ABSTRACT
Transcriptional regulation of inducible nitric oxide synthase (iNOS) is critically involved in the pathogenesis and progression of rheumatoid arthritis (RA); however, the specific ...transcription factors that control this process remain largely unidentified. In the present study, it was discovered that expression of the key erythroid factor, globin transcription factor 1 (GATA1), is significantly greater in human RA synovial tissues than in osteoarthritis (OA) tissues. IL 6 was found to induce synovial GATA1 expression in a signal transducer and activator of transcription 3‐dependent manner. Functionally, knockdown of GATA1 expression using specific small interfering RNA treatment was found to compromise immunoreaction‐elicited expression of proinflammatory cytokines and thus impair invasiveness of the human fibroblast‐like synovial cell line MH7A, whereas introduction of exogenous GATA1 was found to promote production of proinflammatory cytokines, leading to greater aggressiveness of MH7A cells. Mechanistically, GATA1 acts as the transcriptional coactivator of NOS2 (the gene encoding iNOS) transcription. Collectively, these data suggest that synovial GATA1 is an essential contributor to development and exacerbation of RA, presumably by inducing NOS2 transcription.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 ...(PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.
The ketogenic diet (KD) is a high-fat, very-low-carbohydrate diet that triggers a fasting state by decreasing glucose and increasing ketone bodies, such as β-hydroxybutyrate (βHB). In experimental ...models and clinical trials, the KD has shown anti-tumor effects, possibly by reducing energy supplies to cells, which damage the tumor microenvironment and inhibit tumor growth. Here, we determined expression levels of genes encoding the ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase 1 (OXCT1) in 33 human cancer cell lines. We then selected two representative lines, HeLa and PANC-1, for in vivo examination of KD sensitivity in tumors with high or low expression, respectively, of these two enzymes. In mice with HeLa xenografts, the KD increased tumor growth and mouse survival decreased, possibly because these tumors actively consumed ketone bodies as an energy source. Conversely, the KD significantly inhibited growth of PANC-1 xenograft tumors. βHB added to each cell culture significantly increased proliferation of HeLa cells, but not PANCI-1 cells. Downregulation of both BDH1 and OXCT1 rendered HeLa cells sensitive to the KD in vitro and in vivo. Tumors with low ketolytic enzyme expression may be unable to metabolize ketone bodies, thus predicting a better response to KD therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
LPL (lipoprotein lipase) is a rate-limiting enzyme involved in the hydrolysis of triglycerides. Previous studies have shown that microRNA (miR)-467b regulates hepatic LPL expression and plays a role ...in the progression of steatosis or abnormal lipid retention in obese mice. Macrophage-derived LPL has been shown to promote atherosclerosis. However, if miR-476b influences macrophage LPL expression and the subsequent effects are unknown. Here, we utilized oxLDL-treatment RAW 264.7 macrophages that were transfected with miR-467b mimics or inhibitors to investigate the potential roles of macrophage miR-476b. We found that miR-467b significantly decreased lipid accumulation and IL-6, IL-1β, TNF-α and MCP-1 secretions. Furthermore, our studies suggested an additional explanation for the regulatory mechanism of miR-467b on its functional target, LPL in RAW 264.7 macrophages. Thus, our findings indicate that miR-467b may regulate lipid accumulation and proinflammatory cytokine secretion in oxLDL-stimulated RAW 264.7 macrophages by targeting the LPL gene.
► MiR-467b reduces lipid accumulation and proinflammatory cytokine secretion in cell. ► MiR-467b specifically targets LPL by binding to its 3′UTR. ► LPL mediated lipid accumulation and proinflammatory cytokine secretion by miR-467b. ► MiR-467b may regulate the development of atherosclerosis by targeting LPL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Stimuli‐responsive DNA hydrogels are promising candidates for cancer treatment, as they not only possess biocompatible and biodegradable 3D network structures as highly efficient carriers for ...therapeutic agents but also are capable of undergoing programmable gel‐to‐solution transition upon external stimuli to achieve controlled delivery. Herein, a promising platform for highly efficient photothermal‐chemo synergistic cancer therapy is established by integrating DNA hydrogels with Ti3C2TX‐based MXene as a photothermal agent and doxorubicin (DOX) as a loaded chemotherapeutic agent. Upon the irradiation of near‐infrared light (NIR), temperature rise caused by photothermal MXene nanosheets triggers the reversible gel‐to‐solution transition of the DOX‐loaded MXene‐DNA hydrogel, during which the DNA duplex crosslinking structures unwind to release therapeutic agents for efficient localized cancer therapy. Removal of the NIR irradiation results in the re‐formation of DNA duplex structures and the hydrogel matrix, and the recombination of free DOX and adaptive hydrogel transformations can also be achieved. As demonstrated by both in vitro and in vivo models, the MXene‐DNA hydrogel system, with excellent biocompatibility and injectability, dynamically NIR‐triggered drug delivery, and enhanced drug uptake under mild hyperthermia conditions, exhibits efficient localized cancer treatment with fewer side effects to the organisms.
