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Background It has been reported that patients with cholelithiasis may have changes in levels of cytokines and growth factors, while their causal relationships were still unclear. Methods This study was a bidirectional Mendelian randomization (MR) study. Datasets of 41 circulation cytokines and growth factors and the data on cholelithiasis were obtained. Six steps of strict instrumental variable filtration were set, and inverse-variance weighted analysis, MR-Egger regression, and weighted median test were used to identify the causal relationships. Benjamini–Hochberg method was used to adjust the P -values. Results After adjustments of P -values, four cytokines and growth factors were still causally associated with cholelithiasis significantly: interleukin 2 receptor alpha (adjusted P : 4.59E-02), interleukin 8 (adjusted P : 1.09E-02), monocyte-specific chemokine 3 (adjusted P : 2.73E-04), and stem cell factor (adjusted P : 2.73E-04). In the reverse MR analysis, no significant causal relationship was detected after adjustment. Conclusions Four cytokines and growth factors, including interleukin 2 receptor alpha, interleukin 8, monocyte-specific chemokine 3, and stem cell factor, were proven to relate to cholelithiasis causally and unidirectionally. Key messages What is already known on this topic? Patients with cholelithiasis may have changes in levels of cytokines and growth factors, while their causal relationships were still unclear. What this study adds? This study aimed to identify the causal effects of cytokines and growth factors on cholelithiasis. Four cytokines and growth factors, including IL2ra, IL8, MCP3, and SCF, were proven to relate to cholelithiasis causally. How this study might affect research, practice, or policy? Our study may provide evidence for new diagnostic and therapeutic strategies in clinical practices. [ABSTRACT FROM AUTHOR]

Fatty acid synthase (FAS) attracts more and more attention recently as a potential target for metabolic syndrome, such as cancer, obesity, diabetes and cerebrovascular disease. FAS inhibitors are widely existed in plants, consisting of diversiform compounds. These inhibitors exist not only in herbs also in many plant foods, such as teas, allium vegetables and some fruits. These effective components include gallated catechins, theaflavins, flavonoids, condensed and hydrolysable tannins, thioethers, pentacyclic triterpenes, stilbene derivatives, etc, and they target at the different domains of FAS, showing different inhibitory mechanisms. Interestingly, these FAS inhibitor-contained herbs and plant foods and their effective components are commonly related to the prevention of metabolic syndromes including fat-reducing and depression of cancer. From biochemical angle, FAS can control the balance between energy provision and fat production. Some studies have shown that the effects of those effective components in plants on metabolic syndromes are mediated by inhibiting FAS. This suggests that FAS plays a critical role in the regulation of energy metabolism, and the FAS inhibitors from plants have signifi cant potential application value in the treatment and prevention of metabolic syndromes.

Studies on GaAsBi-based devices have been deeply carried out in recent years, strongly driven by their excellent performance. Despite the growing interest in GaAsBi, the systematic researches on its vibrational and thermodynamic properties are still lacking. Hence, in this work, the structural, vibrational and thermodynamic properties of GaBixAs1-x are studied systematically by performing ab initio calculations. Firstly, the calculation structure constants of GaBixAs1-x are in accordance with other available data in the literature. Next, the results of the vibrational frequencies indicate that the phonon frequencies of GaBixAs1-x undergo a sharp decline when the bismuth concentration x is elevated. Besides the reduction of the phonon densities of states at the specified wave vector, the optical branches of GaBixAs1-x narrow and the attenuation of longitudinal modes is greater than that of transverse modes with the enhancement of the Bi concentration x. Then, the splitting degree δ ω suggests that the ionic strength for GaBixAs1-x is declined when increasing the Bi composition. Finally, the thermodynamic functions of GaBixAs1-x ranging from Δ F , Δ E , C v and S are predicted. In addition, the calculation values of the Debye temperature for GaBixAs1-x also confirm the change trend of phonon frequencies of the system. [ABSTRACT FROM AUTHOR]

In this paper a micro multi-phase flow equation is built based on the mechanism of a multi-phase fluid flow in porous media. The authors consider the impact of convection diffusion and the improved component mixing rule. In order to accurately evaluate the fluid flow in a low permeability reservoir, two models are established to simulate simple pore throat structure and complex pore throat structure. The predicted residual oil distribution characteristics of CO2 flooding in low permeability reservoir, calculated by finite element microsimulation, have been further verified by experiment. Furthermore, we analyze the effect of different wettability on microflow characteristics of CO2 flooding. The results show that CO2 flooding improving microsweep volume by convective diffusion is more evident in low permeability reservoirs than in high permeability reservoirs. The residual oil is mainly distributed following a pattern of prismatic, wedge-shape, or membrane microstructure. With decrease in the wetting angle on the fluid-rock boundary, the efficiency of oil displacement is further improved. [ABSTRACT FROM AUTHOR]

