Circular RNA 0007255 regulates the progression of breast cancer through miR-335-5p/SIX2 axis.

BACKGROUND: Breast cancer (BC) is a common cancer in women worldwide. Emerging evidence has indicated that circular RNA hsa-circ_0007255 (circ_0007255) is a prognostic mediator in BC progression. However, the functional role of circ_0007255 needs to be determined. METHODS: The expression of circ_0007255, microRNA (miR)-335-5p, and SIX Homeobox 2 (SIX2) was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Actinomycin D and RNase R treatment was performed to analyze the stability of circ_0007255. Additionally, Seahorse extracellular flux, colony formation and transwell analyses were carried out to detect oxygen consumption ratio (OCR), colony formation and cell mobility, respectively. The interaction between miR-335-5p and circ_0007255 or SIX2 was confirmed via dual-luciferase reporter assay. A xenograft tumor model was established to explore the role of circ_0007255 in vivo. RESULTS: Circ_0007255 and SIX2 were overexpressed, but miR-335-5p was diminished in BC tissues and cells. Circ_0007255 absence inhibited oxygen consumption, colony formation, cell migration and invasion, and these effects were particularly abrogated via miR-335-5p upregulation in BC cells. Moreover, SIX2 deficiency eliminated the promotion effects of miR-335-5p inhibitor on oxygen consumption, colony formation, and cell mobility in BC cells. Importantly, circ_0007255 inhibited tumor growth in vivo. Mechanically, circ_0007255 was a sponge of miR-335-5p to regulate SIX2 expression in BC progression. CONCLUSION: Circ_0007255 functioned as a novel oncogene in the progression of BC by regulating miR-335-5p/SIX2 axis, and might be a promising biomarker for BC treatment. KEY POINTS: Significant findings of the study: Levels of circ_0007255 and SIX2 were upregulated, but miR-335-5p was diminished in BC tissues and cells. Circ_0007255 was an oncogene in BC development and exerted its function via miR-335-5p/SIX2 axis in BC. Tumor growth was reduced by circ_0007255 absence. WHAT THIS STUDY ADDS: Circ_0007255 functioned as a novel oncogene in the progression of BC by regulating miR-335-5p/SIX2 axis, and might be a promising biomarker for BC treatment.

Transcriptomic analysis reveals key factors in fruit ripening and rubbery texture caused by 1-MCP in papaya.

BACKGROUND: Ethylene promotes fruit ripening whereas 1-methylcyclopropene (1-MCP), a non-toxic antagonist of ethylene, delays fruit ripening via the inhibition of ethylene receptor. However, unsuitable 1-MCP treatment can cause fruit ripening disorders. RESULTS: In this study, we show that short-term 1-MCP treatment (400 nL•L- 1, 2 h) significantly delays papaya fruit ripening with normal ripening characteristics. However, long-term 1-MCP treatment (400 nL•L- 1, 16 h) causes a "rubbery" texture of fruit. The comparative transcriptome analysis showed that a total of 5529 genes were differently expressed during fruit ripening compared to freshly harvested fruits. Comprehensive functional enrichment analysis showed that the metabolic pathways of carbon metabolism, plant hormone signal transduction, biosynthesis of amino acids, and starch and sucrose metabolism are involved in fruit ripening. 1-MCP treatment significantly affected fruit transcript levels. A total of 3595 and 5998 differently expressed genes (DEGs) were identified between short-term 1-MCP, long-term 1-MCP treatment and the control, respectively. DEGs are mostly enriched in the similar pathway involved in fruit ripening. A large number of DEGs were also identified between long-term and short-term 1-MCP treatment, with most of the DEGs being enriched in carbon metabolism, starch and sucrose metabolism, plant hormone signal transduction, and biosynthesis of amino acids. The 1-MCP treatments accelerated the lignin accumulation and delayed cellulose degradation during fruit ripening. Considering the rubbery phenotype, we inferred that the cell wall metabolism and hormone signal pathways are closely related to papaya fruit ripening disorder. The RNA-Seq output was confirmed using RT-qPCR by 28 selected genes that were involved in cell wall metabolism and hormone signal pathways. CONCLUSIONS: These results showed that long-term 1-MCP treatment severely inhibited ethylene signaling and the cell wall metabolism pathways, which may result in the failure of cell wall degradation and fruit softening. Our results reveal multiple ripening-associated events during papaya fruit ripening and provide a foundation for understanding the molecular mechanisms underlying 1-MCP treatment on fruit ripening and the regulatory networks.

The interaction of CpEBF1 with CpMADSs is involved in cell wall degradation during papaya fruit ripening.

Ethylene plays a pivotal role in climacteric fruit ripening; whereas 1-MCP, a non-toxic antagonist of ethylene, prevents ethylene-dependent responses and fruit ripening. In this study, a short-term treatment (1 h) with 400 nL L-1 1-MCP delayed the ripening of harvested papaya. However, long-term application of 1-MCP (400 nL L-1, 16 h) resulted in abnormal fruit ripening, with the fruits exhibiting normal yellowing without softening, significantly higher cellulose and lignin contents, and intact cell walls (CW). Furthermore, we found that long-term treatment with 1-MCP significantly inhibited the expression of CpEBF1, an EIN3-binding F-box-1 gene. A protein interaction analysis using yeast two-hybrid, BiFC and GST pull-down assays showed that CpEBF1 interacts with the CpMADS1/3 and CpEIL1 proteins. The interaction of CpEBF1 with CpMADS1/3 further activated the activities of CW-degradation gene promoters. Subcellular localization showed that these proteins were localized in the nucleus. Additionally, the expression levels of CpMADS1/3, CpEIL1, and several CW-degradation-related genes were significantly downregulated by long-term 1-MCP treatment. Therefore, we propose that the inhibited expression of CpEBF1 and CpMADS1/3 resulted in the repressed activation of CW-degradation-related genes via their interaction, thereby resulting in fruit softening disorders.

