Time-dependent hormetic effects of polypeptide antibiotics and two antibacterial agents contribute to time-dependent cross-phenomena of their binary mixtures.

Polypeptide antibiotics (PPAs), silver nanoparticles (plural) (AgNP) and quorum sensing inhibitors (QSIs) are considered to be the ideal antibiotic substitutes. Due to the great potential for the combined use of these antibacterial agents, it is necessary to evaluate their joint effects. In this study, the joint toxic actions for the binary mixtures of PPA + PPA, PPA + AgNP, and PPA + QSI were judged via the independent action (IA) model based on the individual and combined toxicity of test agents to the bioluminescence of Aliivibrio fischeri during 24 h. It was observed that the single agents (PPAs, AgNP, and QSI) and the binary mixtures (PPA + PPA, PPA + AgNP, and PPA + QSI) all triggered the time-dependent hormetic effects on the bioluminescence, where the maximum stimulatory rate, the median effective concentration, and the occurrence of hormesis varied with the increase of time. While bacitracin triggered the maximum stimulatory rate (266.98 % at 8 h) among the single agents, the mixture of capreomycin sulfate and 2-Pyrrolidinone induced the maximum stimulatory rate (262.21 % at 4 h) among the binary mixtures. The cross-phenomenon that the dose-response curve of mixture crossed the corresponding IA curve was observed in all treatments, which also varied with time, exhibiting that the joint toxic actions and corresponding intensities possessed dose- and time-dependent features. Furthermore, three kinds of binary mixtures resulted in three different variation tendencies for the time-dependent cross-phenomena. Mechanistic speculation indicated that test agents possessed the stimulatory modes of action (MOAs) at low-dose and inhibitory MOAs at high-dose to induce the hormetic effects, and the interplays between these MOAs varied with time to trigger the time-dependent cross-phenomenon. This study provides the reference data for the joint effects of PPAs and typical antibacterial agents, which will benefit the application of hormesis in the exploration of time-dependent cross-phenomenon and promote the future development of environmental risk assessment of pollutant mixtures.

Heterogeneous matrix stiffness regulates the cancer stem-like cell phenotype in hepatocellular carcinoma.

BACKGROUND: Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction. METHODS: First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results. RESULTS: AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin-yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness. CONCLUSIONS: Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy.

Huc-MSC-derived exosomes modified with the targeting peptide of aHSCs for liver fibrosis therapy.

BACKGROUND: Effective therapeutics to stop or reverse liver fibrosis have not emerged, because these potential agents cannot specifically target activated hepatic stellate cells (aHSCs) or are frequently toxic to parenchymal cells. Human umbilical cord mesenchymal stem cell (Huc-MSC)-derived exosomes show promise in nanomedicine for the treatment of liver fibrosis. However, systemic injection showed that unmodified exosomes were mainly taken up by the mononuclear phagocyte system. The discovery of ligands that selectively bind to a specific target plays a crucial role in clinically relevant diagnostics and therapeutics. Herein, we aimed to identify the targeting peptide of aHSCs by screening a phage-displayed peptide library, and modify Huc-MSC-derived exosomes with the targeting peptide. RESULTS: In this study, we screened a phage-displayed peptide library by biopanning for peptides preferentially bound to HSC-T6 cells. The identified peptide, HSTP1, also exhibited better targeting ability to aHSCs in pathological sections of fibrotic liver tissues. Then, HSTP1 was fused with exosomal enriched membrane protein (Lamp2b) and was displayed on the surface of exosomes through genetic engineering technology. The engineered exosomes (HSTP1-Exos) could be more efficiently internalized by HSC-T6 cells and outperformed both unmodified exosomes (Blank-Exos) and Lamp2b protein overexpressed exosomes (Lamp2b + Exos) in enhancing the ability of exosomes to promote HSC-T6 reversion to a quiescent phenotype. In vivo results showed HSTP1-Exos could specifically target to the aHSC region after intravenous administration, as demonstrated by coimmunofluorescence with the typical aHSCs marker α-SMA, and enhance the therapeutic effect on liver fibrosis. CONCLUSION: These results suggest that HSTP1 is a reliable targeting peptide that can specifically bind to aHSCs and that HSTP1-modified exosomes realize the precise treatment for aHSCs in complex liver tissue. We provide a novel strategy for clinical liver fibrosis therapy.

