inflammatory cells in the mouse model of paw edema. Enzyme-linked immunosorbent assay (ELISA) results indicated that the levels of inflammatory factors decreased. The western blot and immunohistochemical assay results revealed that the toll-like receptor 4/nuclear factor kappa-B (TLR4/NF-κB) pathway could play a role in the anti-inflammatory functions of Sch A. The findings demonstrated that Sch A exerts anti-inflammatory effects and may provide possible strategies for the treatment of inflammatory diseases.

Background Many tripartite motif (TRIM) family proteins have been reported to be of great importance in the initiation and progression in hepatocellular carcinoma (HCC). However, the biological role and regulatory mechanism of tripartite motif containing 52 (TRIM52) in HCC development and progression are poorly defined. Methods Immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) or Western blot analysis was used to detect TRIM52, p21, matrix metalloproteinase 2 (MMP2), protein phosphatase, Mg2+/Mn2+ dependent 1A (PPM1A), p-Smad2/3 and Smad2/3 levels in HCC tissues and cell lines. HCC cell proliferation and cell cycle were measured by Cell Counting Kit-8 (CCK-8) and flow cytometry analysis, respectively. HCC cell migration and invasion were measured by Transwell assay. Tumor growth of HCC cells in vivo was measured using the nude mouse xenograft model. The correlation between TRIM52 and PPM1A was measured by co-immunoprecipitation (Co-IP) and ubiquitination analysis in vitro. Results TRIM52 was significantly up-regulated in the HCC tissues in comparison with the adjacent non-tumor hepatic tissues. TRIM52 was also up-regulated in HCC cell lines (MHCC-97H and MHCC-97L cells) compared with normal human liver cell line LO2. TRIM52 down-regulation by RNA interfering in MHCC-97H cells enhanced inhibition of cell proliferation, migration and invasion. TRIM52 down-regulation also induced MHCC-97H cells arrest in G0-G1 phase cell cycle and inhibited MHCC-97H cell growth in the nude mice. However, TRIM52 up-regulation in MHCC-97L cells promoted cell proliferation, migration and invasion. Furthermore, TRIM52 down-regulation significantly increased p21 and PPM1A expression, but inhibited MMP2 expression and induced Smad2/3 dephosphorylation in MHCC-97H cells, which were reversed by TRIM52 up-regulation in MHCC-97L cells. TRIM52 was found interacted with PPM1A and TRIM52 down-regulation inhibited the ubiquitination of PPM1A. Importantly, PPM1A up-regulation in MHCC-97L cells significantly suppressed TRIM52-mediated enhancement on cell proliferation, invasion and migration. Conclusions Our findings suggest that TRIM52 up-regulation promotes proliferation, migration and invasion of HCC cells through the ubiquitination of PPM1A.

The ease of genetic manipulation, as well as the evolutionary conservation of gene function, has placedDrosophila melanogasteras one of the leading model organisms used to understand the implication of many proteins with disease development, including caspases and their relation to cancer. The family of proteases referred to as caspases have been studied over the years as the major regulators of apoptosis: the most common cellular mechanism involved in eliminating unwanted or defective cells, such as cancerous cells. Indeed, the evasion of the apoptotic programme resulting from caspase downregulation is considered one of the hallmarks of cancer. Recent investigations have also shown an instrumental role for caspases in non-lethal biological processes, such as cell proliferation, cell differentiation, intercellular communication, and cell migration. Importantly, malfunction of these essential biological tasks can deeply impact the initiation and progression of cancer. Here, we provide an extensive review of the literature surrounding caspase biology and its interplay with many aspects of cancer, emphasising some of the key findings obtained fromDrosophilastudies. We also briefly describe the therapeutic potential of caspase modulation in relation to cancer, highlighting shortcomings and hopeful promises.

