Diabetic Embryopathy Susceptibility in Mice Is Associated with Differential Dependence on Glucosamine and Modulation of High Glucose-Induced Oxidative Stress.

The high K glucose transporter, GLUT2 (SLC2A2), is expressed by embryos and causes high rates of glucose transport during maternal hyperglycemic episodes in diabetic pregnancies and causes congenital malformations (diabetic embryopathy). GLUT2 is also a low K transporter of the amino sugar, glucosamine (GlcN), which enters the hexosamine biosynthetic pathway (HBP) and provides substrate for glycosylation reactions. Exogenous GlcN also increases activity of the pentose phosphate pathway (PPP), which increases production of NADPH reducing equivalents.

Perphenazine Attenuates the Pro-Inflammatory Responses in Mouse Models of Th2-Type Allergic Dermatitis.

Developing dermatitis therapeutics has been faced with challenges including adverse effects of topical steroid and high cost of new developing drugs. Here, we found the expression levels of dopamine receptor D2 is higher in skin biopsies of dermatitis patients and an oxazolone-induced animal model of dermatitis. We used perphenazine, an FDA-approved dopamine receptor antagonist to determine the therapeutic effect.

Metformin ameliorates animal models of dermatitis.

Metformin, a potent AMPK activator is the most commonly used drug for diabetes. According to recent reports, metformin lowers the risk of diabetic complications and inflammatory diseases. We found the expression levels of AMPK subunits including PRKAA1, PRKAA2, PRKAB1 and PRKAB2 are decreased in skin biopsies of dermatitis patients from multiple datasets.

Glucose metabolism regulates expression of hair-inductive genes of dermal papilla spheres via histone acetylation.

Cellular metabolism is one of the crucial factors to regulate epigenetic landscape in various cells including immune cells, embryonic stem cells and hair follicle stem cells. Dermal papilla cells (DP) interact with epithelial stem cells to orchestrate hair formation. Here we show that active DP exhibit robust aerobic glycolysis.

Nintedanib ameliorates animal model of dermatitis.

Nintedanib, a receptor tyrosine kinase (RTK) inhibitor has been developed as therapeutics for idiopathic pulmonary fibrosis and non-small lung cancer. We found that the expression levels of RTK, especially VEGFR1 is increased in skin biopsies of dermatitis patients from multiple independent datasets. Moreover, VEGFR1 is highly expressed by infiltrated cells in dermis from oxazolone (OXA) treated mice.

2-deoxy-d-glucose Ameliorates Animal Models of Dermatitis.

Glucose metabolism is a key metabolic pathway that orchestrates cellular homeostasis by generating ATP, nucleotides, and amino acids. Abnormal glucose signaling has been found in many diseases including cancers and inflammatory diseases. According to recent report, glycolysis contributes to pathogenesis of psoriasis and ablation of Glut1 attenuates animal models of psoriasis.

Human autologous iPSC-derived dopaminergic progenitors restore motor function in Parkinson's disease models.

Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell-based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential.

E3 ligase RCHY1 negatively regulates HDAC2.

HDAC2, one of the class I histone deacetylase regulates epigenetic landscape through histone modification. Because HDAC2 is overexpressed in many cancers, cancer therapeutics against HDAC2 have been developed. Here we show novel mechanism of HDAC2 regulation by E3 ligase RCHY1.

Mdm2 is required for HDAC3 monoubiquitination and stability.

HDAC3, one of the class I histone deacetylase modulates epigenetic landscape through histone modification. HDAC3 also interacts with non-histone proteins including p53 for deacetylation. Moreover, HDAC3 serves as a transcriptional repressor, interacting with NCor1/SMRT complex.

MUL1 E3 ligase regulates the antitumor effects of metformin in chemoresistant ovarian cancer cells via AKT degradation.

Chemoresistance is one of most critical clinical problems encountered when treating patients with ovarian cancer, due to the fact that the disease is usually diagnosed at advanced stages. Metformin is used as a first‑line drug for the treatment of type 2 diabetes; however, drug repositioning studies have revealed its antitumor effects, mainly mediated through AMP‑activated protein kinase (AMPK) activation and AKT/mammalian target of rapamycin (mTOR) pathway inhibition in various types of cancer, including drug‑resistant cancer cells. The current study revealed that the novel antitumor mechanism of metformin is mediated by regulation of mitochondrial E3 ubiquitin protein ligase 1 (MUL1) expression that negatively regulates AKT.

The Protective Effect of Violaxanthin from Nannochloropsis oceanica against Ultraviolet B-Induced Damage in Normal Human Dermal Fibroblasts.

Skin photoaging, which is mainly induced by ultraviolet B (UVB) radiation, is prevented by the application of UV-protective agents. The microalga Nannochloropsis oceanica (N. oceanica) has been primarily reported as a potential biofuel; however, in this study, we investigated whether N.

Pluripotent stem cell-based therapy for Parkinson's disease: Current status and future prospects.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects about 0.3% of the general population. As the population in the developed world ages, this creates an escalating burden on society both in economic terms and in quality of life for these patients and for the families that support them.

Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis.

A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the 'Warburg effect', which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase. Remarkably, knockdown of SIRT2 in human fibroblasts resulted in significantly decreased OXPHOS and increased glycolysis.

TRIAD1 Is a Novel Transcriptional Target of p53 and Regulates Nutlin-3a-Induced Cell Death.

