Identification of key biomarkers for predicting CAD progression in inflammatory bowel disease via machine-learning and bioinformatics strategies.

The study aimed to identify the biomarkers for predicting coronary atherosclerotic lesions progression in patients with inflammatory bowel disease (IBD). Related transcriptome datasets were seized from Gene Expression Omnibus database. IBD-related modules were identified via Weighted Gene Co-expression Network Analysis. The 'Limma' was applied to screen differentially expressed genes between stable coronary artery disease (CAD) and acute myocardial infarction (AMI). Subsequently, we employed protein-protein interaction (PPI) network and three machine-learning strategies to further screen for candidate hub genes. Application of the receiver operating characteristics curve to quantitatively evaluate candidates to determine key diagnostic biomarkers, followed by a nomogram construction. Ultimately, we performed immune landscape analysis, single-gene GSEA and prediction of target-drugs. 3227 IBD-related module genes and 570 DEGs accounting for AMI were recognized. Intersection yielded 85 shared genes and mostly enriched in immune and inflammatory pathways. After filtering through PPI network and multi-machine learning algorithms, five candidate genes generated. Upon validation, CTSD, CEBPD, CYP27A1 were identified as key diagnostic biomarkers with a superior sensitivity and specificity (AUC > 0.8). Furthermore, all three genes were negatively correlated with CD4+ T cells and positively correlated with neutrophils. Single-gene GSEA highlighted the importance of pathogen invasion, metabolism, immune and inflammation responses during the pathogenesis of AMI. Ten target-drugs were predicted. The discovery of three peripheral blood biomarkers capable of predicting the risk of CAD proceeding into AMI in IBD patients. These identified biomarkers were negatively correlated with CD4+ T cells and positively correlated with neutrophils, indicating a latent therapeutic target.

Multimodal Study of the Superior Mesenteric Artery Wall.

BACKGROUND: To quantitatively analyze histological and fiber structure of the superior mesenteric artery (SMA) wall and to further explore the possible relationship between the architecture and histology changes of vessel wall and the occurrence of related diseases. METHODS: Histological and fiber structure analysis were performed on SMA specimens obtained from 22 cadavers. The SMA specimens were divided into initial, curved, and distal segments, and each segment was separated into the anterior and posterior walls. RESULTS: From the initial to the curved to the distal segment, the ratio of elastin decreased (31.4% ± 6.0%, 21.1% ± 5.8%, 18.6% ± 4.7%, respectively; P < 0.001), whereas the ratio of smooth muscle actin (24.5% ± 8.7%, 30.5% ± 6.8%, 36.1% ± 7.3%, respectively; P < 0.001) increased. Elastic fiber longitudinal amplitude of angular undulation was highest in the initial segment [7° (3.25°, 15°)] and lowest in the curved segment [2° (1°, 5°)]. In SMA curved segment, the anterior wall, when compared with the posterior wall, demonstrated a lower ratio of elastin (19.0% ± 5.8% vs. 23.3% ± 5.0%; P = 0.010) and collagen (41.4% ± 12.3% vs. 49.0% ± 10.2%; P = 0.032), a lower elastic fiber longitudinal amplitude of angular undulation [1° (1°, 5°) vs. 3° (2°, 5.25°); P = 0.013], a lower average fiber diameter (8.06 ± 0.36 pixels vs. 8.45 ± 0.50 pixels; P = 0.005), and a lower average segment length (17.96 ± 1.59 pixels vs. 20.05 ± 2.33 pixels; P = 0.001). CONCLUSIONS: SMA wall structure varies along the circumferential and axial directions, the presence of dense undulated elastic fiber protects the SMA initial segment of from dissection and aneurysm, but highly cross-linked collagen fiber here increases the likelihood of plaque formation. In the anterior wall of the curved segment, lower elastin and collagen content, lower elastic fiber undulation, and higher degree of collagen fiber cross-linking leads to the occurrence of SMA dissection and aneurysm. In the distal segment, high levels of vascular smooth muscle cells and bundles of long collagen fiber offer protection against the development of SMA-related diseases.

Fabrication of Eco-Friendly Hydrolyzed Ethylene-Maleic Anhydride Copolymer-Avermectin Nanoemulsion with High Stability, Adhesion Property, pH, and Temperature-Responsive Releasing Behaviors.