Inbreeding depression is the reduction in fitness observed in inbred populations. In plants, it leads to disease, weaker resistance to adverse environmental conditions, inhibition of growth, and decrease of yield. To elucidate molecular mechanisms behind inbreeding depression, we compared global DNA methylation and transcriptome profiles of a normal and a highly inbred heading degenerated variety of the Chinese cabbage (Brassica rapa L. ssp. pekinensis). DNA methylation was reduced in inbred plants, suggesting a change in the epigenetic landscape. Transcriptome analysis by RNA-Seq revealed that genes in auxin-response and synthesis pathways were differentially expressed in the inbreeding depression lines. Interestingly, methylation levels of some of those genes were also changed. Furthermore, endogenous IAA content was decreased in inbred plants, in agreement with expression and methylation data. Chemical inhibition of auxin also replicated the degenerated phenotype in normal plants, while exogenous IAA application had no effect in inbred depression plants, suggesting a more complex mechanism. These data indicate DNA methylation-regulated auxin pathways play a role in establishing inbred depression phenotypes in plants. Our findings reveal new insights into inbreeding depression and leafy head development in Chinese cabbage.

Chinese cordyceps (or caterpillar fungus, Cordyceps sinensis), an expensive medicinal organism, is collected intensively every spring. It is concluded that over-collection has caused vegetation and soil degradation. However, most descriptions of the ecological impact of collection were qualitative and the impact on plant communities has not been quantified precisely. Collection plots and control plots were established in three counties on the Tibetan Plateau in order to measure impacts of collection on plant community composition. The results showed that due to Chinese cordyceps collection, species diversity expressed as the Shannon—Wiener indices significantly decreased by 10–13%, community dominance expressed as the Berger—Parker indices significantly increased by 17–32%, vegetation cover significantly decreased by 11–19% and aboveground biomass significantly decreased by 21–46%. However, root biomass did not change significantly, and only a few soil physical and chemical indicators in some plo...

Monascus purpureus is a key fungus used to produce food pigments from secondary metabolites. Low-frequency magnetic field (LF-MF) affects production of M. purpureus secondary metabolites as one of the cultivation environments. The objective of this study was to measure optimum strength of induced magnetic field and duration of exposure for yellow and red pigment production of M. purpureus in solid-state fermentation. There was a 65.4 and 59.2 % increase in peak yield of yellow and red pigments compared to the control when the treatments were exposed to a magnetic field induction at 0.4 mT on the 8–9th day of incubation time. From kinetics of yellow and red pigment production, yield of yellow and red pigments was significantly increased in the samples exposed to magnetic field from the 8th to 11th day compared with that of the control group. LF-MF could increase the production rates of yellow pigments from 221.25 to 381.75 and red pigments from 165.00 to 292.50 U/g day. It could also significantly prolong the quickly generate time of yellow pigment. The appropriate magnetic field treatment could increase the efficiency of yellow and red pigment production.

Aeruginosins are a class of cyanobacteria-derived bioactive linear tetrapeptides composed of nonproteinogenic amino-acid residues, such as the 2-carboxy-6-hydroxyoctahydroindole (Choi) moiety, which is the hallmark of aeruginosin. The biosynthetic pathway of the Choi moiety remains elusive. Previous studies have suggested that AerE, a protein that possesses two cupin domains, participates in the biosynthesis of the Choi moiety. In this study, recombinant AerE fromMicrocystis aeruginosa, which was overexpressed inEscherichia coliand purified by Ni2+-chelating affinity and gel-filtration chromatography, was successfully crystallized and X-ray diffraction analysis was performed. The crystal belonged to the orthorhombic space groupP212121, with unit-cell parametersa= 34.770,b= 62.133,c= 87.401 Å. The diffraction data from the crystal were scaled to a maximum resolution of 1.60 Å. The calculated Matthews coefficient of the crystal is 1.93 Å3 Da−1, suggesting that there is one molecule in the asymmetric unit.

In SiHa and CaSki cells, E6 and E7-targeting shRNA specifically and effectively knocked down human papillomavirus (HPV) 16 E6 and E7 at the transcriptional level, reduced the E6 and E7 mRNA levels by more than 80% compared with control cells that expressed a scrambled-sequence shRNA. E6 and E7 repression resulted in down-regulation of DNA methyltransferase mRNA and protein expression, decreased DNA methylation and increased mRNA expression levels of tumor suppressor genes, induced a certain apoptosis and inhibited proliferation in E6 and E7 shRNA-infected SiHa and CaSki cells compared with the uninfected cells. Repression of E6 and E7 oncogenes resulted in restoration of DNA methyltransferase suppressor pathways and induced apoptosis in HPV16-positive cervical carcinoma cell lines. Our findings suggest that the potential carcinogenic mechanism of HPV16 through influencing DNA methylation pathway to activate the development of cervical cancer exist, and maybe as a candidate therapeutic strategy for cervical and other HPV-associated cancers.

