PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (137)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Authors
more »
Year of Publication
more »
1.  Involvement of JNK-mediated pathway in EGF-mediated protection against paclitaxel-induced apoptosis in SiHa human cervical cancer cells 
Liu, B | Fang, M | Lu, Y | Lu, Y | Mills, G B | Fan, Z
British Journal of Cancer  2001;85(2):303-311.
We investigated the signalling pathways by which epidermal growth factor (EGF) modulates paclitaxel-induced apoptosis in SiHa human cervical cancer cells. SiHa cells exposed to paclitaxel underwent apoptosis, which was strongly inhibited by EGF. This inhibition of apoptosis by EGF was not altered by pharmacological blockade of phosphatidylinositol 3′-OH kinase (PI-3K) with the PI-3K specific inhibitor LY294002 or blockade of the mitogen-activated protein kinase (MAPK) kinase (MEK) with the MEK specific inhibitor PD98059, or by transfection of the cells with PI-3K or MEK dominant-negative expression vectors. EGF did not stimulate PI-3K/Akt, MEK/MAPK, or p38 MAPK activity in SiHa cells but did transiently activate the c-Jun NH2-terminal kinase (JNK). Co-exposure of SiHa cells to SB202190 at concentrations that inhibit JNK abolished the protective effect of EGF on SiHa cells against paclitaxel-induced apoptosis. Our findings indicate that the JNK signaling pathway plays an important role in EGF-mediated protection from paclitaxel-induced apoptosis in SiHa cells. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1910
PMCID: PMC2364054  PMID: 11461094
paclitaxel; apoptosis; EGF; JNK; PI-3K; MAPK
2.  Cognitive changes preceding clinical symptom onset of mild cognitive impairment and relationship to ApoE genotype 
Current Alzheimer research  2014;11(8):773-784.
Background
This study had two goals (1) to evaluate changes in neuropsychological performance among cognitively normal individuals that might precede the onset of clinical symptoms, and (2) to examine the impact of Apolipoprotein E (ApoE) genotype on these changes.
Methods
Longitudinal neuropsychological, clinical assessments and consensus diagnoses were completed prospectively in 268 cognitively normal individuals. The mean duration of follow-up was 9.2 years (+/− 3.3). 208 participants remained normal and 60 developed cognitive decline, consistent with a diagnosis of MCI or dementia. Cox regression analyses were completed, for both baseline scores and rate of change in scores, in relation to time to onset of clinical symptoms. Analyses were completed both with and without ApoE-4 status included. Interactions with ApoE-4 status were also examined.
Results
Lower baseline test scores, as well as greater rate of change in test scores, were associated with time to onset of clinical symptoms (p<0.001). The mean time from baseline to onset of clinical symptoms was 6.15 (+/− 3.4) years. The presence of an ApoE-4 allele doubled the risk of progression. The rate of change in two of the test scores was significantly different in ApoE-4 carriers vs. non-carriers.
Conclusions
Cognitive performance declines prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI. Cognitive changes in normal individuals who will subsequently decline may be observed at least 6.5 years prior to symptom onset. In addition, the risk of decline is doubled among individuals with an ApoE-4 allele.
PMCID: PMC4163954  PMID: 25212916
preclinical Alzheimer's disease; cognitive decline; Apolipoprotein E genotype; mild cognitive impairment; episodic memory; longitudinal follow-up
3.  P-values in genomics: Apparent precision masks high uncertainty 
Molecular Psychiatry  2014;19(12):1336-1340.
