Low-carbon governance, fiscal decentralization, and enterprise green development: Evidence from China.

Simultaneously achieving economic development and environmental protection is a shared global challenge. While the positive effect of environmental regulations on protecting the environment has been widely recognized, the attention paid to low-carbon governance and corporate green transformation remains insufficient. Based on the two-stage least square regression model (2SLS) of instrumental variables, this paper utilizes panel data from China to identify the influence mechanism of government low-carbon governance on enterprise green development. It explores the effect of low-carbon governance on enterprise green development from the perspective of fiscal decentralization. The findings show that (1) Low-carbon governance significantly promotes corporate green development, primarily through improving industrial structure and technological innovation; (2) Low-carbon governance notably promotes the green development of private enterprises but has little effect on state-owned enterprises. There are also geographical differences, and the results are better in Eastern China than in the Central and Western parts of China; (3) Fiscal decentralization at both central and local levels inhibits the effect of low-carbon governance on driving corporate green development by causing a mismatch of human resources. Therefore, to promote corporate green development, low-carbon governance must prioritize green development, actively guide industrial structural upgrading and enterprise technological innovation, implement differentiated low-carbon governance measures tailored to different ownership enterprises, and optimize the assessment indicators for fiscal decentralization. This paper helps deepen the understanding of the relationship between government low-carbon governance and enterprise green development in developing countries. It can be used as a reference for government departments to formulate relevant policies.

IS6 family insertion sequences promote optrA dissemination between plasmids varying in transfer abilities.

Plasmids are the primary vectors for intercellular transfer of the oxazolidinone and phenicol cross-resistance gene optrA, while insertion sequences (ISs) are mobile genetic elements that can mobilize plasmid-borne optrA intracellularly. However, little is known about how the IS-mediated intracellular mobility facilitates the dissemination of the optrA gene between plasmid categories that vary in transfer abilities, including non-mobilizable, mobilizable, and conjugative plasmids. Here, we performed a holistic genomic study of 52 optrA-carrying plasmids obtained from searches guided by the Comprehensive Antibiotic Resistance Database. Among the 132 ISs identified within 10 kbp from the optrA gene in the plasmids, IS6 family genes were the most prevalent (86/132). Homologous gene arrays containing IS6 family genes were shared between different plasmids, especially between mobilizable and conjugative plasmids. All these indicated the central role of IS6 family genes in disseminating plasmid-borne optrA. Thirty-three of the 52 plasmids were harbored by Enterococcus faecalis found mainly in humans and animals. By Nanopore sequencing and inverse PCR, the potential of the enterococcal optrA to be transmitted from a mobilizable plasmid to a conjugative plasmid mediated by IS6 family genes was further confirmed in Enterococcus faecalis strains recovered from the effluents of anaerobic digestion systems for treating chicken manure. Our findings highlight the increased intercellular transfer abilities and dissemination risk of plasmid-borne optrA gene caused by IS-mediated intracellular mobility, and underscore the importance of routinely monitoring the dynamic genetic contexts of clinically important antibiotic resistance genes to effectively control this critical public health threat. KEY POINTS: • IS6 was prevalent in optrA-plasmids varying in intercellular transfer abilities. • Enterococcal optrA-plasmids were widespread among human, animal, and the environment. • IS6 elevated the dissemination risk of enterococcal optrA-plasmids.

A peptide-engineered alginate aerogel with synergistic blood-absorbing and platelet-binding capabilities to rapidly stop bleeding.

Polysaccharide matrix infused with hemostasis-stimulating chemistry represents a critical medical need of bleeding management. Herein, we describe the development of a polysaccharide-peptide conjugate platform, an alginate engineered with fibrinogen-derived platelet-binding peptides (APE). The alginate backbone was found to allow for multivalent grafting of the peptides. Processing APE conjugate into crosslinked aerogels promoted platelet accumulation, leading to a significant reduction in the coagulation time of whole rabbit blood and improving the stability of the formed clot. The APE aerogels also exhibited a high porosity and fluid uptake capacity (>90 in weight ratio) as well as good biocompatibility in hemostasis. Furthermore, in vivo studies conducted in rat models of tail cut and hepatic hemorrhage showed that APE aerogels reduced bleeding time by >58 % and blood loss by >61 %. The platelet-enrichment capacity of the APE construct synergized by high absorbency in its aerogel form offers a prototype for customized polysaccharide hemostats.

