Stearoyl-CoA desaturase 1 is targeted by EBV-encoded miR-BART20-5p and regulates cell autophagy, proliferation, and migration in EBV-associated gastric cancer.

Epstein-Barr virus (EBV) is the first human oncogenic virus known to express microRNAs (miRNAs), which are closely associated with the development of various tumors, including nasopharyngeal and gastric cancers. Stearoyl-CoA Desaturase 1 (SCD1) is a key enzyme in fatty acid synthesis, highly expressed in numerous tumors, promoting tumor growth and metastasis, making it a potential therapeutic target. In this study, we found that SCD1 expression in EBV-associated gastric cancer (EBVaGC) was significantly lower than in EBV-negative gastric cancer (EBVnGC) at both cellular and tissue levels. In addition, EBV-miR-BART20-5p targets the 3'-UTR of SCD1, downregulating its expression. Moreover, overexpression of SCD1 in EBVaGC cells promoted cell migration and proliferation while inhibiting autophagy. These results suggest that EBV-encoded miRNA-BART20-5p may contribute to EBVaGC progression by targeting SCD1.

Aquaporin-3 is down-regulated by LMP1 in nasopharyngeal carcinoma cells to regulate cell migration and affect EBV latent infection.

Epstein-Barr virus (EBV) infection has a strong correlation with the development of nasopharyngeal carcinoma (NPC). Aquaporin 3 (AQP3), a member of the aquaporin family, plays an important role in tumor development, especially in epithelial-mesenchymal transition. In this study, the expression of AQP3 in EBV-positive NPC cells was significantly lower than that in EBV-negative NPC cells. Western blot and qRT-PCR analysis showed that LMP1 down-regulated the expression of AQP3 by activating the ERK pathway. Cell biology experiments have confirmed that AQP3 affects the development of tumor by promoting cell migration and proliferation in NPC cells. In addition, AQP3 can promote the lysis of EBV in EBV-positive NPC cells. The inhibition of AQP3 expression by EBV through LMP1 may be one of the mechanisms by which EBV maintains latent infection-induced tumor progression.

Downregulation of MUS81 expression inhibits cell migration and maintains EBV latent infection through miR-BART9-5p in EBV-associated gastric cancer.

Epstein-Barr virus (EBV) infection is associated with the occurrence and development of gastric cancer (GC). Methyl methanesulfonate and ultraviolet-sensitive gene 81 (MUS81) is the catalytic component of a structure-specific endonuclease and plays an important role in chromosomal stability. However, the link between EBV infection and MUS81 remains unclear. In the present study, we found that MUS81 expression was much lower in EBV-associated GC cells than in EBV-negative GC. MUS81 acts as an oncogene in GC by inducing the cell migration and proliferation. Western blot and luciferase reporter assays revealed that miR-BART9-5p directly targeted MUS81 and downregulated its expression. Additionally, overexpression of MUS81 in EBV-positive GC cells inhibited the expression of EBV nuclear antigen 1 (EBNA1). EBNA1 is critical for the pathogenesis of EBV-associated tumors and the maintenance of a stable copy number of the viral genomes. Altogether, these results indicated that the lowering MUS81 expression might be a mechanism by EBV to maintain its latent infection.

Nuclear respiratory factor 1 promotes the progression of EBV-associated gastric cancer and maintains EBV latent infection.

This study aimed to investigate the association of Epstein-Barr virus (EBV) with nuclear respiratory factor 1 (NRF1) and the biological function of NRF1 in EBV-associated gastric cancer (EBVaGC). Western blot and qRT-PCR were used to assess the effect of latent membrane protein 2A (LMP2A) on NRF1 expression after transfection with LMP2A plasmid or siLMP2A. The effects of NRF1 on the migration and apoptosis ability of GC cells were investigated by transwell assay and flow cytometry apoptosis analysis in vitro, respectively. In addition, we determined the regulatory role of NRF1 in EBV latent infection by western blot and droplet digital PCR (ddPCR). LMP2A upregulated NRF1 expression by activating the NF-κB pathway. Moreover, NRF1 upregulated the expression of N-Cadherin and ZEB1 to promote cell migration. NRF1 promoted the expression of Bcl-2 to increase the anti-apoptotic ability of cells. In addition, NRF1 maintained latent infection of EBV by promoting the expression of the latent protein Epstein-Barr nuclear antigen 1 (EBNA1) and inhibiting the expression of the lytic proteins. Our data indicated the role of NRF1 in EBVaGC progression and the maintenance of EBV latent infection. This provided a new theoretical basis for further NRF1-based anti-cancer therapy.

