Organophosphate esters in milk across thirteen countries from 2020 to 2023: Concentrations, sources, temporal trends and ToxPi priority to humans.

Recent increases in organophosphate ester (OPE) application have led to their widespread presence, yet little is known about their temporal trends in food. This study collected milk samples from 13 countries across three continents during 2020-2023, finding detectable OPEs in all samples (range: 2.25-19.7; median: 7.06 ng/g ww). Although no statistical temporal differences were found for the total OPEs during the 4-year sampling campaign, it was interesting to observe significant variations in the decreasing trend for Cl-OPEs and concentration variations for aryl-OPEs and alkyl-OPEs (p < 0.05), indicating changing OPE use patterns. Packaged milk exhibited significant higher OPE levels than those found in directly collected raw unpackaged milk, and milk with longer shelf-life showed higher OPE levels, revealing packaging material as a contamination source. No significant geographical differences were observed in milk across countries (p > 0.05), but Shandong Province, a major OPE production site in China, showed relatively higher OPE concentrations. The Monte Carlo simulation of estimated daily intakes indicated no exposure risk from OPEs through milk consumption. The molecular docking method was used to assess human hormone binding affinity with OPEs, amongst which aryl-OPEs had the highest binding energies. The Toxicological-Priority-Index method which integrated chemical property, detection frequency, risk quotients, hazardous quotients and endocrine-disrupting effects was employed to prioritize OPEs. Aryl-OPEs showed the highest scores, deserving attention in the future.

Unravelling bioaccumulation, depletion and metabolism of organophosphate triesters in laying hens: Insight of in vivo biotransformation assisted by diester metabolites.

Organophosphate triesters (tri-OPEs) threaten human health through dietary exposure, but little is known about their feed-to-food transfer and in vivo behavior in farm animals. Herein 135 laying hens were fed with contaminated feed (control group, low-level group and high-level group) to elucidate the bioaccumulation, distribution, and metabolism of the six most commonly reported tri-OPEs. The storage (breast muscle), metabolism and mobilization (liver and blood) and non-invasive (feather) tissues were collected. The exposure-increase (D1∼14) and depuration-decrease (D15∼42) trends indicated that feed exposure caused tri-OPE accumulation in animal tissues. Tissue-specific and moiety-specific behavior was observed for tri-OPEs. The highest transfer factor (TF) and transfer rate (TR) were observed in liver (TF: 14.8%∼82.3%; TR: 4.40%∼24.5%), followed by feather, breast muscle, and blood. Tris(2-chloroisopropyl) phosphate (TCIPP) had the longest half-life in feather (72.2 days), while triphenyl phosphate (TPhP) showed the shortest half-life in liver (0.41 days). Tri-OPEs' major metabolites (organophosphate diesters, di-OPEs) were simultaneously studied, which exhibited dose-dependent and time-dependent variations following administration. In breast muscle, the inclusion of di-OPEs resulted in TF increases of 735%, 1108%, 798%, and 286% than considering TCIPP, tributyl phosphate, tris(2-butoxyethyl) phosphate and tris(2-ethylhexyl) phosphate alone. Feather was more of a proxy of birds' long-term exposure to tri-OPEs, while short-term exposure was better reflected by di-OPEs. Both experimental and in silico modeling methods validated aryl-functional group facilitated the initial accumulation and metabolism of TPhP in the avian liver compared to other moiety-substituted tri-OPEs.

Advances in the correlation between digital eye strain and sleep quality in adolescents / 中国学校卫生

Abstract@#Digital eye strain can affect not only adolescents visual health, but also sleep quality. In order to provide a reference for safeguarding adolescents visual health and physical health, the paper reviews the direct correlation, feedback correlation, mediating role and the mechanisms between their digital eye strain and sleep quality, as well as proposes some strategies to reduce digital eye strain and improve sleep quality, such as screen time limits, adjusting the brightness and contrast of electronic screen devices, maintaining correct posture and viewing distance, increasing eye nutrition and protection, establishing a regular sleep routine, avoiding the use of electronic screen devices before bedtime, creating a comfortable and quiet sleep environment, and paying attention to the effects of diet and exercise.

Hepatocellular Brg1 promotes CCl4-induced liver inflammation, ECM accumulation and fibrosis in mice.