Hyper-thermophilic anaerobic pretreatment enhances the removal of transferable oxazolidinone and phenicol cross-resistance gene optrA in enterococci.

The extensive use of florfenicol in poultry industry results in the emergence of optrA gene, which also confers resistance to clinically important antibiotic linezolid. This study investigated the occurrence, genetic environments, and removal of optrA in enterococci in mesophilic (37 °C) and thermophilic (55 °C) anaerobic digestion systems, and a hyper-thermophilic (70 °C) anaerobic pretreatment system for chicken waste. A total of 331 enterococci were isolated and analyzed for antibiotic resistance against linezolid and florfenicol. The optrA gene was frequently detected in enterococci from chicken waste (42.7%) and effluents from mesophilic (72%) and thermophilic (56.8%) reactors, but rarely detected in the hyper-thermophilic (5.8%) effluent. Whole-genome sequencing revealed that optrA-carrying Enterococcus faecalis sequence type (ST) 368 and ST631 were the dominant clones in chicken waste, and they remained dominant in mesophilic and thermophilic effluents, respectively. The plasmid-borne IS1216E-fexA-optrA-erm(A)-IS1216E was the core genetic element for optrA in ST368, whereas chromosomal Tn554-fexA-optrA was the key one in ST631. IS1216E might play a key role in horizontal transfer of optrA due to its presence in different clones. Hyper-thermophilic pretreatment removed enterococci with plasmid-borne IS1216E-fexA-optrA-erm(A)-IS1216E. A hyper-thermophilic pretreatment is recommended for chicken waste to mitigate dissemination of optrA from animal waste to the environment.

Armoring a liposome-integrated tissue factor with sacrificial CaCO3 to form potent self-propelled hemostats.

The development of hemostatic materials suitable for diverse emergency scenarios is of paramount significance, and there is growing interest in wound-site delivery of hemostasis-enhancing agents that can leverage the body's inherent mechanisms. Herein we report the design and performance of a biomimetic nanoparticle system enclosing tissue factor (TF), the most potent known blood coagulation trigger, which was reconstituted into liposomes and shielded by the liposome-templated CaCO3 mineralization. The mineral coatings, which mainly comprised water-soluble amorphous and vateritic phases, synergized with the lipidated TF to improve blood coagulation in vitro. These coatings served as sacrificial masks capable of releasing Ca2+ coagulation factors or propelling the TF-liposomes via acid-aided generation of CO2 bubbles while endowing them with high thermostability under dry conditions. In comparison to commercially available hemostatic particles, CaCO3 mineralized TF-liposomes yielded significantly shorter hemostasis times and less blood loss in vivo. When mixed with organic acids, the CO2-generating formulation further improved hemostasis by delivering TF-liposomes deep into actively bleeding wounds with good biocompatibility, as observed in a rat hepatic injury model. Therefore, the designed composite mimicry of coagulatory components exhibited strong hemostatic efficacy, which in combination with the propulsion mechanism would serve as a versatile approach to treating a variety of severe hemorrhages.

High-Efficiency 3D-Printed Three-Chamber Electromagnetic Peristaltic Micropump.

This paper describes the design and characteristics of a three-chamber electromagnetic-driven peristaltic micropump based on 3D-printing technology. The micropump is composed of an NdFeB permanent magnet, a polydimethylsiloxane (PDMS) film, a 3D-printing pump body, bolts, electromagnets and a cantilever valve. Through simulation analysis and experiments using a single chamber and three chambers, valved and valveless, as well as different starting modes, the results were optimized. Finally, it is concluded that the performance of the three-chamber valved model is optimal under synchronous starting conditions. The measurement results show that the maximum output flow and back pressure of the 5 V, 0.3 A drive source are 2407.2 µL/min and 1127 Pa, respectively. The maximum specific flow and back pressure of the micropump system are 534.9 µL/min∙W and 250.4 Pa/W, respectively.