Efficacy and safety of microwave ablation and radiofrequency ablation in the treatment of hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Surgical resection is often only possible in the early stages of HCC and among those with limited cirrhosis. Radiofrequency ablation and Microwave ablation are 2 main types of percutaneous thermal ablation for the treatment of HCC. The efficacy and safety between these 2 therapy methods are still under a debate. OBJECTIVE: To compare the efficacy and safety of Radiofrequency ablation and Microwave ablation in treating HCC. METHODS: PubMed, EMBASE, the Cochrane databases and Web of Science were systematically searched. We included randomized controlled trials and cohort studies comparing the efficacy and safety of Radiofrequency ablation and Microwave ablation in HCC patients. Outcome measures on local tumor progression, complete ablation, disease-free survival, overall survival, or major complications were compared between the 2 groups. The random effect model was used when there was significant heterogeneity between studies, otherwise the fixed effect model was used. RESULTS: A total of 33 studies, involving a total of 4589 patients were identified, which included studies comprised 7 RCTs, 24 retrospective observational trials, and 2 prospective observational trial. Microwave ablation had a lower local tumor progression than Radiofrequency ablation in cohort studies (OR = 0.78, 95% CI 0.64-0.96, P = .02). Complete ablation rate of Microwave ablation was higher than that of Radiofrequency ablation in cohort studies (OR = 1.54, 95% CI 1.05-2.25, P = .03). There was no significant difference in overall survival and disease-free survival between the 2 groups. Meta-analysis showed that there was no significant difference in the main complications between Microwave ablation and Radiofrequency ablation. CONCLUSIONS: Microwave ablation has higher complete ablation and lower local tumor progression than Radiofrequency ablation in the ablation treatment of HCC nodules. There was no significant difference in overall survival between the 2 therapy methods.

Gold Nanorods-Based Photothermal Therapy: Interactions Between Biostructure, Nanomaterial, and Near-Infrared Irradiation.

Gold nanorods (AuNRs) are ideal inorganic nanophotothermal agents with unique characteristics, including local surface plasmon resonance effects, easy scale preparation and functional modification, and good biocompatibility. This review summarizes several recent advances in AuNRs-based photothermal therapy (PTT) research. Functionalized AuNRs photothermal agents have optimized biocompatibility and targeting properties. The multifunctional AuNRs nanoplatform composite structure meets the requirements for synergistic effects of PTT, photoacoustic imaging, and other therapeutic methods. Photothermal therapy with AuNRs (AuNRs-PTT) is widely used to treat tumors and inflammatory diseases; its tumor-targeting, tumor metastasis inhibition, and photothermal tumor ablation abilities have remarkable curative effects. An in-depth study of AuNRs in living systems and the interactions between biological structure, nanomaterial, and near-infrared irradiation could lay the foundation for further clinical research and the broad application of AuNRs in PTT.

Incremental robust PCA for vessel segmentation in DSA sequences.

In intervention surgery, DSA images provide a new way to observe the vessels and catheters inside the patient. Extracting coronary artery from the dynamic complex background fast improves the effectiveness directly in clinical interventional surgery. This article proposes an incremental robust principal component analysis (IRPCA) method to extract contrast-filled vessels from x-ray coronary angiograms. RPCA is a matrix decomposition method that decomposes a video matrix into foreground and background, commonly used to model complex backgrounds and extract target objects. IRPCA pre-optimizes an x-ray image sequence. When a new x-ray sequence is received, IRPCA optimizes it based on the pre-optimized matrix according to the strategy of minimizing the energy function to obtain the foreground matrix of the new sequence. Besides, based on the idea that the new x-ray sequence introduces new information to the pre-optimized matrix, we propose UIRPCA to improve the performence of IRPCA. Compared with the traditional RPCA method, IRPCA and UIRPCA save much time while ensuring that other indicators remain basically unchanged. The experiment results based on real data show the superiority of the proposed method over other RPCA algorithms.

Synergy of cobalt vacancies and iron doping in cobalt selenide to promote oxygen electrode reactions in lithium-oxygen batteries.