Scientists often interpret P-values as measures of the relative strength of statistical findings. This is common practice in large-scale genomic studies where P-values are used to choose which of numerous hypothesis test results should be pursued in subsequent research. In this study, we examine P-value variability to assess the degree of certainty P-values provide. We develop prediction intervals for the P-value in a replication study given the P-value observed in an initial study. The intervals depend on the initial value of P and the ratio of sample sizes between the initial and replication studies, but not on the underlying effect size or initial sample size. The intervals are valid for most large-sample statistical tests in any context, and can be used in the presence of single or multiple tests. While P-values are highly variable, future P-value variability can be explicitly predicted based on a P-value from an initial study. The relative size of the replication and initial study is an important predictor of the P-value in a subsequent replication study. We provide a handy calculator implementing these results and apply them to a study of Alzheimer's disease and recent findings of the Cross-Disorder Group of the Psychiatric Genomics Consortium. This study suggests that overinterpretation of very significant, but highly variable, P-values is an important factor contributing to the unexpectedly high incidence of non-replication. Formal prediction intervals can also provide realistic interpretations and comparisons of P-values associated with different estimated effect sizes and sample sizes.
doi:10.1038/mp.2013.184
PMCID: PMC4255087  PMID: 24419042
genome-wide association study; GWAS; multiple hypothesis testing; prediction interval; P-value; P-value variability
4.  SRF expedites metastasis and modulates the epithelial to mesenchymal transition by regulating miR-199a-5p expression in human gastric cancer 
Zhao, X | He, L | Li, T | Lu, Y | Miao, Y | Liang, S | Guo, H | Bai, M | Xie, H | Luo, G | Zhou, L | Shen, G | Guo, C | Bai, F | Sun, S | Wu, K | Nie, Y | Fan, D
Cell Death and Differentiation  2014;21(12):1900-1913.
Dysregulation of transcription factors (TFs) is associated with tumor progression, but little is known about TF expression patterns in the context of gastric cancer (GC) metastasis. Using array-based profile analysis, we found that 22 TFs showed differential activities between GC cell lines with low- and high-metastatic potential. Of this group of TFs, serum response factor (SRF) was significantly upregulated in metastatic GC cells. SRF expression was frequently elevated in a panel of metastatic GC cells and tissues, and high-level expression of SRF was significantly associated with a more aggressive phenotype and poor prognosis in patients with GC. In GC cell lines, overexpression of SRF potently promoted cell migration and invasion in vitro as well as the formation of intrahepatic and pulmonary metastases in vivo, whereas loss of SRF inhibited GC cell invasion and metastasis. We also performed a microRNA microarray to screen for transcriptional targets of SRF and found that SRF transactivates miR-199a-5p and miR-199a-3p by directly binding to their promoters. We further determined that overexpression of miR-199a-5p, but not miR-199a-3p, increased GC cell invasion and metastasis. In contrast, inhibition of miR-199a-5p impaired the metastatic potential of GC cells in vitro and in vivo, and E-cadherin was identified as a direct and functional target of miR-199a-5p in GC cells. Specifically, our results showed that SRF promotes GC metastasis and the epithelial to mesenchymal transition (EMT) though miR-199a-5p-mediated downregulation of E-cadherin. The present study thus provides insight into the specific biological behavior of SRF in GC metastasis. As increased activity of the SRF/miR-199a-5p/E-cadherin pathway appears to promote GC cell EMT and metastasis, these regulators may therefore be developed as therapeutic targets or biomarkers for GC progression.
doi:10.1038/cdd.2014.109
PMCID: PMC4227147  PMID: 25080937
5.  Seasonal pattern of hepatitis E virus prevalence in swine in two different geographical areas in China 
Epidemiology and infection  2013;141(11):2403-2409.
Summary
We studied seasonal patterns of swine hepatitis E virus (HEV) infection in China. From 2008 through 2011, 4200 swine bile specimens were collected for the detection of HEV RNA. A total of 3.83% (92/2400) of specimens in eastern China and 2.61% (47/1800) in southwestern China were positive for HEV. Seasonal patterns differing by geographical area were suggested. In eastern China, the major peak of HEV RNA prevalence was during March-April, with a minor peak during September-October, and a dip during July-August. In southwestern China, the peak was during September-October and the dip during March-April. The majority of subtype 4a cases (76.83%, 63/82) were detected in the first half of the year, while the majority of subtype 4b cases (89.66%, 26/29) were concentrated in the second half of the year, suggesting different subtype contribute to different peaks. Our results indicate that the distribution of HEV subtypes is associated with seasonal patterns.
doi:10.1017/S0950268813000113
PMCID: PMC4071111  PMID: 23388392
6.  The Specific Role of FAM20C in Amelogenesis 
Journal of Dental Research  2013;92(11):995-999.