Sprayable surface-adaptive biocompatible membranes for efficient hemostasis via assembly of chitosan and polyphosphate.

This work describes a hemostatic membrane system (or surface coating) based on spray-assisted layer-by-layer electrostatic assemblies of oppositely charged polyphosphate (polyP) and chitosan (Cs). The as-prepared membrane formed a robust micro-stratified porous structure with high flexibility. Both blood clotting test and rodent hepatic severe hemorrhage model revealed the excellent hemostatic performance of the membrane system, benefitting from the robust assembly and synergistic effect of polyP/Cs as well as membrane surface chemistry. Compared to Cs-topped membrane surface, polyP-sprayed one exhibited further improved hemostatic effect via promoting fibrin formation. Besides, comprehensive in vitro and in vivo evaluations demonstrated good biocompatibility and biodegradability of the membrane. The present approach that integrated the hemostasis-stimulating capability of polyP/Cs with facile spraying method is highly scalable and flexible, which is envisioned to be adapted readily for other hemostatic polyelectrolytes and surface functionalization of diverse existing hemostatic products on demand.

Long noncoding RNA HULC regulates the NF-κB pathway and represents a promising prognostic biomarker in liver cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) are involved in a diverse array of biological processes. While lncRNAs are commonly upregulated in hepatocellular carcinoma (HCC), the specific regulatory roles they play in this oncogenic context require further study and clarification. Although HULC (lncRNA highly upregulated in liver cancer) is involved in disease pathogenesis, its precise role in this context remains unclear. METHODS: Here, we have explored the mechanistic relevance of HULC expression by assessing its expression in patient samples. The importance of this lncRNA in the onset and progression of HCC was investigated through in vitro approaches including Western blotting, quantitative PCR, Transwell assays, electron microscopy, wound healing assays, and real-time cell analysis (RTCA). Additionally, the in vivo functions of this lncRNA were assessed using an orthotopic HCC xenograft in nude mouse model system. RESULTS: HULC was identified as a lncRNA that is highly upregulated in human liver tumors. In vitro, HULC was able to promote HCC malignancy, although its excess overexpression also led robust autophagic induction, promoting the increased expression of autophagy-associated genes including LC3 and Beclin-1. At a mechanistic level, HULC was able to promote the phosphorylation of p65 and IkBkB thus enhancing autophagy by increasing LC3II levels in a manner dependent upon the NF-κB pathway. HULC downregulation was also linked to impaired orthotopic HCC tumor growth in vivo. The link between HULC and autophagy may play a role in disease progression. CONCLUSIONS: These results suggest that HULC is an oncogenic lncRNA, and may thus offer value as a prognostic biomarker and promoter of HCC development, in addition to being a potential therapeutic target in this cancer type.

Injectable thermogelling bioadhesive chitosan-based hydrogels for efficient hemostasis.

Development of an injectable hemostatic for treating noncompressible or irregularly shaped bleeding wounds remains a pressing medical need. Herein, we report an injectable thermogelling chitosan/glycerophosphate formulation that enhances gel-forming capacity and wet tissue adherence by incorporation of dihydrocaffeic acid (DHCA). This was found to decrease gelation time by >2 times around 37 °C while increasing hydrogel internal network structure, with its tissue adhesive strength >2 times greater than that of the non-composite hydrogel or previously reported. The thermosensitive hydrogels significantly reduce whole blood coagulation time in vitro and both hemostasis time and blood loss in vivo using rat hepatic hemorrhage and tail amputation models. These improvements are biocompatible, without adversely affecting cell viability, blood components, biodegradability, or introducing notable inflammation, thus enabling injury healing. Moreover, our results displayed the potential of a facile approach to enhance thermogelling and bioadhesion of chitosan-based hydrogels via noncovalent supramolecular mechanisms.

