ERG mediates the inhibition of NK cell cytotoxicity through the HLX/STAT4/Perforin signaling pathway, thereby promoting the progression of myocardial infarction.

This study aimed to investigate the role of ERG in the HLX/STAT4/Perforin signaling axis, impacting natural killer (NK) cell cytotoxicity and myocardial infarction (MI) progression. NK cell cytotoxicity was assessed via co-culture and 51Cr release assays. Datasets GSE34198 and GSE97320 identified common differentially expressed genes in MI. NK cell gene expression was analyzed in MI patients and healthy individuals using qRT-PCR and Western blotting. ERG's regulation of HLX and STAT4's regulation of perforin were studied through computational tools (MEM) and ChIP experiments. HLX's influence on STAT4 was explored with the MG132 proteasome inhibitor. Findings were validated in a mouse MI model.ERG, a commonly upregulated gene, was identified in NK cells from MI patients and mice. ERG upregulated HLX, leading to STAT4 proteasomal degradation and reduced Perforin expression. Consequently, NK cell cytotoxicity decreased, promoting MI progression. ERG mediates the HLX/STAT4/Perforin axis to inhibit NK cell cytotoxicity, fostering MI progression. These results provide vital insights into MI's molecular mechanisms.

ARFIP2 Regulates EMT and Autophagy in Hepatocellular Carcinoma in Part Through the PI3K/Akt Signalling Pathway.

Purpose: ARFIP2, a canonical BAR domain-containing protein, is closely associated with regulating cargo exit from the Golgi. However, the potential biological functions of ARFIP2 in hepatocellular carcinoma (HCC) have not been well investigated. This study aimed to explore the critical role of ARFIP2 in HCC cells. Methods: The expression of proteins related to epithelial to mesenchymal transition (EMT) and cell autophagy in HCC cells and tissues was assayed by quantitative real-time PCR, Western blotting, immunohistochemistry and immunofluorescence staining. The ability of cells to proliferate, migrate and invade was detected by Cell Counting Kit-8, Transwell migration and invasion assays. In addition, the function of ARFIP2 in vivo was assessed using a tumour xenograft model. Results: ARFIP2 expression is significantly upregulated in early recurrent and metastatic HCC patients and was positively correlated with a poor prognosis. ARFIP2 overexpression promoted cell proliferation, migration, and invasion by inducing EMT and inhibiting autophagy in vitro. Furthermore, the regulatory effects of ARFIP2 on autophagy and EMT were partially attributed to its regulation of the PI3K/AKT signalling pathway. The in vivo results also showed that ARFIP2 modulates HCC progression. Conclusion: Our results substantiate a novel mechanism by which ARFIP2 can regulate the activity/phosphorylation of Akt to promote EMT and inhibit autophagy in part via the PI3K/Akt signalling pathway. The ARFIP2/PI3K/Akt axis may be a potential diagnostic biomarker and therapeutic target for HCC.

Sacubitril Valsartan Enhances Cardiac Function and Alleviates Myocardial Infarction in Rats through a SUV39H1/SPP1 Axis.

Sacubitril valsartan (lcz696) has been demonstrated as a substitute for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the treatment of heart failure. This research is aimed at examining the effects of lcz696 and its target molecules on myocardial infarction (MI). A rat model of MI was induced by left anterior descending artery ligation and treated with lcz696. Lcz696 treatment significantly reduced cardiac injury and heart failure, restored the left ventricular fractional shortening and ejection fraction, and reduced oxidative stress and inflammatory responses in rat myocardium. By analyzing the heart failure-related GSE47495 dataset and performing gene ontology (GO) functional enrichment analysis, we obtained histone lysine methyltransferase SUV39H1 and secreted phosphoprotein 1 (SPP1) as two molecules implicated in the oxidative stress and inflammation processes. An elevation of SUV39H1 whereas a decline of SPP1 were detected in cardiac tissues after lcz696 treatment. Enrichments of SUV39H1 and H3K9me3 at the SPP1 promoter were identified by chromatin immunoprecipitation assay. SUV39H1 catalyzed H3K9me3 modification to suppress the expression of SPP1. Preconditioning of SUV39H1 silencing blocked the protective roles of lcz696, but SPP1 silencing alleviated the myocardial injury. In conclusion, this study demonstrates that lcz696 enhances cardiac function and alleviates MI in rats through a SUV39H1/SPP1 axis.