The 2-carboxy-6-hydroxyoctahydroindole moiety is an essential residue for the antithrombotic activity of aeruginosins, which are a class of cyanobacteria-derived bioactive linear tetrapeptides. The biosynthetic pathway of the 2-carboxy-6-hydroxyoctahydroindole moiety has not yet been resolved. AerF was indicated to be involved in the biosynthesis of the 2-carboxy-6-hydroxyoctahydroindole moiety. This study reports the cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of AerF fromMicrocystis aeruginosawith a C-terminal His6tag. The crystal diffracted to a maximum resolution of 1.38 Å and belonged to the tetragonal space groupP4322, with unit-cell parametersa=b= 101.581,c= 116.094 Å. The calculated Matthews coefficient and solvent content of the crystal were 2.47 Å3 Da−1and 50.32%, respectively. The initial model of the structure was obtained by the molecular-replacement method and refinement of the structure is in progress.

AIM: To investigate the protective effect of glutamine (Gln) on intestinal injury and the bacterial community in rats exposed to hypobaric hypoxia environment. METHODS: Sprague-Dawley rats were divided into control, hypobaric hypoxia (HH), and hypobaric hypoxia + Gln (5.0 g/kg BW·d) (HG) groups. On the first 3 d, all rats were placed in a normal environment. After the third day, the HH and HG groups were transferred into a hypobaric chamber at a simulated elevation of 7000 m for 5 d. The rats in the HG group were given Gln by gavage daily for 8 d. The rats in the control and HH groups were treated with the same volume of saline. The intestinal morphology, serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ) and diamino oxidase (DAO) were examined. We also evaluated the expression levels of occludin, toll-like receptor 4 (TLR4), nuclear factor-κB p65 (NF-κB p65) and myeloid differentiation factor 88 (MyD88), and examined the bacterial community in caecal contents. RESULTS: Hypobaric hypoxia induced the enlargement of the heart, liver, lung and kidney, and caused spleen atrophy. Intestinal villi damage was also observed in the HH group. Supplementation with Gln significantly alleviated hypobaric-induced damage to main organs including the intestine, increased serum SOD (1.14 ± 0.03 vs 0.88 ± 0.04, P < 0.05) and MDA (8.35 ± 1.60, P < 0.01) levels and decreased serum IL-6 (1172.13±30.49 vs 1407.05 ± 34.36, P < 0.05), TNF-α (77.46 ± 0.78 vs 123.70 ± 3.03, P < 0.001), IFN-γ (1355.42 ± 72.80 vs 1830.16 ± 42.07, P < 0.01) and DAO (629.30 ± 9.15 vs 524.10 ± 13.34, P < 0.001) levels. Moreover, Gln significantly increased occludin (0.72 ± 0.05 vs 0.09 ± 0.01, P < 0.001), TLR4 (0.15 ± 0.05 vs 0.30 ±0.09, P < 0.05), MyD88 (0.32 ± 0.08 vs 0.71 ± 0.06, P < 0.01), and NF-κB p65 (0.16 ± 0.04 vs 0.44 ± 0.03, P < 0.01) expression levels and improved the intestinal bacterial community. CONCLUSION: Gln treatment protects from intestinal injury and regulates the gut flora imbalance in hypoxia environment. These effects may be related to the TLR4/MyD88/NF-κB signaling pathway.

The study was conducted to investigate the role of vitamin E in the high altitude hypoxia-induced damage to the intestinal barrier in rats. Sprague-Dawley rats were divided into control (Control), high altitude hypoxia (HH), and high altitude hypoxia+vitamin E (250 mg/kg BW*d) (HV) groups. After the third day, the HH and HV groups were placed in a hypobaric chamber at a stimulated elevation of 7000 m for 5 days. The rats in the HV group were given vitamin E by gavage daily for 8 days. The other rats were given equal volume saline. The results showed that high altitude hypoxia caused the enlargement of heart, liver, lung and kidney, and intestinal villi damage. Supplementation with vitamin E significantly alleviated hypoxia-caused damage to the main organs including intestine, increased the serum superoxide dismutase (SOD) (p< 0.05), diamino oxidase (DAO) (p< 0.01) levels, and decreased the serum levels of interleukin-2 (IL-2) (p< 0.01), interleukin-4 (IL-4) (p