MiR-BART1-3p and BART18-5p inhibit cell migration, proliferation and activate autophagy in Epstein-Barr virus-associated gastric cancer by targeting erythropoietin-producing human hepatocellular 2.

Epstein-Barr virus (EBV) is a human tumor-associated virus that encodes various microRNAs. EBV infection causes a variety of malignant tumors, including nasopharyngeal carcinoma and gastric cancer, etc. EBV-associated gastric cancer (EBVaGC) has unique molecular characteristics from other gastric cancers, but its pathogenic mechanism remains unclear. In recent years, erythropoietin-producing human hepatocellular 2 (EphA2) has been reported to be highly expressed in various cancers and promote tumor growth and metastasis. As an important cancer oncogene, EphA2 is a potential therapeutic target. However, whether EBV is involved in the regulation of EphA2 and thus affects the progression of EBVaGC remains unclear. In this study, we found that the expression of EphA2 in EBVaGC cells was significantly lower than that in EBV-negative gastric cancer (EBVnGC) cells. Additionally, overexpression of EphA2 in EBVaGC cells promoted migration and proliferation, and inhibited autophagy. EBV-miR-BART1-3p and BART18-5p were found to target the 3'-UTR of EphA2 and down-regulate its expression. Our results suggest that EBV may be involved in gastric cancer progression by targeting EphA2 through BART1-3p and BART18-5p.

Zearalenone exposure impairs ovarian primordial follicle formation via down-regulation of Lhx8 expression in vitro.

Zearalenone (ZEA) is an estrogenic mycotoxin mainly produced as a secondary metabolite by numerous species of Fusarium. Previous work showed that ZEA had a negative impact on domestic animals with regard to reproduction. The adverse effects and the mechanisms of ZEA on mammalian ovarian folliculogenesis remain largely unknown, particularly its effect on primordial follicle formation. Thus, we investigated the biological effects of ZEA exposure on murine ovarian germ cell cyst breakdown and primordial follicle assembly. Our results demonstrated that newborn mouse ovaries exposed to 10 or 30µM ZEA in vitro had significantly less germ cell numbers compared to the control group. Moreover, the presence of ZEA in vitro increased the numbers of TUNEL and γH2AX positive cells within mouse ovaries and the ratio of mRNA levels of the apoptotic genes Bax/Bcl-2. Furthermore, ZEA exposure reduced the mRNA of oocyte specific genes such as LIM homeobox 8 (Lhx8), newborn ovary homeobox (Nobox), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and factor in the germline alpha (Figlα) in a dose dependent manner. Exposure to ZEA led to remarkable changes in the Lhx8 3'-UTR DNA methylation dynamics in oocytes and severely impaired folliculogenesis in ovaries after transplantation under the kidney capsules of immunodeficient mice. In conclusion, ZEA exposure impairs mouse primordial follicle formation in vitro.

Effectiveness of Antibiotic Use Management in Tianjin (2011-2013): A Quasi-Experimental Study.