Integrated Analysis of Circular RNA-Associated ceRNA Network Reveals Potential circRNA Biomarkers in Human Breast Cancer.

Circular RNA (circRNA) is closely related to tumorigenesis and cancer progression. Yet, the roles of cancer-specific circRNAs in the circRNA-related ceRNA network of breast cancer (BRCA) remain unclear. The aim of this study was to construct a ceRNA network associated with circRNA and to explore new therapeutic and prognostic targets and biomarkers for breast cancer. We downloaded the circRNA expression profile of BRCA from Gene Expression Omnibus (GEO) microarray datasets and downloaded the miRNA and mRNA expression profiles of BRCA from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNAs (DEmRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed circRNAs (DEcircRNAs) were identified, and a competitive endogenous RNA (ceRNA) regulatory network was constructed based on circRNA-miRNA pairs and miRNA-mRNA pairs. Gene ontology and pathway enrichment analyses were performed on mRNAs regulated by circRNAs in ceRNA networks. Survival analysis and correlation analysis of all mRNAs and miRNAs in the ceRNA network were performed. A total of 72 DEcircRNAs, 158 DEmiRNAs, and 2762 DE mRNAs were identified. The constructed ceRNA network contains 60 circRNA-miRNA pairs and 140 miRNA-mRNA pairs, including 40 circRNAs, 30 miRNAs, and 100 mRNAs. Functional enrichment indicated that DEmRNAs regulated by DEcircRNAs in ceRNA networks were significantly enriched in the PI3K-Akt signaling pathway, microRNAs in cancer, and proteoglycans in cancer. Survival analysis and correlation analysis of all mRNAs and miRNAs in the ceRNA network showed that 13 mRNAs and 6 miRNAs were significantly associated with overall survival, and 48 miRNA-mRNA interaction pairs had a significant negative correlation. A PPI network was established, and 21 hub genes were determined from the network. This study provides an effective bioinformatics basis for further understanding of the molecular mechanisms and predictions of breast cancer. A better understanding of the circRNA-related ceRNA network in BRCA will help identify potential biomarkers for diagnosis and prognosis.

Circular RNA Foxo3 Relieves Myocardial Ischemia/Reperfusion Injury by Suppressing Autophagy via Inhibiting HMGB1 by Repressing KAT7 in Myocardial Infarction.

INTRODUCTION: Myocardial infarction is coronary artery-related heart disease, and the leading cause of mortality globally. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progression. METHODS: However, the function of circFoxo3 in MI-induced myocardial injury remains obscure. RESULTS: Significantly, we identified that circFoxo3 was downregulated in the MI rat model and the overexpression of circFoxo3 ameliorated MI-induced cardiac dysfunction and attenuated MI-induced autophagy in rat model. Meanwhile, the overexpression of circFoxo3 repressed oxygen-glucose deprivation (OGD)-induced autophagy, apoptosis, inflammation, and injury of cardiomyocyte in vitro. Mechanically, we identified that the expression of KAT7 was reduced by circFoxo3 overexpression in cardiomyocytes. Meanwhile, the expression of HMGB1 was repressed by the depletion of KAT7 in cardiomyocytes. The enrichment of histone H3 lysine 14 acetylation (H3K14ac) and RNA polymerase II (RNA pol II) on HMGB1 promoter was inhibited by the knockdown of KAT7. Moreover, the overexpression of circFoxo3 suppressed HMGB1 expression and KAT7 overexpression rescued the expression of HMGB1 in cardiomyocytes. The enrichment of KAT7, H3K14ac, and RNA poly II on HMGB1 promoter was decreased by circFoxo3 overexpression, while the overexpression of KAT7 could reverse the effect. The overexpression of KAT7 or HMGB1 could reverse circFoxo3-attenuated cardiomyocyte injury and autophagy in vitro. Thus, we conclude that circular RNA circFoxo3 relieved myocardial ischemia/reperfusion injury by suppressing autophagy via inhibiting HMGB1 by repressing KAT7 in MI. DISCUSSION: Our finding provides new insight into the mechanism by which circFoxo3 regulates MI-related cardiac dysfunction by targeting KAT7/HMGB1 axis.

