Lack of clinical benefit from preoperative short-term parenteral nutrition on the clinical prognosis of patients treated with radical gastrectomy for gastric cancer: a two-center retrospective study based on propensity score matching analysis.

Background: Preoperative nutritional support studies for patients undergoing gastrointestinal (GI) surgery mostly focused on enteral nutrition (EN) or long-term (≥7 days) parenteral nutrition (PN). Some studies also found that preoperative short-term PN could improve the postoperative short-term nutritional status of tumor patients. But whether short-term PN support (1-6 days) before surgery can improve the prognosis of patients undergoing surgery for gastric cancer (GC) remains unclear. Therefore, we focused on assessing the effect of preoperative short-term PN on the outcomes of patients undergoing radical surgery for GC. Methods: A retrospective analysis of 1,155 patients who underwent radical gastrectomy for GC between July 2014 and February 2019 was conducted. According to whether patients received short-term (1-6 days) PN support before surgery, patients were divided into non-PN group and PN group. After 1:1 propensity score matching (PSM), two groups of patients with similar baseline clinical characteristics were obtained. The incidence of various complications and overall survival (OS) rate were compared between the two groups, and logistic regression analysis for complications, Cox regression analysis for OS, and subgroup analysis were performed. Results: Each group had 478 patients after PSM, and the clinical characteristics were balanced. There were no significant differences in overall postoperative complications (pre-PSM: P=0.495; post-PSM: P>0.99), postoperative length of stay (LOS; pre-PSM: P=0.092; post-PSM: P=0.460), or readmission rate within 30 days (pre-PSM: P=0.496; post-PSM: P=0.793) between the two groups before and after PSM. The OS of PN group before matching was lower than that of non-PN group (P=0.023), but this difference was not significant after matching (P=0.950), but the PN group's hospitalization expenses were substantially greater than those of the control group (post-PSM: P<0.001). Preoperative short-term PN support was not an independent factor in the incidence of postoperative complications (P>0.99) and OS (P=0.949). Subgroup analyses failed to identify those patients who might benefit from preoperative short-term PN support. Conclusions: Preoperative short-term PN support may have no significant benefit on short-term postoperative complications or the long-term OS of patients with GC but increase hospitalization costs. It thus should not be the first choice of treatment for these patients.

Physiological effects of maize stressed by HPPD inhibitor herbicides via multi-spectral technology and two-dimensional correlation spectrum technology.

Understanding the physiological effects of herbicides on crops is crucial for crop production and environmental management. The effects of 4-hydroxyphenylpyruvate dioxygenase inhibitor (HPPDi) herbicides at different concentrations on chlorophyll content in maize leaves, fresh weight of roots, stems and leaves, and fluorescence substances and functional groups in root exudates (REs) were studied by UV-Vis absorption spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR) and two-dimensional correlation analysis (2D-COS). The results showed that 5 mg/L and 10 mg/L HPPDi herbicides inhibited the synthesis of chlorophyll in maize leaves. The weight of roots, stems and leaves of maize after application was lighter than that of the control group. HPPDi herbicides affected the early growth of maize seedlings, and the effect was most obvious at high concentration. Synchronous fluorescence spectrum and three-dimensional (3D) fluorescence spectrum revealed that the fluorescence intensity of protein, fulvic acid and humic acid in maize REs changed prominently. With the increase of HPPDi herbicides concentration, the fluorescence intensity decreased gradually. Through FTIR and 2D-COS, functional groups such as C-H, CO, Cl, NO3-, C-O and O-H were found to participate in the interaction between HPPDi herbicides and maize REs as binding sites. C-O, C-Cl and C-C have the strongest binding ability, while CC and CO of aromatic rings, quinones or ketones first take part in the binding between HPPDi herbicides and maize REs. The results can provide a theoretical basis for evaluating the safety of HPPDi herbicides on maize and a method for discovering the effects of pesticides on environmental media and plant physiological effects.

What is the next step of ICT development? The changes of ICT use in promoting elderly healthcare access: A systematic literature review.