Downregulation of Sirt6 by CD38 promotes cell senescence and aging.

Decreased nicotinamide adenine dinucleotide (NAD+) levels accompany aging. CD38 is the main cellular NADase. Cyanidin-3-O-glucoside (C3G), a natural inhibitor of CD38, is a well-known drug that extends the human lifespan. We investigated mechanisms of CD38 in cell senescence and C3G in antiaging. Myocardial H9c2 cells were induced to senescence with D-gal. CD38 siRNA, C3G and UBCS039 (a chemical activator of Sirt6) inhibited D-gal-induced senescence by reducing reactive oxygen species, hexokinase 2 and SA-ß-galactosidase levels. These activators also stimulated cell proliferation and telomerase reverse transcriptase levels, while OSS-128167 (a chemical inhibitor of Sirt6) and Sirt6 siRNA exacerbated the senescent process. H9c2 cells that underwent D-gal-induced cell senescence increased CD38 expression and decreased Sirt6 expression; CD38 siRNA and C3G decreased CD38 expression and increased Sirt6 expression, respectively; and Sirt6 siRNA stimulated cell senescence in the presence of C3G and CD38 siRNA. In D-gal-induced acute aging mice, CD38 and Sirt6 exhibited increased and decreased expression, respectively, in myocardial tissues, and C3G treatment decreased CD38 expression and increased Sirt6 expression in the tissues. C3G also reduced IL-1ß, IL-6, IL-17A, TNF-α levels and restored NAD+ and NK cell levels in the animals. We suggest that CD38 downregulates Sirt6 expression to promote cell senescence and C3G exerts an antiaging effect through CD38-Sirt6 signaling.

Lestaurtinib Has the Potential to Inhibit the Proliferation of Hepatocellular Carcinoma Uncovered by Bioinformatics Analysis and Pharmacological Experiments.

Patients diagnosed with hepatocellular carcinoma (HCC) seek a satisfactory prognosis. However, most HCC patients present a risk of recurrence, thus highlighting the lack of effectiveness of current treatments and the urgent need for improved treatment options. The purpose of this study was to identify new candidate factors in the STAT family, which is involved in hepatocellular carcinogenesis, and new targets for the treatment of HCC. Bioinformatics web resources, including Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), The Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), and GSCALite, were used to identify candidate genes among the STAT family in HCC. STAT1 was significantly overexpressed in hepatocellular carcinoma. More meaningfully, the high STAT1 expression was significantly associated with poor prognosis. Therefore, STAT1 is expected to be a therapeutic target. The JAK2 inhibitor lestaurtinib was screened by the Genomics of Cancer Drug Sensitivity Project (GDSC) analysis. Pharmacological experiments showed that lestaurtinib has the ability to prevent cell migration and colony formation from single cells. We also found that STAT1 is involved in inflammatory responses and immune cell infiltration. Immune infiltration analysis revealed a strong association between STAT1 levels and immune cell abundance, immune biomarker levels, and immune checkpoints. This study suggests that STAT1 may be a key oncogene in hepatocellular carcinoma and provides evidence that the JAK2 inhibitor lestaurtinib is a potent antiproliferative agent that warrants further investigation as a targeted therapy for HCC.

Identification and validation of the N6-methyladenosine RNA methylation regulator ZC3H13 as a novel prognostic marker and potential target for hepatocellular carcinoma.