In this study, novel amphiphilic polymer emulsifiers for avermectin (Avm) were synthesized facilely via the hydrolysis of ethylene-maleic anhydride copolymer (EMA) with different agents, and their structures were confirmed by various techniques. Then, water-based Avm-nanoemulsions were fabricated with the emulsifiers via phase inversion emulsification process, and superior emulsifier was selected via the emulsification effects. Using the superior emulsifier, an optimal Avm-nanoemulsion (defined as Avm@HEMA) with satisfying particle size of 156.8 ± 4.9 nm, encapsulation efficiency (EE) of 69.72 ± 4.01% and drug loading capacity (DLC) of 54.93 ± 1.12% was constructed based on response surface methodology (RSM). Owing to the emulsifier, the Avm@HEMA showed a series of advantages, including high stability, ultraviolet resistance, low surface tension, good spreading and high affinity to different leaves. Additionally, compared to pure Avm and Avm-emulsifiable concentrate (Avm-EC), Avm@HEMA displayed a controlled releasing feature. The encapsulated Avm was released quite slowly at normal conditions (pH 7.0, 25 °C or 15 °C) but could be released at an accelerated rate in weak acid (pH 5.5) or weak alkali (pH 8.5) media or at high temperature (40 °C). The drug releasing profiles of Avm@HEMA fit the Korsmeyer-Peppas model quite well at pH 7.0 and 25 °C (controlled by Fickian diffusion) and at pH 7.0 and 10 °C (controlled by non-Fickian diffusion), while it fits the logistic model under other conditions (pH 5.5 and 25 °C, pH 8.5 and 25 °C, pH 7.0 and 40 °C).

Nonrelativistic Spin-Momentum Coupling in Antiferromagnetic Twisted Bilayers.

Spin-momentum coupling, which depends strongly on the relativistic effect of heavy elements in solids, is the basis of many phenomena in spintronics. In this Letter, we theoretically predict nonrelativistic spin-momentum coupling in two-dimensional materials. By proposing magnetic symmetry requirements for spin splitting in two-dimensional systems, we find that a simple twisting operation can realize nonrelativistic spin splitting in antiferromagnetic bilayers. Through first-principles calculations, we demonstrate that momentum-dependent spin splitting exists extensively in antiferromagnetic twisted bilayers with different crystal structures and twist angles. The size of the spin splitting caused by twisting is of the same order of magnitude as that arising from spin-orbit coupling. In particular, a transverse spin current with an extremely high charge-spin conversion ratio can be generated in twisted structures under an external electric field. The findings demonstrate the potential for achieving electrically controlled magnetism in materials without spin-orbit coupling.

Nephrotoxicity assessment of Esculentoside A using human-induced pluripotent stem cell-derived organoids.

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI). A major obstacle in predicting AKI is the lack of a comprehensive experimental model that mimics stable and physiologically relevant kidney functions and accurately reflects the changes a drug induces. Organoids derived from human-induced pluripotent stem cells (iPSCs) are promising models because of their reproducibility and similarity to the in vivo conditions. In this study, Esculentoside A, the triterpene saponin with the highest concentration isolated from the root of Phytolacca acinose Roxb., was used to induce kidney injury models in vivo and kidney organoids. Esculentoside A induced AKI in mice, together with pathological changes and enhanced apoptosis. Moreover, Esculentoside A damaged podocytes and proximal tubular endothelial cells in kidney organoids in a similar way as in vivo. We also found that treatment with 60 µM Esculentoside A induced the known biomarkers of kidney damage and inflammatory cytokines (such as kidney injury molecule (KIM-1), ß2-microglobulin (ß2-M), and cystatin C (CysC)) in the organoids, in which activation of Cleaved Caspase-3 was involved, possibly due to lowered mitochondrial membrane potential. In summary, this study strongly suggests using kidney organoids as a reliable platform to assess Chinese medicine-induced nephrotoxicity.

Fabrication of Novel Crosslinking Carboxylic Styrene-Acrylate Latices as Binders for Exterior Flexible Facing Tiles.

