Maternal obesity may compromise the micronutrient status of the offspring. Vitamin A (VA) is an essential micronutrient during neonatal development. Its active metabolite, retinoic acid (RA), is a key regulator of VA homeostasis, which also regulates adipose tissue (AT) development in obese adults. However, its role on VA status and AT metabolism in neonates was unknown and it was determined in the present study. Pregnant Sprague-Dawley rats were randomised to a normal fat diet (NFD) or a high fat diet (HFD). From postnatal day 5 (P5) to P20, half of the HFD pups received oral RA every 3 d (HFDRA group). NFD pups and the remaining HFD pups (HFD group) received placebo. Six hours after dosing on P8, P14 and P20, n 4 pups per group were euthanised for different measures. It was found that total retinol concentration in neonatal liver and lung was significantly lower in the HFD group than the NFD group, while the concentrations were significantly increased in the HFDRA group. The HFD group exhibited significantly higher body weight (BW) gain, AT mass, serum leptin and adiponectin, and gene expression of these adipokines in white adipose tissue compared with the NFD group; these measures were significantly reduced in the HFDRA group. BAT UCP2 and UCP3 gene expression were significantly higher in pups receiving RA. In conclusion, repeated RA treatment during the suckling period improved the tissue VA status of neonates exposed to maternal obesity. RA also exerted a regulatory effect on neonatal obesity development by reducing BW gain and adiposity and modulating AT metabolism.

UNASSIGNED: Efficient induction of the otic placode, the developmental origin of the inner ear from human pluripotent stem cells (hPSCs), provides a robust platform for otic development and sensorineural hearing loss modelling. Nevertheless, there remains a limited capacity of otic lineage specification from hPSCs by stepwise differentiation methods, since the critical factors for successful otic cell differentiation have not been thoroughly investigated. In this study, we developed a novel differentiation system involving the use of a three-dimensional (3D) floating culture with signalling factors for generating otic cell lineages via stepwise differentiation of hPSCs.
UNASSIGNED: We differentiated hPSCs into preplacodal cells under a two-dimensional (2D) monolayer culture. Then, we transferred the induced preplacodal cells into a 3D floating culture under the control of the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), retinoic acid (RA) and WNT signalling pathways. We evaluated the characteristics of the induced cells using immunocytochemistry, quantitative PCR (qPCR), population averaging, and single-cell RNA-seq (RNA-seq) analysis. We further investigated the methods for differentiating otic progenitors towards hair cells by overexpression of defined transcription factors.
UNASSIGNED: We demonstrated that hPSC-derived preplacodal cells acquired the potential to differentiate into posterior placodal cells in 3D floating culture with FGF2 and RA. Subsequent activation of WNT signalling induced otic placodal cell formation. By single-cell RNA-seq (scRNA-seq) analysis, we identified multiple clusters of otic placode- and otocyst marker-positive cells in the induced spheres. Moreover, the induced otic cells showed the potential to generate hair cell-like cells by overexpression of the transcription factors ATOH1, POU4F3 and GFI1.
UNASSIGNED: We demonstrated the critical role of FGF2, RA and WNT signalling in a 3D environment for the in vitro differentiation of otic lineage cells from hPSCs. The induced otic cells had the capacity to differentiate into inner ear hair cells with stereociliary bundles and tip link-like structures. The protocol will be useful for in vitro disease modelling of sensorineural hearing loss and human inner ear development and thus contribute to drug screening and stem cell-based regenerative medicine.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, and CKD is a serious global health problem. Low glomerular number is one of the risk factors for CKD; therefore, the glomerular number is associated with the risk of CKD. Increasing the glomerular number above normal levels may reduce the risk of CKD. It has been reported that, in vitro, the addition of retinoic acid (RA) to the culture medium increases the glomerular number. However, there is no report of an increase in glomerular number above normal levels with the addition of RA in vivo. In this study, RA (20 mg/kg) was administered intraperitoneally to pregnant mice once at embryonic day (E) 10.5, E12.5, E14.5, or E16.5. The fetuses were harvested at E18.5 and fetal mouse kidneys were evaluated. Fetal kidney volume and weight were significantly increased in the E16.5 group compared to the control group. The total glomerular number in the E16.5 group was also approximately 1.46 times higher than that in the control group. In summary, we established a method to increase the glomerular number in the fetal kidney by administration of RA to pregnant mice at E16.5. These results will facilitate the investigation of whether CKD risk is reduced when the glomerular number increases above normal.

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

In a previous clinical study, the moisture content in the stratum corneum of healthy Japanese women who consumed a beverage rich in oligomeric proanthocyanidins (OPCs) made from red wine extract was found to be higher than that in the control group. This finding suggested that OPCs can increase skin moisture content. In this study, we determined the expression level of aquaporin-3 (AQP3) in keratinocytes to elucidate the mechanism by which compounds in red wine grape increase moisture content in stratum corneum. Through in vitro studies, we confirmed that normal human epidermal keratinocytes (NHEK) incubated with red wine induced AQP3 expression. Furthermore, the supplementation of red wine fractions enriched in OPC was shown to increase AQP3 expression. Besides, the component of OPC-rich fractions that upregulated AQP3 expression was found to be a gallic acid (GA)-binding flavan-3-ol, particularly oligomeric compounds. We found that GA-binding OPC were able to upregulate AQP3 expression and that these compounds were enriched in red wine. Our findings might suggest that the mechanism of enhancement of moisture content in stratum corneum by red wine might be via the upregulation of AQP3 expression in the epidermal keratinocytes.