The objective of this study was to undertake a comprehensive review of the evidence published, with a focus on understanding the experiences of the elderly in leveraging Information and Communication Technology (ICT) for their healthcare needs during the COVID-19 period. In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this review scrutinized all peer-reviewed articles in English sourced from PubMed, PsycINFO, Scopus, and Web of Science, targeting studies that focused exclusively on the elderly within the COVID-19 timeframe, incorporated ICT-based technology as intervention, and were associated with the assessment of the process of employing ICT for healthcare needs. The search strategy identified 1752 records, of which 34 studies met the inclusion criteria. The functionality of ICT was categorized, types of barriers were identified, and the subsequent changes that the elderly population underwent were synthesized and deliberated. This review offers valuable insights into the elderly's subjective experiences in utilizing ICT, which may offer guidance for future ICT development geared towards enhancing the well-being of the elderly. Future research should incorporate the perspectives of relevant healthcare providers in evaluating the effectiveness of ICT usage. Further studies are also needed on underserved elderly groups to provide a more holistic view.

Combining transcriptomics and metabolomics to identify key response genes for aluminum toxicity in the root system of Brassica napus L. seedlings.

KEY MESSAGE: By integrating QTL mapping, transcriptomics and metabolomics, 138 hub genes were identified in rapeseed root response to aluminum stress and mainly involved in metabolism of lipids, carbohydrates and secondary metabolites. Aluminum (Al) toxicity has become one of the important abiotic stress factors in areas with acid soil, which hinders the absorption of water and nutrients by roots, and consequently retards the growth of crops. A deeper understanding of the stress-response mechanism of Brassica napus may allow us to identify the tolerance gene(s) and use this information in breeding-resistant crop varieties. In this study, a population of 138 recombinant inbred lines (RILs) was subjected to aluminum stress, and QTL (quantitative trait locus) mapping was used to preliminarily locate quantitative trait loci related to aluminum stress. Root tissues from seedlings of an aluminum-resistant (R) line and an aluminum-sensitive (S) line from the RIL population were harvested for transcriptome sequencing and metabolome determination. By combining the data on quantitative trait genes (QTGs), differentially expressed genes (DEGs), and differentially accumulated metabolites (DAMs), key candidate genes related to aluminum tolerance in rapeseed were determined. The results showed that there were 3186 QTGs in the RIL population, 14,232 DEGs and 457 DAMs in the comparison between R and S lines. Lastly, 138 hub genes were selected to have a strong positive or negative correlation with 30 important metabolites (|R|≥ 0.95). These genes were mainly involved in the metabolism of lipids, carbohydrates and secondary metabolites in response to Al toxicity stress. In summary, this study provides an effective method for screening key genes by combining QTLs, transcriptome sequencing and metabolomic analysis, but also lists key genes for exploring the molecular mechanism of Al tolerance in rapeseed seedling roots.

Effects of HPPD inhibitor herbicides on soybean root exudates: A combination study of multispectral technique and 2D-COS analysis.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor herbicides are widely used in modern agriculture. Plant root exudates (REs) play an important role in the adsorption, degradation, migration and transformation of pesticides in soil. In the present study, the structural affinity and interaction mechanism between four HPPD inhibitors (HPPDi) and soybean REs were investigated via multispectral technologies and two-dimensional correlation analysis (2D-COS). UV-vis absorption and fluorescence spectra showed that mesotrione, tembotrione, sulcotrione and topramezone effectively quench the intrinsic fluorescence of soybean REs through static quenching. The binding constant Ka revealed that the binding ability of HPPDi to soybean REs takes the following order: mesotrione > tembotrione > sulcotrione > topramezone. According to the thermodynamic parameters, the main interaction force between tembotrione, sulcotrione, topramezone and soybean REs is electrostatic interaction, while the main interaction force is a hydrogen bond or van der Waals force between mesotrione and soybean REs. The conformational changes of REs were attributed to HPPDi by 3D spectral evaluation. FTIR spectroscopy and 2D-COS analysis suggested that soybean REs mainly formed stable complexes with HPPDi through functional groups such as carbonyl, carboxyl, methoxy and nitrate, and the first binding groups were carbonyl and carboxyl. These results provide helpful information for the adsorption and desorption process of environmental pollutants on the surface of plants and soil.