Nutlin-3a is a non-genotoxic, p53-activating, MDM2 inhibitor being investigated as an anticancer agent. Although Nutlin-3a selectively antagonizes the ubiquitin E3 ligase activity of MDM2, its efficacy is not entirely regulated by MDM2 levels in cancer cells. Here, we report that the cytotoxic effects of Nutlin-3a are regulated by TRIAD1 via a positive feedback loop with p53.

Embryonic Stem Cell Proliferation Stimulated By Altered Anabolic Metabolism From Glucose Transporter 2-Transported Glucosamine.

The hexose transporter, GLUT2 (SLC2A2), which is expressed by mouse embryos, is important for survival before embryonic day 10.5, but its function in embryos is unknown. GLUT2 can transport the amino sugar glucosamine (GlcN), which could increase substrate for the hexosamine biosynthetic pathway (HBSP) that produces UDP-N-acetylglucosamine for O-linked N-acetylglucosamine modification (O-GlcNAcylation) of proteins.

Use of a murine embryonic stem cell line that is sensitive to high glucose environment to model neural tube development in diabetic pregnancy.

Background: Neural tube defects (NTDs) are significantly increased by maternal diabetes. Embryonic stem cells (ESC) that can differentiate into neuroepithelium and can sense supraphysiological glucose concentrations would be very valuable to simulate the effects of maternal diabetes on molecular and cellular processes during neural tube formation.

Methods: LG-ESC, a recently established ESC line that expresses the glucose transporter, Scl2a2, and is sensitive to elevated glucose concentrations, were grown for up to 8 days in a three-dimensional culture to form neural cysts.

Mouse embryonic stem cells established in physiological-glucose media express the high KM Glut2 glucose transporter expressed by normal embryos.

Glut2 is one of the facilitative glucose transporters expressed by preimplantation and early postimplantation embryos. Glut2 is important for survival before embryonic day 10.5.

TRIAD1 is negatively regulated by the MDM2 E3 ligase.

Two RING fingers and DRIL1 (TRIAD1) is a proapoptotic protein that promotes p53 activation in several cancer cell lines, including MCF7, U2OS and A549 cells. In this study, we demonstrated that TRIAD1 is a novel ubiquitination target for proteasome-dependent degradation by murine double minute 2 (MDM2). TRIAD1 was found to interact with and be ubiquitinated by MDM2.

Serine 123 phosphorylation modulates p21 protein stability and activity by suppressing ubiquitin-independent proteasomal degradation.

The cyclin-dependent kinase inhibitor p21(Waf1/Cip1) is a major regulator of the cell cycle and plays an important role in many cellular processes, including differentiation, stress response, apoptosis, and tumorigenesis. We previously cloned the gene encoding dog p21 and found that unlike its human ortholog, dog p21 is expressed as two isoforms, one high molecular mass band of 23 kDa and one low molecular mass band of 19 kDa. In the current study, we found that the high molecular mass band is phosphorylated, whereas the low molecular mass band is hypophosphorylated.

TRIAD1 inhibits MDM2-mediated p53 ubiquitination and degradation.

Murine double minute (MDM2) is an E3 ligase that promotes ubiquitination and degradation of tumor suppressor protein 53 (p53). MDM2-mediated regulation of p53 has been investigated as a classical tumorigenesis pathway. Here, we describe TRIAD1 as a novel modulator of the p53-MDM2 axis that induces p53 activation by inhibiting its regulation by MDM2.

Akt is negatively regulated by the MULAN E3 ligase.

The serine/threonine kinase Akt functions in multiple cellular processes, including cell survival and tumor development. Studies of the mechanisms that negatively regulate Akt have focused on dephosphorylation-mediated inactivation. In this study, we identified a negative regulator of Akt, MULAN, which possesses both a RING finger domain and E3 ubiquitin ligase activity.

Triad 1 induces apoptosis by p53 activation.

Triad 1 (2 RING [really interesting new gene] fingers and DRIL [double RING finger linked] 1) is an E3 ligase that induces apoptosis and clonogenic inhibition in myeloid cells through Gfi-1 stabilization. Here we demonstrate that Triad 1 induces apoptosis in several cancer cell lines including MCF7, A549, U2OS, and HCT 116 p53(+/+) cells via its RING ligase activity. Interestingly, in these cancer cells, Triad 1-induced apoptosis is not mediated by Gfi-1 stabilization but is instead p53-dependent.

MicroRNAs that respond to histone deacetylase inhibitor SAHA and p53 in HCT116 human colon carcinoma cells.

MicroRNAs (miRNAs) are important post-transcriptional regulators involved in many biological processes. We investigated the expression profiles of miRNAs affected by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), and p53 in the human colon cancer cell line, HCT116 (wt-p53) and its derivative, HCT116 (null-p53). In a microarray assay, 144 of 275 human miRNAs showed several-fold changes in transcription.

Identification of specific microRNAs responding to low and high dose gamma-irradiation in the human lymphoblast line IM9.

MicroRNAs (miRNAs) are short single-stranded RNA molecules that regulate the stability or translational efficiency of target messenger RNAs. Specific miRNAs are required for strict tissue- and developmental stage-specific expression. These miRNAs have roles in many human tumor malignancies and their expression is specifically regulated on each stage of oncogenic process.

Suberoylanilide hydroxamic acid (SAHA) changes microRNA expression profiles in A549 human non-small cell lung cancer cells.

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor (HDACI) with antitumor effects that is being explored as a therapeutic drug. However, it has been reported that non-small cell lung cancer (NSCLC) is resistant to HDACIs. MicroRNAs (miRNAs) are a key class of small, non-coding RNA molecules that modulate post-transcriptional regulation of gene expression in multi-cellular organisms.