Electronic structural engineering plays a key role in the design of high-efficiency catalysts. Here, to achieve optimal electronic states, introduction of exotic Fe dopant and Co vacancy into CoSe2 nanosheet (denoted as Fe-CoSe2-VCo) is presented. The obtained Fe-CoSe2-VCo demonstrates excellent catalytic activity as compared to CoSe2. Experimental results and density functional theory (DFT) calculations confirm that Fe dopant and Co defects cause significant electron delocalization, which reduces the adsorption energy of LiO2 intermediate on the catalyst surface, thereby obviously improving the electrocatalytic activity of Fe-CoSe2-VCo towards oxygen redox reactions. Moreover, the synergistic effect between Co vacancy and Fe dopant is able to optimize the microscopic electronic structure of Co ion, further reducing the energy barrier of oxygen electrode reactions on Fe-CoSe2-VCo. And the lithium-oxygen batteries (LOBs) based on Fe-CoSe2-VCo electrodes demonstrate a high Coulombic efficiency (CE) of about 72.66%, a large discharge capacity of about 13723 mA h g-1, and an excellent cycling life of about 1338 h. In general, the electronic structure modulation strategy with the reasonable introduction of vacancy and dopant is expected to inspire the design of highly efficient catalysts for various electrochemical systems.

Dual role of cadmium in rat liver: Inducing liver injury and inhibiting the progression of early liver cancer.

The heavy metal cadmium (Cd) can induce damage in liver and liver cancer cells; however, the mechanism underlying its toxicity needs to be further verified in vivo. We daily administered CdCl2 to adult male rats at different dosages via gavage for 12 weeks and established rat liver injury model and liver cancer model to study the dual role of Cd in rat liver. Increased exposure to Cd resulted in abnormal liver function indicators, pathological degeneration, rat liver cell necrosis, and proliferation of collagen fibres. Using immunohistochemistry, we found that the area of GST-P-positive precancerous liver lesions decreased in a dose-dependent manner. Real-time quantitative polymerase chain reaction, western blot, immunohistochemistry, and transmission electron microscopy revealed that Cd induced mitophagy, as well as mitophagy blockade, as evidenced by the downregulation of TOMM20 and upregulation of LC3II and P62 with increasing Cd dose. Next, the expression of PINK1/Parkin, a classic signalling pathway protein that regulates mitophagy, was examined. Cd was found to promote PINK1/Parkin expression, which was proportional to the Cd dose. In conclusion, Cd activates PINK1/Parkin-mediated mitophagy in a dose-dependent manner. Mitophagy blockade likely aggravates Cd toxicity, leading to the dual role of inducing liver injury and inhibiting the progression of early liver cancer.

Restricted fiber contraction during amidoximation process for reinforced-concrete structured nanofiber sphere with superior Sb(V) adsorption capacity.

Amidoxime-polyacrylonitrile (APAN) nanofiber possesses advantages of adsorbing heavy metals for abundant amidoxime groups. However, it easily suffers from poor mechanical property caused by fiber contraction during amidoximation process. Inspired by high mechanical strength of reinforced concrete, we embedded stiff polylactic acid (PLA) skeletons into PAN matrix to prepare reinforced-concrete structured nanofiber sphere (APAN/PLA NFS) through solution blending. Preparation parameters including polymer concentration and PAN/PLA ratio were optimized as 4.0% and 1:1, and coarse sphere surface, numerous mesopores and large pore volume (19.3 mL/g) were endowed. Scanning electron microscope results showed restricted fiber contraction with nitrile conversion of 58.1%. APAN/PLA NFS showed robust compressive strength of 3.28 MPa with strain of 80%, and X-ray diffraction and differential scanning calorimeter analysis revealed that crystalline PLA reinforced non-crystalline PAN through molecule-level compatibility. Compared with plain APAN sphere, Sb(V) adsorption from water for APAN/PLA NFS showed better performance with superhigh capacity of 949.7 mg/g and fast rate (equilibrium time of 2 h), which was owing to abundant mesopores preserved by PLA skeletons. These findings indicated that PLA was a promising skeletal candidate which could protect APAN from fiber contraction during amidoximation process and could strongly expand adsorption capacity of APAN for heavy metals.

Induction and Maturation of Hepatocyte-Like Cells In Vitro: Focus on Technological Advances and Challenges.