BACKGROUND In this study we investigated changes in the status of antibiotic use in Tianjin since the implementation of the Antibiotic Stewardship Program (ASP) (2011-2013), as well as existing problems, strategies, and outcomes to promote rational clinical antibiotic use. MATERIAL AND METHODS A quasi-experimental study was performed to investigate situations of antibiotic use in secondary and tertiary general hospitals in Tianjin from April 2011 to 2013. Five major indicators were analyzed: percentage of antibiotic use in inpatient cases (%), antibacterial use density (AUD), proportion of prophylactic antibiotic application for type I surgical incision, compliance rate of medication administration 0.5-2.0 h before such procedures, and antibiotic prophylaxis for ≤24 h in patients receiving these surgeries. RESULTS There was a decrease in the percentage of antibiotic use across general hospitals (60.38% to 46.88%), in AUD (51.60% to 35.37%), and in the proportion of prophylactic antibiotic applications for type I incisions (86.67% to 25.08%). For patients undergoing these procedures, there was an increased compliance rate of medication administration of 0.5-2.0 h prior to surgery (86.38% to 100%), and of antibiotic prophylactic use for ≤24 h (40.30% to 96.37%). CONCLUSIONS Implementation of the ASP campaign has reduced irrational antibiotic use, promoted rational antibiotic use, and delayed antibiotic resistance.

Regulation mechanism of EBV-encoded EBER1 and LMP2A on YAP1 and the impact of YAP1 on the EBV infection status in EBV-associated gastric carcinoma.

This study aims to explore the role and regulatory mechanism of Yes-associated protein 1 (YAP1) in the development of Epstein-Barr virus-associated gastric cancer (EBVaGC). Here we showed that EBV can upregulate the expression and activity of YAP1 protein through its encoded latent products EBV-encoded small RNA 1 (EBER1) and latent membrane protein 2A (LMP2A), enhancing the malignant characteristics of EBVaGC cells. In addition, we also showed that overexpression of YAP1 induced the expression of EBV encoding latent and lytic phase genes and proteins in the epithelial cell line AGS-EBV infected with EBV, and increased the copy number of the EBV genome, while loss of YAP1 expression reduced the aforementioned indicators. Moreover, we found that YAP1 enhanced EBV lytic reactivation induced by two known activators, 12-O-tetradecanoylhorbol-13-acetate (TPA) and sodium butyrate (NaB). These results indicated a bidirectional regulatory mechanism between EBV and YAP1 proteins, providing new experimental evidence for further understanding the regulation of EBV infection patterns and carcinogenic mechanisms in gastric cancer.

Protein-protein interactions in cGAS-STING pathway: a medicinal chemistry perspective.

Protein-protein interactions (PPIs) play pivotal roles in biological processes and are closely linked with human diseases. Research on small molecule inhibitors targeting PPIs provides valuable insights and guidance for novel drug development. The cGAS-STING pathway plays a crucial role in regulating human innate immunity and is implicated in various pathological conditions. Therefore, modulators of the cGAS-STING pathway have garnered extensive attention. Given that this pathway involves multiple PPIs, modulating PPIs associated with the cGAS-STING pathway has emerged as a promising strategy for modulating this pathway. In this review, we summarize an overview of recent advancements in medicinal chemistry insights into cGAS-STING PPI-based modulators and propose alternative strategies for further drug discovery based on the cGAS-STING pathway.

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Effects of methylation and imprinting expression of Insulin-like growth factor 2 gene in gastric cancer.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a common malignant tumor associated with EBV infection. Insulin-like growth factor 2 (IGF2) is an imprinted gene and a key protein that regulates growth, especially during normal fetal development. Loss of imprinting (LOI), is a common epigenetic anomaly in a variety of human cancers. However, the promoter methylation, imprinting status and function of IGF2 gene in GC are unclear. OBJECTIVE: To explore the role of IGF2 in the occurrence and development of gastric cancer. METHODS: The biological function of IGF2 in gastric cancer was investigated by Transwell, wound healing, CCK-8 and flow cytometry assays. IGF2 imprinting status and gene promoter methylation in gastric cancer tissues were detected by PCR-RFLP and BGS. RESULTS: The results showed that the expression of IGF2 was higher in GC tissues than adjacent tissues. IGF2 gene promoter methylation and LOI were significantly higher in EBVaGC tissues than in EBV-negative gastric cancer (EBVnGC) tissues. The high expression of IGF2 in gastric cancer can promote the migration and proliferation of gastric cancer cells. CONCLUSION: Our data suggest that IGF2 is involved in the occurrence and development of gastric cancer. Targeting IGF2 may be a potential therapeutic target for gastric cancer.

