关键词： apoptosis   cancer cells   free radicals   monoydroxyflavones   silica nanoparticles   ADAPTIVE-RESPONSE GENE   TERMINAL KINASE JNK   DIETARY FLAVONOIDS   C-JUN   CANCER   PATHWAYS   ATF3   QUERCETIN   PROTEIN   PROLIFERATION  

摘要： The treatment of drug-resistant cancer is a clinical challenge, hence screening for novel anticancer drugs is critically important. In this study, we investigated the anti-tumor potential of three plant-derived flavone compounds: 3-hydroxy flavone (3-HF), 6-hydroxy flavone (6-HF), and 7-hydroxy flavone (7-HF), either alone or combined with silica nanoparticles (3-HF + NP, 6-HF + NP, and 7-HF + NP), on the human breast carcinoma cell lines MDA-MB-231 and MCF-7, as well as on non-tumorigenic normal breast epithelial cells (MCF-10). The IC50 values of these flavone compounds loaded with NP (flavones + NP) in these cell lines were determined to be 1.5 mu/mL without affecting the viability of normal MCF-10 cells. Additionally, using annexin V - opidium iodide double-staining followed by flow cytometry analysis, we found that the combination of flavones with NP significantly induced apoptosis in MCF-7 and MDA-MB-231 cancer cells. Furthermore, flavones + NP increased the expression of cytochrome c and caspase-9, mediating the growth arrest of these cancer cells. Most importantly, the combination of flavones with NP significantly abolished the expression of ATF-3, which is responsible for the proliferation and invasion of bone-mastatic breast cancer cells. Our data revealed the potential therapeutic effects of these flavones in fighting breast cancer cells, and provide the first insights concerning the underlying molecular mechanisms.

关键词： Oxaliplatin   Metformin   Neurotoxicity   PAIN   NEUROTOXICITY   RAT   ACTIVATION   MECHANISMS   PLASTICITY   DIAGNOSIS   MARKER   AMPK  

摘要： Oxaliplatin is a third-generation platinum drug commonly used as the first line treatment of metastatic colorectal cancer. Oxaliplatin-based anticancer regimens course with dose-limiting neurotoxicity. The pharmacological strategies used to manage such side effect are not totally effective. Metformin is an anti-diabetic drug that is described to negatively modulate painful diabetic neuropathy. Then, this study aimed to assess the effect of metformin in the oxaliplatin-induced peripheral sensory neuropathy in mice. For that purpose, Swiss male mice were injected with oxaliplatin (1, 2 or 4 mg/kg, i.v., twice a week with a total of nine injections) alone or in combination with daily administration of metformin (250 mg/kg, p.o.). Thermal and mechanical nociceptive tests were performed once a week for five weeks. Then, the animals were euthanized on day 35 post-first injection of oxaliplatin and the dorsal root ganglia were harvested for the assessment of c-Fos and ATF3 expressions. Oxaliplatin caused a nociceptive response accompanied by the increased expression of c-Fos and ATF3 in the dorsal root ganglia and spinal cord. In addition, the oxaliplatin-associated nociception was significantly attenuated by metformin (P < 0.05), which also reduced the expression of c-Fos and ATF3 (P < 0.05). Therefore, metformin protected from the peripheral sensory neuropathy induced by oxaliplatin, which was confirmed by the reduction of c-Fos and ATF3 expression, two known neuronal activation and damage markers, respectively.

关键词： Pirfenidone   Activating transcription factor 3 (ATF3)   Rheumatoid arthritis   Interstitial lung disease   PULMONARY-FIBROSIS   ADAPTIVE-RESPONSE   GROWTH-FACTOR   BETA   MECHANISMS   DIFFERENTIATION   SUPPRESSION  

摘要： Objective: Pirfenidone (PFD) is an oral anti-fibrotic drug used for idiopathic pulmonary fibrosis (IPF) therapy. We determined the role of activating transcription factor 3 (ATF3) and the effect of PFD on fibroblast to myofibroblast transition (FMT) in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods: RA-ILD lung specimens were obtained by CT-guided percutaneous transthoracic biopsy. A pulmonary fibrosis mouse model was established by the intratracheal injection of bleomycin. Pathological variation and the expression of alpha-SMA and ATF3 were observed by H&E, Masson and immunofluorescence staining. Primary human lung fibroblasts (pHLFs) were isolated from lung tissues that were pathologically confirmed to be normal by pneumonectomy. Cell viability was detected using an MTT assay. Cell migration and invasion were detected using a Transwell chamber. The protein levels of alpha-SMA, ATF3, Smad3 and p-Smad3 were measured by Western blot. HLFs were infected with lentiviruses expressing ATF3 or scrambled shRNA. Results: ATF3 was dramatically upregulated in lung tissues from both bleomycin-induced mice and patients with RA-ILD compared with controls. The upregulation of ATF3 and the accumulation of collagen in the lung tissues of mice with pulmonary fibrosis were reduced by PFD. PFD significantly inhibited increases in the proliferation, invasion and migration of pHLFs stimulated by TGF-beta 1. Moreover, we observed the inhibitory effect of PFD on FMT via the downregulation of ATF3, which was further confirmed in ATF3 knockdown (KD) pHLFs. Conclusions: This work shows the inhibitory effect of PFD on FMT in pHLFs, which is mediated by the downregulation of ATF3. Our findings suggest that PFD might have therapeutic potential for the treatment of RA-ILD.