To overcome the shortcomings of the temperature sensitivity of exterior flexible facing tiles (EFFIs), a series of crosslinking carboxylic styrene-acrylate (SA) latices were prepared via the semicontinuous seed emulsion polymerization of glycidyl methacrylate (GMA), methacrylic acid (MAA), acrylic acid (AA), butyl acrylate (BA), and styrene (St), and were applied as binders to fabricate EFFTs with mineral powder. The obtained latices exhibited Bragg diffraction because of the narrow particle size distribution. Owing to the low dosage of emulsifiers and the crosslinking reaction between the epoxy group and the carboxyl group, the latex films displayed excellent water resistance, with water adsorption as low as 7.1%. The tensile test, differential scanning calorimeter (DSC) test, and dynamic mechanical analysis (DMA) indicated that at a GMA dosage of 4-6% the latex films had high mechanical strengths, which remained relatively stable in the temperature range of 10 to 40 °C. The optimal AA dosage was found in the range of 2 to 3%, at which the wet mixture exhibited good processability, conducive to forming an EFFT with a compact microstructure. Using the optimal SA latex, the obtained EFFT displayed a series of improved performances, including low water absorption, high mechanical strength, and stable self-supporting ability over a wide temperature range, exhibiting the application potential in the decoration and construction industries.

Systematic molecular analysis of the human secretome and membrane proteome in gastrointestinal adenocarcinomas.

The human secretome and membrane proteome are a large source of cancer biomarkers. Membrane-bound and secreted proteins are promising targets for many clinically approved drugs, including for the treatment of tumours. Here, we report a deep systematic analysis of 957 adenocarcinomas of the oesophagus, stomach, colon and rectum to examine the cancer-associated human secretome and membrane proteome of gastrointestinal tract adenocarcinomas (GIACs). Transcriptomic data from these GIACs were applied to an innovative majority decision-based algorithm. We quantified significantly expressed protein-coding genes. Interestingly, we found a consistent pattern in a small group of genes found to be overexpressed in GIACs, which were associated with a cytokine-cytokine interaction pathway (CCRI) in all four cancer subtypes. These CCRI associated genes, which spanned both one secretory and one membrane isoform were further analysed, revealing a putative biomarker, interleukin-1 receptor accessory protein (IL1RAP), which indicated a poor overall survival, a positive correlation with cancer stemness and a negative correlation with several kinds of T cells. These results were further validated in vitro through the knockdown of IL1RAP in two human gastric carcinoma cell lines, which resulted in a reduced indication of cellular proliferation, migration and markers of invasiveness. Following IL1RAP silencing, RNA seq results showed a consistent pattern of inhibition related to CCRI, proliferation pathways and low infiltration of regulatory T cells (Tregs) and CD8 naive cells. The significance of the human secretome and membrane proteome is elucidated by these findings, which indicate IL1RAP as a potential candidate biomarker for cytokine-mediated cancer immunotherapy in gastric carcinoma.

27-Hydroxycholesterol is a specific factor in the neoplastic microenvironment of HCC that causes MDR via GRP75 regulation of the redox balance and metabolic reprogramming.

OBJECTIVE: Due to the tissue specificity of the liver, long-term exposure to a high concentration of 27-hydroxycholesterol (27HC) is a special characteristic of the tumour microenvironment in hepatocellular carcinoma (HCC). However, what occurs after HCC cells are long-term exposure to 27HC and the molecular mechanisms involved remain largely unexamined. METHODS: A long-term 27HC-treated HepG2 cell line and the xenografts in nude mice were used as experimental models. Molecular mechanisms were investigated using bioinformatics analysis and molecular biological experiments. RESULTS: Here, we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75). On the one hand, GRP75 resulted in a change in the redox balance by regulating ROS generation and antioxidant system activity via affecting MMP, NRF2, HO-1, and NQO1 levels. On the other hand, GRP75 modified the metabolic reprogramming process by regulating key factors (HIF-1α, p-Akt, and c-myc) and glucose uptake, facilitating HCC cell growth in the inhospitable microenvironment. These two factors caused HCC cells to resist 27HC-induced cytotoxicity and attain multidrug resistance (MDR). CONCLUSIONS: Our present study not only identified 27HC, a characteristic component of the neoplastic microenvironment of HCC that causes MDR via GRP75 to regulate the redox balance and metabolic reprogramming, but also revealed that targeted intervention by the "switch"-like molecule GRP75 could reverse the effect of 27HC from cancer promotion to cytotoxicity in HCC, suggesting a new strategy for specific intervention of HCC.