Imidazo[1,2-a]Pyridine Derivatives as Novel Dual-Target Inhibitors of ABCB1 and ABCG2 for Reversing Multidrug Resistance.

ABCB1 and ABCG2 are the important ATP-binding cassette (ABC) transporters associated with multidrug resistance (MDR). Herein, we designed a series of imidazo[1,2-a]pyridine derivatives as dual-target inhibitors of ABCB1 and ABCG2 through the scaffold hopping strategy. Compound Y22 displayed potential efflux function inhibitory toward both ABCB1 and ABCG2 (reversal fold: ABCB1 = 8.35 and ABCG2 = 2.71) without obvious cytotoxicity. Y22 also enhanced the potency of antiproliferative drugs in vitro. Mechanistic studies demonstrated that Y22 slightly suppressed ATPase activity but did not affect the protein expression of ABCB1 or ABCG2. Notably, Y22 exhibited negligible CYP3A4 inhibition and enhanced the antiproliferative activity of adriamycin in vivo by restoring the sensitivity of resistant cells. Thus, Y22 may be effective clinically in combination with common chemotherapy agents. In summary, Y22 is a potential dual-target inhibitor that reverses MDR by blocking the efflux function of ABCB1 and ABCG2.

Complete genome sequence of Acinetobacter baumannii MDR-TJ and insights into its mechanism of antibiotic resistance.

OBJECTIVES: To determine the genome sequence of Acinetobacter baumannii strain MDR-TJ and characterize the mechanisms of multidrug resistance in this strain. METHODS: The whole-genome sequence was determined using Roche 454 GS FLX Titanium. Subsequently, the gaps were closed by sequencing PCR products. The genome of strain MDR-TJ was annotated using IMG ER, the RAST annotation server and the BASys bacterial annotation system. The comM gene of MDR-TJ was examined to identify a possible antibiotic resistance island. Based on the results of multilocus sequence typing, we investigated seven multidrug-resistant A. baumannii strains belonging to global clone 2 (GC2) isolated from Asia, Australia and Europe to determine the backbone shared by resistance islands of GC2 isolates. RESULTS: The A. baumannii strain MDR-TJ genome consists of a circular chromosome and a plasmid, pABTJ1. Strain MDR-TJ was assigned to sequence type ST2. Strain MDR-TJ harbours a 41.6 kb resistance island designated RI(MDR-TJ), which can be derived from the backbone of Tn6167 through the insertion of a Tn6022 into the 3'-end of the tetA(B) gene. Comparative analysis showed that transposon Tn6022 and its truncated forms prevailed in the antibiotic resistance islands of GC2 isolates. The carbapenem resistance gene bla(OXA-23) carried by transposon Tn2009 is located on a putatively conjugative plasmid, pABTJ1. CONCLUSIONS: A. baumannii strain MDR-TJ belongs to GC2 and is resistant to multiple antibiotics. A. baumannii MDR-TJ harbours a genomic resistance island that interrupts the comM gene. The carbapenem resistance of MDR-TJ is mediated by a putatively conjugative plasmid, pABTJ1.

Design, synthesis, and activity evaluation of broad-spectrum small-molecule inhibitors of anti-apoptotic Bcl-2 family proteins: characteristics of broad-spectrum protein binding and its effects on anti-tumor activity.

On the basis of the comparison of the structure of the Bim BH3: Bcl-x(L) complex and that of the ABT-737: Bcl-x(L) complex, a series of class A compounds were designed. These compounds had the basic skeleton of ABT-737 and the h2 residues of Bim BH3. These residues had shown themselves to be relevant to Bim BH3's broad-spectrum binding properties in saturation mutagenesis assays. Unlike ABT-737, which is a selective inhibitor of anti-apoptotic members of the Bcl-2 protein family, the class A compounds showed broad-spectrum binding activity to target proteins similar to those of Bim BH3 peptide. Then class B compounds were synthesized by modifying the structure of the most effective class A compound, A-4. Most of these class B compounds showed better binding affinity to the target proteins than the class A compounds had. They also showed themselves more effective than ABT-737 at inhibiting growth in multiple tumor cell lines known to express Bcl-x(L), Bcl-2, and Mcl-1 proteins at high levels. Compounds B-11 and B-12 had the strongest anti-tumor activity of any compounds we produced. This study suggests that it is feasible to design small-molecule inhibitors based on the structure of Bim BH3, which shows broad-spectrum binding to Bcl-x(L), Bcl-2, and Mcl-1 proteins. Our results also suggest that the broad-spectrum properties of small-molecule inhibitors binding to target proteins play a critical role in inhibiting the growth of many tumor cells. Finally, our study provides a series of lead compounds that merit further research into anti-cancer therapeutics.

