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1.  Antioxidant activity of chito-oligosaccharides on pancreatic islet cells in streptozotocin-induced diabetes in rats 
AIM: To investigate the antioxidant activity of chito-oligosaccharides (COSs) on pancreatic islet cells in diabetic rats induced by streptozotocin.
METHODS: The antioxidant effect of COSs on pancreatic islet cells was detected under optical microscopy and with colorimetric assay and gel electrophoresis. The activities of glutathione peroxidase and superoxide dismutase, total antioxidant capacity, and content of malondialdehyde in serum and tissue slices of pancreas were examined after 60 d to determine the effect of COSs in streptozotocin-induced diabetes in rats.
RESULTS: COSs can prohibit the apoptosis of pancreatic islet cells. All concentrations of COSs can improve the capability of total antioxidant capacity and activity of superoxide dismutase and decrease the content of malondialdehyde drastically. Morphological investigation in the pancreas showed that COSs have resulted in the reduction of islets, loss of pancreatic cells, and nuclear pyknosis of pancreatic cells.
CONCLUSION: COSs possess various biological activities and can be used in the treatment of diabetes mellitus.
doi:10.3748/wjg.15.1339
PMCID: PMC2658843  PMID: 19294763
Chito-oligosaccharides; Diabetes mellitus; Apoptosis; Antioxidant ability; Pancreastic islet cells; Streptozotocin
2.  Costs associated with febrile neutropenia in solid tumor and lymphoma patients – an observational study in Singapore 
Background
The primary objective was to describe the total direct inpatient costs among solid tumor and lymphoma patients with chemotherapy-induced febrile neutropenia (FN) and the factors that were associated with higher direct cost. The secondary objective was to describe the out-of-pocket patient payments and the factors that were associated with higher out-of-pocket patient payments.
Methods
This was a single-center observational study conducted at the largest cancer center in Singapore. All of the adult cancer patients hospitalized due to FN from 2009 to 2012 were studied. The primary outcomes were the total hospital cost and the out-of-pocket patient payments (adjusted by government subsidy) per FN episode. Univariate analysis and multiple linear regression were conducted to identify the factors associated with higher FN costs.
Results
Three hundred and sixty seven adult cancer patients were documented with FN-related hospitalizations. The mean total hospital cost was US$4,193 (95% CI: US$3,779-4,607) and the mean out-of-pocket patient payment was US$2,230 (95% CI: US$1,976-2,484), per FN episode. The factors associated with a higher total hospital cost were longer length of stay, severe sepsis, and lymphoma as underlying cancer. The out-of-pocket patient payment was positively associated with longer length of stay, severe sepsis, lymphoma diagnosed as underlying cancer, the therapeutic use of granulocyte colony-stimulating factor (GCSF), the private ward class, and younger patients.
Conclusions
The total hospital cost and out-of-pocket patient payments of FN management in lymphoma cases were substantial compared with other solid tumors. Factors associated with a higher FN management cost may be useful for developing appropriate strategies to reduce the cost of FN for cancer patients.
doi:10.1186/1472-6963-14-434
PMCID: PMC4263105  PMID: 25252614
Febrile neutropenia; Neutropenia; Fever; Cost analysis; Factors
3.  Development and translational imaging of a TP53 porcine tumorigenesis model 
The Journal of Clinical Investigation  2014;124(9):4052-4066.
Cancer is the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer are informative, but translating promising imaging approaches and therapies to clinical practice has been challenging. In particular, the lack of a large-animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools along with surgical and therapeutic interventions. Here, we developed a genetically modified porcine model of cancer in which animals express a mutation in TP53 (which encodes p53) that is orthologous to one commonly found in humans (R175H in people, R167H in pigs). TP53R167H/R167H mutant pigs primarily developed lymphomas and osteogenic tumors, recapitulating the tumor types observed in mice and humans expressing orthologous TP53 mutant alleles. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathological evaluation after necropsy. Molecular genetic analyses confirmed that these animals expressed the R167H mutant p53, and evaluation of tumors revealed characteristic chromosomal instability. Together, these results demonstrated that TP53R167H/R167H pigs represent a large-animal tumor model that replicates the human condition. Our data further suggest that this model will be uniquely suited for developing clinically relevant, noninvasive imaging approaches to facilitate earlier detection, diagnosis, and treatment of human cancers.
doi:10.1172/JCI75447
PMCID: PMC4151205  PMID: 25105366
4.  Sudden asystole during radiofrequency ablation: a case report and literature review 
BMC Research Notes  2014;7:351.