Construction of a circRNA-miRNA-mRNA network based on differentially co-expressed circular RNA in gastric cancer tissue and plasma by bioinformatics analysis.

BACKGROUND: Increasing evidence implicates circular RNAs (circRNAs) have been involved in human cancer progression. However, the mechanism remains unclear. In this study, we identified novel circRNAs related to gastric cancer and constructed a circRNA-miRNA-mRNA network. METHODS: Microarray datasets GSE83521 and GSE93541 were obtained from the Gene Expression Omnibus (GEO). Then, we used computational biology to identify circRNAs that were differentially expressed in both GC tissue and plasma compared to normal controls; then, we detected the expression of the selected circRNAs in gastric cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). We also identified circRNA-related candidate miRNAs and their target genes with online tools. Combining the predicted miRNAs and target mRNAs, a competing endogenous RNA regulatory network was established. Functional and pathway enrichment analyses were performed, and interactions between proteins were predicted by using String and Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to elucidate the possible functions of these differentially expressed circRNAs. The regulatory network constructed using the microarray datasets (GSE83521 and GSE93541) contained three differentially co-expressed circRNAs (DECs). A circRNA-miRNA-mRNA network was constructed based on 3 circRNAs, 43 miRNAs and 119 mRNAs. RESULTS: GO and KEGG analysis showed that the regulation of apoptotic signaling pathway and PI3K-Akt signaling pathway were highest degrees of enrichment respectively. We established a protein-protein interaction (PPI) network consisting of 165 nodes and 170 edges and identified hub genes by using MCODE plugin in Cytoscape. Furthermore, a core circRNA-miRNA-mRNA network was constructed based on hub genes. Hsa_circ_0001013 was finally determined to play an important role in the pathogenesis of GC according to the core circRNA-miRNA-mRNA network. CONCLUSIONS: We propose a new circRNA-miRNA-mRNA network that is associated with the pathogenesis of GC. The network may become a new molecular biomarker and could be used to develop potential therapeutic strategies for gastric cancer.

Evaluation of Calu-3 cell lines as an in vitro model to study the inhalation toxicity of flavoring extracts.

This study aimed to evaluate the characteristics of Calu-3 cells as a model to examine the toxicological responses of inhalable substances. Calu-3 cells were grown to the confluence at an air-liquid interface (ALI) using a Transwell® permeable support system. The ALI resulted in biomimetic native bronchial epithelium displaying pseudostratified columnar epithelium with more microvilli and secretory vesicles. We further characterized and optimized the Calu-3 cell line model using ALI culturing conditions, immunolabeling of protein expression, ultrastructural analysis using scanning electron microscopy (SEM), and transepithelial electrical resistance (TEER) measurements, and then screened for the cytotoxicity of tobacco flavoring extracts. Calu-3 cells displayed dose-dependent responses when treated with the flavoring extract. Within 8-10 days, cell monolayers developed TEER ≥1000 Ω·cm2. During this time, Calu-3 cells exposed to flavoring extracts X01 and X06 exhibited a loss of cellular integrity and decreased ZO-1 and E-cadherin protein expression. In conclusion, we investigated the Calu-3 cell line culture conditions, culture time, and barrier integrity and tested the effect of six new synthetic tobacco flavoring extracts. Our data demonstrate that the Calu-3 human bronchial epithelial cell monolayer system is a potential in vitro model to assess the inhalation toxicity of inhalable substances.

A multi-responsive organogel and colloid based on the self-assembly of a Ag(i)-azopyridine coordination polymer.

In this work, through the coordination of C3 symmetric azopyridine ligands and Ag(i), coordination polymers with azo groups on the main chain were prepared. The trans coordination polymer formed an organogel with a network of nanofibers at low critical gelation concentrations, and it exhibited the abilities of self-healing and multi-stimuli response to heating, light, mechanical shearing, and chemicals due to the presence of dynamic coordinating bonds. On the other hand, the cis coordination polymer was found to assemble into nanoparticles to give a responsive colloid, which can produce fibrous precipitation in several days upon visible light irradiation due to the isomerization of the azo groups. This work provides a novel example for the design of a multi-responsive organogel and colloid based on the structural transformation of coordination polymers.