Tetrahydropalmatine exerts analgesic effects by promoting apoptosis and inhibiting the activation of glial cells in rats with inflammatory pain.

BACKGROUND: Pain is an unpleasant sensory experience that usually plays a protective role. Inflammatory pain is often severe and stubborn, which has a great impact on the quality of life of patients. However, there has been no breakthrough in the treatment strategy and mechanism of inflammatory pain. METHODS: This study investigated the analgesic effect of tetrahydropalmatine (THP) in rats injected with complete Freund's adjuvant (CFA)-induced inflammatory pain. Allodynia and gait analysis of rats were used to evaluate the analgesic effect at different time points before and after operation. THP (2.5, 5, and 10 mg/kg) was administered intraperitoneally once daily for 7 days post Day 3. The expression levels of TNF-α and IL-1ß in the spinal cord were measured by enzyme-linked immunosorbent assay. The activation of astrocytes and microglial cells in the spinal cord was tested by western blot before and after THP treatment. The apoptosis of glial cells was tested by flow cytometry after treatment with THP in the primary cultured glial cell model. RESULTS: CFA treatment induced significant allodynia and caused abnormal gait in rats. Administration of THP at 10 mg/kg significantly alleviated CFA-induced inflammatory pain behaviors. Moreover, CFA-induced activation of glial cells and the increased levels of TNF-α and IL-1ß were inhibited by THP administration. In addition, THP promotes apoptosis in primary cultured glial cells. This study suggests the possible clinical utility of THP in the treatment of inflammatory pain. CONCLUSION: THP plays an analgesic role by inhibiting the activation of glial cells and promoting apoptosis.

Sacubitril/valsartan (LCZ696) reduces myocardial injury following myocardial infarction by inhibiting NLRP3­induced pyroptosis via the TAK1/JNK signaling pathway.

The present study aimed to investigate the protective effects of sacubitril/valsartan (LCZ696) on ventricular remodeling in myocardial infarction (MI) and the effects of the inflammasome­mediated inflammatory response. First, a rat model was established. Animals were then treated with LCZ696 so that the histopathological changes associated with ventricular remodeling could be investigated. The serum levels of the inflammatory factors IL­18 and IL­1ß were also determined by ELISA. Immunofluorescence was used to investigate the ratio of pyroptosis following MI modelling. Western blotting and reverse transcription­quantitative PCR were used to detect the relative expression levels of proteins and mRNAs in the transforming growth factor ß­activated kinase­1 (TAK1)/JNK pathway and those associated with the NLR pyrin family domain containing 3 (NLRP3) inflammasome, respectively. The present study also investigated the regulatory mechanisms and associations between the TAK1 and JNK pathways, NOD­, leucine­rich repeat­ and the NLRP3 inflammasome, in H9C2 cells and myocardial cells from the rat model of MI. LCZ696 improved MI­induced myocardial fibrosis, rescued myocardial injury and suppressed the release of inflammatory factors. With regards to myocardial cell damage, pyroptosis in cardiomyocytes was observed. The in vitro experiments demonstrated that the overexpression of TAK1 promoted lysis of the N­terminal of GSDMD, thereby activating the NLRP3 inflammasome and promoting the conversion of pro­IL­1ß and pro­IL­18 into mature IL­1ß and IL­18, respectively. In contrast, the silencing of TAK1 inhibited the expression levels of the NLRP3 inflammasome. In summary, LCZ696 reduced the expression levels of the NLRP3 inflammasome, suppressed inflammatory responses, improved the ventricular remodeling and exhibited protective effects in the MI heart by inhibiting the TAK1/JNK signaling pathway.