关键词： complex traits   genetics   gene expression   computational modeling   Genomic Prediction   GenPred   Shared Data Resources   INFLUENZA   HOST   CLASSIFICATION   EXPRESSION   INFECTION   PATHWAYS   TARGETS   ATF3  

摘要： Uncovering relationships between molecular and phenotypic diversity presents a substantial challenge. Harel et al. devised InPhenotype, a computational approach that combines gene-expression and genotype data to predict quantitative traits. The key advance... Despite the importance of complex phenotypes, an in-depth understanding of the combined molecular and genetic effects on a phenotype has yet to be achieved. Here, we introduce InPhenotype, a novel computational approach for complex phenotype prediction, where gene-expression data and genotyping data are integrated to yield quantitative predictions of complex physiological traits. Unlike existing computational methods, InPhenotype makes it possible to model potential regulatory interactions between gene expression and genomic loci without compromising the continuous nature of the molecular data. We applied InPhenotype to synthetic data, exemplifying its utility for different data parameters, as well as its superiority compared to current methods in both prediction quality and the ability to detect regulatory interactions of genes and genomic loci. Finally, we show that InPhenotype can provide biological insights into both mouse and yeast datasets.

关键词： NONCODING RNAS   BREAST-CANCER   CARCINOMA   RADIOTHERAPY   CHEMORADIOTHERAPY   TUMORIGENICITY   PROGRESSION   MIR-27B   GROWTH   NPC  

摘要： Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo-TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5- dimethylthiazol- 2- yl]- 2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo-TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.

关键词： ATF3   MMP13   Smad4   TGF-beta 1   GROWTH-FACTOR-BETA   TRANSFORMING GROWTH-FACTOR-BETA-1 REGULATION   EPITHELIAL-MESENCHYMAL TRANSITION   TRANSCRIPTION FACTOR-3   TGF-BETA   COLLAGENASE-3 EXPRESSION   SIGNALING PATHWAYS   ADAPTIVE-RESPONSE   BONE METASTASIS   C-JUN  

摘要： We previously reported that transforming growth factor-beta 1 (TGF-beta 1) stimulated the sustained and prolonged expression of activating transcription factor 3 (ATF3) in highly metastatic and invasive human breast cancer cells (MDA-MB231), in contrast to normal human mammary epithelial cells. However, the mechanism behind the stability of ATF3 expression is not yet known. Based on an in silico approach with co-immunoprecipitation and mass spectrometric analyses, we identified a number of proteins, including Smad4, that interacted with ATF3 after TGF-beta 1 treatment in MDA-MB231 cells. The knockdown of Smad4 using the siRNA technique resulted in a significant loss of ATF3 expression in these cells. Chromatin immunoprecipitation was then used to identify the formation of an ATF3 and Smad4 complex at the matrix metalloproteinase 13 (MMP13) promoter upon TGF-beta 1-treatment and the knockdown of Smad4 decreased MMP13 promoter activity in MDA-MB231 cells. Our findings indicate that Smad4 is a pre-requisite for providing stability to ATF3 via TGF-beta 1 in human breast cancer cells. The targeting of Smad4 may thus provide the sustainable loss of ATF3 expression that is needed to control breast cancer progression. (C) 2019 Elsevier B.V. All rights reserved.

关键词： ZnO nanoparticle   ATF3   DNA repair   Apoptosis   p53   ACTIVATING TRANSCRIPTION FACTOR-3   ZINC-OXIDE   GENE-EXPRESSION   P53   STRESS   INFLAMMATION   RESPONSES   PROMOTES   LUNG   NRF2  

摘要： ZnO nanoparticle (ZnO NP) exposure causes oxidative stress in the respiratory system, leading to pulmonary damage. Activating transcription factor 3 (ATF3) participates in a variety of cellular stress responses. However, the role of ATF3 in ZnO NP genotoxicity and cytotoxicity remains to be explored. Here we reported that ZnO NP treatment dramatically induced the expression of ATF3 in human bronchial epithelial (HBE) cells, which was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2). ATF3 was required for the repair of ZnO NP-induced DNA damage as gamma foci number increased when endogenous ATF3 was silenced. Moreover, ATF3 also contributed to ZnO NP-induced cell apoptosis. Mechanistic study revealed that ATF3 interacted with the p53 protein and upregulated its expression under ZnO NP treatment. Collectively, our findings demonstrated ATF3 as an important regulator of epithelial homeostasis by promoting both DNA repair and the death of damaged cells under ZnO NP-induced genotoxic stress.