N6-methyladenosine (m6A) RNA methylation has been implicated in various malignancies. This study aimed to identify prognostic signature based on m6A methylation regulators for hepatocellular carcinoma (HCC) and provide candidate targets for HCC treatment. In this study, the expression levels, prognostic values, correlation with tumor grades and genetic variations of m6A-related genes in HCC were evaluated using bioinformatics analyses. Interestingly, the results show that methyltransferase zinc finger CCCH-type containing 13 (ZC3H13) was expressed at a significantly low level in HCC. Survival outcome analysis suggested that significant correlations existed between ZC3H13 downregulation and poor overall survival (OS) and poor recurrence-free survival (RFS) in HCC patients. Therefore, ZC3H13 was chosen for further experimental validation. The expression of ZC3H13 in HCC cell lines was investigated by western blotting. Knockdown of ZC3H13 significantly enhanced the migration and invasion of HCC cells, as demonstrated by wound healing and transwell assays. Moreover, upregulating ZC3H13 repressed the growth of xenograft tumors in vivo. Functional and pathway enrichment analyses indicated that ZC3H13 might be involved in transcriptional dysregulation or the JAK-STAT signaling pathway in cancer. Additionally, ZC3H13 expression was significantly correlated with lymphocytes and immunomodulators. Therefore, ZC3H13 is a promising candidate as a novel biomarker and therapeutic target for HCC.

Downregulation of ZC3H13 by miR-362-3p/miR-425-5p is associated with a poor prognosis and adverse outcomes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is notorious for its poor prognosis. Previous studies identified several N6-methyladenosine (m6A)-related genes that play key roles in the initiation and progression of HCC patients. In particular, the N6-methyladenosine RNA methylation regulator ZC3H13 could be a candidate as a novel biomarker and therapeutic target for hepatocellular carcinoma. In HCC, low expression of ZC3H13 was reported, but the molecular reason is unclear. In this study, we performed pan cancer analysis for ZC3H13 expression and prognosis using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data and found that ZC3H13 might be a potential tumor suppressor gene in HCC. Subsequently, miRNAs contributing to ZC3H13 downregulation were identified by a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. Finally, the miR-362-3p/miR-425-5p-ZC3H13 axis was identified as the most likely upstream miRNA-related pathway of ZC3H13 in HCC. Additionally, miR-362-3p/miR-425-5p mimic and inhibitor results were detected by quantitative real-time PCR (qPCR) analysis and western blotting. We identified an upstream regulatory mechanism of ZC3H13 in HCC, namely, the miR-362-3p/miR-425-5p-ZC3H13 axis. Moreover, the ZC3H13 level was significantly positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. Collectively, our findings elucidated that ncRNA-mediated downregulation of ZC3H13 was correlated with a poor prognosis and tumor immune infiltration in HCC. In conclusion, this study demonstrates that ZC3H13 is a direct target of miR-362-3p/miR-425-5p in liver hepatocellular carcinoma (LIHC) that regulates immune modulation in the microenvironment of LIHC.

Ferroptosis-related gene NOX4, CHAC1 and HIF1A are valid biomarkers for stomach adenocarcinoma.

Ferroptosis is a regulated cell death nexus linking metabolism, redox biology and diseases including cancer. The aim of the present study was to identify a ferroptosis-related gene prognostic signature for stomach adenocarcinoma (STAD) by systematic analysis of transcriptional profiles from The Cancer Genome Atlas (TCGA), GEO and a clinical cohort from our centre. We developed a predictive model based on three ferroptosis-related genes (CHAC1, NOX4 and HIF1A), gene expression data and corresponding clinical outcomes were obtained from the TCGA database, and the reliability of this model was verified with GSE15459 and 51 queues in our centre. ROC curve showed better predictive ability using the risk score. Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. The experimental results confirmed that NOX4 was upregulated and CHAC1 was downregulated in the STAD tissues compared with the normal stomach mucosal tissues (p < 0.05). In sum, the ferroptosis-related gene signature can accurately predict the outcomes of patients with STAD, providing valuable insights for personalized treatment. As the signature also has relevance to the immune characteristics, it may help improve the efficacy of personalized immunotherapy.

The Role of Non-Coding RNAs in Breast Cancer Drug Resistance.

