Background/Aims: Hepatocellular carcinoma (HCC) represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1), an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored. Methods: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP) assay was used to show the interaction between DAX-1 and β-Catenin. Small interfering RNA (siRNA) was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells. Results: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with β-Catenin and attenuate its transcriptional activity. Conclusion: Therefore, our results suggest a previously unknown DAX-1/β-Catenin molecular network controlling HCC development.
Background Radiation exposure negatively affects the regenerative ability and makes reconstruction of bone defects after tumor section difficult. miR-34a is involved in radiation biology and bone metabolism. The aim of this study was to investigate whether miR-34a could contribute to bone regeneration in irradiated bone defects. Methods The expression of miR-34a was analyzed during the osteoblastic differentiation of irradiated BMSCs and bone formation in irradiated bone defects. miR-34a mimics and miR-34a inhibitor were used to upregulate or suppress the expression of miR-34a in BMSCs irradiated with 2 or 4 Gy X-ray radiation. In vitro osteogenesis and subcutaneous osteogenesis were used to assess the effects of miR-34a on the osteogenic ability of radiation-impaired BMSCs. Collagen-based hydrogel containing agomiR-34a or antagomiR-34a were placed into the 3-mm defects of irradiated rat tibias to test the effect of miR-34a on bone defect healing after irradiation. Results miR-34a was upregulated in the process of bone formation after irradiation. Transfecting radiation-impaired BMSCs with miR-34a mimics enhanced their osteoblastic differentiation in vitro by targeting NOTCH1. Overexpression of miR-34a enhanced the ectopic bone formation of irradiated BMSCs. In situ delivery of miR-34a promoted bone regeneration in irradiated bone defects. Conclusions miR-34a promoted the osteoblastic differentiation of BMSCs and enhanced the ectopic bone formation after irradiation. miR-34a promoted bone defect healing in irradiated rat tibias. miR-34a-targeted therapy might be a promising strategy for promoting the reconstruction of bone defects after radiotherapy. Electronic supplementary material The online version of this article (10.1186/s13287-019-1285-y) contains supplementary material, which is available to authorized users.
It has been well established that hypoxia significantly increases both cellular and tumor resistance to ionizing radiation. Hypoxia associated radiation resistance has been known for some time but there has been limited success in sensitizing cells to radiation under hypoxic conditions. These studies show that, when irradiated with low linear energy transfer (LET) gamma-rays, poly (ADP-ribose), polymerase (PARP), Fanconi Anemia (FANC), and mutant Chinese Hamster Ovary (CHO) cells respond similarly to the non-homologous end joining (NHEJ) and the homologous recombination (HR) repair mutant CHO cells. Comparable results were observed in cells exposed to 13 keV/μm carbon ions. However, when irradiated with higher LET spread out Bragg peak (SOBP) carbon ions, we observed a decrease in the oxygen enhancement ratio (OER) in all the DNA of repair mutant cell lines. Interestingly, PARP mutant cells were observed as having the largest decrease in OER. Finally, these studies show a significant increase in the relative biological effectiveness (RBE) of high LET SOBP carbon and iron ions in HR and PARP mutants. There was also an increase in the RBE of NHEJ mutants when irradiated to SOBP carbon and iron ions. However, this increase was lower than in other mutant cell lines. These findings indicate that high LET radiation produces unique types of DNA damage under hypoxic conditions and PARP and HR repair pathways play a role in repairing this damage.
Polyether-ether-ketone (peek) is one of the most common materials used for load-bearing orthopedic devices owing to its radiolucency and favorable mechanical properties. However, current smooth-surfaced peek implants can lead to fibrous capsule formation. To overcome this issue, here, peek specimens with well-defined internal cross-linked structures (macropore diameters of 1.0–2.0 mm) were fabricated using a three-dimensional (3D) printer, and an acid-etched microporous surface was achieved using injection-molding technology. The cell adhesion properties of smooth and microporous peek specimens was compared in vitro through a scanning electron microscope (SEM), and the soft tissue responses to the both microporous and cross-linked structure of different groups were determined in vivo using a New Zealand white rabbit model, and examined through histologic staining and separating test. The results showed that the acid-etched microporous surface promoted human skin fibroblasts (HSF) adherence, while internal cross-linked structure improved the ability of the peek specimen to form a mechanical combination with soft tissue, especially with the 1.5 mm porous specimen. The peek specimens with both the internal cross-linked structure and external acid-etched microporous surface could effectively promote the close integration of soft tissue and prevent formation of fibrous capsules, demonstrating the potential for clinical application in surgical repair.
The primary objective of the present study was to develop extended-release matrix formulations of apremilast for the oral delivery and to study their in vitro and in vivo correlation. Five extended-release formulations containing hydroxypropylmethylcellulose (HPMC) as the retarding excipient with different release rate of apremilast were prepared. Dissolution tests of all the formulated tablets were performed in water, pH 4.0 and 6.8 buffer solutions. The in vitro release kinetics was studied and supported by Korsmeyer-Peppas's equation as it presented highest values of correlation coefficients (r 2 up to 0.966). Among all formulated tablets, F2 (HPMC 25%) and F4 (HPMC 35%) were selected to perform an in vivo study in beagle dogs to obtain various pharmacokinetic parameters, i.e., peak plasma concentration (C max ), time to peak plasma concentration (t max ), area under the plasma-concentration vs. time curve (AUC). Higher t max and t 1/2 , lower C max and elimination coefficient (K e ) were observed for both extended formulations compared to marketed immediate-release products (Otezla ® ). Level A in vitro-in vivo correlations were created with the help of Wagner-Nelson and numeric deconvolution methods. Both formulations showed good in vitro-in vivo correlations whose accuracies were further verified by an internal validation.
Novel glucosyl flavonoids are developed by the addition of glucose to naturally occurring flavonoids. Flavonoids are known antioxidants that possess radioprotective properties. In order to investigate the radioprotective properties of novel glucosyl flavonoids, in vitro DNA double-strand breaks (DSBs) analysis was carried out. In the present study, Quercetin, Naringenin, and Hesperetin groups of flavonoids included in the natural and novel glucosyl 13 flavonoids were investigated. Flavonoids were mixed with Lambda DNA, and subsequently exposed to gamma‑rays. Furthermore, DNA DSB yields were visualized by gel electrophoresis. Quercetin derivatives displayed reduced DNA DSB formation at 10 µM. At a high concentration, the majority of flavonoids displayed radioprotective properties as a reduction of DSB yields. Suppression of DSB formation was confirmed via the molecular combing assay for Quercetin, and three monoglucosyl flavonoids. Glucosylation showed positive effects for radioprotection and monoglucosyl-Rutin showed superior radioprotective properties when compared to monoglucosyl-Naringin and Hesperidin. In addition, Quercetin derivatives had greater total antioxidant capacities and DPPH radical scavenging ability than other flavonoid groups. Since Quercetin, Isoquercetin, and Rutin display poor water solubility, monoglucosyl-Rutin, maltooligosyl-Isoquercetin, and maltooligosyl-Rutin may be better radioprotective agents and easily bioavailable with increased water solubility.
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