Metastasis associated 1 protein (MTA1) is one of the prime facilitators of metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the underlying regulatory mechanism of MTA1 expression in HCC is not clear. In this study, we evaluated MTA1 transcript and protein expression in HCC and normal hepatic cell lines. The results revealed that MTA1 protein expression had a significantly increase in HCC cell line, HuH6, compared with that in normal hepatic cell line, THLE-2. Determination of protein half-life using cycloheximide (CHX) treatment did not reveal any statistically significant difference in protein turn-over rates between THLE-2 (3.3 ± 0.25 h) and HuH6 (3.6 ± 0.15 h) cell lines. MTA1 protein level was stabilized in THLE-2 cells after treatment with MG-132 to levels similar to those observed in HuH6 cells. Mass spectrometric analysis of FLAG immunoprecipitates of FLAG- MTA1 transfected THLE-2 cells after MG-132 treated revealed candidate ubiquitin ligases that were interacting with MTA1. RNAi-mediated silencing of each prospective ubiquitin ligase in THLE-2 cells indicated that knockdown of TRIM25 resulted in stabilization of MTA1 protein, indicating TRIM25 as a putative E3 ligase for MTA1. Coimmunoprecipitation of FLAG-tagged MTA1, but not IgG, in MG-132 treated and untreated THLE-2 cells cotransfected with either FLAG- MTA1 or Myc- TRIM25 revealed robust polyubiquitinated MTA1, confirming that the TRIM25 is the ubiquitin ligase for MTA1 degradation. Overexpression of TRIM25 in HuH6 and RNAi mediated silencing of TRIM25 in THLE-2 cells inhibited and increased the cell migration and invasion, respectively. Analysis of The Cancer Genome Atlas data for assessment of TRIM25 transcript level and MTA1 protein expression in 25 HCC patients confirmed an inverse correlation between the expression of TRIM25 and MTA1. Cumulatively, our data reveal a novel mechanism of post-translational to regulate MTA1 expression in normal hepatic cells, which is repressed in HCC. © 2017 IUBMB Life, 69(10):795-801, 2017 [ABSTRACT FROM AUTHOR]

Liver fibrosis results from a sustained wound healing response to chronic liver injury, and the activation of nonparenchymal hepatic stellate cells (HSCs) is the pivotal process. MicroRNA-34a (miR-34a) is the direct target gene of p53 and activates p53 through sirtuin 1 (SIRT1) simultaneously. The miR-34a/SIRT1/p53 signaling pathway thus forms a positive feedback loop wherein p53 induces miR-34a and miR-34a activates p53 by inhibiting SIRT1, playing an important role in cell proliferation and apoptosis. miR-34a expression has been found to be increased in animal models or in human patients with different liver diseases, including liver fibrosis. However, the exact role of this classical miR-34a/SIRT1/p53 signaling pathway in liver fibrosis remains unclear. In the present study, using a CCl4-induced rat liver fibrosis model, we found that the miR-34a/SIRT1/p53 signaling pathway was activated and could be inhibited by SIRT1 activator SRT1720. Further studies showed that the miR-34a/SIRT1/p53 signaling pathway was activated in hepatocytes but not in HSCs. The activation of this pathway in hepatocytes resulted in the apoptosis of hepatocytes and thus activated HSCs. Our data indicate that the miR-34a/SIRT1/p53 signaling pathway might be a promising therapeutic target for liver fibrosis. [ABSTRACT FROM AUTHOR]