Curcumin analog B14 has high bioavailability and enhances the effect of anti-breast cancer cells in vitro and in vivo.

Curcumin has a variety of anticancer properties, but low bioavailability prevents its use in chemotherapeutic applications. To address this problem, we tested the efficacy of the synthetic curcumin analog B14 in breast cancer cells and explored the mechanism by which B14 inhibits proliferation and metastasis of breast cancer cells. We used the breast cancer cell line MCF-7, MDA-MB-231 to study the anticancer effects of B14 and assessed cell viability, cell migration and invasion, cell cycle, and apoptosis, in addition, the antitumor effect of B14 in vivo was examined in mice bearing MDA-MB-231 cells. We found that, as the concentration of B14 increased, cell viability decreased in a dose-dependent manner. Compound B14 exerted the best antitumor activity and selectivity for MCF-7 and MDA-M-231 cells (IC50  = 8.84 µmol/L and 8.33 µmol/L, respectively), while its IC50 value for MCF-10A breast epithelial cells was 34.96 µmol/L. B14 has been shown to be a multi-targeted drug that alters the expression of cyclin D1, cyclin E1, and cyclin-dependent kinase 2 (CDK2), and ultimately induces G1 phase cell cycle arrest. At the same time, B14 activates the mitochondrial apoptosis pathway in breast cancer cells. Furthermore, B14 was more effective than curcumin in inhibiting cell migration, invasion, and colony formation. In tumor-bearing mice, analog B14 significantly reduced tumor growth and inhibited cell proliferation and angiogenesis. The pharmacokinetic test found that B14 was more stable than curcumin in vivo. Our data reveal the therapeutic potential of the curcumin analog B14 and the underlying mechanisms to fight breast cancer cells.

The durability of carbon nanotubes in the selective reduction of nitrobenzene.

Surface oxidized carbon nanotubes (oCNTs) were quite stable for the selective reduction of nitrobenzene, while notable deactivation was observed for the un-oxidized sample (rCNTs). The adsorption of N-containing compounds had a negligible effect, but the formation of a carboxyl group and anhydride was mainly responsible for the deactivation of rCNTs.

AdipoRon Alleviates Free Fatty Acid-Induced Myocardial Cell Injury Via Suppressing Nlrp3 Inflammasome Activation.

BACKGROUND: Hypoadiponectinemia is a high risk factor for type 2 diabetes and cardiovascular disease. Although adiponectin is a protective molecule in cardiovascular diseases, it is hampered due to short plasma half-life and high cost of production. This study aimed to investigate whether AdipoRon, a small-molecule adiponectin receptor agonist, alleviated saturated free fatty acids such as palmitic acid (PA)-induced cardiomyocyte injury by suppressing Nlrp3 inflammasome activation. METHODS: Cell viability was used with MTT assay. Cell apoptosis and mitochondria membrane potential were detected by flow cytometry. We also detected the ROS production and colocolization of inflammasome protein with fluorescence and immunofluorescence microscopic analysis, respectively. Then, IL-1ß was detected by Elisa assay and other protein expression was analyzed by Western blot. RESULTS: Our observations demonstrated PA dose-dependently promoted the cell injury, and such high lipotoxicity induced impairment of cardiomyocytes was significantly attenuated by AdipoRon treatment. Moreover, PA markedly activated the first phase of Nlrp3 inflammasome (NF-ƙb) signaling. Notably, the stimulation of PA enhanced ROS production as regulators of Nlrp3 inflammasome activation. In addition, treatment with PA increased the Nlrp3 inflammasome protein expression and complex formation, while AdipoRon abolished it. Lastly, the suppressive effect of AdipoRon to PA-induced cell injury and Nlrp3 inflammasome activation was significantly reversed by Nlrp3 siRNA and pan-caspase inhibitor (z-vad-fmk). CONCLUSION: Taken together, these data suggested that AdipoRon suppressed PA-induced myocardial cell injury by suppressing Nlrp3 inflammasome activation. Thus, AdipoRon might possess potent protective effect in lipotoxicity injury such as obesity leading to cardiac disease.