关键词： JUN DIMERIZATION PROTEIN-2   ADAPTIVE-RESPONSE   AP-1 REPRESSOR   CELLS   MICROENVIRONMENT   ANGIOGENESIS   SDF-1/CXCL12   FACTOR-3   GENE   BETA  

摘要： The activating transcription factor 3 (ATF3) and the c-Jun dimerization protein 2 (JDP2) are members of the basic leucine zipper (bZIP) family of transcription factors. These proteins share a high degree of homology and both can activate or repress transcription. Deficiency of either one of them in the non-cancer host cells was shown to reduce metastases. As ATF3 and JDP2 compensate each other's function, we studied the double deficiency of ATF3 and JDP2 in the stromal tumor microenvironment. Here, we show that mice with ATF3 and JDP2 double deficiency (designated thereafter dKO) developed larger tumors with high vascular perfusion and increased cell proliferation rate compared to wild type (WT) mice. We further identify that the underlying mechanism involves tumor associated fibroblasts which secrete high levels of stromal cell-derived factor 1 (SDF-1) in dKO fibroblasts. SDF-1 depletion in dKO fibroblasts dampened tumor growth and blood vessel perfusion. Furthermore, ATF3 and JDP2 were found to regulate SDF-1 transcription and secretion in fibroblasts, a phenomenon that is potentiated in the presence of cancer cells. Collectively, our results suggest that ATF3 and JDP2 regulate the expression of essential tumor promoting factors expressed by fibroblasts within the tumor microenvironment, and thus restrain tumor growth.

关键词： Quercetin   Sepsis   Macrophage polarization   TRPM2   AMPK   ATF3   TOLL-LIKE RECEPTOR   INFLAMMATION   PROTEIN   AMPK   PHAGOCYTOSIS   SUPPRESSION   INHIBITION   INDUCTION   MECHANISM   CURCUMIN  

摘要： M2 macrophage polarization plays a crucial role in counteracting inflammatory disorders such as sepsis. Quercetin is a dietary flavonoid that possesses robust anti-inflammatory properties. However, it is not known whether quercetin takes effects by directly promoting M2 polarization in macrophages. In this study, we observed that quercetin enhanced macrophage M2 polarization and exerted anti-inflammatory activity in LPS stimulated murine peritoneal macrophages. Moreover, quercetin triggered TRPM2 dependent calcium influx and induced calcium dependent activation of AMPKa and ATF3, both were required to mediate M2 macrophage polarization and facilitate the anti-inflammatory activity by quercetin. In a murine endotoxaemia model, quercetin improved survival and ameliorated acute lung injury. Quercetin also induced AMPKa phosphorylation, upregulated ATF3 expression and promoted M2 macrophage polarization in model mice. In conclusion, our results suggest that quercetin promotes macrophage M2 polarization and confers protection of murine sepsis by inducing calcium dependent activation of the AMPK-ATF3 pathway.

关键词： ATF-3   Bothrops   Pain   Iridoids   Specioside   BOTHROPS-JARARACA   PHOSPHOLIPASES A(2)   NORTHWEST REGION   NEUTRALIZATION   EDEMA   INFLAMMATION   ATF3   PAIN   SENSITIZATION   ETHNOBOTANY  

摘要： Ethnopharmacological relevance: Tabebuia aurea (Silva Manso) Benth. & Hook. f. ex S. Moore is used as anti-inflammatory, analgesic and antiophidic in traditional medicine, though its pharmacological proprieties are still underexplored. In the bothropic envenoming, pain is a key symptom drove by an intense local inflammatory and neurotoxic event. The antivenom serum therapy is still the main treatment despite its poor local effects against pain and tissue injury. Furthermore, it is limited to ambulatorial niches, giving space for the search of new and more inclusive pharmacological approaches. Aim of the study: evaluation of Tabebuia aurea hydroethanolic extract (HEETa) in hyperalgesia and neuronal injury induced by Bothrops mattogrossensis venom (VBm). Materials and methods: Stem barks from Tabebuia aurea were extracted with ethanol and water (7:3, v/v) to yield the extract HEETa. Then, HEETa was analyzed by LC-DAD-MS and its constituents were identified. Snake venoms were extracted from adult specimens of Bothrops mattogrossensis, lyophilized and kept at -20 degrees C until use. Male Swiss mice, weighting 20-25 g, were used to hyperalgesia (electronic von Frey), motor impairment (Rotarod test) and tissue injury evaluation (histopatology and ATF-3 immunohistochemistry). Therefore, three experimental groups were formed: VBm (1 pg, 1 ng, 0.3 mu g, 1 mu g, 3 and 6 mu g/paw), HEETa orally (180, 540, 720, 810 or 1080 mg/kg; 10 mL/kg, 30 min prior VBm inoculation) and VBm neutralized (VBm: HEETa, 1:100 parts, respectively). In all set of experiments a control (saline group) was used. First, we made a dose-time-response course curve of VBm's induced hyperalgesia. Next, VBm maximum hyperalgesic dose was employed to perform HEETa orally dose-time-response course curve and analyses of VBm neutralized. Paw tissues for histopathology and DRGs were collected from animals inoculated with VBm maximum dose and treated with HEETa anti-hyperalgesic effective dose or neutralized VBm.