While bisphenol F (BPF) has been frequently detected in various environmental compartments, limited information is available on its effect on thyroid endocrine system. In the present study, zebrafish ( Danio rerio ) embryos were exposed to 0.2, 2, 20, and 200 μg/L of BPF from 2 h post-fertilization (hpf) to 144 hpf. The whole-body content of thyroid hormones, thyroid-stimulating hormone (TSH), and transcription of genes belonging to the hypothalamic-pituitary-thyroid (HPT) axis were investigated. BPF exposure resulted in alterations of both T3 and T4 contents, increased the ratios of T3/T4, demonstrating thyroid endocrine disruption. Moreover, TSH content was significantly induced in a concentration-dependent manner after exposure to BPF. The increased gene transcription of dio2 might assist to degrade increased T3 contents. Treatment with BPF also significantly increased transcription of genes involved in thyroid hormone regulation ( crh ) and synthesis ( nis and tg ) as a compensatory mechanism for the decrease of T4 contents. However, the gene encoding protein involved in TH transport ( ttr ) was transcriptionally significantly down-regulated after exposure to BPF. Taken together, these results suggest that BPF alters the transcription of genes involved in the HPT axis as well as changes whole-body contents of thyroid hormones and TSH in zebrafish embryos/larvae, thus causing an endocrine disruption of the thyroid system. [ABSTRACT FROM AUTHOR]

Highlights: [•] The absorption of water on UO2 (111) surface was studied by DFT calculation. [•] The structures of molecular water on UO2 (111) by GGA and GGA+ U are different. [•] Water on stoichiometric surface is apt to molecular absorption. [•] Dissociative adsorption of water is favorable on reduced surface. [Copyright &y& Elsevier]

Carbides of Fe3A1Cx precipitated from iron aluminides can strengthen the matrix; the empirical electron theory (EET) was applied to analyze the attribute of carbides in the paper, giving theoretical explanation on the matrix and precipitation. Valence electron structure (VES) of Fe3A1Cx was studied in detail, comparison with the iron aluminides matrix, the hard and brittle phase of Fe3AlCx can be interpreted form the viewpoint of valence electron structure. [ABSTRACT FROM AUTHOR]

Molecular dynamics calculation of UO2 in a wide temperature range are presented and discussed. The calculated lattice parameters, mean square displacements, and dynamic property of phonon-level density of the velocity auto-correlation functions for UO2 are provided. The Morelon potential and the Basak potential are employed. It confirms that the calculated lattice parameters using the Basak potential are in nearly perfect agreement with the reported values. The models successfully predict mean square displacement and Bredig transition. Furthermore, the phonon-level density of uranium dioxide are discussed. The intensity of phonon-level density increases with temperature, and the properties of UO2 are characterized by large thermal vibrations rather than extensive disorder. [ABSTRACT FROM AUTHOR]

Purposes: Recent research has shown netrin-1 to promote neovascularization. We evaluate the expression of netrin-1 during retinal neovascularization in a murine model of oxygen-induced retinopathy. Methods: C57BL/6J mice were exposed to 75 ± 5% oxygen for 5 days and returned to room air to induce retinal neovascularization. Retinal neovascularization was observed by fluorescence angiography and was quantified by counting the endothelial nuclei protruding into the vitreous cavity after hematoxylin-eosin staining. RT-PCR and Western blot analyses were used to determine retinal netrin-1 mRNA and protein levels at postnatal days (PN) 13, 15 and 17. Results: In fluorescence angiograms, irregular neovascularization and fluorescein leakage were observed surrounding the unperfused areas in the hypoxic group. The hypoxic group had, on average, 50.70 ± 4.56 neovascular nuclei protruding into the vitreous body, while similar nuclei were absent in the control group. Compared to the normoxic group, there were significant increases in both retinal netrin-1 mRNA and protein levels in the hypoxic group at PN13, PN15 and PN17. Conclusion: The netrin-1 level increases in murine retina under hypoxia and may be key in inducing retinal neovascularization. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Density functional theory (DFT) calculations employed at two levels, B3LYP/6-31G+(d) and B3P86/6-31G+(d), are reported for the geometry, enthalpy, and free energy of reaction of a number of dithiobenzoate reversible addition fragmentation transfer (RAFT) reagents (S=C(Ph)S–R, S=C(Z)S–CH2Ph). Based on these theoretical data, the effectiveness of these RAFT reagents is analyzed. The conclusions, especially obtained at B3LYP/6-31G+(d) level, are in good agreement with the experimental results. Our calculations suggest that the dithiobenzoate (S=C(Z)S–CH2Ph), where Z is OC6H5 or N(alkyl)2, is a poor RAFT reagent. Contrarily, the compound S=C(Ph)S–R, where R is C(Me)2Ph or C(Me)2CN, is a highly efficient RAFT reagent. Our results reveal the utility of the theoretical calculations of physical magnitudes for the rationalization of judging the effectiveness of RAFT reagents and demonstrated that DFT is a good method to calculate these data. In addition, our results on the enthalpies and Gibbs free energies of formation for the R radicals are calculated with the same method. These data are important for the design of logical and economical chemical process. Finally, the B3LYP hybrid functional is employed to predict the values of thermodynamic magnitudes for several new ithiobenzoates. Those results need to be verified by future experimental measurements or theoretical calculations. [ABSTRACT FROM AUTHOR]

Abstract Ninety percent of all cancer related deaths happen due to metastatic progression. One important protein facilitating metastatic progression in hepatocellular carcinoma (HCC) is the metastasis associated 1 protein (MTA-1). We have earlier shown that in the context of HCC and normal liver cell lines, HuH6 and THLE-2, respectively. MTA-1 protein is actively stabilized in HCC cell lines and actively degraded in normal liver cells. We had also shown that TRIM25 is the E3 ligase that interacts with and degrades MTA-1 protein in normal liver cells. However, the exact mechanism by which TRIM25 degrades MTA-1 protein has still not been elucidated. In the study, we used both in situ prediction algorithms and mass spectrometry based post-translational modification analysis to map the lysine residues in MTA-1 that are polyubiquitinated. Whereas UbPred algorithm revealed a combination of medium and low confidence sites, it revealed only one high confidence lysine (K98) residue. The hCKSAAP_UbSite algorithm also predicted K98 site. Mass spectrometry analysis also showed that K98 has ubiquitin modification. Immunofluorescence analysis showed that in normal liver cell line, THLE-2, which has high expression of TRIM25, ectopically expressed FLAG-tagged wild-type MTA-1 was actively degraded, but the K98R mutant MTA-1 was not. In vitro ubiquitination assay using recombinant wild-type and K98R mutant MTA-1 confirmed that MTA-1 is poly-ubiquitinated at K98 residue by TRIM25. The K98R mutant had a longer half-life than wild-type MTA-1 protein in an in vitro protein stability assay. We establish that TRIM25 ubiquitinates MTA-1 at lysine 98 and degrades it normal liver cells. [ABSTRACT FROM AUTHOR]

Background: Netrin-1 has been reported to promote retinal neovascularization in oxygen-induced retinopathy (OIR). However, netrin-1 receptors, which may mediate netrin-1 action during retinal neovascularization, have not been characterized. In this study, we investigated netrin-1 receptor subtype expression and associated changes in the retinas of mice with OIR.Methods: C57BL/6J mice were exposed to 75±2% oxygen for 5 days and then returned to normal air to induce retinal neovascularization. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot were used to examine the expression of netrin-1 receptor subtypes in the mouse retinas. Double staining of netrin-1 receptor subtypes and isolectin B4 was used to determine the location of the netrin-1 receptor subtypes in the retinas. Inhibition of retinal neovascularization was achieved by UNC5B shRNA plasmid intravitreal injection. Retinal neovascularization was examined by fluorescein angiography and quantification of preretinal neovascular nuclei in retinal sections.Results: RT-PCR results showed that, except for UNC5A, netrin-1 receptor subtypes UNC5B, UNC5C, UNC5D, DCC, neogenin, and A2b were all expressed in the retinas of OIR mice 17 days after birth. Western blots showed that only UNC5B expression was significantly increased on that day, and immunofluorescence results showed that only UNC5B and neogenin were expressed in retinal vessels. Treatment of OIR mice with the UNC5B shRNA plasmid dramatically reduced neovascular tufts and neovascular outgrowth into the inner limiting membrane.Conclusions: UNC5B may promote retinal neovascularization in OIR mice. [ABSTRACT FROM AUTHOR]

Abstract: A detailed theoretical study of structural, electronic, and elastic properties of cubic UAl x (x=1,2,3) is presented employing the pseudopotential plane-wave method based on density-functional theory. The structure parameters of these three compounds have been calculated within generalized gradient approximation (GGA) and local density approximation (LDA). The calculated results were compared with the experimental data and previous research. With the GGA approximation, the elastic constants, shear modulus, Young''s modulus, and Poisson''s ratio of UAl x (x=1,2,3) are derived. According to the generalized mechanical stability criteria for cubic crystals, our calculation suggested that C15 UAl2 and L12 UAl3 are stable substance under hydrostatic pressures, but B2 UAl might be expected as a metastable compound, which is not reported in previous literature, and future experimental confirmation is needed. Furthermore, the calculated energy band structure and density of state (DOS) are found to be in good agreement with the theoretical values. Additionally, the charge density of these compounds have also been worked out and analyzed. [Copyright &y& Elsevier]

Tumor metastasis accounts for 90% of all cancer-related deaths. Epithelial to mesenchymal transition (EMT) considered to be centrally important in acquired resistance to chemotherapy and in progression of tumors to secondary organs. One of the important mediators of metastatic progression in hepatocellular carcinoma (HCC) is the metastasis associated protein 1 (MTA-1). We have earlier shown that in the context of HCC and normal liver cell lines, MTA-1 protein is actively stabilized in HCC cell lines and actively degraded in normal liver cells. We have also shown that TRIM25 is the E3 ligase that interacts with and degrades MTA-1 protein. The identity of the factor regulating expression of TRIM25 in normal liver cells and HCC is unknown. In the current work we elucidate that microRNA (miR)− 873 targets TRIM25 in HCC cells. Both metagenomic analysis and quantification of miR-873 and TRIM25 in 25 HCC patients revealed an inverse correlation between the two in HCC patients with high miR-873 and low TRIM25 expression, respectively. The expression pattern was mimicked in the normal liver cells THLE-2 and the HCC cell line, HuH6. In vitro luciferase reporter assays confirmed TRIM25 as the target of miR-873. Transient transfection of HuH6 cells with an anti-miR-873 antagomir significantly decreased both transwell motility in these cells. Furthermore, in in vivo xenograft assays treatment with anti-miR-873 antagomir significantly decreased hepatic nodules formation. Cumulatively, our data indicate that suppression of TRIM25 expression by high levels of miR-873 dictates MTA1 protein upregulation in HCC. [ABSTRACT FROM AUTHOR]

Background: MG132 is a potent antioxidant and has been reported to play a protective role in ischemia/reperfusion (I/R) of many organs. Recent studies have shown that the Aryl hydrocarbon receptor (AhR) may play a beneficial role in I/R of many organs and an AhR agonist has been implicated in an anti-inflammatory role. MG132 might function as an AhR agonist through proteasome inhibition, possibly through the inhibition of NFκB. Herein, we hypothesized that MG132 may play a protective role in liver injury induced by intestinal I/R and we analyzed the expression behavior of AhR and NFκB to determine whether the two factors play a role in intestinal I/R. Materials and Methods: Thirty-two Sprague-Dawley rats were divided into four groups: control, I/R, MG132 control, and MG132 pretreatment. The I/R and MG132 pretreatment groups were subjected to mesenteric arterial ischemia for 1 h and reperfusion for 3 h. The control and MG132 control groups underwent surgical preparation including isolation of the superior mesenteric artery (SMA) without occlusion. The MG132 control and MG132 pretreatment groups were subjected to intraperitoneal administration of 0.5 mg/kg MG132 30 min before surgery. We collected serum specimens to measure TNF-α, IL-6, liver tissue levels of malondialdehyde (MDA), AhR, and cyp1a2; NFκB, IκBα, and ICAM-1 were also tested. Histologic changes of liver and intestine were subsequently evaluated. Results: Compared with the control group, significant increases in MDA, NFκB, and ICAM-1 levels were accompanied by decreases in AhR, cyp1a2, and IκBα expression in the liver in the I/R group, which is consistent with liver and intestinal tissue injury. MG132 blocked the alterations of the indicators above. There were no changes in the MG132 control group compared with the control group in the indicators above. Conclusions: This study demonstrated that MG132 has a significant effect in protection against liver injury induced by intestinal I/R, which may be due to modulation of the AhR and NFκB pathways. [Copyright &y& Elsevier]

The microstructures and mechanical properties of nanocrystalline Li 2 SiO 3 have been investigated via molecular dynamics calculations. The results indicate that the mean atomic mass densities of nanostructured Li 2 SiO 3 with different mean grain size are slightly lower than that of ordinary crystal Li 2 SiO 3 . Interestingly, a significant anti-Hall-Petch effect between yield stress and average grain size is observed in the tensile deformation simulation of the samples. In fact, the curve changes linearly until the strain reaches approximately 0.016-0.018. Next, when the strain is between 0.27 and 0.38, the stress of the sample has a small peak in the plastic flow region. Then, all the samples will begin to fracture at a strain of about 0.39-0.41. Moreover, due to the influence of grain boundary sliding and grain rotation, there are a few dislocations in the samples with the small average grain sizes, highlighting the strong influence of the mechanical properties on the overall tensile deformation of the samples., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Recent studies have demonstrated that circular RNA AKT3 (circAKT3) plays a crucial role in regulating the malignant phenotypes of tumor cells. However, the potential effects of circAKT3 on esophageal cancer have not been investigated., Aim: To illuminate the role of circAKT3 in malignant behaviors of esophageal cancer cells and its underlying mechanism., Methods: Clinical samples were collected to detect the expression of circAKT3 . The role of circAKT3 in proliferation, migration, invasion, and apoptosis of esophageal cancer cells was evaluated using Cell Counting Kit-8, wound healing assays, Transwell assays, and fluorescence analysis, respectively. The target of circAKT3 was screened and identified using an online database and luciferase reporter assay. A xenograft nude mouse model was established to investigate the role of circAKT3 in vivo ., Results: In vitro assays showed that proliferative, migratory, and invasive capacities of esophageal cancer cells were significantly enhanced by circAKT3 overexpression. Furthermore, miR-17-5p was screened as the target of circAKT3, and miR-17-5p antagonized the effects of circAKT3 on esophageal cancer cells. Moreover, we identified RHOC and STAT3 as the direct target molecules of miR-17-5p, and circAKT3 facilitated expression of RHOC and STAT3 by inhibiting miR-17-5p. In vivo assays showed circAKT3 knockdown inhibited growth of esophageal cancer., Conclusion: CircAKT3 contributed to the malignant behaviors of esophageal cancer in vitro and in vivo by sponging miR-17-5p thus providing a potential target for treatment of esophageal cancer., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Global incidence and mortality associated with hepatocellular carcinoma (HCC) is steadily increasing. Metastasis-associated 1 (MTA1) can induce tumorigenesis and metastatic progression in HCC. However, the mechanistic details of MTA1-mediated regulation of HCC has not been completely defined. Epigenetic histone modification is closely related to tumor development. Histone cluster 1 H1 family member c (H1.2) is important for epigenetic histone modification and chromatin remodeling; however, whether it has a role in HCC tumorigenesis is not known. In the current study, we confirmed that MTA1 promoted HCC cell growth and migration. Our results further show that MTA1 inhibited the phosphorylation of histone cluster 1 H1 family member c (H1.2) at threonine-146 residue (T146) (H1.2 T146ph ). MTA1 inhibited H1.2 T146ph by mediating proteasomal degradation of the DNA protein kinase (DNA-PK). Pharmacological inhibition of proteasomal degradation of DNA-PK or genetic ablation of E3 ligase mouse double minute 2 (MDM2) rescued expression of DNA-PK, and subsequent phosphorylation of H1.2. MTA1's role in HCC was inhibited by ectopic expression of H1.2 T146ph in HCC cell lines. Our results showed that H1.2 T146ph can bind to MTA1 target genes. Collectively, our study confirms that MTA1 functions as an oncogene and promotes HCC progression. The epigenetic histone modifier H1.2 T146ph exerts critical role in the regulation of MTA1-induced tumorigenesis. MTA1 regulates posttranslational activation of H1.2 by regulating the cognate kinase, DNA-PK, via the ubiquitin proteasome system. MTA1 expression was inversely correlated to both DNA-PK and phosphorylated H1.2 in HCC tissue specimens compared to tumor adjacent normal hepatic tissue, revealing that the MTA1/MDM2/DNA-PK/H1.2 is an important therapeutic axis in HCC., (Copyright © 2020 Li, Zhong, Zang and Tian.)