Background
Radiofrequency (RF) ablation is a widely accepted and ideal therapeutic tool to cure some tachycardias. The occurrence of complications varies depending on the procedure being performed. Sudden unexpected prolonged asystole is rare for most ablation procedures and the underlying mechanisms remain unclear.
Case presentation
A case of sudden prolonged asystole induced by RF ablation of a concealed left free wall accessory in a 59-year-old woman with recurrent tachycardia. RF application provoked progressive slowing of the sinus rhythm and then a 13.2-second period of asystole ensued. Asystole was self-healing and no complications were seen in the following follow-up.
Conclusions
RF ablation may develop prolonged asystole due to vagus response caused by stimulation of unmyelinated vagal C-fibers or ganglionated plexus (GP). Reflexible asystole is reproducible and resolves independently, without affecting the procedure of RF ablation.
doi:10.1186/1756-0500-7-351
PMCID: PMC4065241  PMID: 24917352
Radiofrequency ablation; Asystole; Vagal response; Ganglionated plexus
5.  Targeted Disruption of LDLR Causes Hypercholesterolemia and Atherosclerosis in Yucatan Miniature Pigs 
PLoS ONE  2014;9(4):e93457.
Recent progress in engineering the genomes of large animals has spurred increased interest in developing better animal models for diseases where current options are inadequate. Here, we report the creation of Yucatan miniature pigs with targeted disruptions of the low-density lipoprotein receptor (LDLR) gene in an effort to provide an improved large animal model of familial hypercholesterolemia and atherosclerosis. Yucatan miniature pigs are well established as translational research models because of similarities to humans in physiology, anatomy, genetics, and size. Using recombinant adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer, male and female LDLR+/− pigs were generated. Subsequent breeding of heterozygotes produced LDLR−/− pigs. When fed a standard swine diet (low fat, no cholesterol), LDLR+/− pigs exhibited a moderate, but consistent increase in total and LDL cholesterol, while LDLR−/− pigs had considerably elevated levels. This severe hypercholesterolemia in homozygote animals resulted in atherosclerotic lesions in the coronary arteries and abdominal aorta that resemble human atherosclerosis. These phenotypes were more severe and developed over a shorter time when fed a diet containing natural sources of fat and cholesterol. LDLR-targeted Yucatan miniature pigs offer several advantages over existing large animal models including size, consistency, availability, and versatility. This new model of cardiovascular disease could be an important resource for developing and testing novel detection and treatment strategies for coronary and aortic atherosclerosis and its complications.
doi:10.1371/journal.pone.0093457
PMCID: PMC3972179  PMID: 24691380
6.  Maintenance of Interphase Chromosome Compaction and Homolog Pairing in Drosophila Is Regulated by the Condensin Cap-H2 and Its Partner Mrg15 
Genetics  2013;195(1):127-146.
Dynamic regulation of chromosome structure and organization is critical for fundamental cellular processes such as gene expression and chromosome segregation. Condensins are conserved chromosome-associated proteins that regulate a variety of chromosome dynamics, including axial shortening, lateral compaction, and homolog pairing. However, how the in vivo activities of condensins are regulated and how functional interactors target condensins to chromatin are not well understood. To better understand how Drosophila melanogaster condensin is regulated, we performed a yeast two-hybrid screen and identified the chromo-barrel domain protein Mrg15 to interact with the Cap-H2 condensin subunit. Genetic interactions demonstrate that Mrg15 function is required for Cap-H2-mediated unpairing of polytene chromosomes in ovarian nurse cells and salivary gland cells. In diploid tissues, transvection assays demonstrate that Mrg15 inhibits transvection at Ubx and cooperates with Cap-H2 to antagonize transvection at yellow. In cultured cells, we show that levels of chromatin-bound Cap-H2 protein are partially dependent on Mrg15 and that Cap-H2-mediated homolog unpairing is suppressed by RNA interference depletion of Mrg15. Thus, maintenance of interphase chromosome compaction and homolog pairing status requires both Mrg15 and Cap-H2. We propose a model where the Mrg15 and Cap-H2 protein–protein interaction may serve to recruit Cap-H2 to chromatin and facilitates compaction of interphase chromatin.
doi:10.1534/genetics.113.153544
PMCID: PMC3761296  PMID: 23821596
condensin; homolog pairing; Mrg15; chromosome structure; transvection
7.  Enhancing Pancreatic Beta-Cell Regeneration In Vivo with Pioglitazone and Alogliptin 
PLoS ONE  2013;8(6):e65777.
Aims/Hypothesis
Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.
Methods
In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.
Results
Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.
Conclusions/Interpretation
These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.
doi:10.1371/journal.pone.0065777
PMCID: PMC3675063  PMID: 23762423
8.  A Rationally Designed Nitrogen-Rich Metal-Organic Framework and Its Exceptionally High CO2 and H2 Uptake Capability 
Scientific Reports  2013;3:1149.
On the way towards a sustainable low-carbon future, the design and construction of chemical or physical adsorbents for CO2 capture and clean energy storage are vital technology. The incorporation of accessible nitrogen-donor sites into the pore walls of porous adsorbents can dramatically affect the CO2 uptake capacity and selectivity on account of the dipole-quadrupole interactions between the polarizable CO2 molecule and the accessible nitrogen site. In the present work, a nitrogen-rich rth-type metal-organic framework (MOF) was constructed based on rational design and careful synthesis. The MOF presents exceptionally high uptake capacity not only for CO2 but also for H2, which is attributed to favorable interactions between the gas molecules and the nitrogen-rich triazole units of the MOF proved by both experimental measurements and theoretical molecular simulations.
doi:10.1038/srep01149
PMCID: PMC3556676  PMID: 23359632
9.  2-(1,3-Benzothiazol-2-ylsulfanyl)-N-(2-methylphenyl)acetamide 
In the title mol­ecule, C16H14N2OS2, the benzene ring and the benzo[d]thia­zole mean plane form a dihedral angle of 75.5 (1)°. The acetamide group is twisted by 47.7 (1)° from the attached benzene ring. In the crystal, mol­ecules related by translation along the a axis are linked into chains through N—H⋯O hydrogen bonds.
doi:10.1107/S1600536812042109
PMCID: PMC3515240  PMID: 23284460
10.  Activation of BKCa Channels in Zoledronic Acid-Induced Apoptosis of MDA-MB-231 Breast Cancer Cells 
PLoS ONE  2012;7(5):e37451.
Background
Zoledronic acid, one of the most potent nitrogen-containing biphosphonates, has been demonstrated to have direct anti-tumor and anti-metastatic properties in breast cancer in vitro and in vivo. In particular, tumor-cell apoptosis has been recognized to play an important role in the treatment of metastatic breast cancer with zoledronic acid. However, the precise mechanisms remain less clear. In the present study, we investigated the specific role of large conductance Ca2+-activated potassium (BKCa) channel in zoledronic acid-induced apoptosis of estrogen receptor (ER)-negative MDA-MB-231 breast cancer cells.
Methodology/Principal Findings
The action of zoledronic acid on BKCa channel was investigated by whole-cell and cell-attached patch clamp techniques. Cell apoptosis was assessed with immunocytochemistry, analysis of fragmented DNA by agarose gel electrophoresis, and flow cytometry assays. Cell proliferation was investigated by MTT test and immunocytochemistry. In addition, such findings were further confirmed with human embryonic kidney 293 (HEK293) cells which were transfected with functional BKCa α-subunit (hSloα). Our results clearly indicated that zoledronic acid directly increased the activities of BKCa channels, and then activation of BKCa channel by zoledronic acid contributed to induce apoptosis in MDA-MB-231 cells. The possible mechanisms were associated with the elevated level of intracellular Ca2+ and a concomitant depolarization of mitochondrial membrane potential (Δψm) in MDA-MB-231 cells.
Conclusions
Activation of BKCa channel was here shown to be a novel molecular pathway involved in zoledronic acid-induced apoptosis of MDA-MB-231 cells in vitro.
doi:10.1371/journal.pone.0037451
PMCID: PMC3360057  PMID: 22655048
11.  Get Phases from Arsenic Anomalous Scattering: de novo SAD Phasing of Two Protein Structures Crystallized in Cacodylate Buffer 
PLoS ONE  2011;6(9):e24227.
The crystal structures of two proteins, a putative pyrazinamidase/nicotinamidase from the dental pathogen Streptococcus mutans (SmPncA) and the human caspase-6 (Casp6), were solved by de novo arsenic single-wavelength anomalous diffraction (As-SAD) phasing method. Arsenic (As), an uncommonly used element in SAD phasing, was covalently introduced into proteins by cacodylic acid, the buffering agent in the crystallization reservoirs. In SmPncA, the only cysteine was bound to dimethylarsinoyl, which is a pentavalent arsenic group (As (V)). This arsenic atom and a protein-bound zinc atom both generated anomalous signals. The predominant contribution, however, was from the As anomalous signals, which were sufficient to phase the SmPncA structure alone. In Casp6, four cysteines were found to bind cacodyl, a trivalent arsenic group (As (III)), in the presence of the reducing agent, dithiothreitol (DTT), and arsenic atoms were the only anomalous scatterers for SAD phasing. Analyses and discussion of these two As-SAD phasing examples and comparison of As with other traditional heavy atoms that generate anomalous signals, together with a few arsenic-based de novo phasing cases reported previously strongly suggest that As is an ideal anomalous scatterer for SAD phasing in protein crystallography.
doi:10.1371/journal.pone.0024227
PMCID: PMC3166297  PMID: 21912678
12.  High levels of Nrf2 determine chemoresistance in type II endometrial cancer 
Cancer research  2010;70(13):5486-5496.
Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor, Nrf2, was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species (ROS) and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia (CH) and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than that of the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs while it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and SCID mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy.
doi:10.1158/0008-5472.CAN-10-0713
PMCID: PMC2896449  PMID: 20530669
Nrf2; chemoresistance; and endometrial cancer
13.  A Noncanonical Mechanism of Nrf2 Activation by Autophagy Deficiency: Direct Interaction between Keap1 and p62▿  
Molecular and Cellular Biology  2010;30(13):3275-3285.
In response to stress, cells can utilize several cellular processes, such as autophagy, which is a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. The Nrf2-Keap1 pathway functions as a critical regulator of the cell's defense mechanism against oxidative stress by controlling the expression of many cellular protective proteins. Under basal conditions, Nrf2 is ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and targeted to the 26S proteasome for degradation. Upon induction, the activity of the E3 ubiquitin ligase is inhibited through the modification of cysteine residues in Keap1, resulting in the stabilization and activation of Nrf2. In this current study, we identified the direct interaction between p62 and Keap1 and the residues required for the interaction have been mapped to 349-DPSTGE-354 in p62 and three arginines in the Kelch domain of Keap1. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62-mediated Nrf2 upregulation is Keap1 dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a noncanonical cysteine-independent mechanism.
doi:10.1128/MCB.00248-10
PMCID: PMC2897585  PMID: 20421418
14.  Nrf2 promotes neuronal cell differentiation 
Free radical biology & medicine  2009;47(6):867-879.
The transcription factor Nrf2 has emerged as a master regulator for the endogenous antioxidant response, which is critical in defending cells against environmental insults and in maintaining intracellular redox balance. However, whether Nrf2 has any role in neuronal cell differentiation is largely unknown. In this report, we have examined the effects of Nrf2 on cell differentiation using a neuroblastoma cell line, SH-SY5Y. Retinoic acid (RA) and 12-O-tetradecanoylphorbol-13-acetate (TPA), two well-studied inducers for neuronal differentiation, are able to induce Nrf2 and its target gene NAD(P)H quinone oxidoreductase 1 (NQO1) in a dose- and time- dependent manner. RA-induced Nrf2 up-regulation is accompanied by neurite outgrowth and an induction of two neuronal differentiation markers, neurofilament-M (NF-M) and microtubule-associated protein 2 (MAP-2). Overexpression of Nrf2 in SH-SY5Y cells promotes neuronal differentiation whereas inhibition of endogenous Nrf2 expression inhibited neuronal differentiation. More remarkably, the positive role of Nrf2 in neuronal differentiation was verified ex vivo in primary neuron culture. Primary neurons isolated from Nrf2-null mice showed a retarded progress in differentiation, compared to that from wild-type mice. Collectively, our data demonstrate a novel role for Nrf2 in promoting neuronal cell differentiation, which will open new perspectives for therapeutic uses of Nrf2 activators in patients with neurodegenerative diseases.
doi:10.1016/j.freeradbiomed.2009.06.029
PMCID: PMC2748111  PMID: 19573594
Nrf2; Keap1; Oxidative Stress; Neuronal differentiation; SH-SY5Y; NQO1
15.  Bis(2,2′-bipyridine)(2-hy­droxy-2,2-diphenyl­acetato)­copper(II) nitrate dihydrate 
In the title complex, [Cu(C14H11O3)(C10H8N2)2]NO3·2H2O, the CuII atom is coordinated by four N atoms from two 2,2′-bipyridine ligands and two O atoms from one benzilate ligand in a distorted octa­hedral geometry. A supra­molecular network is formed via inter­molecular O—H⋯O and C—H⋯O hydrogen-bonding inter­actions. π–π stacking inter­actions between neighboring pyridine rings are also present, the centroid—centroid distance being 3.808 (2) Å.
doi:10.1107/S1600536810035555
PMCID: PMC2983227  PMID: 21587395
16.  Direct interaction between Nrf2 and p21Cip1/WAF1 upregulates the Nrf2-mediated antioxidant response 
Molecular cell  2009;34(6):663-673.
Summary
In response to oxidative stress, Nrf2 and p21 Cip1/WAF1 are both upregulated to protect cells from oxidative damage. Nrf2 is constantly ubiquitinated by a Keap1 dimer that interacts with a weak-binding 29DLG motif and a strong-binding 79ETGE motif in Nrf2, resulting in degradation of Nrf2. Modification of the redox-sensitive cysteine residues on Keap1 disrupts the Keap1-29DLG binding, leading to diminished Nrf2 ubiquitination and activation of the antioxidant response. However, the underlying mechanism by which p21 protects cells from oxidative damage remains unclear. Here, we present molecular and genetic evidence suggesting that the antioxidant function of p21 is mediated through activation of Nrf2 by stabilizing the Nrf2 protein. The 154KRR motif in p21 directly interacts with the 29DLG and 79ETGE motifs in Nrf2, and thus, competes with Keap1 for Nrf2 binding, compromising ubiquitination of Nrf2. Furthermore, the physiological significance of our findings was demonstrated in vivo using p21-deficient mice.
doi:10.1016/j.molcel.2009.04.029
PMCID: PMC2714804  PMID: 19560419
17.  1-Methyl-4,5-dinitro-1H-imidazole 
In the title compound, C4H4N4O4, the two nitro groups are twisted with respect to the imidazole plane, making dihedral angles of 24.2 (3) and 33.4 (4)°. In the crystal structure, the mol­ecules are linked through non-classical inter­molecular C—H⋯O hydrogen bonds.
doi:10.1107/S1600536809047126
PMCID: PMC2972105  PMID: 21578803
18.  Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction 
Toxicology and applied pharmacology  2008;230(3):383-389.
Drinking water contaminated with arsenic, a human carcinogen, is a worldwide health issue. An understanding of cellular signaling events in response to arsenic exposure and rational designing of strategies to reduce arsenic damages by modulating signaling events are important to fight against arsenic-induced diseases. Previously, we reported that activation of the Nrf2-mediated cellular defense pathway confers protection against toxic effects induced by sodium arsenite [As(III)] or monomethylarsonous acid [MMA(III)]. Paradoxically, arsenic has been reported to induce the Nrf2-dependent signaling pathway. Here, we report the unique mechanism of Nrf2 induction by arsenic. Similar to tert-butylhydroquinone (tBHQ) or sulforaphane (SF), arsenic induced the Nrf2-dependent response through enhancing Nrf2 protein levels by inhibiting Nrf2 ubiquitination and degradation. However, the detailed action of arsenic in Nrf2 induction is different from that of tBHQ or SF. Arsenic markedly enhanced the interaction between Keap1 and Cul3, subunits of the E3 ubiquitin ligase for Nrf2, which led to impaired dynamic assembly/disassembly of the E3 ubiquitin ligase and thus decreased its ligase activity. Furthermore, induction of Nrf2 by arsenic is independent of the previously identified C151 residue in Keap1 that is required for Nrf2 activation by tBHQ or SF. Distinct mechanisms of Nrf2 activation by seemingly harmful and beneficial reagents provide a molecular basis to design Nrf2-activating agents for therapeutic intervention.
doi:10.1016/j.taap.2008.03.003
PMCID: PMC2610481  PMID: 18417180
19.  Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2 
Carcinogenesis  2008;29(6):1235-1243.
Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a ‘good’ transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2–small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.
doi:10.1093/carcin/bgn095
PMCID: PMC3312612  PMID: 18413364
20.  Ectodermal-Neural Cortex 1 Down-Regulates Nrf2 at the Translational Level 
PLoS ONE  2009;4(5):e5492.
The transcription factor Nrf2 is the master regulator of a cellular defense mechanism against environmental insults. The Nrf2-mediated antioxidant response is accomplished by the transcription of a battery of genes that encode phase II detoxifying enzymes, xenobiotic transporters, and antioxidants. Coordinated expression of these genes is critical in protecting cells from toxic and carcinogenic insults and in maintaining cellular redox homeostasis. Activation of the Nrf2 pathway is primarily controlled by Kelch-like ECH-associated protein 1 (Keap1), which is a molecular switch that turns on or off the Nrf2 signaling pathway according to intracellular redox conditions. Here we report our finding of a novel Nrf2 suppressor ectodermal-neural cortex 1 (ENC1), which is a BTB-Kelch protein and belongs to the same family as Keap1. Transient expression of ENC1 reduced steady-state levels of Nrf2 and its downstream gene expression. Although ENC1 interacted with Keap1 indirectly, the ENC1-mediated down-regulation of Nrf2 was independent of Keap1. The negative effect of ENC1 on Nrf2 was not due to a change in the stability of Nrf2 because neither proteasomal nor lysosomal inhibitors had any effects. Overexpression of ENC1 did not result in a change in the level of Nrf2 mRNA, rather, it caused a decrease in the rate of Nrf2 protein synthesis. These results demonstrate that ENC1 functions as a negative regulator of Nrf2 through suppressing Nrf2 protein translation, which adds another level of complexity in controlling the Nrf2 signaling pathway.
doi:10.1371/journal.pone.0005492
PMCID: PMC2675063  PMID: 19424503
21.  Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity 
Toxicology and applied pharmacology  2007;225(2):206-213.
Arsenic is widely spread in our living environment and imposes a big challenge on human health worldwide. Arsenic damages biological systems through multiple mechanisms including the generation of reactive oxygen species. The transcription factor Nrf2 regulates the cellular antioxidant response that protects cells from various insults. In this study, the protective role of Nrf2 in arsenic toxicity was investigated in a human bladder urothelial cell line, UROtsa. Using an UROtsa cell line stably infected with Nrf2-siRNA, we clearly demonstrate that compromised Nrf2 expression sensitized the cells to As(III)- and MMA(III)-induced toxicity. On the other hand, the activation of the Nrf2 pathway by tert-butylhydroquinone (tBHQ) and sulforaphane (SF), the known Nrf2-inducers, rendered UROtsa cells more resistant to As(III)- and MMA(III). Furthermore, the wild type mouse embryo fibroblast (WT-MEF) cells were protected from As(III)- and MMA(III)-induced toxicity following Nrf2 activation by tBHQ or SF whereas neither tBHQ nor SF conferred protection in the Nrf2−/−-MEF cells, demonstrating that tBHQ- or SF-mediated protection against As(III)- and MMA(III)-induced toxicity depends on Nrf2 activation. These results, obtained by both loss of function and gain of function analyses, clearly demonstrate the protective role of Nrf2 in arsenic-induced toxicity. The current work lays the groundwork for using Nrf2 activators for therapeutic and dietary interventions against adverse effects of arsenic.
doi:10.1016/j.taap.2007.07.016
PMCID: PMC2610476  PMID: 17765279
Nrf2; Keap1; arsenic; arsenite; MMA(III); UROtsa
22.  Oridonin Confers Protection against Arsenic-Induced Toxicity through Activation of the Nrf2-Mediated Defensive Response 
Environmental Health Perspectives  2008;116(9):1154-1161.
Background
Groundwater contaminated with arsenic imposes a big challenge to human health worldwide. Using natural compounds to subvert the detrimental effects of arsenic represents an attractive strategy. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of the cellular antioxidant response and xenobiotic metabolism. Recently, activation of the Nrf2 signaling pathway has been reported to confer protection against arsenic-induced toxicity in a cell culture model.
Objectives
The goal of the present work was to identify a potent Nrf2 activator from plants as a chemopreventive compound and to demonstrate the efficacy of the compound in battling arsenic-induced toxicity.
Results
Oridonin activated the Nrf2 signaling pathway at a low subtoxic dose and was able to stabilize Nrf2 by blocking Nrf2 ubiquitination and degradation, leading to accumulation of the Nrf2 protein and activation of the Nrf2-dependent cytoprotective response. Pretreatment of UROtsa cells with 1.4 μM oridonin significantly enhanced the cellular redox capacity, reduced formation of reactive oxygen species (ROS), and improved cell survival after arsenic challenge.
Conclusions
We identified oridonin as representing a novel class of Nrf2 activators and illustrated the mechanism by which the Nrf2 pathway is activated. Furthermore, we demonstrated the feasibility of using natural compounds targeting Nrf2 as a therapeutic approach to protect humans from various environmental insults that may occur daily.
doi:10.1289/ehp.11464
PMCID: PMC2535615  PMID: 18795156
antioxidant responsive element; antitumor; ARE; arsenic; chemoprevention; diterpenoid; Keap1; Nrf2; oridonin; oxidative stress; rubescensin
23.  Niobium(V) Oxynitride: Synthesis, Characterization, and Feasibility as Anode Material for Rechargeable Lithium-Ion Batteries 
Abstract
The decomposition reaction of niobium(V) oxytrichloride ammoniate to the oxynitride of niobium in the 5+ oxidation state was developed in a methodological way. By combining elemental analysis, Rietveld refinements of X-ray and neutron diffraction data, SEM and TEM, the sample compound was identified as approximately 5 nm-diameter particles of NbO1.3(1)N0.7(1) crystallizing with baddeleyite-type structure. The thermal stability of this compound was studied in detail by thermogravimetric/differential thermal analysis and temperature-dependent X-ray diffraction. Moreover, the electrochemical uptake and release by the galvanostatic cycling method of pure and carbon-coated NbO1.3(1)N0.7(1) versus lithium was investigated as an example of an Li-free transition-metal oxynitride. The results showed that reversible capacities as high as 250 and 80 A h kg−1 can be reached in voltage ranges of 0.05–3 and 1–3 V, respectively. Furthermore, a plausible mechanism for the charge–discharge reaction is proposed.
doi:10.1002/chem.201102653
PMCID: PMC3528069  PMID: 22461147
electrochemistry; nanoparticles; niobium; oxynitrides; solid-state reactions

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