Radiotherapy significantly improves the therapeutic outcomes and survival of breast cancer patients. However, the acquired resistance to this therapeutic modality is a major clinical challenge. Here we show that ionizing irradiation (IR)-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) at the Tyr705 residue and the induction of reactive oxygen species (ROS) in wild-type and radioresistant MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) cell lines. Comparing with radiosensitive parental TNBC cells, significantly low levels of ROS and higher protein levels of phospho-STAT3 and Bcl-2 were observed in TNBC cells with acquired radioresistance. Moreover, knockdown of STAT3 by shRNA sensitized the TNBC cells to IR. Niclosamide, a potent inhibitor of STAT3, overcame the radioresistance in TNBC cells via inhibition of STAT3 and Bcl-2 and induction of ROS. In combination with radiation, niclosamide treatment resulted in significant increase of ROS generation and induction of apoptosis in parental and radioresistant TNBC cells in vitro and TNBC xenograft tumors in vivo. These findings demonstrate that activation of STAT3 and Bcl-2 and reduction of ROS contribute to the development of radioresistance in TNBC, and niclosamide acts as a potent radiosensitizer via inhibiting STAT3 and Bcl-2 and increasing ROS generation in TNBC cells and xenograft tumors. Our findings suggest that niclosamide in combination with irradiation may offer an effective alternative approach for restoring the sensitivity of radioresistant TNBC cells to IR for improved therapeutic efficacy and outcomes.

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This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. AbstractObjectives: This research aims to verify that the long non-coding RNA differentiation antagonizing nonprotein coding RNA (LncRNA DANCR) could modulate the proliferation and metastasis of hepatocellular carcinoma (HCC), and it thus may work as a novel biomarker to render new orientation for early diagnosis and clinical therapy of HCC. Materials and methods:Firstly, qRT-PCR was used to detect the expression of genes including LncRNA DANCR and miR-27a-3p. Next, MTT assay, Ethynyldeoxyuridine (EdU) analysis and clone formation assay were used for investigating cell growth and proliferation. Meanwhile, transwell assay and wound healing assay were applied to evaluate the capacity of cell metastasis and motility, respectively. In addition, bioinformatic analysis and dual-luciferase reporter assay were applied to analyse molecular interaction. Next, we conducted immunofluorescence and Western blot for mechanic investigation. Last but not the least, xenograft tumours in nude mice were built by subcutaneously injecting Hep3B cells stably transfected with sh-NC and sh-DANCR to detect proliferation and SMMC-7721 cells stably transfected with sh-NC and sh-DANCR to investigate metastasis. Results:The results of qRT-PCR and bioinformatic analysis revealed the high expression of DANCR in HCC. DANCR accelerated proliferation and metastasis of HCC cells and the knockdown of DANCR had the opposite effect. Meanwhile, xenograft tumours in sh-DANCR group grow slower and have smaller volumes compared with negative control group. Next, the antineoplastic effect of miR-27a-3p on cell growth and motility of HCC was confirmed. In addition, we clarified that DANCR acted as a ceRNA to decoy miR-27a-3p via mediating ROCK1/LIMK1/COFILIN1 pathway. In the end, we validated that DANCR/miR-27a-3p axis regulates EMT progression by cell immunofluorescence and Western blot. Conclusions:In a word, DANCR promotes HCC development and induces EMT by decoying miR-27a-3p to regulate ROCK1/LIMK1/COFILIN1 pathway.