Background: Intestinal ischemia reperfusion (I/R) occurs in various diseases, such as trauma and intestinal transplantation. Excessive reactive oxygen species (ROS) accumulation and subsequent apoptotic cell death in intestinal epithelia are important causes of I/R injury. PTEN-induced putative kinase 1 (PINK1) and phosphorylation of dynamin-related protein 1 (DRP1) are critical regulators of ROS and apoptosis. However, the correlation of PINK1 and DRP1 and their function in intestinal I/R injury have not been investigated. Thus, examining the PINK1/DRP1 pathway may help to identify a protective strategy and improve the patient prognosis., Aim: To clarify the mechanism of the PINK1/DRP1 pathway in intestinal I/R injury., Methods: Male C57BL/6 mice were used to generate an intestinal I/R model via superior mesenteric artery occlusion followed by reperfusion. Chiu's score was used to evaluate intestinal mucosa damage. The mitochondrial fission inhibitor mdivi-1 was administered by intraperitoneal injection. Caco-2 cells were incubated in vitro in hypoxia/reoxygenation conditions. Small interfering RNAs and overexpression plasmids were transfected to regulate PINK1 expression. The protein expression levels of PINK1, DRP1, p-DRP1 and cleaved caspase 3 were measured by Western blotting. Cell viability was evaluated using a Cell Counting Kit-8 assay and cell apoptosis was analyzed by TUNEL staining. Mitochondrial fission and ROS were tested by MitoTracker and MitoSOX respectively., Results: Intestinal I/R and Caco-2 cell hypoxia/reoxygenation decreased the expression of PINK1 and p-DRP1 Ser637. Pretreatment with mdivi-1 inhibited mitochondrial fission, ROS generation, and apoptosis and ameliorated cell injury in intestinal I/R. Upon PINK1 knockdown or overexpression in vitro , we found that p-DRP1 Ser637 expression and DRP1 recruitment to the mitochondria were associated with PINK1. Furthermore, we verified the physical combination of PINK1 and p-DRP1 Ser637., Conclusion: PINK1 is correlated with mitochondrial fission and apoptosis by regulating DRP1 phosphorylation in intestinal I/R. These results suggest that the PINK1/DRP1 pathway is involved in intestinal I/R injury, and provide a new approach for prevention and treatment., Competing Interests: Conflict-of-interest statement: All the authors have nothing to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The incidence of colon cancer (CC) is currently high, and is mainly treated with chemotherapy. Oxaliplatin (L-OHP) is a commonly used drug in chemotherapy; however, long-term use can induce drug resistance and seriously affect the prognosis of patients. Therefore, this study investigated the mechanism of Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) on L-OHP resistance by determining the expression of OIP5-AS1 and microRNA-137 (miR-137) in CC cells and the effects on L-OHP resistance, with the goal of identifying new targets for the treatment of CC., Aim: To study the effects of long non-coding RNA OIP5-AS1 on L-OHP resistance in CC cell lines and its regulation of miR-137., Methods: A total of 114 CC patients admitted to China-Japan Union Hospital of Jilin University were enrolled, and the expression of miR-137 and OIP5-AS1 in tumor tissues and corresponding normal tumor-adjacent tissues was determined. The influence of OIP5-AS1 and miR-137 on the biological behavior of CC cells was evaluated. Resistance to L-OHP was induced in CC cells, and their activity was determined and evaluated using cell counting kit-8. Flow cytometry was used to analyze the apoptosis rate, Western blot to determine the levels of apoptosis-related proteins, and dual luciferase reporter assay combined with RNA-binding protein immunoprecipitation to analyze the relationship between OIP5-AS1 and miR-137., Results: OIP5-AS1 was up-regulated in CC tissues and cells, while miR-137 was down-regulated in CC tissues and cells. OIP5-AS1 was inversely correlated with miR-137 ( P < 0.001). Silencing OIP5-AS1 expression significantly hindered the proliferation, invasion and migration abilities of CC cells and markedly increased the apoptosis rate. Up-regulation of miR-137 expression also suppressed these abilities in CC cells and increased the apoptosis rate. Moreover, silencing OIP5-AS1 and up-regulating miR-137 expression significantly intensified growth inhibition of drug-resistant CC cells and improved the sensitivity of CC cells to L-OHP. OIP5-AS1 targetedly inhibited miR-137 expression, and silencing OIP5-AS1 reversed the resistance of CC cells to L-OHP by promoting the expression of miR-137., Conclusion: Highly expressed in CC, OIP5-AS1 can affect the biological behavior of CC cells, and can also regulate the resistance of CC cells to L-OHP by mediating miR-137 expression., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: As the malignant tumor, pancreatic cancer with a meager 5-years survival rate has been widely concerning. However, the molecular mechanisms that result in malignant transformation of pancreatic cells remain elusive., Aim: To investigate the gene expression profiles in normal or malignant transformed pancreas development., Methods: MaSigPro and ANOVA were performed on two pancreas development datasets downloaded from the Gene Expression Omnibus database. Six pancreatic cancer datasets collected from TCGA database were used to establish differentially expressed genes related to pancreas development and pancreatic cancer. Moreover, gene clusters with highly similar interpretation patterns between pancreas development and pancreatic cancer progression were established by self-organizing map and singular value decomposition. Additionally, the hypergeometric test was performed to compare the corresponding interpretation patterns. Abnormal regions of metabolic pathway were analyzed using the Sub-pathway-GM method., Results: This study established the continuously upregulated and downregulated genes at different stages in pancreas development and progression of pancreatic cancer. Through analysis of the differentially expressed genes, we established the inverse and consistent direction development-cancer pattern associations. Based on the application of the Subpathway-GM analysis, we established 17 significant metabolic sub-pathways that were closely associated with pancreatic cancer. Of note, the most significant metabolites sub-pathway was related to glycerophospholipid metabolism., Conclusion: The inverse and consistent direction development-cancer pattern associations were established. There was a significant correlation in the inverse patterns, but not consistent direction patterns., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest.