Recurrent hemorrhage risk associated with medial target medullary artery anastomosis from the periventricular collateral vessel in adult patients with moyamoya disease.

BACKGROUND: Although the association between periventricular target collateral anastomosis and recurrent ipsilateral hemorrhage has been evaluated in adult patients with moyamoya disease (MMD), no studies have investigated the relationship between target anastomotic territory and recurrent ipsilateral hemorrhage. The goal of this study was to assess this association. METHODS: Consecutive adult MMD patients who had experienced initial intracranial hemorrhage and undergone conservative treatment were included. Two readers assessed angiographic results to identify the target anastomotic territory (medial medullary artery, lateral medullary artery, multiple medullary arteries, or nonmedullary artery) responsible for the hemorrhage. Cox proportional hazard regression models were used to estimate the risk of recurrent hemorrhage. RESULTS: In the 36 hemispheres with initial hemorrhage, the target anastomotic territory was in the anastomotic territory of the medial medullary artery in 10 (27.8%), lateral medullary artery in 15 (41.7%), multiple medullary arteries in 2 (5.6%), and a nonmedullary artery in 9 (25.0%) hemispheres. During 45.1 ± 40.0 months of follow-up, recurrent ipsilateral hemorrhage occurred in 44.4% (16/36) of hemispheres. The target anastomotic territories responsible for the recurrent event were in the anastomotic territory of the medial medullary artery in 9 (56.3%) hemispheres, lateral medullary artery in 6 (37.5%) hemispheres, and multiple medullary arteries in 1 (6.3%) hemisphere. The anastomotic territory of the medial medullary artery was associated with recurrent hemorrhage before (HR = 2.94; 95% CI, 1.07-8.08; p = 0.037) and after (HR = 6.65; 95% CI, 1.32-33.60; p = 0.022) adjustments were made for confounding factors. CONCLUSIONS: The incidence of recurrent ipsilateral hemorrhage varies with the target anastomotic territory in adult patients with MMD. Medial target medullary artery anastomosis is a significant risk factor for recurrent ipsilateral hemorrhage.

Facet Selectivity Guided Assembly of Nanoarchitectures onto Two-Dimensional Metal-Organic Framework Nanosheets.

Facet-selective nanostructures in living systems usually exhibit outstanding optical and enzymatic properties, playing important roles in photonics, matter exchange, and biocatalysis. Bioinspired construction of facet-selective nanostructures offers great opportunities for sophisticated nanomaterials, but remains a formidable task. We have developed a macromolecule-mediated strategy for the assembly of upconversion nanoparticles (UCNPs)/two-dimensional metal-organic frameworks (2DMOFs) heterostructures with facet selectivity. Both experimental and theoretical results demonstrate that polyvinylpyrrolidone (PVP) can be utilized as an interface-selective mediator to further promote the facet-selective assembly of MOFs onto the surface of UCNPs. The UCNPs/2DMOFs nanostructures with facet selectivity display specific optical properties and show great advantages in anti-counterfeiting. Our demonstration of UCNPs/2DMOFs provides a vivid example for the controlled fabrication of facet-selective nanostructures and can promote the development of advanced functional materials for applications in biosensing, energy conversion, and information assurance.

TMEM158 promotes pancreatic cancer aggressiveness by activation of TGFß1 and PI3K/AKT signaling pathway.

Pancreatic cancer (PC) is one of the most deadly digestive cancers world-wide, with a dismal five-year survival rate of <8%. Upregulation of transmembrane protein 158 (TMEM158) is known to facilitate the progression of several carcinomas. However, little is known concerning the potential roles of TMEM158 in PC. Herein, we first found that TMEM158 was significantly upregulated in PC samples as well as PC cell lines. The overexpression of TMEM158 was significantly correlated with advanced clinicopathologic features (including tumor size, TNM stage, and blood vessel invasion) and poorer prognosis of patients with PC in clinic. Evidenced based on a series of loss- and gain-of-function assays uncovered that TMEM158 enhanced PC cell proliferation, migration, and invasion by stimulating the progression of cell cycle, epithelial-mesenchymal transition, and MMP-2/9 production. Furthermore, mechanism-related investigations disclosed that activation of TGFß1 and PI3K/AKT signal might be responsible for TMEM158-triggered PC aggressiveness. Collectively, TMEM158 was upregulated in PC and promoted PC cell proliferation, migration, and invasion through the activation of TGFß1 and PI3K/AKT signaling pathways, highlighting its potential as a tumor promoter and a therapeutic target for PC.

