Role of G{alpha}12 and G{alpha}13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor

G{alpha}12 and G{alpha}13 function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by G{alpha}12 and G{alpha}13. A deficiency of G{alpha}12, but not of G{alpha}13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, G{alpha}12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by G{alpha}12 gene knockout. G{alpha}12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did G{alpha}13 deficiency. The absence of G{alpha}12, but not of G{alpha}13, increased protein kinase C {delta} (PKC {delta}) activation and the PKC {delta}-mediated serine phosphorylation of Nrf2. G{alpha}13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by G{alpha}12 deficiency, suggesting that relief from G{alpha}12 repression leads to the G{alpha}13-mediated activation of Nrf2. Constitutive activation of G{alpha}13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC {delta} activation, corroborating positive regulation by G{alpha}13. In summary, G{alpha}12 and G{alpha}13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas G{alpha}13 regulates Rho-PKC {delta}-mediated Nrf2 phosphorylation, which is negatively balanced by G{alpha}12

A Novel Mechanism of PPARγ Regulation of TGFβ1: Implication in Cancer Biology

Peroxisome proliferator-activated receptor-γ (PPARγ) and retinoic acid X-receptor (RXR) heterodimer, which regulates cell growth and differentiation, represses the TGFβ1 gene that encodes for the protein involved in cancer biology. This review will introduce the novel mechanism associated with the inhibition of the TGFβ1 gene by PPARγ activation, which regulates the dephosphorylation of Zf9 transcription factor. Pharmacological manipulation of TGFβ1 by PPARγ activators can be applied for treating TGFβ1-induced pathophysiologic disorders such as cancer metastasis and fibrosis. In this article, we will discuss the opposing effects of TGFβ on tumor growth and metastasis, and address the signaling pathways regulated by PPARγ for tumor progression and suppression

Effect of Internal Bias Field on Poling Behavior in Mn-Doped Pb(Mg1/3Nb2/3)O3-29 mol%PbTiO3 Single Crystal

Electrical poling is a crucial step to convert ferroelectrics to piezoelectrics. Nevertheless, no systematic investigation on the effect of poling has been reported. Given that the poling involves an alignment of spontaneous polarization,the condition for poling should be different when a material has an internal bias field that influences the domain stability. Here, we present the effect of poling profile on the dielectric and piezoelectric properties in Mn-doped Pb(Mg1/3Nb2/3)O3-29 mol%PbTiO3 single crystal with an internal bias field. We showed that both the dielectric permittivity and the piezoelectric coefficient were further enhanced when the poling procedure ends with a field application along the opposite direction to the internal bias field. We expect that the current finding would give a clue to understanding the true mechanism for the electrical poling

Changes of empathy in medical college and medical school students: 1-year follow up study

BACKGROUND: This study aims to determine the correlation between medical education systems, medical college (MC) and medical school (MS), and empathy by investigating the changes in empathy among students with each additional year of medical education. METHODS: The subjects were MC and MS students who had participated in the same study the previous year. All participants completed the same self-report instruments: a questionnaire on sociodemographic characteristics, and the Korean edition of the Student Version of the Jefferson Scale of Empathy (JSE-S-K), Among 334 students, the final analysis was conducted on the data provided by 113 MC and 120 MS students, excluding 101 with incomplete data. RESULTS: The age and sex did not affect the changes in empathy. Though the JSE-S-K score of MS was significantly higher than that of MC in initial investigation, this study found no difference of empathy between MC and MS. CONCLUSION: Empathy increased significantly after one year of medical education. The difference between two education systems, MC and MS, did not affect the changes in empathy

Association Between Hearing Impairment and Albuminuria With or Without Diabetes Mellitus

Objectives Few studies have evaluated the accurate association between hearing loss (HL) and albuminuria in patients with or without diabetes mellitus (DM). The aim of our study was to identify the clinical effects of albuminuria on HL with or without DM. Methods This study included 9,762 patients from the Korean National Health and Nutrition Examination Survey between 2011 and 2013. Participants were divided into 4 groups based on DM and urine albumin/creatinine ratio levels: group 1 included participants with neither DM nor albuminuria, group 2 included participants without DM and with albuminuria, group 3 included patients with DM and without albuminuria, and group 4 included patients with both DM and albuminuria. The low- or mid-frequency and high-frequency, and average hearing threshold values were obtained. Results There were 7,508, 545, 1,325, and 384 participants in groups 1, 2, 3, and 4, respectively. Univariate and multivariate analyses showed that the 3 hearing thresholds in group 1 were the lowest and those in group 4 were the highest among the 4 groups. No significant differences were observed in those thresholds between groups 2 and 3. Group 4 was associated with HL compared with the other groups, but moderate to severe HL was not associated with DM or albuminuria. Conclusion The presence of albuminuria was associated with a modest effect on hearing thresholds regardless of presence of DM

Therapeutic genome editing for Charcot-marie-tooth disease type 1a

Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted regulatory region of human PMP22 to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multi copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a potential therapeutic efficacy of CRISPR/Cas9-mediated targeting of regulatory region of PMP22 to treat CMT1A. Please click Additional Files below to see the full abstract