Antihypertensive effects and safety of eprosartan: a meta-analysis of randomized controlled trials.

PURPOSE: The benefits of reducing blood pressure (BP) have been well established, but uncertainty remains about the comparative effects of different BP-lowering regimens. We aimed to estimate the efficacy and the tolerability of eprosartan compared with other agents as monotherapy. METHODS: PubMed, EMBASE, and Cochrane Library were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) meeting the criteria was performed using Review Manager and Stata/SE. RESULTS: Twenty-two articles were ultimately included out of 78 studies, involving 6,460 patients. Eprosartan had a greater systolic blood pressure (SBP) reduction than placebo [weighted mean difference (WMD): 6.55, 95% confidence interval (CI) 4.86-8.25] and losartan (WMD: 2.24, 95% CI 0.08-4.40) and a greater diastolic blood pressure (DBP) reduction than placebo (WMD 3.95, 95% CI 2.77-5.13). Therapeutic response rate of BP favored eprosartan [risk ratio (RR) 1.13, 95% CI 1.03-1.24] compared with enalapril. There were no statistical differences in SBP or DBP reductions comparing eprosartan with enalapril or telmisartan. Original RCTs included comparing eprosartan with valsartan and nitrendipine reported no differences in BP-lowering efficacy. CONCLUSIONS: Eprosartan monotherapy is equivalent to many first-line antihypertensive agents and is effective for the treatment of essential hypertension, especially for isolated systolic hypertension. The favorable efficacy and tolerability make eprosartan worthwhile to be taken into consideration by physicians.

Synthesis and biological evaluation of 1-phenyl-1,2,3,4-dihydroisoquinoline compounds as tubulin polymerization inhibitors.

A series of 1-phenyl-3,4-dihydroisoquinoline derivatives and several 1-phenyl-1,2,3,4-tetrahydroisoquinoline, 1-phenyl-isoquinoline analogues were synthesized, and their cytotoxicity and tubulin polymerization inhibitory activity were evaluated. The 1-phenyl-3,4-dihydroisoquinoline compounds were found to be potential tubulin polymerization inhibitors. Compound 5n, bearing a 3'-OH and 4'-OCH(3) substituted 1-phenyl B-ring, was shown to confer optimal bioactivity. The single-crystal structure of 5n was further determined by X-ray diffraction, and the binding mode of 5n to tubulin was obtained by molecular docking, which can explain the structure-activity relationships. The studies presented here provide a new structural type for the development of novel antitumor agents.

The promoter aberrant methylation status of TMEM130 is associated with gastric cancer.

BACKGROUND AND AIMS: Gastric cancer (GC) is a malignant tumor that seriously affects human health and Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a molecular subtype of GC. This study aims to determine the relationship between the methylation status of the TMEM130 gene and GC, and to explore the influence of EBV infection. METHODS: qRT-PCR was conducted to investigate the transcriptional expression of TMEM130 in GC. BSP and MSP assays were used to detect the methylation level of the TMEM130 promoter. The cell migration ability was detected by Transwell and western blot after transfection of TMEM130 plasmids in GC cells. RESULTS: The transcriptional expression of TMEM130 decreased in GC with hypermethylation of the promoter region. The DNA methyltransferase inhibitor could increase the mRNA expression of TMEM130. Moreover, hypermethylation of the TMEM130 promoter in GC tissues was associated with EBV infection. Overexpression of TMEM130 in GC cell lines suppresses cell migration ability. CONCLUSION: This study was the first to research the expression and function of TMEM130 and found that TMEM130 gene hypermethylation might contribute to GC migration and EBV infection as a cause of hypermethylation of the TMEM130 gene. TMEM130 is a promising biomarker for the diagnosis of GC.