Breast cancer (BC) is one of the commonly occurring malignancies in females worldwide. Despite significant advances in therapeutics, the mortality and morbidity of BC still lead to low survival and poor prognosis due to the drug resistance. There are certain chemotherapeutic, endocrine, and target medicines often used for BC patients, including anthracyclines, taxanes, docetaxel, cisplatin, and fluorouracil. The drug resistance mechanisms of these medicines are complicated and have not been fully elucidated. It was reported that non-coding RNAs (ncRNAs), such as micro RNAs (miRNA), long-chain non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) performed key roles in regulating tumor development and mediating therapy resistance. However, the mechanism of these ncRNAs in BC chemotherapeutic, endocrine, and targeted drug resistance was different. This review aims to reveal the mechanism and potential functions of ncRNAs in BC drug resistance and to highlight the ncRNAs as a novel target for achieving improved treatment outcomes for BC patients.

Long Non-Coding RNA TP53TG1 Upregulates SHCBP1 to Promote Retinoblastoma Progression by Sponging miR-33b.

Long non-coding RNA (lncRNA) TP53 target 1 (TP53TG1) is known to be strongly associated with tumor and cancer progression. However, its expression profile, unique role, and regulatory pathways in retinoblastoma (RB) are not known. Here, we revealed a large expression of TP53TG1 in RB tissues and cell lines. Conversely, we showed marked suppression of cell proliferation, migration, and invasion in TP53TG1 knocked down RB cells. Mechanistically, we established that TP53TG1 directly interacted with microRNA (miR)-33b in RB cells. Furthermore, TP53TG1 transcripts were found to be inversely correlated with miR-33b in RB tissues. We also showed that miR-33b suppression partly reversed the TP53TG1 knockdown mediated effects on tumor biology. Finally, TP53TG1 was shown to modulate the levels of SHC Binding and Spindle Associated 1 (SHCBP1), a direct target of miR-33b in RB cells. Based on the above data, we propose that TP53TG1 regulates RB progression via its modulation of the miR-33b/SHCBP1 pathway.

E2F2 inhibition induces autophagy via the PI3K/Akt/mTOR pathway in gastric cancer.

BACKGROUND: E2F2 is a member of the E2F transcription factor family and has important but not fully understood biological functions in cancers. The biological role of E2F2 in gastric cancer (GC) also remains unclear. METHODS: We examined the expression levels of E2F2 in GC using publicly available datasets such as TIMER, Oncomine, GEPIA, UALCAN, etc., and in our patient cohort, using quantitative real-time PCR, western blotting, and immunohistochemistry. We further investigated the effects of E2F2 on phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling, autophagy, and the migration and invasion of GC cells by the wound healing assay, Transwell assay and transmission electron microscopy. RESULTS: E2F2 was highly expressed in both GC tissues and cells compared with normal gastric tissues/cells. High E2F2 expression was associated with poor overall survival (OS). In addition, the expression of E2F2 in GC was strongly correlated with a variety of immune markers. E2F2 overexpression promoted the migration and invasiveness of GC cells in vitro through inhibition of PI3K/Akt/mTOR-mediated autophagy. CONCLUSION: High E2F2 expression was associated with the characteristics of invasive tumors and poor prognosis. E2F2 also had potential modulatory effects on tumor immunity. We discovered a novel function of E2F2 in the regulation of PI3K/Akt/mTOR-mediated autophagy and the downstream processes of cell migration and invasion.

Identification and Validation of SNP-Containing Genes With Prognostic Value in Gastric Cancer via Integrated Bioinformatics Analysis.

