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Physiological root resorption of deciduous teeth is a normal phenomenon. How the angiogenesis process is regulated to provide adequate levels of oxygen and nutrients in hypoxic conditions when the dental pulp tissue is reduced at the stage of root resorption is not fully understood. In this study, we designed hypoxic preconditioning (2%) to mimic the physiological conditions. We isolated exosomes from hypoxic-preconditioned SHED (Hypo-exos) cells and from normally cultured SHED cells (Norm-exos). We found that treatment with Hypo-exos significantly enhanced the growth, migration and tube formation of endothelial cells in vitro compared with Norm-exos. We also performed matrigel plug assays in vivo and higher expression of VEGF and higher number of lumenal structures that stained positive for CD31 were found in the Hypo-exos treated group. To understand the potential molecular mechanism responsible for the positive effects of Hypo-exos, we performed exosomal miRNA sequencing and validated that Hypo-exos transferred both let-7f-5p and miR-210-3p to promote the tube formation of endothelial cells. Further study revealed that those two miRNAs regulate angiogenesis via the let-7f-5p/AGO1/VEGF and/or miR-210-3p/ephrinA3 signal pathways. Finally, we found that the increased release of exosomes regulated by hypoxia treatment may be related to Rab27a. Taking these data together, the present study demonstrates that exosomes derived from hypoxic-preconditioned SHED cells promote angiogenesis by transferring let-7f-5p and miR-210-3p, which suggests that they can potentially be developed as a novel therapeutic approach for pro-angiogenic therapy in tissue regeneration engineering.

Phenformin is a drug in the biguanide class that was previously used to treat type 2 diabetes. We have reported the antitumor activities of phenformin to enhance the efficacy of BRAFeMAPK kinaseeextracellular signaleregulated kinase pathway inhibition and to inhibit myeloid-derived suppressor cells in various melanoma models. Here we demonstrate that phenformin suppresses tumor growth and promotes keratinocyte differentiation in the 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis mouse model. Moreover, phenformin enhances the suspension-induced differentiation of mouse and human keratinocytes. Mechanistically, phenformin induces the nuclear translocation of NFATc1 in keratinocytes in an AMPK-dependent manner. Pharmacologic or genetic inhibition of calcineurin and NFAT signaling reverses the effects of phenformin on keratinocyte differentiation. Taken together, our study reveals an antitumor activity of phenformin to promote keratinocyte differentiation that warrants future translational efforts to repurpose phenformin for the treatment of cutaneous squamous cell carcinomas.

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A Gram-staining-negative, aerobic, motile, oxidase-and catalase-positive, rod-shaped strain, designated ZS2-30 T , was isolated from Antarctic intertidal sandy sediment. The strain grew at 4-35 6C (optimum, 25 6C) and in 0-25 % (w/v) NaCl (optimum, 3.0-4.0 %). It could reduce nitrate to nitrite and hydrolyse Tween 80. The predominant cellular fatty acids of strain ZS2-30 T were summed feature 3 (C 16 : 1 v7c and/or C 16 : 1 v6c), C 16 : 0 , C 18 : 1 v9c, C 16 : 1 v9c, C 12 : 0 3-OH and C 12 : 0 . The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and an unidentified aminophospholipid. The genomic DNA G+C content of strain ZS2-30 T was 55.8 mol%. Analyses of 16S rRNA gene sequences revealed that strain ZS2-30 T was affiliated with the genus Marinobacter. It showed highest 16S rRNA gene sequence similarities to the type strains of three species of the genus Marinobacter, namely Marinobacter maritimus (98.3 %), Marinobacter psychrophilus (98.1 %) and Marinobacter goseongensis (97.1 %), but the DNA-DNA relatedness values between strain ZS2-30 T and the above three species were all lower than 45 %. Moreover, strain ZS2-30 T could be distinguished from closely related species of the genus Marinobacter by various phenotypic properties. Based on this taxonomic study using a polyphasic approach, strain ZS2-30 T is considered to represent a novel species in the genus Marinobacter, for which the name Marinobacter antarcticus sp. nov. is proposed. The type strain of Marinobacter antarcticus is ZS2-30 T (5CGMCC 1.10835 T 5KCTC 23684 T ).The genus Marinobacter in the class Gammaproteobacteria was originally proposed by Gauthier et al. (1992) for a Gram-negative, extremely halotolerant, hydrocarbondegrading, rod-shaped bacterium isolated from Mediterranean seawater near a petroleum refinery. At the time of writing, the genus comprised 29 species (Gauthier et al.,

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Purpose To compare the clinical outcomes after day 3 embryo transfer, day 5 single blastocyst transfer (SBT) and frozenthawed embryo transfer (FET) in high responder patients (>15 retrieved oocytes) undergoing IVF/ICSI treatment. Methods A retrospective analysis of three embryo transfer strategies for the high responder patients in IVF/ICSI cycles. The 1041 high responder patients diagnosed as primary infertility with more than 15 oocytes retrieved were recruited in Day 3 ET group, 308 patients with more than 15 oocytes retrieved first transferred with one blastocyst in SBT group and 425 patients with more than 15 oocytes retrieved in fresh cycle, first transferred with one frozen-thawed blastocyst were assigned in FET group. Results In the high responder patients, the clinical pregnancy rate after day 5 SBT was significantly lower than that of day 3 ET (43.18 % VS 57.16 %, p <0.05). In addition, the clinical pregnant rate and implantation rate of FET cycles were significantly higher than SBT cycles (59.06 % vs. 43.18 % and 64.70 % vs. 47.40 %, p <0.05). The multiple pregnancy rate in FET cycles was markedly lower than that of day 3 ET (2.35 % VS 34.97 %, p <0.05).Conclusions FET was the preferable strategy for the high responder patients in IVF/ICSI cycles to obtain both desirable clinical outcome and lower multiple pregnancy rates.