Limited by the poor proliferation and restricted sources of adult hepatocytes, there is an urgent need to find substitutes for proliferation and cultivation of mature hepatocytes in vitro for use in disease treatment, drug approval, and toxicity testing. Hepatocyte-like cells (HLCs), which originate from undifferentiated stem cells or modified adult cells, are considered good candidates because of their advantages in terms of cell source and in vitro expansion ability. However, the majority of induced HLCs are in an immature state, and their degree of differentiation is heterogeneous, diminishing their usability in basic research and limiting their clinical application. Therefore, various methods have been developed to promote the maturation of HLCs, including chemical approaches, alteration of cell culture systems, and genetic manipulation, to meet the needs of in vivo transplantation and in vitro model establishment. This review proposes different cell types for the induction of HLCs, and provide a comprehensive overview of various techniques to promote the generation and maturation of HLCs in vitro.

Transcription profiling of cadmium-exposed livers reveals alteration of lipid metabolism and predisposition to hepatic steatosis.

1. Cadmium (Cd) is a ubiquitous environmental toxicant that can cause liver steatosis and nonalcoholic fatty liver disease (NAFLD) on long-term exposure.2. Sixteen Sprague Dawley rats were randomly divided into two groups, and were administered normal saline and 5 mg/(kg·d) cadmium chloride by gavage. In vitro, BRL3A cells, a rat normal liver cell line, were treated with different concentrations of Cd to verify the sequencing results.3. The RNA-seq revealed 146 upregulated genes and 127 downregulated genes in the Cd intervention group. The key genes of lipid metabolism were significantly overexpressed, such as Cyp1a1 and Pla2g2d. The GO enrichment analysis showed that the 'sterol biosynthetic process' was the most obvious difference. The KEGG analysis showed that six of the top 10 differential pathways were related to lipid metabolism. The expression of the essential genes in BRL3A was consistent with the sequencing results. The protein-protein interaction (PPI) yielded that Cyp1a1 is in the central region of the differentially expressed gene network.4. The chronic Cd exposure is still an important environmental health problem with a probable tendency to cause NAFLD. It may possibly act by affecting the lipid metabolism in the liver, especially the synthesis and decomposition of unsaturated fatty acids.

Rationalizing Surface Electronic Configuration of Ni-Fe LDO by Introducing Cationic Nickel Vacancies as Highly Efficient Electrocatalysts for Lithium-Oxygen Batteries.

Cationic defect engineering is an effective strategy to optimize the electronic structure of active sites and boost the oxygen electrode reactions in lithium-oxygen batteries (LOBs). Herein, Ni-Fe layered double oxides enriched with cationic nickel vacancies (Ni-Fe LDO-VNi ) are first designed and studied as the electrocatalysts for LOBs. Based on the density functional theory calculation, the existence of nickel vacancy in Ni-Fe LDO-VNi significantly improves its intrinsic affinity toward intermediates, thereby fundamentally optimizing the formation and decomposition pathway of Li2 O2 . In addition, the number of eg electrons on each nickel site is 1.19 for Ni-Fe LDO-VNi , which is much closer to 1 than 1.49 for Ni-Fe LDO. The near-unity occupation of eg orbital enhances the covalency of transition metal-oxygen bonds and thus improves the electrocatalytic activity of Ni-Fe LDO-VNi toward oxygen electrode reactions. The experimental results show that the LOBs with Ni-Fe LDO-VNi electrode deliver low overpotentials of 0.11/0.29 V during the oxygen reduction reaction/oxygen evolution reaction, respectively, large specific capacities of 13 933 mA h g-1 and superior cycling stability of over 826 h. This study provides a novel approach to optimize the electrocatalytic activity of LDO through reasonable defect engineering.

Effect of Helicobacter Pylori on Plasma Metabolic Phenotype in Patients With Gastric Cancer.