LMP2A inhibits the expression of KLF5 through the mTORC1 pathway in EBV-associated gastric carcinoma.

OBJECTIVE: To investigate the expression and biological role of KLF5 in EBV-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC), and to clarify the relationship between EBV and KLF5. METHODS: The expression of KLF5 in GC tissues was detected by immunohistochemistry. Western blot and immunofluorescence assay were used to examine the expression and localization of KLF5 in EBV positive and negative GC cell lines. The effect of LMP2A on KLF5 was analyzed by transfection of LMP2A plasmid or siRNA. The function of KLF5 in GC was elucidated by molecular biology experiments. RESULTS: The expression of KLF5 was significantly reduced in EBVaGC tissues and cell lines. LMP2A inhibited KLF5 expression through inactivating mTORC1 pathway in EBV positive GC cell lines. Meanwhile, KLF5 could enhance the migration ability of GC cells and induce autophagy. CONCLUSION: LMP2A downregulated KLF5 expression by inhibiting the mTORC1 pathway in EBV positive GC cells. KLF5 might play an oncogene-like role by promoting the migration of GC cells and inducing autophagy.

Genome sequence of Acinetobacter baumannii MDR-TJ.

Acinetobacter baumannii is a pathogenic species of bacteria, identified as an aerobic gram-negative bacterium, that is resistant to most antibiotics. In this study, the MDR-TJ strain was isolated at the Second Hospital of Tianjin Medical University, China, and was found to be resistant to penicillin, cephalosporins, aminoglycosides, quinolones, and also imipenem. The genome sequence of Acinetobacter baumannii strain MDR-TJ was determined by using a combination of 454 pyrosequencing and paired-end sequencing performed with the Roche Genome Sequencer FLX system to generate a scaffolded assembly.

Lipid metabolism and peroxisome proliferator-activated receptor signaling pathways participate in late-phase liver regeneration.

Liver regeneration (LR) is of great clinical significance in various liver-associated diseases. LR proceeds along a sequence of three distinct phases: priming/initiation, proliferation, and termination. Compared with the recognition of the first two phases, little is known about LR termination and structure/function reorganization. A combination of "omics" techniques, along with bioinformatics, may provide new insights into the molecular mechanism of the late-phase LR. Gene, protein, and metabolite profiles of the rat liver were determined by cDNA microarray, two-dimensional electrophoresis, and HPLC-MS analysis. Pathway enrichment analysis was performed to identify the pathways: 427 differentially expressed genes extracted from the microarray experiment revealed two expression patterns representing the early and late phase of LR. Functionally, the genes expressing at a higher level at the early phase than at the late phase were mainly involved in the response to stress, proliferation, and resistance to apoptosis, while those expressing at a lower level at the early phase than at the late phase were mainly engaged in lipid metabolism. Compared with the sham-operation control (SH) group, 5 proteins in the 70% partial hepatectomy (70%PHx) group were upregulated at the protein level, and 3 proteins were downregulated at 168 h after the 70%PHx. E-FABP, an upregulated fatty acid binding protein, was found to be involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The metabolomic data confirmed the enhancement of lipid metabolism by the detection of the intermediate and final metabolites. We've concluded that increased lipid metabolism and activated PPAR signaling pathways play important roles in late-phase LR.

Imidazolone-amide bridges and their effects on tubulin polymerization in cis-locked vinylogous combretastatin-A4 analogues: synthesis and biological evaluation.

A series of novel combretastatin-A4 analogues in which the cis-olefinic bridge is replaced by an imidazolone-amide were synthesized, and their cytotoxicity and tubulin-polymerization inhibitory activities were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors. Compounds 10, 9b and 9c, bearing 3'-NH2-4'-OCH3, 4'-CH3 and 3'-CH3-substituted 1-phenyl B-ring, confer optimal bioactivity. The binding modes of these compounds to tubulin were obtained by molecular docking, which can explain the compounds' structure-activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents.