Yves Gorin, and Fabien WauquierMol. Cells 2015; 38(4): 285-296 https://doi.org/10.14348/molcells.2015.0010
Abstract : Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, the complication of diabetes in the kidney. NADPH oxidases of the Nox family, and in particular the homologue Nox4, are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current knowledge related to the understanding of the role of Nox enzymes in the processes that control mesangial cell, podocyte and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-β. The nature of the upstream modulators of Nox enzymes as well as the downstream targets of the Nox NADPH oxidases implicated in the propagation of the redox processes that alter renal biology in diabetes will be highlighted.
Samuel LaBarge, Christopher Migdal, and Simon SchenkMol. Cells 2015; 38(4): 297-303 https://doi.org/10.14348/molcells.2015.0020
Abstract : Skeletal muscle insulin resistance, which increases the risk for developing various metabolic diseases, including type 2 diabetes, is a common metabolic disorder in obesity and aging. If potential treatments are to be developed to treat insulin resistance, then it is important to fully understand insulin signaling and glucose metabolism. While recent large-scale “omics” studies have revealed the acetylome to be comparable in size to the phosphorylome, the acetylation of insulin signaling proteins and its functional relevance to insulin-stimulated glucose transport and glucose metabolism is not fully understood. In this Mini Review we discuss the acetylation status of proteins involved in the insulin signaling pathway and review their potential effect on, and relevance to, insulin action in skeletal muscle.
Rui Cao, Wang Jun Wu, Xiao Long Zhou, Peng Xiao, Yi Wang, and Hong Lin LiuMol. Cells 2015; 38(4): 304-311 https://doi.org/10.14348/molcells.2015.2122
Abstract : Most follicles in the mammalian ovary undergo atresia. Granulosa cell apoptosis is a hallmark of follicle atresia. Our previous study using a microRNA (miRNA) microarray showed that the let-7 microRNA family was differentially expressed during follicular atresia. However, whether the let-7 miRNA family members are related to porcine (
Hyun-Lim Kim, Hana Ra, Ki-Ryeong Kim, Jeong-Min Lee, Hana Im, and Yang-Hee KimMol. Cells 2015; 38(4): 312-317 https://doi.org/10.14348/molcells.2015.2142
Abstract : Depletion of intracellular zinc by
Yu Jeong Jeong, Su Gyeong Woo, Chul Han An, Hyung Jae Jeong, Young-Soo Hong, Young-Min Kim, Young Bae Ryu, Mun-Chual Rho, Woo Song Lee, and Cha Young KimMol. Cells 2015; 38(4): 318-326 https://doi.org/10.14348/molcells.2015.2188
Abstract : We previously reported that the SbROMT3syn recombinant protein catalyzes the production of the methylated resveratrol derivatives pinostilbene and pterostilbene by methylating substrate resveratrol in recombinant
Ha-Na Lee, Hyeon-Ok Jin, Jin-Ah Park, Jin-Hee Kim, Ji-Young Kim, BoRa Kim, Wonki Kim, Sung-Eun Hong, Yun-Han Lee, Yoon Hwan Chang, Seok-Il Hong, Young Jun Hong, In-Chul Park, Young-Joon Surh, and Jin Kyung LeeMol. Cells 2015; 38(4): 327-335 https://doi.org/10.14348/molcells.2015.2235
Abstract : Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic α,β-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine.
Jeung-Eun Lee, Jung-Min Kim, Hyun-Jun Jang, Se-young Lim, Seon-Jeong Choi, Nan-Hee Lee, Pann-Ghill Suh, and Ung-Kyu ChoiMol. Cells 2015; 38(4): 336-342 https://doi.org/10.14348/molcells.2015.2238
Abstract : Propyl gallate (PG) used as an additive in various foods has antioxidant and anti-inflammatory effects. Although the functional roles of PG in various cell types are well characterized, it is unknown whether PG has effect on stem cell differentiation. In this study, we demonstrated that PG could inhibit adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells (hAMSCs) by decreasing the accumulation of intracellular lipid droplets. In addition, PG significantly reduced the expression of adipocyte-specific markers including peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT enhancer binding protein-α (C/EBP-α), lipoprotein lipase (LPL), and adipocyte fatty acid-binding protein 2 (aP2). PG inhibited adipogenesis in hAMSCs through extracellular regulated kinase (ERK) pathway. Decreased adipogenesis following PG treatment was recovered in response to ERK blocking. Taken together, these results suggest a novel effect of PG on adipocyte differentiation in hAMSCs, supporting a negative role of ERK1/2 pathway in adipogenic differentiation.
Todd J. Cohen, Moon-Chang Choi, Meghan Kapur, Vitor A. Lira, Zhen Yan, and Tso-Pang YaoMol. Cells 2015; 38(4): 343-348 https://doi.org/10.14348/molcells.2015.2278
Abstract : Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in slow/oxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers. Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers. Indeed, HDAC4 represses the MEF2-dependent, PGC-1α-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.
Haeryung Lee, Sunjung Park, Young-Sook Kang, and Soochul ParkMol. Cells 2015; 38(4): 349-355 https://doi.org/10.14348/molcells.2015.2279
Abstract : EphA7 has been implicated in the regulation of apoptotic cell death in neural epithelial cells. In this report, we provide evidence that EphA7 interacts with caspase-8 to induce apoptotic cell signaling. First, a pull-down assay using biotinylated ephrinA5-Fc showed that EphA7 co-precipitated with wild type caspase-8 or catalytically inactive caspase-8 mutant. Second, co-transfection of EphA7 with caspase-8 significantly increased the number of cleaved caspase-3 positive apoptotic cells under an experimental condition where transfection of EphA7 or caspase-8 alone did not affect cell viability or apoptosis. EphA4 also had a causative role in inducing apoptotic cell death with caspase-8, whereas EphA8 did not. Third, caspase-8 catalytic activity was essential for the apoptotic signaling cascade, whereas tyrosine kinase activity of the EphA4 receptor was not. Interestingly, we found that kinase-inactive EphA4 was well co-localized at the plasma membrane with catalytically inactive caspase-8, suggesting that an interaction between these mutant proteins was more stable. Finally, we observed that the extracellular region of the EphA7 receptor was critical for interacting with caspase-8, whereas the cytoplasmic region of EphA7 was not. Therefore, we propose that Eph receptors physically associate with a transmembrane protein to form an apoptotic signaling complex and that this unidentified receptor-like protein acts as a biochemical linker between the Eph receptor and caspase-8.
Seung Eun Lee, Young Do Koo, Ji Seon Lee, Soo Heon Kwak, Hye Seung Jung, Young Min Cho, Young Joo Park, Sung Soo Chung, and Kyong Soo ParkMol. Cells 2015; 38(4): 356-361 https://doi.org/10.14348/molcells.2015.2280
Abstract : Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor α (RXRα) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether RXRα activation or overexpression can restore IRS1 expression. Both IRS1 and RXRα protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of RXRα agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. RXRα overexpression also increased IRS1 transcription and mitochondrial function. Because RXRα overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that RXRα directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that RXRα bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor δ (PPARδ). These results suggest that RXRα overexpression or activation alleviates insulin resistance by increasing IRS1 expression.