BACKGROUND: Gastric cancer is one of the most common malignancies worldwide. Although the diagnosis and treatment of this disease have substantially improved in recent years, the five-year survival rate of gastric cancer is still low due to local recurrence and distant metastasis. An in-depth study of the molecular pathogenesis of gastric cancer and related prognostic markers will help improve the quality of life and prognosis of patients with this disease. The purpose of this study was to identify and verify key SNPs in genes with prognostic value for gastric cancer. METHODS: SNP-related data from gastric cancer patients were obtained from The Cancer Genome Atlas (TCGA) database, and the functions and pathways of the mutated genes were analyzed using DAVID software. A protein-protein interaction (PPI) network was constructed using the STRING database and visualized by Cytoscape software, and molecular complex detection (MCODE) was used to screen the PPI network to extract important mutated genes. Ten hub genes were identified using cytoHubba, and the expression levels and the prognostic value of the central genes were determined by UALCAN and Kaplan-Meier Plotter. Finally, quantitative PCR and Western blotting were used to verify the expression of the hub genes in gastric cancer cells. RESULTS: From the database, 945 genes with mutations in more than 25 samples were identified. The PPI network had 360 nodes and 1616 edges. Finally, cytoHubba identified six key genes (TP53, HRAS, BRCA1, PIK3CA, AKT1, and SMARCA4), and their expression levels were closely related to the survival rate of gastric cancer patients. CONCLUSION: Our results indicate that TP53, HRAS, BRCA1, PIK3CA, AKT1, and SMARCA4 may be key genes for the development and prognosis of gastric cancer. Our research provides an important bioinformatics foundation and related theoretical foundation for further exploring the molecular pathogenesis of gastric cancer and evaluating the prognosis of patients.

5-Fluorouracil enhances the chemosensitivity of gastric cancer to TRAIL via inhibition of the MAPK pathway.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to selectively trigger cancer cell apoptosis and can be used as a target for tumor therapy. However, gastric cancer cells are usually insensitive to TRAIL so reducing this drug resistance may improve the treatment of gastric cancer. In this study, we used Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) experiments to determine the effects of 5-fluorouracil (5-FU) and TRAIL on the proliferation of gastric cancer cells. An Annexin V/propidium iodide (PI) staining experiment was used to detect apoptosis, and Western blotting was used to analyze the expression levels of apoptosis-related proteins and mitogen-activated protein kinase (MAPK) pathway proteins. The antitumor effects of 5-FU and TRAIL were verified in vivo using a nude mouse tumorigenesis experiment, and a TUNEL assay was performed to evaluate apoptosis in tumor tissue from the nude mice. We found the combination of 5-FU and TRAIL had a greater inhibitory effect on the proliferation of gastric cancer cells than 5-FU or TRAIL alone both in vivo and in vitro. 5-FU enhanced TRAIL-induced gastric cancer cell apoptosis by inactivating the MAPK pathway. Overall, our analysis firstly provided new insights into the role of 5-FU in increasing sensitivity to TRAIL. 5-FU can be used as a sensitizer for TRAIL, and its administration is a potential strategy for the treatment of gastric cancer.

Identification and Analysis of Key Genes Driving Gastric Cancer Through Bioinformatics.

Objective: The aim of this study was to use bioinformatic analyses to identify key genes and pathways driving gastric cancer (GC). Materials and Methods: The gene expression profiles, from human gastric tissue samples were downloaded from the Gene Expression Omnibus (GSE)29272 dataset. These data revealed 284 differentially expressed genes (DEGs) that included a group upregulated in cancer tissues (n = 142) and another group that were downregulated in cancer tissues. (n = 142). These DEGs were identified using the GEO2R. We used multiple online analysis tools, including, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction networks, gene expression profiling interactive analysis (GEPIA), and the cBio Cancer Genomics Portal (cBioportal) database. Next, we identified the most significant DEGs using the Kaplan-Meier plotter (KM-plotter) database. Multiple bioinformatic platforms were used to identify candidate prognostic marker genes. We then analyzed freshly frozen GC tissues for the expression of these marker genes to validate the informatic findings. Results: We identified three DEGs related to overall survival from our analyses of the GEO data. Next, we analyzed these three DEGs in GEPIA and the cBioportal database and found that the biglycan (BGN) gene was related to invasion and metastases of GCs. This finding of differential gene expression was confirmed in a separate laboratory analysis of normal and GC tissues. In this analysis we found that high levels of BGN expression were correlated with GC clinicopathological characteristics, including microvascular tumor thrombus (p = 0.018), lymph node metastases (p = 0.013), and vessel invasion (p = 0.004). Conclusions: BGN expression levels appear to be an independent prognostic factor for predicting the survival times of GC patients.