Comparative anti-inflammatory effect of curcumin at air-liquid interface and submerged conditions using lipopolysaccharide stimulated human lung epithelial A549 cells.

BACKGROUND: Inhalation of aerosolized drugs is a promising entry route for rapid and non-invasive therapeutics delivery to the lung. Curcumin exhibits potent anti-inflammatory properties, which are effective for use in lung diseases. The anti-inflammatory properties of curcumin have been widely studied in vitro with cells cultured in submerged conditions, however, the effectiveness using air-liquid interface (ALI) exposure is currently unknown. METHODS: The anti-inflammatory effect of curcumin under both ALI and submerged conditions was investigated in the present study. Lipopolysaccharide (LPS) stimulated A549 cells were exposed to curcumin under ALI (10-100 µM) using a dose-controlled air-liquid interface cell exposure (ALICE)-CLOUD system and submerged cell culture conditions (1-20 µM). The expression of pro-inflammatory cytokines (interleukin (IL)-6, IL-8), cell viability and cytotoxicity were studied for each exposure scenario. The cellular uptake behaviour of curcumin was studied with an equipotent cell-based dose (200 pmol/106 cell) at various time points up to 24 h. RESULTS: The ALI delivery profile proved to be rapid, efficient and reproducible. For the doses studied, no significant effect on cell viability and cytotoxicity were observed. ALI exposure of curcumin was more effective in reducing pro-inflammatory cytokines expression in lung epithelial cells compared with submerged cell cultures. Furthermore, rapid cellular uptake and higher intracellular doses were achieved by ALI conditions. CONCLUSIONS: The ALICE-CLOUD system combined with lung epithelial cells cultured under ALI conditions offers a reliable and relevant in vitro method for preclinical aerosolized drug screening. Curcumin might be a promising anti-inflammatory candidate drug for inhalation therapy of lung diseases.

RNA-seq analysis of testes from flurochloridone-treated rats.

Flurochloridone (FLC) is a widely used herbicide in developing countries. Although the testes are a target organ for FLC in rats, the adverse effects of FLC on testes have not been fully elucidated. To clarify them, we performed RNA-seq analysis using the testes of FLC-treated rats from our previous subchronic toxicity tests. Unilateral testes of three male rats from solvent control groupand three FLC-treated groups (3 mg/kg, 31.25 mg/kg and 125 mg/kg) were used for RNA extraction. A poly A selection protocol coupled with an Illumina TruSeq RNA-Seq library protocol was used to construct RNA-Seq libraries. Principal component analysis (PCA), differentially expressed gene (DEG) analysis, and hierarchical clustering analysis (HCA) were conducted using R. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to understand the biological characteristics of the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The results indicated that many up-regulated DEGs were enriched in pathways associated with testicular injury, such as mitogen-activated protein kinase (MAPK) signaling, lysosome and focal adhesion. Many down-regulated DEGs were enriched in pathways associated with testicular reproduction function, such as sexual reproduction, spermatogenesis and germ cell development. Moreover, we confirmed the oral no-observed-adverse-effect level (NOAEL) of 3 mg/kg in subchronic toxicity test, because the overall testicular gene expression in 3 mg/kg FLC-treated group was similar to that of the solvent control group. In 31.25 mg/kg and 125 mg/kg groups, DEGs revealed that testicular injury was related to oxidative stress.

PARP14 promotes the proliferation and gemcitabine chemoresistance of pancreatic cancer cells through activation of NF-κB pathway.