The synergistic effect of 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside combined with Adriamycin on MCF-7 breast cancer cells.

OBJECTIVE: Breast cancer has been reported to be a serious disease and a threat to women's health. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside (THSG) is a bioactive natural compound originating from Polygonum multiflorum Thunb., which has been shown to possess anti-inflammatory and antitumor properties. Adriamycin (ADM) is a chemotherapy agent used in tumor therapy that is limited by its side effects. However, little is known about the synergistic effect of THSG combined with ADM on breast cancer. This study seeks to investigate the effects of the combination of THSG plus ADM on MCF-7 breast cancer cells and to test the mechanisms involved. MATERIALS AND METHODS: MTT assay was detected to determine cell viability. Furthermore, cell apoptosis was tested by flow cytometry and TUNEL assay. In addition, protein expression was measured by Western blot analysis. RESULTS: The individual treatment of THSG and ADM induced cell injury. Moreover, cotreatment further increased it, which the effect may be associated with the elevation of the apoptotic-related protein expression such as Bax/Bcl-2 and cleaved caspase-3/caspase-3. Lastly, our results also show the reduction of vascular endothelial growth factor/phosphatidylinositol 3-kinase/Akt protein expression in the individual or synergistic treatment. CONCLUSION: Taken together, cotreatment of THSG and ADM may exert a synergistic reduction of cell injury via the inhibition of vascular endothelial growth factor/phosphatidylinositol 3-kinase/Akt pathway. Thus, THSG might possess potent anti-breast cancer effect with ADM.

[Driving force analysis of land use change in the developed area based on Probit regression model: A case study of Nanjing City, China].

Based on the remote sensing image in 1996, 2002 and 2010, with the help of RS and GIS technology, and using the Probit regression model, this paper analyzed the characteristics of land use change in Nanjing City from 1996 to 2010, and the driving factors of land use change. The results showed that the cultivated land and woodland decreased, constructive land, garden plot and grassland continued to increase, and the comprehensive land use change rate was rising since 1996. The results of regression model for cultivated land and woodland change indicated that the change of cultivated land in the years 1996-2002 was mainly affected by the factors of "distance to the nearest rural settlement" and "farmers' population density". However, in the years 2002-2010 it was mainly affected by the factors of "change of per area GDP", "distance to the rural settlement" and "distance to the nearest road". The change of woodland in the years 1996-2002 was mainly affected by the factors of "the elevation" and "distance to the rural settlement". However, in the years 2002-2010 it was mainly affected by the factors of "change of per area GDP", "population density" and "distance to the nearest road". By comparison, the early driving factors of land use change were mainly natural factors, but in recent years, they were mainly social, economic and demographic factors.

Inhibitory effect of midkine-binding peptide on tumor proliferation and migration.

BACKGROUND: To investigate the inhibitory effect of midkine-binding peptides on human umbilical vein endothelial cells (HUVECs) proliferation and angiogenesis of xenograft tumor. METHODS: The midkine-binding peptides were panned by Ph.D.-7(™) Phage Display Peptide Library Kit, and the specific binding activities of positive clones to target protein were examined by phage ELISA. The effect of midkine-binding peptides on proliferation of HUVECs was confirmed by MTT test. The xenograft tumor model was formed in BALB/c mice with the murine hepatocarcinoma cells H22 (H22). Microvessel density (MVD) was analyzed by immunohistochemistry of factor VIII staining. RESULTS: Midkine-binding peptides have the inhibitory effects on tumor angiogenesis, a proliferation assay using human umbilical vein endothelial cells (HUVECs) indicated that particular midkine-binding peptides significantly inhibited the proliferation of the HUVECs. Midkine-binding peptides were also observed to efficiently suppress angiogenesis induced by murine hepatocarcinoma H22 cells in BALB/c nude mice. CONCLUSION: The midkine-binding peptides can inhibit solid tumor growth by retarding the formation of new blood vessels. The results indicate that midkine-binding peptides may represent potent anti-angiogenesis agents in vivo.