INTRODUCTION: Hepatic fibrosis is a progressive pathological process involving the exhaustion of hepatocellular regenerative capacity and ultimately leading to the development of cirrhosis and even hepatocellular carcinoma. Brg1, the core subunit of the SWI/SNF chromatin-remodeling complex, was recently identified as important for liver regeneration. This study investigates the role of Brg1 in hepatic fibrosis development. METHODS: Hepatocyte-specific Brg1 knockout mice were generated and injected with carbon tetrachloride (CCl4) for 4, 6, 8, and 12 weeks to induce liver fibrosis. Afterwards, liver fibrosis and liver damage were assessed. RESULTS: Brg1 expression was significantly increased in the fibrotic liver tissue of wild-type mice, as compared to that of untreated wild-type mice. The livers of the Brg1 knockout animals showed reduced liver inflammation, extracellular matrix accumulation, and liver fibrosis. TNF-α and NF-κB-mediated inflammatory response was reduced in Brg1 knockout animals. CONCLUSION: Brg1 promotes the progression of liver fibrosis in mice and may therefore be used as a potential therapeutic target for treating patients with liver fibrosis due to chronic injury.

Closed-Loop Recyclable Silica-Based Nanocomposites with Multifunctional Properties and Versatile Processability.

Most plastics originate from limited petroleum reserves and cannot be effectively recycled at the end of their life cycle, making them a significant threat to the environment and human health. Closed-loop chemical recycling, by depolymerizing plastics into monomers that can be repolymerized, offers a promising solution for recycling otherwise wasted plastics. However, most current chemically recyclable polymers may only be prepared at the gram scale, and their depolymerization typically requires harsh conditions and high energy consumption. Herein, it reports less petroleum-dependent closed-loop recyclable silica-based nanocomposites that can be prepared on a large scale and have a fully reversible polymerization/depolymerization capability at room temperature, based on catalysis of free aminopropyl groups with the assistance of diethylamine or ethylenediamine. The nanocomposites show glass-like hardness yet plastic-like light weight and toughness, exhibiting the highest specific mechanical strength superior even to common materials such as poly(methyl methacrylate), glass, and ZrO2 ceramic, as well as demonstrating multifunctionality such as anti-fouling, low thermal conductivity, and flame retardancy. Meanwhile, these nanocomposites can be easily processed by various plastic-like scalable manufacturing methods, such as compression molding and 3D printing. These nanocomposites are expected to provide an alternative to petroleum-based plastics and contribute to a closed-loop materials economy.

Comparative genetic and epigenetic of the Sphagneticola trilobata (L.) Pruski from different regions in China.

BACKGROUND: Sphagneticola trilobata (L.) Pruski is a prevalent and widely distributed invasive plant in South China. To investigate the molecular mechanisms underlying its rapid adaptation, we employed DNA methylation-sensitive amplified polymorphism (MSAP) and simple sequence repeat (SSR) analysis to study 60 S. trilobata individuals collected from Fuzhou (FZ), Haikou (HK), Jinghong (JH) and Guangzhou (GZ). RESULTS: In this study, we computed the Shannon diversity index (I) of SSR and MSAP as 0.354 and 0.303, respectively. The UPGMA phylogenetic tree and PCoA analyses showed that MSAP had a better discriminatory power to distinguish populations from different regions. Notably, the GZ population was found to be the most distinct from the other three populations. Moreover, Mantel analysis revealed a significantly higher correlation between epigenetic distance and geographic distance as compared to genetic distance and geographic distance. Consequently, the correlation between epigenetic distance and geographic distance observed to be markedly stronger than that between genetic distance and geographical distance on Mantel analysis. CONCLUSIONS: The S. trilobata populations in various regions displayed a high of complementary genetic and epigenetic diversity, which was a key feature contributing to their rapid invasion. Interestingly, the correlation between epigenetics and geographical distance was significantly stronger than that observed for genetics and geographical distance. These findings indicated that the epigenetic mechanism of S. trilobar exhibited high plasticity, leading to significant differences in methylation pattern across different populations.

FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer.