Previously, we showed that Sox2-Cre;Fam20Cfl/fl mice in which Fam20C was ubiquitously inactivated had severe defects in dentin, enamel, and bone, along with hypophosphatemia. It remains to be determined if the enamel defects in the mice with universal inactivation of Family with sequence similarity 20-C (FAM20C) were associated with the dentin defects and whether hypophosphatemia in the knockout mice contributed to the enamel defects. In this study, we crossed Fam20Cfl/fl mice with keratin 14-Cre (K14-Cre) transgenic mice to specifically inactivate Fam20C in the epithelial cells, including the dental epithelial cells that are responsible for forming tooth enamel. X-ray, backscattered scanning electron microscopic, and histological analyses showed that the K14-Cre;Fam20Cfl/fl mice had severe enamel and ameloblast defects, while their dentin and alveolar bone were not significantly affected. Accordingly, serum biochemistry of the K14-Cre;Fam20Cfl/fl mice showed normal phosphate and FGF23 levels in the circulation. Analysis of these data indicates that, while FAM20C is a molecule essential to amelogenesis, its inactivation in the dental epithelium does not significantly affect dentinogenesis. Hypophosphatemia makes no significant contribution to the enamel defects in the mice with the ubiquitous deletion of Fam20C.
doi:10.1177/0022034513504588
PMCID: PMC3797537  PMID: 24026952
FGF23; biomineralization; hypophosphatemia; FAM20C; amelogenesis; kinase
7.  BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1 
Cell Death and Differentiation  2013;20(10):1393-1403.
Bcl-2-interacting mediator of cell death (Bim) is a pro-apoptotic B-cell lymphoma 2 family member implicated in numerous apoptotic stimuli. In particular, Bim is required for cell death mediated by antimitotic agents, however, mitotic regulation of Bim remains poorly understood. Here, we show that the major splice variant of Bim, BimEL, is regulated during mitosis by the Aurora A kinase and protein phosphatase 2A (PP2A). We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL. These findings describe a novel mechanism by which the oncogenic kinase Aurora A promotes cell survival during mitosis by downregulating proapoptotic signals. Notably, we observed that knockdown of Bim significantly increased resistance of cells to the Aurora A inhibitor MLN8054. Inhibitors of Aurora A are currently under investigation as cancer chemotherapeutics and our findings suggest that efficacy of this class of drugs may function in part by enhancing apoptotic activity of BimEL.
doi:10.1038/cdd.2013.93
PMCID: PMC3770328  PMID: 23912711
Bim; apoptosis; cell cycle; mitosis; aurora kinase
8.  MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy 
Li, X | Du, N | Zhang, Q | Li, J | Chen, X | Liu, X | Hu, Y | Qin, W | Shen, N | Xu, C | Fang, Z | Wei, Y | Wang, R | Du, Z | Zhang, Y | Lu, Y
Cell Death & Disease  2014;5(10):e1479-.
Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which can result in cardiac hypertrophy and subsequent heart failure, associated with pyroptosis, the pro-inflammatory programmed cell death. MicroRNAs (miRNAs), small endogenous non-coding RNAs, have been shown to be involved in diabetic cardiomyopathy. However, whether miRNAs regulate pyroptosis in diabetic cardiomyopathy remains unknown. Our study revealed that mir-30d expression was substantially increased in streptozotocin (STZ)-induced diabetic rats and in high-glucose-treated cardiomyocytes as well. Upregulation of mir-30d promoted cardiomyocyte pyroptosis in diabetic cardiomyopathy; conversely, knockdown of mir-30d attenuated it. In an effort to understand the signaling mechanisms underlying the pro-pyroptotic property of mir-30d, we found that forced expression of mir-30d upregulated caspase-1 and pro-inflammatory cytokines IL-1β and IL-18. Moreover, mir-30d directly repressed foxo3a expression and its downstream protein, apoptosis repressor with caspase recruitment domain (ARC). Furthermore, silencing ARC by siRNA mimicked the action of mir-30d: upregulating caspase-1 and inducing pyroptosis. These findings promoted us to propose a new signaling pathway leading to cardiomyocyte pyroptosis under hyperglycemic conditions: mir-30d↑→foxo3a↓→ ARC↓→caspase-1↑→IL-1β, IL-18↑→pyroptosis↑. Therefore, mir-30d may be a promising therapeutic target for the management of diabetic cardiomyopathy.
doi:10.1038/cddis.2014.430
PMCID: PMC4237254  PMID: 25341033
9.  A Critical Role for Immune System Response in Mediating Anti-influenza Drug Synergies Assessed by Mechanistic Modeling 
Influenza virus infections represent a serious public health problem worldwide, due to the rapid emergence of drug resistance. One strategy to improve treatment efficacy is to combine drugs that act synergistically. Potentially useful drug combinations are typically identified through empirical testing using in vitro and animal models, but the complexity of the clinical situation warrants the use of more careful analysis and sophisticated approaches. To explore new approaches, we constructed a mechanistic model representing the interaction of antiviral drugs with the viral replication pathway and human immune responses. Simulation of combination therapy using oseltamivir and amantadine predicted significant therapeutic synergy only when immune response was included, in agreement with previous in vitro and in vivo studies using amantadine-resistant strains. Our model can be used to predict the optimal doses for combination therapy, and also raises questions about current drug evaluation methods that do not account for immune system interactions.
doi:10.1038/psp.2014.32
PMCID: PMC4211263  PMID: 25207611
10.  MiR-630 inhibits proliferation by targeting CDC7 kinase, but maintains the apoptotic balance by targeting multiple modulators in human lung cancer A549 cells 
Cell Death & Disease  2014;5(9):e1426-.
MicroRNAome analyses have shown microRNA-630 (miR-630) to be involved in the regulation of apoptosis. However, its apoptotic role is still debated and its participation in DNA replication is unknown. Here, we demonstrate that miR-630 inhibits cell proliferation by targeting cell-cycle kinase 7 (CDC7) kinase, but maintains the apoptotic balance by targeting multiple activators of apoptosis under genotoxic stress. We identified a novel regulatory mechanism of CDC7 gene expression, in which miR-630 downregulated CDC7 expression by recognizing and binding to four binding sites in CDC7 3'-UTR. We found that miR-630 was highly expressed in A549 and NIH3T3 cells where CDC7 was downregulated, but lower in H1299, MCF7, MDA-MB-231, HeLa and 2BS cells where CDC7 was upregulated. Furthermore, the induction of miR-630 occurred commonly in a variety of human cancer and immortalized cells in response to genotoxic agents. Importantly, downregulation of CDC7 by miR-630 was associated with cisplatin (CIS)-induced inhibitory proliferation in A549 cells. Mechanistically, miR-630 exerted its inhibitory proliferation by blocking CDC7-mediated initiation of DNA synthesis and by inducing G1 arrest, but maintains apoptotic balance under CIS exposure. On the one hand, miR-630 promoted apoptosis by downregulation of CDC7; on the other hand, it reduced apoptosis by downregulating several apoptotic modulators such as PARP3, DDIT4, EP300 and EP300 downstream effector p53, thereby maintaining the apoptotic balance. Our data indicate that miR-630 has a bimodal role in the regulation of apoptosis in response to DNA damage. Our data also support the notion that a certain mRNA can be targeted by several miRNAs, and in particular an miRNA may target a set of mRNAs. These data afford a comprehensive view of microRNA-dependent control of gene expression in the regulation of apoptosis under genotoxic stress.
doi:10.1038/cddis.2014.386
PMCID: PMC4225225  PMID: 25255219
11.  Associations of blood glucose and prevalent diabetes with risk of cardiovascular disease in 500 000 adult Chinese: the China Kadoorie Biobank 
Diabetic Medicine  2014;31(5):540-551.