Pancreatic cancer (PC) is the most fatal gastrointestinal malignancy in the world, with a 5-year relative survival of only 8%. Poly(ADP-ribose) polymerase (PARP)14, a member of the macro-PARP subfamily proteins, has been reported to participate in various biologic and pathologic processes in multiple cancers. The roles and underlying molecular mechanisms of PARP14 in PC carcinogenesis, however, remain to be elucidated. In this study, we for the first time discovered that PARP14 was highly expressed in human primary PC specimens and significantly correlated with poor patient prognosis. Using loss-of-function studies in vitro and in vivo, we showed that the knockdown of PARP14 led to enhanced apoptosis, repressed proliferation, and gemcitabine (GEM) resistance of PC cells. Further investigations revealed that PARP14 was significantly overexpressed in GEM-resistant PC cells (SW1990/GZ). And silencing of PARP14 significantly reversed the GEM resistance of SW1990/GZ cells. To the mechanism, PARP14 could stimulate PC progression by the activation of nuclear factor-κB (NF-κB) signaling pathway. And inhibition of NF-κB signal could significantly reverse PARP14-overexpression triggered PC carcinogenesis. In conclusion, PARP14 could promote PC cell proliferation, antiapoptosis, and GEM resistance via NF-κB signaling pathway, highlighting its potential role as a therapeutic target for PC.

Low dose of flurochloridone affected reproductive system of male rats but not fertility and early embryonic development.

BACKGROUND: Fluorochloridone (FLC) is a widely used herbicide, and its target organs are testes and epididymides. The Globally Harmonized System of Classification and Labelling of Chemicals classified FLC as Level 2-possibly cause fertility or fetal damage (no relevant data support). The maximum residue levels of FLC in processed crops have been reviewed in the latest European Food Safety Authority (EFSA) report in 2018. However, the toxic effect of FLC on fertility and early embryonic development is limited, and the health risk assessment of FLC needs further consideration. This study investigated the potential effects of FLC on fertility and early embryonic development in rats. METHODS: One hundred rats of each sex were divided into four groups including three FLC-treated groups at doses of 2 mg/kg, 5 mg/kg and 15 mg/kg, and a vehicle control group (0.5% (w/v) sodium carboxymethyl cellulose). Male and female rats were dosed for 9 and 2 consecutive weeks, intragastrically, prior to cohabitation and lasted throughout the mating period for males and continued until Gestation Day 7 (GD7) for females. Parameters such as weights and coefficients of reproductive organs, epididymal sperm number and motility, indexes of copulation, fecundity and fertility indexes, mating period, estrous cycle, corporalutea number, implantations, live, dead and resorbed fetuses, preimplantation loss rate, and postimplantation loss rate were observed in this study. RESULTS: Obvious toxicity of male reproductive system was found at the dose of 15 mg/kg including decreases in testicular and epididymal weight, also in sperm motility rate. Whereas the increase in sperm abnormality rate was observed. However, no significant effects of FLC were found on lutea count, implantations count, fetuses count and weight, live fetuses count (rate), dead fetuses count (rate), resorbed fetuses count (rate), placentas weight, fetuses gender, preimplantation loss (rate) and postimplantation loss (rate). Furthermore, FLC had no adverse effects on fertility and early embryonic development in rats. CONCLUSION: The no-observable-adverse-effect level (NOAEL) of FLC on fertility and early embryonic development in rats was considered to be 5 mg/kg/day.

Methylxanthine derivatives promote autophagy in gastric cancer cells targeting PTEN.

Methylxanthine derivatives, such as caffeine and theophylline, enhance cell apoptosis and autophagy and reportedly induce the activity of phosphatase and tensin homologue (PTEN) and inhibit the mammalian target of rapamycin (mTOR). This study investigated the impacts of caffeine and theophylline on gastric cancer cell apoptosis and autophagy using a gastric cancer cell line (MGC-803) and a nude mouse model. Peritumoural and tumour tissues were collected from five patients diagnosed with gastric carcinoma who underwent laparoscopic radical gastrectomy at our hospital. Autophagy was suppressed in gastric cancer tumour tissue compared with peritumoural tissue. In vitro, both caffeine and theophylline effectively suppressed MGC-803 cell proliferation and migration and induced autophagy. To assess the involvement of PTEN in caffeine-mediated and theophylline-mediated gastric cancer cell death, we transiently transfected MGC-803 cells with an siRNA targeting PTEN. PTEN knockdown impaired the methylxanthine derivative-mediated inhibition of PI3K/Akt/mTOR signalling. In nude mice treated with caffeine or theophylline, MGC-803 cell tumours injected with siPTEN were larger than those injected with negative control siRNA. These results show that the methylxanthine derivatives (caffeine and theophylline) effectively induce gastric cancer cell apoptosis and autophagy by PTEN activation and PI3K/Akt/mTOR pathway suppression and strongly support the use of methylxanthine derivatives as potential anticancer therapeutics.