BACKGROUND: FYN is a nonreceptor tyrosine kinase that regulates diverse pathological processes. The pro-cancer role of FYN in multiple malignancies has been elucidated. However, the mechanisms that FYN promotes gastric cancer (GC) progression remain largely unknown. METHODS: In vitro and in vivo assays were used to investigate the function of FYN. FYN, TOPK, p-TOPK expression in GC specimens were detected by immunohistochemistry. Phosphoproteomics assays identify TOPK downstream substrate molecules. The molecular mechanism was determined using COIP assays, pull-down assays, immunofluorescence co-localization assays, western blotting, 32p-labeled isotope radioautography assays, vitro kinase assays, and TOPK knockout mice. RESULTS: FYN was found to be significantly upregulated in GC tissues as well as in GC cells. Knockdown of FYN expression markedly attenuated the malignant phenotype of GC cells in vitro and in vivo. Mechanistically, we identified TOPK/PBK as a novel downstream substrate of FYN, FYN directly phosphorylates TOPK at Y272. One phosphospecific antibodies against Y272 was developed to validate the phosphorylation of TOPK by FYN. Moreover, the TOPK-272F mutation impaired the interaction between TOPK and FYN, leading to disappeared TOPK phosphorylation. Consistently, human GC tissues displayed increased p-TOPK(Y272), which correlated with poor survival. Phosphoproteomics results showed a significant downregulation of both HSPB1 and p-HSPB1(ser15) in TOPK-knockdown cells, which was confirmed by TOPK-konckout mice. CONCLUSIONS: FYN directly binds to TOPK in GC cells and phosphorylates TOPK at the Y272, which leads to proliferation and metastasis of GC. FYN-TOPK axis facilitates GC progression by phosphorylating HSPB1. Collectively, our study elucidates the pivotal role of the FYN-TOPK-HSPB1 cascade in GC.

Occurrence of some legacy and emerging contaminants in feed and food and their ranking priorities for human exposure.

The "feed-to-food" pathway is one of the most important routes for human exposure to manmade contaminants. The contaminants could threaten human health through the "feed-to-food" route and have recently become of great public concern. This review selects the representative legacy and emerging contaminants (ECs), such as polybrominated diphenyl ethers (PBDEs), novel brominated flame retardants (NBFRs), organophosphate esters (OPEs), short-chain chlorinated paraffins (SCCPs), and per- and polyfluoroalkyl substances (PFASs), regarding their occurrence in feed and food, as well as their metabolites and transport in farming and livestock ecosystems. Factors that might influence their presence and behavior are discussed. This review raises an approach to rank the priority of ECs using the EC concentrations in feed and food and using the hazard quotient (HQ) method for human health. Although SCCPs have the highest levels in feed and food, their potential risks appear to be the lowest. PFASs have the highest HQs on account of human exposure risk. Future research should pay more attention to the combined effects of multiple ECs.

Gut microbiota promote liver regeneration through hepatic membrane phospholipid biosynthesis.

BACKGROUND & AIMS: Hepatocyte growth and proliferation depends on membrane phospholipid biosynthesis. Short-chain fatty acids (SCFAs) generated by bacterial fermentation, delivered through the gut-liver axis, significantly contribute to lipid biosynthesis. We therefore hypothesized that dysbiotic insults like antibiotic treatment not only affect gut microbiota, but also impair hepatic lipid synthesis and liver regeneration. METHODS: Stable isotope labeling and 70% partial hepatectomy (PHx) was carried out in C57Bl/6J wild-type mice, in mice treated with broad-spectrum antibiotics, in germ-free mice and mice colonized with minimal microbiota. The microbiome was analyzed by 16S rRNA gene sequencing and microbial culture. Gut content, liver, blood and primary hepatocyte organoids were tested by mass spectrometry-based lipidomics, quantitative reverse-transcription PCR (qRT-PCR), immunoblot and immunohistochemistry for expression of proliferative and lipogenic markers. Matched biopsies from hyperplastic and hypoplastic liver tissue of patients subjected to surgical intervention to induce hyperplasia were analyzed by qRT-PCR for lipogenic enzymes. RESULTS: Three days of antibiotic treatment induced persistent dysbiosis with significantly decreased beta-diversity and richness, but a massive increase of Proteobacteria, accompanied by decreased colonic SCFAs. After PHx, antibiotic-treated mice showed delayed liver regeneration, increased mortality, impaired hepatocyte proliferation and decreased hepatic phospholipid synthesis. Expression of the lipogenic enzyme SCD1 was upregulated after PHx but delayed by antibiotic treatment. Germ-free mice essentially recapitulated the phenotype of antibiotic treatment. Phospholipid biosynthesis, hepatocyte proliferation, liver regeneration and survival were rescued in gnotobiotic mice colonized with a minimal SCFA-producing microbial community. SCFAs induced the growth of murine hepatocyte organoids and hepatic SCD1 expression in mice. Further, SCD1 was required for proliferation of human hepatoma cells and was associated with liver regeneration in human patients. CONCLUSION: Gut microbiota are pivotal for hepatic membrane phospholipid biosynthesis and liver regeneration. IMPACT AND IMPLICATIONS: Gut microbiota affect hepatic lipid metabolism through the gut-liver axis, but the underlying mechanisms are poorly understood. Perturbations of the gut microbiome, e.g. by antibiotics, impair the production of bacterial metabolites, which normally serve as building blocks for membrane lipids in liver cells. As a consequence, liver regeneration and survival after liver surgery is severely impaired. Even though this study is preclinical, its results might allow physicians in the future to improve patient outcomes after liver surgery, by modulation of gut microbiota or their metabolites.

Identifying the Role of Oxidative Stress-Related Genes as Prognostic Biomarkers and Predicting the Response of Immunotherapy and Chemotherapy in Ovarian Cancer.

Background: Ovarian cancer (OC) is one of the most frequently seen and fatal gynecological malignancies, and oxidative stress (OS) plays a critical role in the development and chemoresistance of OC. Materials and Methods: OS-related genes (OSRGs) were obtained from the Molecular Signatures Database. Besides, gene expression profiles and clinical information from The Cancer Genome Atlas (TCGA) were selected to identify the prognostic OSRGs. Moreover, univariate Cox regression, LASSO, and multivariate Cox regression analyses were conducted sequentially to establish a prognostic signature, which was later validated in three independent Gene Expression Omnibus (GEO) datasets. Next, gene set enrichment analysis (GSEA) and tumor mutation burden (TMB) analysis were performed. Afterwards, immune checkpoint genes (ICGs) and the tumor immune dysfunction and exclusion (TIDE) algorithm, together with IMvigor210 and GSE78220 cohorts, were applied to comprehensively explore the role of OSRG signature in immunotherapy. Further, the CellMiner and Genomics of Drug Sensitivity in Cancer (GDSC) databases were also applied in investigating the significance of OSRG signature in chemotherapy. Results: Altogether, 34 prognostic OSRGs were identified, among which 14 were chosen to establish the most valuable prognostic signature. The Kaplan-Meier (KM) analysis suggested that patients with lower OS-related risk score had better prognosis. The area under the curve (AUC) values were 0.71, 0.76, and 0.85 in 3, 5, and 7 years separately, and the stability of this prognostic signature was confirmed in three GEO datasets. As revealed by GSEA and TMB analysis results, OC patients in low-risk group might have better immunotherapeutic response, which was consistent with ICG expression and TIDE analyses. Moreover, both IMvigor210 and GSE78220 cohorts demonstrated that patients with lower OS-related risk score were more likely to benefit from anti-PD-1/L1 immunotherapy. In addition, the association between prognostic signature and drug sensitivity was explored. Conclusion: According to our results in this work, OSRG signature can act as a powerful prognostic predictor for OC, which contributes to generating more individualized therapeutic strategies for OC patients.

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization.

Objectives: This study aimed to identify key AAA-related m1A RNA methylation regulators and their association with immune infiltration in AAA. Furthermore, we aimed to explore the mechanism that m1A regulators modulate the functions of certain immune cells as well as the downstream target genes, participating in the progression of AAA. Methods: Based on the gene expression profiles of the GSE47472 and GSE98278 datasets, differential expression analysis focusing on m1A regulators was performed on the combined dataset to identify differentially expressed m1A regulatory genes (DEMRGs). Additionally, CIBERSORT tool was utilized in the analysis of the immune infiltration landscape and its correlation with DEMRGs. Moreover, we validated the expression levels of DEMRGs in human AAA tissues by real-time quantitative PCR (RT-qPCR). Immunofluorescence (IF) staining was also applied in the validation of cellular localization of YTHDF3 in AAA tissues. Furthermore, we established LPS/IFN-γ induced M1 macrophages and ythdf3 knockdown macrophages in vitro, to explore the relationship between YTHDF3 and macrophage polarization. At last, RNA immunoprecipitation-sequencing (RIP-Seq) combined with PPI network analysis was used to predict the target genes of YTHDF3 in AAA progression. Results: Eight DEMRGs were identified in our study, including YTHDC1, YTHDF1-3, RRP8, TRMT61A as up-regulated genes and FTO, ALKBH1 as down-regulated genes. The immune infiltration analysis showed these DEMRGs were positively correlated with activated mast cells, plasma cells and M1 macrophages in AAA. RT-qPCR analysis also verified the up-regulated expression levels of YTHDC1, YTHDF1, and YTHDF3 in human AAA tissues. Besides, IF staining result in AAA adventitia indicated the localization of YTHDF3 in macrophages. Moreover, our in-vitro experiments found that the knockdown of ythdf3 in M0 macrophages inhibits macrophage M1 polarization but promotes macrophage M2 polarization. Eventually, 30 key AAA-related target genes of YTHDF3 were predicted, including CD44, mTOR, ITGB1, STAT3, etc. Conclusion: Our study reveals that m1A regulation is significantly associated with the pathogenesis of human AAA. The m1A "reader," YTHDF3, may participate in the modulating of macrophage polarization that promotes aortic inflammation, and influence AAA progression by regulating the expression of its target genes.

Occurrence of per- and polyfluoroalkyl substances (PFASs) in raw milk and feed from nine Chinese provinces and human exposure risk assessment.

The per- and polyfluoroalkyl substances (PFASs) are substantially produced and applied in industrial and domestic products, which have recently aroused great public concern for their potential toxicity to humans. In the present study, raw milk (n = 107) and cow feed samples (n = 70) were collected across nine Chinese provinces, in order to investigate the occurrence of PFASs in milk and feed, and the human exposure risk to milk. The concentrations of PFASs are in the range of < method detection limit -9.82 ng/g dw (average: 1.03 ng/g dw) for milk and 0.99-144 ng/g dw (7.68 ng/g dw) for feed. Perfluorobutanoic acid (34.0%) dominates in feed, while perfluorooctanesulfonic acid (67.5%) dominates in milk. No significant positive correlations of PFASs are observed between paired feed and milk (p > 0.05). However, feeds collected around fluorination production area show relatively higher PFAS levels than those from other areas, which also increase PFAS levels in milk. Risk assessment of PFASs through milk consumption is carried out according to evolving reference doses (RfDs). The hazard quotient is more than one for both adults and children when the strictest RfDs are applied. The Monte Carlo Simulation shows that children face higher PFAS exposure risk than adults.

Systemic characterization of alternative splicing related to prognosis, immune infiltration, and drug sensitivity analysis in ovarian cancer.

Background: Alternative splicing (AS) plays an essential role in tumorigenesis and progression. This study intended to construct an innovative prognostic model based on AS events to gain more precise survival prediction and search for potential therapeutic targets in ovarian cancer. Methods: Seven types of AS events in ovarian serous cystadenocarcinoma (OV) patients with RNA-seq were obtained using The Cancer Genome Atlas (TCGA) SpliceSeq tool and database. Cox and Kaplan-Meier curve analyses were employed to establish the prognostic models. Relying on drug sensitivity data from the CellMiner database, Genomics of Drug Sensitivity (GDS) was adopted to estimate the platinum-sensitive analysis. Furthermore, a prognostic splicing factor (SF)-AS network was constructed using Cytoscape. Finally, in order to explore the influence of the tumor microenvironment on the prognosis of OV patients, we first combined a similar network fusion and consensus clustering (SNF-CC) algorithm to identify three OV subtypes based on survival-related AS events and then utilized single-sample Gene Set Enrichment Analysis (ssGSEA) method to perform immune cell infiltration analysis. Results: A total of 48,049 AS events and 21,841 related genes were selected from 318 OV samples, and 2,206 AS events associated with disease-free survival (DFS) were identified. Multivariate Cox and Kaplan-Meier curve analyses were then employed to establish the prognostic models. Receiver operating characteristic (ROC) analysis from 0.59 to 0.75 showed that these models were highly efficient in distinguishing patient survival. GDS was adopted with the CellMiner database to provide some insights for platinum-sensitive analysis of OV. Furthermore, a prognostic SF-AS network, which discovered a significant connection between SFs and prognostic AS genes, was constructed using Cytoscape. The combined SNF-CC algorithm revealed three distinct OV subtypes based on the prognostic AS events, and the associations between this novel molecular classification and immune cell infiltration were further explored. Conclusions: We developed a powerful prognostic AS signature for OV and provided a deeper understanding of SF-AS network regulatory mechanisms, as well as platinum-sensitive and cancer immune microenvironments. These results revealed various candidate biomarkers and potential targets for OV treatment strategies.