Respiratory exposure to PM2.5 soluble extract induced chronic lung injury by disturbing the phagocytosis function of macrophage.

Exposure to airborne urban particles is a contributing factor for the development of multiple types of respiratory diseases; its pathological role as a cause of lung injury is still unclear. In this study, PM2.5 soluble extract was collected, and its toxicological effect on lung pathological changes was examined. To assess its pathological mechanism, Human Monocyte-Like Cell Line, THP-1, and mouse macrophage, RAW264.7, were used to determine the effects of PM2.5 soluble extract on cell toxicity, phagocytosis, and transcriptome. We found that PM2.5 soluble extract exposure activated NF-κB and MAPK signaling pathways, then induces the production of pro-inflammatory cytokines. RNA-seq results showed that the transcription profiles, including 1213 genes, have been changed in responses to PM2.5 exposure. Additionally, PM2.5 led to phagocytic dysfunction, which may exacerbate the cause of lung injury. Exposure to PM2.5 soluble extract triggers the death of respiratory macrophages, impairs its phagocytosis capacity, thus delaying the inflammatory cell clearance in the lung, which results in chronic lung injury.

Synthesis, structure and in vitro biological properties of a new copper(II) complex with 4-{[3-(pyridin-2-yl)-1H-pyrazol-1-yl]methyl}benzoic acid.

The new copper(II) complex dichloridobis(4-{[3-(pyridin-2-yl-κN)-1H-pyrazol-1-yl-κN2]methyl}benzoic acid)copper(II) methanol sesquisolvate hemihydrate, [CuCl2L2]·1.5CH3OH·0.5H2O, (1), has been synthesized from CuCl2·2H2O and the ligand 4-{[3-(pyridin-2-yl)-1H-pyrazol-1-yl]methyl}benzoic acid (L, C15H11N3O2). The complex was characterized by elemental analysis, Fourier transform IR spectroscopy, electrospray ionization mass spectrometry and single-crystal X-ray diffraction. Two chloride ligands and two bidentate L ligands coordinate the CuII centre in 1 in a Jahn-Teller-distorted octahedral geometry of rather unusual configuration: a chloride substituent and a pyrazole N atom of an N,N'-chelating ligand occupy the more distant axial positions. Classical O-H...O hydrogen bonds and O-H...Cl interactions link neighbouring complex molecules and cocrystallized methanol molecules into chains that propagate parallel to the b direction. The title compound shows intriguing bioactivity: the effects of 1 on the enzymatic activity of protein tyrosine phosphatase 1B (PTP1B) and on the viability of human breast cancer cells of cell line MCF7 were evaluated. Complex 1, with an IC50 value of 0.51 µM, can efficiently inhibit PTP1B activity. An enzyme kinetic assay suggests that 1 inhibits PTP1B in a noncompetitive manner. A fluorescence titration assay indicates that 1 has a strong affinity for PTP1B, with a binding constant of 4.39 × 106 M-1. Complex 1 may also effectively decrease the viability of MCF7 cells in an extent comparable to that of cisplatin (IC50 = 6.3 µM). The new copper complex therefore represents a promising PTP1B inhibitor and an efficient antiproliferation reagent against MCF7 cells.

Comparative transcriptomic analysis of THP-1-derived macrophages infected with Mycobacterium tuberculosis H37Rv, H37Ra and BCG.