BACKGROUND: Although Helicobacter pylori (Hp) as high risk factor for gastric cancer have been investigated from human trial, present data is inadequate to explain the effect of Hp on the changes of metabolic phenotype of gastric cancer in different stages. PURPOSE: Herein, plasma of human superficial gastritis (Hp negative and positive), early gastric cancer and advanced gastric cancer analyzed by UPLC-HDMS metabolomics can not only reveal metabolic phenotype changes in patients with gastric cancer of different degrees (30 Hp negative, 30 Hp positive, 20 early gastric cancer patients, and 10 advanced gastric cancer patients), but also auxiliarily diagnose gastric cancer. RESULTS: Combined with multivariate statistical analysis, the results represented biomarkers different from Hp negative, Hp positive, and the alterations of metabolic phenotype of gastric cancer patients. Forty-three metabolites are involved in amino acid metabolism, and lipid and fatty acid metabolism pathways in the process of cancer occurrence, especially 2 biomarkers glycerophosphocholine and neopterin, were screened in this study. Neopterin was consistently increased with gastric cancer progression and glycerophosphocholine tended to consistently decrease from Hp negative to advanced gastric cancer. CONCLUSION: This method could be used for the development of rapid targeted methods for biomarker identification and a potential diagnosis of gastric cancer.

Cadmium causes hepatopathy by changing the status of DNA methylation in the metabolic pathway.

Toxicity caused by the heavy metal Cadmium leads to liver diseases; this finding has generated interest among researchers. We detected DNA methylation using Whole Genome Bisulfite Sequencing (WGBS) to study the relationship between Cadmium exposure and liver damage. Forty-eight Sprague-Dawley rats were randomly divided into six groups, and given normal saline or 2.5, 5, 10, 20, and 40 mg/kg body weight per day CdCl2 by gavage. Twelve weeks later, their liver tissues were collected for pathological examination and DNA extraction. Increased exposure to Cadmium led to a reduction in the amount of weight gain as well as pathological degeneration and necrosis of liver cells of the rats. Using WGBS, we found that DNA methylation changes in the high-dose exposure group were more remarkable, and most of the changes occurred in the gene promoter region. GO enrichment analysis showed that the genes were enriched in the biological process of "response to stimulus." KEGG analysis revealed that metabolic pathways, like MAPK, PI3K-Akt and cAMP, had the largest number of enriched genes. Using Integrative Genomics Viewer (IGV), the demethylation of F2rl3 after Cadmium poisoning was established. This finding may explain why there are changes in liver metabolism after Cadmium poisoning.

UBR5 oncogene as an indicator of poor prognosis in gastric cancer.

The human ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene, which is localized to chromosome 8q22, encodes an ~10 kb mRNA and a >300 kDa protein, which can be detected in a number of cell types. UBR5 is implicated in several types of cancer, including ovarian cancer, gallbladder cancer and lymphoma; however, its role in gastric cancer is not completely understood. In the present study, the expression levels of UBR5 in human gastric cancer tissues and cell lines were examined via immunohistochemistry, reverse transcription-quantitative PCR analysis and western blotting. Furthermore, the association between UBR5 expression and clinicopathological characteristics, as well as the prognosis of patients with gastric cancer, were examined. In addition, the role of UBR5 in gastric cancer cell proliferation, invasion and migration was investigated by conducting MTS, Transwell and wound healing assays, respectively. The results indicated that the mRNA and protein expression levels of UBR5 were significantly increased in gastric cancer tissues compared with para-carcinoma tissues. High UBR5 expression levels were significantly associated with larger tumor size, advanced TNM stage and lymph node metastasis. In addition, high UBR5 expression indicated a poor prognosis in patients with gastric cancer. Furthermore, in vitro experiments demonstrated that UBR5 knockdown was associated with reduced HGC-27 gastric cancer cell proliferation, invasion and migration compared with the small interfering RNA control group. Therefore, the results indicated that UBR5 may serve a key role in gastric cancer, indicating that UBR5 may also serve as an important prognostic biomarker.

Detecting cadmium during ultrastructural characterization of hepatotoxicity.