Construction of the circRNA-miRNA-mRNA Regulatory Network of an Abdominal Aortic Aneurysm to Explore Its Potential Pathogenesis.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a progressive cardiovascular disease, which is a permanent and localized dilatation of the abdominal aorta with potentially fatal consequence of aortic rupture. Dysregulation of circRNAs is correlated with the development of various pathological events in cardiovascular diseases. However, the function of circRNAs in abdominal aortic aneurysm (AAA) is unknown and remains to be explored. This study is aimed at determining the regulatory mechanisms of circRNAs in AAAs. This study was aimed at exploring the underlying molecular mechanisms of abdominal aortic aneurysms based on the competing endogenous RNA (ceRNA) regulatory hypothesis of circRNA, miRNA, and mRNA. METHODS: The expression profiles of circRNAs (GSE144431), miRNAs (GSE62179), and mRNAs (GSE7084, GSE57691, and GSE47472) in human tissue sample from the aneurysm group and normal group were obtained from the Gene Expression Omnibus database, respectively. The circRNA-miRNA-mRNA network was constructed by using Cytoscape 3.7.2 software; then, the protein-protein interaction (PPI) network was constructed by using the STRING database, and the hub genes were identified by using the cytoHubba plug-in. The circRNA-miRNA-hub gene regulatory subnetwork was formed to understand the regulatory axis of hub genes in AAAs. RESULTS: The present study identified 40 differentially expressed circRNAs (DECs) in the GSE144431, 90 differentially expressed miRNAs (DEmiRs) in the GSE62179, and 168 differentially expressed mRNAs (DEGs) with the same direction regulation (130 downregulated and 38 upregulated) in the GSE7084, GSE57691, and GSE47472 datasets identified regarding AAAs. The miRNA response elements (MREs) of three DECs were then predicted. Four overlapping miRNAs were obtained by intersecting the predicted miRNA and DEmiRs. Then, 17 overlapping mRNAs were obtained by intersecting the predicted target mRNAs of 4 miRNAs with 168 DEGs. Furthermore, the circRNA-miRNA-mRNA network was constructed through 3 circRNAs, 4 miRNAs, and 17 mRNAs, and three hub genes (SOD2, CCR7, and PGRMC1) were identified. Simultaneously, functional enrichment and pathway analysis were performed within genes in the circRNA-miRNA-mRNA network. Three of them (SOD2, CCR7, and PGRMC1) were suggested to be crucial based on functional enrichment, protein-protein interaction, and ceRNA network analysis. Furthermore, the expression of SOD2 and CCR7 may be regulated by hsa_circ_0011449/hsa_circ_0081968/hsa-let-7f-5p; the expression of PGRMC1 may be regulated by hsa_circ_0011449/hsa_circ_0081968-hsa-let-7f-5p/hsa-let-7e-5p. CONCLUSION: In conclusion, the ceRNA interaction axis we identified may be an important target for the treatment of abdominal aortic aneurysms. This study provided further understanding of the potential pathogenesis from the perspective of the circRNA-related competitive endogenous RNA network in AAAs.

Angiocrine Hepatocyte Growth Factor Signaling Controls Physiological Organ and Body Size and Dynamic Hepatocyte Proliferation to Prevent Liver Damage during Regeneration.