Cancer cells reprogram their gene expression to promote growth, survival, proliferation, and invasiveness. The unique expression of certain uptake transporters in cancers and their innate function to concentrate small molecular substrates in cells make them ideal targets for selective delivering imaging and therapeutic agents into cancer cells. In this review, we focus on several solute carrier (SLC) transporters known to be involved in transporting clinically used radiopharmaceutical agents into cancer cells, including the sodium/iodine symporter (NIS), norepinephrine transporter (NET), glucose transporter 1 (GLUT1), and monocarboxylate transporters (MCTs). The molecular and functional characteristics of these transporters are reviewed with special emphasis on their specific expressions in cancers and interaction with imaging or theranostic agents [e.g., I-123, I-131, 123I-iobenguane (mIBG), 18F-fluorodeoxyglucose (18F-FDG) and 13C pyruvate]. Current clinical applications and research areas of these transporters in cancer diagnosis and treatment are discussed. Finally, we offer our views on emerging opportunities and challenges in targeting transporters for cancer imaging and treatment. By analyzing the few clinically successful examples, we hope much interest can be garnered in cancer research towards uptake transporters and their potential applications in cancer diagnosis and treatment.

We previously used a chemical genetics approach with the larval zebrafish to identify small molecule inhibitors of tissue regeneration. This led to the discovery that glucocorticoids (GC) block early stages of tissue regeneration by the inappropriate activation of the glucocorticoid receptor (GR). We performed a microarray analysis to identify the changes in gene expression associated with beclomethasone dipropionate (BDP) exposure during epimorphic fin regeneration. Oncofetal cripto-1 showed > eight-fold increased expression in BDP-treated regenerates. We hypothesized that the mis-expression of cripto-1 was essential for BDP to block regeneration. Expression of cripto-1 was not elevated in GR morphants in the presence of BDP indicating that cripto-1 induction was GR-dependent. Partial translational suppression of Cripto-1 in the presence of BDP restored tissue regeneration. Retinoic acid exposure prevented increased cripto-1 expression and permitted regeneration in the presence of BDP. We demonstrated that BDP exposure increased cripto-1 expression in mouse embryonic stem cells and that regulation of cripto-1 by GCs is conserved in mammals.

The regulation of Sertoli cells by some hormones and signaling factors is important for normal spermatogenesis. Notch signaling is considered to be necessary for normal spermatogenesis in mouse. In this study, we revealed two new facts about Sertoli cells by western blotting experiments on different types of primary cells and microdissected tubules. The first is that Sertoli cells express the Jagged1 ligand in mice testes. The second is that the expression level of Jagged1 oscillates in the seminiferous epithelial cycle. Therefore, we inferred that Jagged1 in Sertoli cells contributes to the Notch signaling involved in spermatogenesis. Furthermore, we examined the regulation of Jagged1 expression and found that Jagged1 expression was suppressed by cAMP signaling and was promoted by TNF-α signaling in Sertoli cells. When cAMP and TNF-α were simultaneously added to Sertoli cells, Jagged1 expression was suppressed. Therefore, cAMP signaling dominates Jagged1 expression over TNF-α signaling. These results suggest that cAMP signaling may cause the periodicity of Jagged1 expression in the seminiferous epithelial cycle, and controlling Jagged1 expression by adding TNF-α or cAMP may contribute to normal spermatogenesis in vitro.

Obesity is increasing in an alarming rate worldwide, which causes higher risks of some diseases, such as type 2 diabetes, cardiovascular diseases, and cancer. Current therapeutic approaches, either pancreatic lipase inhibitors or appetite suppressors, are generally of limited effectiveness. Brown adipose tissue (BAT) and beige cells dissipate fatty acids as heat to maintain body temperature, termed non-shivering thermogenesis; the activity and mass of BAT and beige cells are negatively correlated with overweight and obesity. The existence of BAT and beige cells in human adults provides an effective weight reduction therapy, a process likely to be amenable to pharmacological intervention. Herein, we combed through the physiology of thermogenesis and the role of BAT and beige cells in combating with obesity. We summarized the thermogenic regulators identified in the past decades, targeting G protein-coupled receptors, transient receptor potential channels, nuclear receptors and miscellaneous pathways. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of thermogenesis in energy homeostasis to the representative thermogenic regulators for treating obesity. Thermogenic regulators might have a large potential for further investigations to be developed as lead compounds in fighting obesity.

Gemcitabine and pemetrexed are clinically approved antimetabolites for the therapy of mesothelioma diseases. These drugs are often applied in combination with platinum complexes and other drugs. The activity of antimetabolites depended on the expression levels of certain non-coding RNAs, in particular, of small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The development of tumor resistance towards antimetabolites was regulated by non-coding RNAs. An overview of the interplay between gemcitabine/pemetrexed antimetabolites and non-coding RNAs in mesothelioma is provided. Further to this, various non-coding RNA-modulating agents are discussed which displayed positive effects on gemcitabine or pemetrexed treatment of mesothelioma diseases. A detailed knowledge of the connections of non-coding RNAs with antimetabolites will be constructive for the design of improved therapies in future.