Tuberculosis (TB) remains a worldwide healthcare concern, and the exploration of the host-pathogen interaction is essential to develop therapeutic modalities and strategies to control Mycobacterium tuberculosis (M.tb). In this study, RNA sequencing (transcriptome sequencing) was employed to investigate the global transcriptome changes in the macrophages during the different strains of M.tb infection. THP-1 cells derived from macrophages were exposed to the virulent M.tb strain H37Rv (Rv) or the avirulent M.tb strain H37Ra (Ra), and the M.tb BCG vaccine strain was used as a control. The cDNA libraries were prepared from M.tb-infected macrophages and then sequenced. To assess the transcriptional differences between the expressed genes, the bioinformatics analysis was performed using a standard pipeline of quality control, reference mapping, differential expression analysis, protein-protein interaction (PPI) networks, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Q-PCR and Western blot assays were also performed to validate the data. Our findings indicated that, when compared to BCG or M.tb H37Ra infection, the transcriptome analysis identified 66 differentially expressed genes in the M.tb H37Rv-infected macrophages, out of which 36 genes were up-regulated, and 30 genes were down-regulated. The up-regulated genes were associated with immune response regulation, chemokine secretion, and leucocyte chemotaxis. In contrast, the down-regulated genes were associated with amino acid biosynthetic and energy metabolism, connective tissue development and extracellular matrix organization. The Q-PCR and Western blot assays confirmed increased expression of pro-inflammatory factors, altered energy metabolic processes, enhanced activation of pro-inflammatory signalling pathways and increased pyroptosis in H37Rv-infected macrophage. Overall, our RNA sequencing-based transcriptome study successfully identified a comprehensive, in-depth gene expression/regulation profile in M.tb-infected macrophages. The results demonstrated that virulent M.tb strain H37Rv infection triggers a more severe inflammatory immune response associated with increased tissue damage, which helps in understanding the host-pathogen interaction dynamics and pathogenesis features in different strains of M.tb infection.

Statin Treatment Induced a Lipogenic Expression Hierarchical Network Centered by SREBF2 in the Liver.

Statin treatment is a major prevention treatment for hypercholesterolemia and the management of patients with increased risk of cardiovascular disease (CVD) due to its protective effects. However, its long-term safety was questioned regarding its potential role in new-onset type 2 diabetes mellitus, and its effect on gene regulation in the liver is not yet fully understood. By reanalyzing the transcriptome of the livers of patients with obesity and hypercholesterolemia, this study shows a multiple module organization that is related to various clinical metabolic parameters and identified an expression hierarchical network involving cholesterol and fatty acid syntheses in the liver of statin-treated patients. The key genes of the network were validated by QPCR in the hepatocytes upon statin treatment. The upregulation of the key enzymes involving the synthesis of Acetyl-CoA and the induction of gentle global acetylation of pan-protein and histone H4 in hepatocytes were observed. The study provides an overall view of the statin effect on transcriptional and post-transcriptional regulation of genes in the liver.

Inhibition of heat shock protein (HSP) 90 reverses signal transducer and activator of transcription (STAT) 3-mediated muscle wasting in cancer cachexia mice.

BACKGROUND AND PURPOSE: Cancer cachexia is a common cause of death among cancer patients with no currently effective treatment available. In animal models, aberrant activation of STAT3 in skeletal muscle contributes to muscle wasting. However, clinically the factors regulating STAT3 activation and the molecular mechanisms involved remain incompletely understood. EXPERIMENTAL APPROACH: The expression of HSP90 and the activation of STAT3 were detected in muscle from the patients with cancer cachexia or the tumour-bearing cachectic mice. HSP90 inhibitors, including 17DMAG (alvespimycin) and PU-H71, were administered to cachexic mice and cachexia parameters, weight loss, food intake, survival rate, body composition, serum metabolites, muscle wasting pathology and catabolic activation were analysed. The co-culture of C2C12 myotube cells with C26 conditioned media was performed to investigate the pathological mechanism involved in catabolic muscle wasting. The roles of HSP90, STAT3 and FOXO1 in myotube atrophy were explored via overexpression or knockdown. RESULTS: An enhanced interaction between activated STAT3 and HSP90 in the skeletal muscle of cancer cachexia patients, is a crucial for the development of cachectic muscle wasting. HSP90 inhibitors 17DMAG and PU-H71 alleviated the muscle wasting in C26 and models or the myotube atrophy of C2C12 cells induced by C26 conditional medium. Prolonged STAT3 activation transactivated FOXO1 by binding directly to its promoter and triggered the muscle wasting in a FOXO1-dependent manner in muscle cells. CONCLUSION AND IMPLICATIONS: The HSP90/STAT3/FOXO1 axis plays a critical role in cachectic muscle wasting, which might be a potential therapeutic target for the treatment of cancer cachexia.