BACKGROUND: The threat of cadmium (Cd), which is the cause of itai-itai disease in Japan, is still complicated and confusing, especially for digestive system, such as liver disease. One of the most keys of this problem is demonstrating that the hepatotoxicity is indeed induced by Cd. Therefore, we attempt detecting Cd at microscale during ultrastructural imaging of liver tissue. METHODS: 12 rats were divided randomly into two experimental groups: control and Cd-treated. Treated rats were intraperitoneal injected with 1 mg/kg body weight cadmium chloride (CdCl2) for 4 weeks (5 P.M each day for 6 days/week). At the end of the exposure period, liver tissue samples were processed into ultrathin sections for analysis of advanced analytical transmission electron microscopy and X-ray energy dispersive spectroscopy (TEM/X-EDS) investigations. Ultrastructural images and X-ray energy dispersive spectrum were acquired at microscale. RESULTS: Cd can cause changes in the structure of the organelle, including the collapse of the membrane structure in the cell, the destruction of the internal structure of the organelle, the mitochondrial swelling, the expansion of the endoplasmic reticulum, and the appearance of inclusions. Cadmium bioaccumulation is detected in the mitochondria at microscale by TEM/X-EDS, which is the visual evidence of morphological changes of mitochondria related to Cd. CONCLUSION: The combination of detailed ultrastructure and microscale X-ray energy dispersive spectroscopy (X-EDS) characterization of cadmium hepatotoxicity demonstrate that cadmium indeed leads to mitochondrial damage, which is helpful for further investigation of the pathological mechanism of cadmium hepatotoxicity.

Bimodal Molecule as NIR-CT Contrast Agent for Hepatoma Specific Imaging.

With currently available molecular imaging techniques, hepatocellular carcinoma (HCC), a liver cancer with high mortality rates and poor treatment responses, is mostly diagnosed at its late stage. This is largely due to the lack of highly sensitive contrast agents with high liver specificity. Herein, we report a novel bimodal contrast agent molecule CNCI-1 for the effective detection of HCC at its early stage both in vitro and in vivo. The agent has high liver specificity with effective X-ray computed tomography (CT)/near-infrared (NIR) imaging functions. It has been successfully applied to in vivo NIR imaging with high sensitivity and high selectivity to the HCC region of the HepG2 tumor-xenografted mice model and LM3 orthotopic hepatoma mice model. Moreover, the agent was found to be noninvasive and hepatocarcinoma cells preferential. Furthermore, it also enhanced the tumor imaging by revealing the blood vessels nearby for the CT image acquisition in the VX2 orthotopic hepatoma rabbit model. Our design strategy provides a new avenue to develop the medical relevant bimodal contrast agents for diagnosis of HCC at its early stage.

Plasma microRNAs as potential new biomarkers for early detection of early gastric cancer.

BACKGROUND: Early gastric cancer (EGC), compared with advanced gastric cancer (AGC), has a higher 5-year survival rate. However, due to the lack of typical symptoms and the difficulty in diagnosing EGC, no effective biomarkers exist for the detection of EGC, and gastroscopy is the only detection method. AIM: To provide new biomarkers with high specificity and sensitivity through analyzed the differentially expressed microRNAs (miRNAs) in EGC and AGC and compared them with those in benign gastritis (BG). METHODS: We examined the differentially expressed miRNAs in the plasma of 30 patients with EGC, AGC, and BG by miRNA chip analysis. Then, we analyzed and selected the significantly different miRNAs using bioinformatics. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) confirmed the relative transcription level of these miRNAs in another 122 patients, including patients with EGC, AGC, Helicobacter pylori (H. pylori)-negative gastritis (Control-1), and H. pylori-positive atrophic gastritis (Control-2). To establish a diagnostic model for the detection of plasma miRNA in EGC, we chose miRNAs that can be used to determine EGC and AGC from Control-1 and Control-2 and miRNAs in EGC from all other groups. RESULTS: Among the expression profiles of the miRNA chips in the three groups in the discovery set, of 117 aberrantly expressed miRNAs, 30 confirmed target prediction, whereas 14 were included as potential miRNAs. The RT-qPCR results showed that 14 potential miRNAs expression profiles in the two groups exhibited no differences in terms of H. pylori-negative gastritis (Control-1) and H. pylori-positive atrophic gastritis (Control-2). Hence, these two groups were incorporated into the Control group. A combination of four types of miRNAs, miR-7641, miR-425-5p, miR-1180-3p and miR-122-5p, were used to effectively distinguish the Cancer group (EGC + AGC) from the Control group [area under the curve (AUC) = 0.799, 95% confidence interval (CI): 0.691-0.908, P < 0.001]. Additionally, miR-425-5p, miR-24-3p, miR-1180-3p and miR-122-5p were utilized to distinguish EGC from the Control group (AUC = 0.829, 95%CI: 0.657-1.000, P = 0.001). Moreover, the miR-24-3p expression level in EGC was lower than that in the AGC (AUC = 0.782, 95%CI: 0.571-0.993, P = 0.029), and the miR-4632-5p expression level in EGC was significantly higher than that in AGC (AUC = 0.791, 95%CI: 0.574-1.000, P = 0.024). CONCLUSION: The differentially expressed circulatory plasma miR-425-5p, miR-1180-3p, miR-122-5p, miR-24-3p and miR-4632-5p can be regarded as a new potential biomarker panel for the diagnosis of EGC. The prediction and early diagnosis of EGC can be considerably facilitated by combining gastroscopy with the use of these miRNA biomarkers, thereby optimizing the strategy for effective detection of EGC. Nevertheless, larger-scale human experiments are still required to confirm our findings.