Abstract
Aims
To examine the relationship of self‐reported diabetes, and of random blood glucose levels among individuals without known diabetes, with the prevalence of cardiovascular disease in Chinese adults.
Methods
We examined cross‐sectional data from the China Kadoorie Biobank of 0.5 million people aged 30–79 years recruited from 10 diverse regions of China in the period 2004–2008. Logistic regression was used to estimate the odds ratios of prevalent cardiovascular disease associated with self‐reported diabetes, and with measured random blood glucose levels among participants with no history of diabetes, adjusting simultaneously for age, sex, area, education, smoking, alcohol, blood pressure and physical activity.
Results
A total of 3.2% of participants had self‐reported diabetes (men 2.9%; women 3.3%) and 2.8% had screen‐detected diabetes (men 2.6%; women 2.8%), i.e. they had no self‐reported history of diabetes but a blood glucose level suggestive of a diagnosis of diabetes. Compared with individuals without a history of diabetes, the odds ratios associated with self‐reported diabetes were 2.18 (95% CI 2.06–2.30) and 1.88 (95% CI 1.75–2.01) for prevalent ischaemic heart disease and stroke/transient ischaemic attack, respectively. Among participants without self‐reported diabetes there was a positive association between random blood glucose and ischaemic heart disease and stroke/transient ischaemic attack prevalence (P for trend <0.0001). Below the diabetic threshold (<11.1 mmol/l) each additional 1 mmol/l of random blood glucose was associated with 4% (95% CI 2–5%) and 5% (95% CI 3–7%) higher odds of prevalent ischaemic heart disease and stroke/transient ischaemic attack, respectively.
Conclusions
In this adult Chinese population, self‐reported diabetes was associated with a doubling of the odds of prevalent cardiovascular disease. Below the threshold for diabetes there was still a modest, positive association between random blood glucose and prevalent cardiovascular disease.
doi:10.1111/dme.12392
PMCID: PMC4114560  PMID: 24344928
12.  IRF4 is a novel mediator for neuronal survival in ischaemic stroke 
Cell Death and Differentiation  2014;21(6):888-903.
Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4–SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4–SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.
doi:10.1038/cdd.2014.9
PMCID: PMC4013523  PMID: 24510125
IRF4; SRF; ischaemic stroke; neuronal survival
13.  Integrated analyses identify the involvement of microRNA-26a in epithelial–mesenchymal transition during idiopathic pulmonary fibrosis 
Liang, H | Gu, Y | Li, T | Zhang, Y | Huangfu, L | Hu, M | Zhao, D | Chen, Y | Liu, S | Dong, Y | Li, X | Lu, Y | Yang, B | Shan, H
Cell Death & Disease  2014;5(5):e1238-.
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and highly lethal fibrotic lung disease with poor treatment and unknown etiology. Emerging evidence suggests that epithelial–mesenchymal transition (EMT) has an important role in repair and scar formation following epithelial injury during pulmonary fibrosis. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of IPF, limited studies have payed attention on the participation of miRNAs in EMT in lung fibrosis. In our study, we identified and constructed a regulation network of differentially expressed IPF miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental pulmonary fibrosis. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-β1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in pulmonary fibrosis, and suggests that miR-26a may be a potential therapeutic target for IPF.
doi:10.1038/cddis.2014.207
PMCID: PMC4047861  PMID: 24853416
microRNA-26a; HMGA2; EMT; Idiopathic Pulmonary Fibrosis
14.  Research on Dynamic Routing Mechanisms in Wireless Sensor Networks 
The Scientific World Journal  2014;2014:165694.