A photothermal‐chemo synergistic therapy system for localized cancer treatment is established by integrating responsive DNA hydrogel with MXene as the photothermal agent and doxorubicin as the chemotherapeutic agent. With excellent biocompatibility and biodegradability, good injectability, and highly efficient near‐infrared irradiation‐triggered drug delivery and uptake, the system exhibits efficient localized cancer treatment with less side effects to the organisms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
6.
Risk Factors and Preventions of Breast Cancer Sun, Yi-Sheng; Zhao, Zhao; Yang, Zhang-Nv ...
International journal of biological sciences,
01/2017, Volume:
13, Issue:
11
Journal Article
Peer reviewed
Open access
Breast cancer is the second leading cause of cancer deaths among women. The development of breast cancer is a multi-step process involving multiple cell types, and its prevention remains challenging ...in the world. Early diagnosis of breast cancer is one of the best approaches to prevent this disease. In some developed countries, the 5-year relative survival rate of breast cancer patients is above 80% due to early prevention. In the recent decade, great progress has been made in the understanding of breast cancer as well as in the development of preventative methods. The pathogenesis and tumor drug-resistant mechanisms are revealed by discovering breast cancer stem cells, and many genes are found related to breast cancer. Currently, people have more drug options for the chemoprevention of breast cancer, while biological prevention has been recently developed to improve patients' quality of life. In this review, we will summarize key studies of pathogenesis, related genes, risk factors and preventative methods on breast cancer over the past years. These findings represent a small step in the long fight against breast cancer.
ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 ...epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inorganic perovskite ferroelectrics are widely used in nonvolatile memory elements, capacitors, and sensors because of their excellent ferroelectric and other properties. Organic ferroelectrics are ...desirable for their mechanical flexibility, low weight, environmentally friendly processing, and low processing temperatures. Although almost a century has passed since the first ferroelectric, Rochelle salt, was discovered, examples of highly desirable organic perovskite ferroelectrics are lacking. We found a family of metal-free organic perovskite ferroelectrics with the characteristic three-dimensional structure, among which MDABCO (
-methyl-
-diazabicyclo2.2.2octonium)-ammonium triiodide has a spontaneous polarization of 22 microcoulombs per square centimeter close to that of barium titanate (BTO), a high phase transition temperature of 448 kelvins (above that of BTO), and eight possible polarization directions. These attributes make it attractive for use in flexible devices, soft robotics, biomedical devices, and other applications.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Compare with preterm formula, donor human milk (DM) is associated with a lower risk of mortality and morbidity in preterm infants. It is thus deemed superior to preterm formula as the sole diet or ...supplement to own mother's milk (OMM) for preterm infants, especially for those with very low birthweight (VLBW). This historic cohort study investigated the relationship between DM availability, and enteral feeding, body growth of VLBW infants by comparing two cohorts before and after the establishment of a human milk bank. A sub‐analysis was also conducted between small‐for‐gestational‐age (SGA) and non‐SGA infants in our cohorts. Our results showed that DM availability was associated with earlier initiation and faster advancement of enteral feeding, earlier attainment of full enteral feeding, and a higher proportion of OMM in enteral feeding. DM availability was also associated with earlier regain of birthweight, but not with better body growth. SGA and non‐SGA infants responded differently to DM availability with only the non‐SGA group showing improved enteral feeding associated with DM availability. The poor growth of VLBW infants with fortified DM warrants further investigations on better fortification strategies to further improve body growth. Studies are also needed on long‐term effects of DM feeding on the development of VLBW infants.
Compared with the infants before the introduction of donor human milk (DM), very low birthweight infants after that had improved enteral feeding process and had increased use of own mother's milk in this study. However, DM availability affects body growth to a limited extent, which calls for a better fortification strategy for DM‐fed infants.
Key points
Compared with the infants before the introduction of donor human milk (DM), very low birthweight infants after that had improved enteral feeding process, shown as earlier enteral feeding introduction, faster advancement, and earlier attainment of full enteral feeding.
DM availability affects body growth to a limited extent, which calls for a better fortification strategy for DM‐fed infants.
The setup of a human donor milk bank increased the use of own mother's milk for enteral feeding.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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