Background: Intestinal ischemia reperfusion (I/R) injury is a serious but common pathophysiological process of many diseases, resulting in a high mortality rate in clinical practice. Ubiquitin-specific protease 22 (USP22) acts as regulator of cell cycle progression, proliferation, and tumor invasion. Depleted USP22 expression has been reported to contribute to arrested cell cycle and disrupted generation of differentiated cell types in crypts and villi. However, the role of USP22 in intestinal damage recovery has not been investigated. Therefore, elucidation of the underlying mechanism of USP22 in intestinal I/R injury may help to improve the tissue repair and patient prognosis in clinical practice., Aim: To investigate the role of USP22 in intestinal cell proliferation and regeneration after intestinal I/R injury., Methods: An animal model of intestinal I/R injury was generated in male Sprague-Dawley rats by occlusion of the superior mesenteric artery followed by reperfusion. Chiu's scoring system was used to grade the damage to the intestinal mucosa. An in vitro model was developed by incubating rat intestinal epithelial IEC-6 cells in hypoxia/reoxygenation conditions in order to simulate I/R in vivo . siRNA and overexpression plasmid were used to regulate the expression of USP22. USP22, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression levels were measured by Western blot analysis and immunohistochemistry staining. Cell survival (viability) and cell cycle were evaluated using the Cell Counting Kit-8 and flow cytometry, respectively., Results: USP22 expression was positively correlated with the expression levels of PCNA and Cyclin D1 both in vivo and in vitro , which confirmed that USP22 was involved in cell proliferation and intestinal regeneration after intestinal I/R injury. Decreased levels of Cyclin D1 and cell cycle arrest were observed in the USP22 knockdown group ( P < 0.05), while opposite results were observed in the USP22 overexpression group ( P < 0.05). In addition, increased expression of USP22 was related to improved intestinal pathology or IEC-6 cell viability after I/R or hypoxia/reoxygenation. These results suggested that USP22 may exert a protective effect on intestinal I/R injury by regulating cell proliferation and facilitating tissue regeneration., Conclusion: USP22 is correlated with promoting intestinal cell proliferation and accelerating intestinal tissue regeneration after intestinal I/R injury and may serve as a potential target for therapeutic development for tissue repair during intestinal I/R injury., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.

This study aims to determine whether insulin-like growth factor binding protein2 (IGFBP2) is a useful biomarker for early diagnosis of acute kidney injury (AKI), evaluate the therapeutic effects of resveratrol-loaded nanoparticles (Res-NPs), and investigate the possible underlying mechanisms in a rat model of AKI induced by IRI. Forty male Sprague-Dawley rats were randomly divided into four groups (10 animals per group): sham, IRI control, resveratrol, and Res-NPs injection. Kidney injury and the effects of Resveratrol and Res-NPs were determined by histological examination, renal function, cell apoptosis profile, and gene expression. Changes in IGFBP2 were similar with the pattern of well-known renal biomarkers, namely, kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, in all groups. Compared with the IRI control and resveratrol groups, the Res-NPs groups displayed significantly reduced apoptotic rate, reactive oxygen species level, and malondialdehyde content, downregulated protein expression levels of Caspase3 and Bax with increased antioxidant glutathione peroxidase level, and upregulated expression of Bcl-2 protein. Thus, IGFBP2 may serve as a promising novel biomarker of AKI, and Res-NPs may prevent kidney injury from ischemia/reperfusion in a rat model., Competing Interests: CONFLICTS OF INTEREST None.