Liver sinusoidal endothelial cells (LSECs) control organ functions, metabolism, and development through the secretion of angiokines. LSECs express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiological homeostasis and liver regeneration. Stab2-iCretg/wt;Hgffl/fl (HgfΔLSEC) mice were generated to abrogate Hgf expression selectively in LSECs from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH). Although zonation and liver/body weight ratios were not altered, total body weight and total liver weight were reduced in HgfΔLSEC. Necrotic organ damage was more marked in HgfΔLSEC mice, and regeneration was delayed 72 hours after PH. This was associated with decreased hepatocyte proliferation at 48 hours after PH. Molecularly, HgfΔLSEC mice showed down-regulation of Hgf/c-Met signaling and decreased expression of Deptor in hepatocytes. In vitro knockdown of Deptor was associated with decreased proliferation. Therefore, angiocrine Hgf controls hepatocyte proliferation and susceptibility to necrosis after partial hepatectomy via the Hgf/c-Met axis involving Deptor to prevent excessive organ damage.

Small nucleolar RNA host gene 1 promotes development and progression of colorectal cancer through negative regulation of miR-137.

Small nucleolar RNA host gene 1 (SNHG1) is critical in the progression of cancers. However, the mechanism by which SNHG1 regulates the progression of colorectal cancer (CRC) remains unclear. Expressions of SNHG1 and miR-137 in CRC tissues and cell lines were evaluated by quantitative real-time polymerase chain reaction. A luciferase reporter gene assay was conducted to investigate miR-137 target. Additionally, RNA pull-down assay was performed to explore the physical association between miR-137, SNHG1, and RNA induced silencing complex (RISC). Cell cycling and invasion were examined by flow cytometry (FCM) and transwell assays. The in vivo carcinogenic activity of SNHG1 was examined using murine xenograft models. Expression of RICTOR, serine/threonine kinase 1 (AKT), serum and glucocorticoid-inducible kinase 1 (SGK1), p70S6K1, and LC3II/LC3I ratio was examined by Western blot analysis. SNHG1 upregulation was observed in CRC tissues and cell lines, which was associated with the lymph node metastasis, advanced TNM stage and poorer prognosis. SNHG1 increased RICTOR level in CRC via sponging miR-137. In addition, SNHG1 silencing inhibited CRC cell proliferation and migration in vitro and in vivo. SNHG1 regulated RICTOR expression by sponging miR-137 and promoted tumorgenesis in CRC.

Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation.

Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treating colon cancer in combination with chemotherapy drugs. This study was designed to explore whether dasatinib disturbed 5-Fu-triggered apoptosis in colon carcinoma. As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. Dasatinib dramatically decreased 5-Fu triggered apoptosis in colon carcinoma via suppression of Src activation. Our findings may have partially explained why dasatinib combined with FOLFOX failed to show a meaningful clinical response in mCRC.

[Dynamic changes of sciatic nerve conduction velocity in rats infected with Toxoplasma gondii].

OBJECTIVE: To observe the dynamic changes of sciatic nerve conduction velocity of Toxoplasma gondii-infected rats at different time points. METHODS: Twenty SD rats were randomly divided into control group and Toxoplasma gondii infection group. Rats in T. gondii infection group were intraperitoneal injected with 4x10(7) T. gondii tachyzoites, while those in control group were given equivalent normal saline. Motor and sensory nerve conduction velocities (MNCV, SNCV) in sciatic nerve were measured by Medtronic Keypoint4 Workstation electromyography at pre-infection, and 2, 4, 8, 12 months post-infection. RESULTS: Within two months after infection, there was no difference in SNCV and MNCV between control group and infection group (P>0.05). From 4 months after T. gondii injection, infected rats began to show the slowness of SNCV and MNCV, which progressed with the course of infection. At 4, 8, and 12 months after infection, SNCV and MNCV of infection group were (35.26±3.02) and (25.94±3.20) m/s, (33.57±2.27) and (22.75±2.31) m/s, and (32.38±2.38) and (22.03±2.08) m/s, respectively. Compared with control group, SNCV and MNCV of infection group reduced by (7.47±2.11)% and (12.57±1.89)%, (8.92±2.64)% and (13.72±2.65)%, and (12.18±1.94)% and (15.46±2.37)%, respectively (P<0.05). CONCLUSION: From 4 months after infection, Toxoplasma gondii-infected rats show a slowness of motor and sensory nerve conduction velocities in sciatic nerve.