Hepatitis B virus X protein (HBx) is a multifunctional protein, and it activates multiple signal transduction pathways in multiple types of cells and regulates the process of cell apoptosis. In the present study, we mainly investigated the correlation between HBx and renal tubular epithelial cell apoptosis in hepatitis B virus-associated glomerulonephritis (HBVGN) and the possible signaling mechanism. Cell apoptosis in nephridial tissues of patients with HBVGN were determined by the TUNEL method. HBx, p-STAT3 and STAT3 levels in nephridial tissues were determined by immunohistochemical assay, and a correlation analysis between HBx expression levels and apoptosis index in nephridial tissues was conducted. The activation of the JAK2/STAT3 signaling pathway in HK-2 cells and the expression of the apoptosis-related proteins Bax and Bcl-2 were determined by western blot analysis following transfection with the HBx eukaryotic expression vector. Cellular proliferation activity was determined by the CCK-8 method, and cell apoptosis was determined with HO33342 staining using transmission electron microscopy and Annexin V/PI double staining flow cytometry. The results revealed that the apoptosis index in nephridial tissues of patients with HBVGN was significantly higher when compared to that of the control group, and p-STAT3 expression levels in HBVGN nephridial tissues were significantly increased. In the control group, no HBx expression was observed in the nephridial tissues, whereas HBx expression was found in the nephridial tissues of 86% of the patients with HBVGN. The HBx expression levels had a linear correlation with the apoptosis index in the nephridial tissues. After target gene HBx infection, expression levels of both p-JAK2 and p-STAT3 in human proximal HK-2 cells were significantly increased, and the Bax/Bcl-2 ratio was also significantly increased. At the same time, cellular proliferation of HK-2 cells was significantly inhibited, and the rate of apoptosis was increased. After incubation with AG490, the JAK2/STAT3 signaling pathway was partially blocked, which caused a decrease in the Bax/Bcl-2 ratio and reduced cell apoptosis caused by HBx. In conclusion, HBx upregulates the Bax/Bcl-2 ratio by activating the JAK2/STAT3 signaling pathway to cause renal tubular epithelial cell apoptosis, and it is possibly involved in the pathogenic mechanism of nephridial tissue damage caused by HBV.

In recent decades, reduced antimicrobial effectiveness, increased bacterial infection, and newly emerged microbial resistance have become global public issues, leading to an urgent need to find effective strategies to counteract these problems. Strategies targeting bacterial virulence factors rather than bacterial survival have attracted increasing interest, since the modulation of virulence factors may prevent the development of drug resistance in bacteria. Spices are promising natural sources of antivirulence compounds owing to their wide availability, diverse antivirulence phytochemical constituents, and generally favorable safety profiles. Essential oils are the predominant and most important antivirulence components of spices. This review addresses the recent efforts of using spice essential oils to inhibit main bacterial virulence traits, including the quorum sensing system, biofilm formation, motility, and toxin production, with an intensive discussion of related mechanisms. We hope that this review can provide a better understanding of the antivirulence properties of spice essential oils, which have the potential to be used as antibiotic alternatives by targeting bacterial virulence. K E Y W O R D Sbiofilm, mechanisms, motility, quorum sensing, spice essential oils, toxin 1018

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Although whey protein hydrolysate (WPH) possesses good physiological functionality, its bitter taste and hygroscopic property limit its direct utilization as food ingredient. The aim of this work was to encapsulate whey protein hydrolysate by spray drying using maltodextrin or maltodextrin/b-cyclodextrin mixture as wall materials to attenuate the bitter taste and enhance the stability of whey protein hydrolysate. Hygroscopicity, glass transition temperature, bitter taste, and morphology of non-encapsulated WPH and encapsulated WPH were evaluated. Solubility, particle size, bulk density, and moisture content were also measured. Compared with the non-encapsulated WPH, the encapsulated WPH exhibited significantly lower hygroscopicity and higher glass transition temperature. The bitterness of both maltodextrin-encapsulated WPH and maltodextrin/b-cyclodextrin-encapsulated WPH was significantly lower than that of the original non-encapsulated WPH. Morphological analysis by scanning electron microscopy showed that the microcapsules of the spraydried encapsulated WPH were matrix-type with less link bridge and had a continuous wall with many concavities. In addition, encapsulation process did not exert negative effect on the solubility of whey protein hydrolysate. The results indicated that encapsulation with maltodextrin and b-cyclodextrin as carriers was helpful to attenuate the bitter taste and enhance the stability of whey protein hydrolysate.