An integrative transcriptome study reveals Ddit4/Redd1 as a key regulator of cancer cachexia in rodent models.

Cancer cachexia is a multifactorial metabolic syndrome that causes up to 20% of cancer-related deaths. Muscle atrophy, the hallmark of cancer cachexia, strongly impairs the quality of life of cancer patients; however, the underlying pathological process is still poorly understood. Investigation of the disease pathogenesis largely relies on cachectic mouse models. In our study, the transcriptome of the cachectic gastrocnemius muscle in the C26 xenograft model was integrated and compared with that of 5 more different datasets. The bioinformatic analysis revealed pivotal gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the disease, and the key genes were validated. Construction of the protein-protein interaction network and the comparison of pathways enriched in cancer cachexia with 5 other muscle atrophy models revealed Ddit4 (DNA damage-inducible transcript 4), as a key protein in cancer cachexia. The higher expression of Ddit4 in cachectic muscle was further validated in animal models and cachectic cancer patients. Further study revealed that p38 induced the expression of Ddit4, which in turn inhibited the mTOR pathway in atrophic cells.

Soluble IL-6R-mediated IL-6 trans-signaling activation contributes to the pathological development of psoriasis.

IL-6 has been suggested to function as an autocrine mitogen in the psoriatic epidermis. The biological activity of IL-6 relies on interactions with its receptors, including the membrane-bound IL-6 receptor (mIL-6R) and soluble IL-6 receptor (sIL-6R). Our study presents data showing that the levels of plasma IL-6 and sIL-6R were elevated in psoriatic patients. Genotyping of two single-nucleotide polymorphisms (SNPs) in IL-6R (rs4845617 and rs2228145) demonstrated that the SNP IL-6R (rs4845617) rather than IL-6R (rs2228145) shows a significant association with psoriasis (P = 0.006). To verify the functions of sIL-6R, cultured keratinocytes and imiquimod (IMQ)-induced psoriatic model mice were treated with sIL-6R. We found that the presence of sIL-6R in the HaCaT cell culture medium enhanced the IL-6-induced Stat3 activation, which resulted in abnormal keratinocyte proliferation and aberrant differentiation. Furthermore, the application of sIL-6R in vivo accelerated the pathological development of the disease. Our results demonstrate for the first time that genetic polymorphisms in the IL-6R gene are associated with psoriasis disease phenotypes in a Chinese psoriatic patient population; sIL-6R-mediated trans-signaling pathway plays a pivotal role in keratinocyte proliferation and differentiation, suggesting potential therapeutics for psoriasis. KEY MESSAGES: Patients with psoriasis displayed higher levels of IL-6 and sIL-6R compared with healthy controls. Analysis of genotypes revealed that IL-6R rs4845617 GG genotype associated with the risk of psoriasis. Supplement of sIL-6R further enhanced IL-6-induced Stat3 activation in keratinocytes. In vivo administration of sIL-6R accelerated, whereas sgp130FC alleviated, the pathological development of psoriasis.

Targeting HSP90 Inhibits Proliferation and Induces Apoptosis Through AKT1/ERK Pathway in Lung Cancer.

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer.

Respiratory exposure to PM2.5 soluble extract disrupts mucosal barrier function and promotes the development of experimental asthma.