Glutathione Might Attenuate Cadmium-Induced Liver Oxidative Stress and Hepatic Stellate Cell Activation.

The liver is a major organ involved in cadmium (Cd)-induced oxidative damage. Following liver injury, hepatic stellate cells (HSCs) are activated to participate in the wound healing process, but also facilitate liver fibrosis. Previous studies have observed fibrogenic effects of Cd on liver. However, the oxidative stress mechanisms of Cd-induced HSC activation as well as whether administration of glutathione (GSH) alleviates this activation, remain unclear. In this study, 24 rats were divided randomly into four experimental groups: control, GSH-treated, Cd-treated, and Cd + GSH-treated. After 4 weeks, the liver injury index, HSC-specific activation markers, oxidative stress-related antioxidants, and enzyme activities and signals were measured. Cd uptake and the generation of reactive oxygen species (ROS) in hepatocytes were detected by mass cytometry and fluorescence microscopy, respectively. Levels of aspartate aminotransferase, xanthine oxidase, γ-glutamyl transpeptidase, and α-smooth muscle actin (αSMA) were significantly increased in Cd-treated rats. Activated HSCs positive for αSMA expression and excess collagen deposition were detected in the Cd-treated group. In contrast, activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were reduced. Supplementation with GSH reversed some of the Cd-induced effects and increased the protein level of phosphorylated (p)-P65 while decreasing p-JNK. Pretreatment with GSH lowered Cd uptake and ROS generation in hepatocytes in vitro. These results indicate that administration of GSH was effective in attenuating Cd-induced oxidative stress via decreasing Cd uptake, restoring the activities of oxidative enzymes, activating NF-κB, inhibiting the JNK signaling pathway, and preventing excessive ROS generation and HSC activation.

Occurrence, impact variables and potential risk of PPCPs and pesticides in a drinking water reservoir and related drinking water treatment plants in the Yangtze Estuary.

PPCPs and pesticides have been documented throughout the world over the years, yet relatively little is known about the factors affecting their spatial distribution and temporal change in order to know their potential risk to the ecosystem or human health in the future. In our study, 5 PPCPs and 9 pesticides were selected to study their occurrence, impact variables and potential risk in a drinking water reservoir in Yangtze Estuary and related drinking water treatment plants (DWTPs) in China. The detection results showed the presence of PPCPs and pesticides reflected in a large part of croplands and urban and built-up land in the adjacent basin. The discrepancy of concentration among the different PPCPs and pesticides was mainly decided by their application amount or daily usage. Then, the major factors regulating the occurrence of these contaminants in the surface water were found as the living expenditure attributed to food and medicine based on a correlation analysis. Also, the PPCPs were found to negatively correlate to the effectiveness of sewage management. The detection of the PPCPs and pesticides in DWTPs indicated that, except for atrazine and simazine, the removal percentages were increased significantly in advanced DWTPs. Moreover, risk assessment estimated by a Risk Quotient and Hazard Quotient showed that while caffeine, bisphenol A, estrone and simazine were at a high-risk level in the reservoir water, all of the contaminants detected posed no risk to human health through drinking water. It's possible that atrazine could pose a high risk to the ecosystem while simazine could pose a risk to human health in the future considering the increasing expenditure attributed to food.