Anti-IgE therapy for IgE-mediated allergic diseases: from neutralizing IgE antibodies to eliminating IgE+ B cells.

Allergic diseases are inflammatory disorders that involve many types of cells and factors, including allergens, immunoglobulin (Ig)E, mast cells, basophils, cytokines and soluble mediators. Among them, IgE plays a vital role in the development of acute allergic reactions and chronic inflammatory allergic diseases, making its control particularly important in the treatment of IgE-mediated allergic diseases. This review provides an overview of the current state of IgE targeted therapy development, focusing on three areas of translational research: IgE neutralization in blood; IgE-effector cell elimination; and IgE+ B cell reduction. IgE-targeted medicines such as FDA approved drug Xolair (Omalizumab) represent a promising avenue for treating IgE-mediated allergic diseases given the pernicious role of IgE in disease progression. Additionally, targeted therapy for IgE-mediated allergic diseases may be advanced through cellular treatments, including the modification of effector cells.

The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression.

Currently, there is a considerable need to develop new treatments for osteosarcoma (OS), a very aggressive bone cancer. The activation of STAT3 signaling is positively associated with poor prognosis and aggressive progression in OS patients. Our previous study reported that the FDA-approved antipsychotic drug pimozide had anti-tumor activity against hepatocellular carcinoma and prostate cancer cells by suppressing STAT3 activity. Therefore, the aim of this study was to investigate the specific effect of pimozide on OS cells and the underlying molecular mechanism. Pimozide inhibited cell proliferation, colony formation, and sphere formation capacities of the OS cells in a dose-dependent manner, inducing G0/G1 phase cell cycle arrest. Pimozide reduced the percentage of side population cells representing cancer stem-like cells and enhanced the sensitivity of OS cells to 5-FU induced proliferative inhibition. In addition, pimozide induced apoptosis of U2OS cells, which showed increased expression of cleaved-PARP, a marker of programmed cell death. Moreover, pimozide suppressed Erk signaling in OS cells. Importantly, pimozide induced ROS generation by downregulating the expression of the antioxidant enzyme catalase (CAT). NAC treatment partially reversed the ROS generation and cytotoxic effects induced by pimozide. CAT treatment attenuated the pimozide-induced proliferation inhibition. The decrease of CAT expression induced by pimozide was potentially mediated through the suppression of cellular STAT3 activity in OS cells. Thus, pimozide may be a novel STAT3 inhibitor that suppresses cellular STAT3 activity to inhibit OS cells or stem-like cells and is a novel potential anti-cancer agent in OS treatment.

Pains and Gains from China's Experiences with Emerging Epidemics: From SARS to H7N9.

Over the recent decades, China experienced several emerging virus outbreaks including those caused by the severe acute respiratory syndrome- (SARS-) coronavirus (Cov), H5N1 virus, and H7N9 virus. The SARS tragedy revealed faults in China's infectious disease prevention system, propelling the Chinese government to enact reforms that enabled better combating of the subsequent H1N1 and H7N9 avian flu epidemics. The system is buttressed by three fundamental, mutually reinforcing components: (1) enduring government administration reforms, including legislation establishing a unified public health emergency management system; (2) prioritized funding for biotechnology and biomedicine industrialization, especially in the areas of pathogen identification, drug production, and the development of vaccines and diagnostics; and (3) increasing investment for public health and establishment of a rapid-response infectious diseases prevention and control system. China is now using its hard-gained experience to support the fight against Ebola in Africa and the Middle East Respiratory Syndrome in its own country.

The relationship between the expression of ethylene-related genes and papaya fruit ripening disorder caused by chilling injury.

Papaya (Carica papaya L.) is sensitive to low temperature and easy to be subjected to chilling injury, which causes fruit ripening disorder. This study aimed to investigate the relationship between the expression of genes related to ethylene and fruit ripening disorder caused by chilling injury. Papaya fruits were firstly stored at 7°C and 12°C for 25 and 30 days, respectively, then treated with exogenous ethylene and followed by ripening at 25°C for 5 days. Chilling injury symptoms such as pulp water soaking were observed in fruit stored at 7°C on 20 days, whereas the coloration and softening were completely blocked after 25 days, Large differences in the changes in the expression levels of twenty two genes involved in ethylene were seen during 7°C-storage with chilling injury. Those genes with altered expression could be divided into three groups: the group of genes that were up-regulated, including ACS1/2/3, EIN2, EIN3s/EIL1, CTR1/2/3, and ERF1/3/4; the group of genes that were down-regulated, including ACO3, ETR1, CTR4, EBF2, and ERF2; and the group of genes that were un-regulated, including ACO1/2, ERS, and EBF1. The results also showed that pulp firmness had a significantly positive correlation with the expression of ACS2, ACO1, CTR1/4, EIN3a/b, and EBF1/2 in fruit without chilling injury. This positive correlation was changed to negative one in fruit after storage at 7°C for 25 days with chilling injury. The coloring index displayed significantly negative correlations with the expression levels of ACS2, ACO1/2, CTR4, EIN3a/b, ERF3 in fruit without chilling injury, but these correlations were changed into the positive ones in fruit after storage at 7°C for 25 days with chilling injury. All together, these results indicate that these genes may play important roles in the abnormal softening and coloration with chilling injury in papaya.