BACKGROUND: Air pollutants are important factors that contribute to the development and exacerbation of asthma, but experimental evidence still needs to be collected and the mechanisms still need to be addressed. In this study, we aimed to assess the association between PM2.5 exposure and asthma development. The effects of PM2.5 exposure on the barrier functions of airway epithelial cells were also determined. METHODS: PM2.5 was collected from Nanjing, China, and its soluble extract was prepared. Human lung epithelial cells (BEAS-2B) were treated with different concentrations of soluble PM2.5 extract, and cell viability was detected by FACS using Annexin V-FITC staining. PM2.5-induced oxidative stress and inflammatory events were assessed by DCF-DA staining and qPCR. PM2.5-induced dysfunction of the airway epithelial barrier was assessed by measuring the expression of tight junction molecules. In vivo, BALB/c mice were treated with OVA in the presence or absence of PM2.5 solution, followed by exposure to OVA aerosols. Allergy-induced airway inflammation and lung injury were assessed by histopathological analyses. RESULTS: Soluble PM2.5 extract exposure in vitro decreased the viability and increased apoptosis of airway epithelial cells. Soluble PM2.5 extract induced oxidative stress and enhanced pro-inflammatory factor expression by activating the NF-κB and MAPK signalling pathways, which were accompanied by reduced airway barrier function. The in vivo data demonstrated that PM2.5 exposure increased the effects of allergy sensitization after respiratory exposure to allergens, which led to the development of asthma. CONCLUSION: This study suggests that exposure to soluble PM2.5 extract contributes to airway barrier dysfunction. The soluble mediators generated by airway epithelial cells in response to PM2.5 exposure orchestrate the breaking of inhalational tolerance and sensitization to allergic antigens, leading to the exacerbated development of asthma.

Serum metabolomics analysis of mice that received repeated airway exposure to a water-soluble PM2.5 extract.

BACKGROUND: Air pollutant exposure negatively affects human health; however, the molecular mechanisms causing disease remain largely unclear. OBJECTIVES: To explore the effects of respiratory particulate matter (PM2.5) exposure on the serum metabolome and to identify biomarkers for risk assessment of PM2.5 exposure. METHODS: PM2.5 from Nanjing, China, was collected, and its water-soluble extract was subjected to component analysis. BALB/c mice received acute or prolonged exposure to insoluble PM2.5 particles or its water-soluble extract, and lung tissue was submitted to histopathological analyses. Serum samples were collected pre- and post-PM2.5 exposure and analyzed by liquid chromatography/mass spectrometry. RESULTS: Component analysis revealed that metals and inorganic ions were the most abundant components in the soluble PM2.5 samples. Acute exposure to insoluble PM2.5 particles and prolonged exposure to the water-soluble PM2.5 extract both induced severe lung injury, and the lung histopathological scores were significantly associated with PM2.5 exposure. Metabolomics analysis showed that prolonged exposure to the water-soluble PM2.5 extract was associated with statistically significant metabolite changes; the serum concentrations of 30 known metabolites, including metabolites of phospholipids, amino acids and sphingolipids, differed significantly between the control and PM2.5 exposure group. Pathway analysis identified an association of the tricarboxylic acid cycle (TCA) and the phospholipase metabolism pathway with PM2.5 exposure. The most influential metabolites for discriminating between the PM2.5-exposure group serum and the control serum were LysoPE, LysoPC, LGPC, citric acid, PAF C-18, NeuAcalpha2-3Galbeta-Cer, Lyso-PAF C-16, ganglioside GA2, 1-sn-glycero-3-phosphocholine, PC and L-tryptophan. CONCLUSIONS: Respiratory exposure to water-soluble PM2.5 extract has developmental consequences affecting not only the respiratory system but also metabolism.

S1PR1 predicts patient survival and promotes chemotherapy drug resistance in gastric cancer cells through STAT3 constitutive activation.

BACKGROUND: S1PR1-STAT3 inter-regulatory loop was initially suggested to be oncogenic in several cancer cells. However, the clinical relevance of this mechanism in tumor progression, disease prognosis and drug response was not established. METHODS: The correlations between S1PR1 transcription, overall survival and chemotherapy response of GC patients were tested using a large clinical database. The relevance of S1PR1 expression and STAT3 activation in both tumor tissues and cancer cell lines was also tested. The effect of S1PR1 high expression achieved by persistent STAT3 activation on tumor cell drug resistance was investigated in vitro and in vivo. FINDINGS: An enhanced S1PR1 expression was highly related with a reduced overall survival time and a worse response to chemotherapy drug and closer correlation to STAT3 in gastric cancer patients. The issue chip analysis showed that the expressions of S1PR1 and STAT3 activation were increased in higher graded gastric cancer (GC) tissues. Cellular studies supported the notion that the high S1PR1 expression was responsible for drug resistance in GC cells through a molecular pattern derived by constitutive activation of STAT3. The disruption of S1PR1-STAT3 signaling significantly re-sensitized drug resistance in GC cells in vitro and in vivo. INTERPRETATION: S1PR1-STAT3 signaling may participate drug resistance in GC, thus could serve as a drug target to increase the efficacy of GC treatment. FUND: This work was supported by the National Natural Science Foundation of China (No. 81570775, 81471095), the grant from the research projects in traditional Chinese medicine industry of China (No. 201507004-2).

Correction: Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1.

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Simultaneous induction of Graves' hyperthyroidism and Graves' ophthalmopathy by TSHR genetic immunization in BALB/c mice.

BACKGROUND: Graves' disease is the most common form of autoimmune thyroid disorder, characterized by hyperthyroidism due to circulating autoantibodies. To address the pathological features and establish a therapeutic approach of this disease, an animal model carrying the phenotype of Graves' disease (GD) in concert with Graves' Ophthalmopathy (GO) will be very important. However, there are no ideal animal models that are currently available. The aim of the present study is to establish an animal model of GD and GO disease, and its pathological features were further characterized. METHODS: A recombinant plasmid pcDNA3.1- T289 was constructed by inserting the TSHR A-subunit gene into the expression vector pcDNA3.1, and genetic immunization was successfully performed by intramuscular injection of the plasmid pcDNA3.1-T289 on female 8-week-old BALB/c mice. Each injection was immediately followed by in vivo electroporation using ECM830 square wave electroporator. Morphological changes of the eyes were examined using 7.0T MRI scanner. Levels of serum T4 and TSHR antibodies (TRAb) were assessed by ELISA. The pathological changes of the thyroid and orbital tissues were examined by histological staining such as H&E staining and Alcian blue staining. RESULTS: More than 90% of the immunized mice spontaneously developed goiter, and about 80% of the immunized mice manifested increased serum T4 and TRAb levels, combined with hypertrophy and hyperplasia of thyroid follicles. A significantly increased synthesis of hyaluronic acid was detected in in the immunized mice compared with the control groups. CONCLUSION: We have successfully established an animal model manifesting Graves' hyperthyroidism and ophthalmopathy, which provides a useful tool for future study of the pathological features and the development of novel therapies of the diseases.

Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1.

The antitumor effect of luteolin, a plant flavonoid, in gastric cancer (GC) cells has not been fully understood. Here we show that luteolin selectively kills STAT3 overactivated GC cells that are often drug resistant. The treatment of luteolin in these GC cells significantly inhibited STAT3 phosphorylation and reduced the expression of STAT3 targeting gene Mcl-1, Survivin and Bcl-xl. Silencing of SHP-1, a protein tyrosine phosphatase, abolished the inhibitory effect of luteolin on STAT3 and cell apoptosis, suggesting that SHP-1 is crucial in luteolin-mediated cellular function. Moreover, this luteolin effect of STAT3 dephosphorylation by SHP-1 involved in HSP-90, which protected STAT3 phosphorylation by forming HSP-90/STAT3 complex. Thus, luteolin inhibited STAT3 activation through disrupting the binding of HSP-90 to STAT3, which promoted its interaction to SHP-1, resulted in the dephosphorylation of STAT3. The GC cell xenograft mouse model confirmed the effectiveness of luteolin induced inhibition of tumor growth in vivo.

Catalyst System for Hydrogenation Catalysis Based on Multiarm Hyperbranched Polymer Templated Metal (Au, Pt, Pd, Cu) Nanoparticles.

With a hyperbranched poly(amidoamine) core and many water-soluble poly(ethylene glycol) monomethyl ether arms connected by pH-sensitive acylhydrazone bonds, multiarm hyperbranched polymer was used as nanoreactor and reductant to prepare metal nanoparticles endowed with intelligence and biocompatibility. The multiarm hyperbranched polymer encapsulated nanoparticles (NPs) showed excellent catalytic activity for hydrogenation, thus an excellent catalyst system for hydrogenation was established. The rate constants could reach as high as 3.48 L·s-1·m-2, which can be attributed to the lack of surface passivation afforded by the multiarm hyperbranched polymer.