WirelessHART is the most widely applied standard in wireless sensor networks nowadays. However, it does not provide any dynamic routing mechanism, which is important for the reliability and robustness of the wireless network applications. In this paper, a collection tree protocol based, dynamic routing mechanism was proposed for WirelessHART network. The dynamic routing mechanism was evaluated through several simulation experiments in three aspects: time for generating the topology, link quality, and stability of network. Besides, the data transmission efficiency of this routing mechanism was analyzed. The simulation and evaluation results show that this mechanism can act as a dynamic routing mechanism for the TDMA-based wireless sensor network.
doi:10.1155/2014/165694
PMCID: PMC4005053  PMID: 24982927
15.  Sublytic C5b-9 triggers glomerular mesangial cell apoptosis via XAF1 gene activation mediated by p300-dependent IRF-1 acetylation 
Qiu, W | Zhou, J | Zhu, G | Zhao, D | He, F | Zhang, J | Lu, Y | Yu, T | Liu, L | Wang, Y
Cell Death & Disease  2014;5(4):e1176-.
The apoptosis of glomerular mesangial cells (GMCs) in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis (MsPGN), is accompanied by sublytic C5b-9 deposition. However, the mechanism by which sublytic C5b-9 induces GMC apoptosis is unclear. In the present studies, the effect of X-linked inhibitor of apoptosis-associated factor 1 (XAF1) expression on GMC apoptosis and the role of p300 and interferon regulatory factor-1 (IRF-1) in mediating XAF1 gene activation were determined, both in the GMCs induced by sublytic C5b-9 (in vitro) and in the renal tissues of rats with Thy-1N (in vivo). The in vitro studies demonstrated that IRF-1-enhanced XAF1 gene activation and its regulation by p300-mediated IRF-1 acetylation were involved in GMC apoptosis induced by sublytic C5b-9. The element of IRF-1 binding to XAF1 promoter and two acetylated sites of IRF-1 protein were also revealed. In vivo, silence of p300, IRF-1 or XAF1 genes in the renal tissues diminished GMC apoptosis and secondary GMC proliferation as well as urinary protein secretion in Thy-1N rats. Together, these data implicate that sublytic C5b-9 induces the expression of both p300 and IRF-1, as well as p300-dependent IRF-1 acetylation that may contribute to XAF1 gene activation and subsequent GMC apoptosis in Thy-1N rats.
doi:10.1038/cddis.2014.153
PMCID: PMC4001307  PMID: 24743731
Thy-1 nephritis (Thy-1N); glomerular mesangial cell (GMC) apoptosis; sublytic C5b-9 complexes; p300; interferon regulatory factor-1 (IRF-1)
16.  HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation 
Cell Death and Differentiation  2012;20(3):408-418.
Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1α expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1α represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1α-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1α-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1α-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1α regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action.
doi:10.1038/cdd.2012.130
PMCID: PMC3569981  PMID: 23059786
hypoxia-inducible factor 1α (HIF-1α); microRNA; acute myeloid leukemia (AML)
17.  PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma 
Leukemia  2012;27(3):702-710.
Chemoresistance is the major obstacle in multiple myeloma (MM) management. We previously showed that macrophages protect myeloma cells, on a cell contact basis, from melphalan or dexamethasone-induced apoptosis in vitro. In this study, we found that macrophage-mediated myeloma drug resistance was also seen with purified macrophages from myeloma patients’ bone marrow (BM) in vitro and was confirmed in vivo using the human myeloma-SCID (severe combined immunodeficient) mouse model. By profiling differentially regulated and paired plasma membrane protein genes, we showed that PSGL-1 (P-selectin glycoprotein ligand-1)/selectins and ICAM-1/CD18 played an important role in macrophage-mediated myeloma cell drug resistance, as blocking antibodies against these molecules or genetic knockdown of PSGL-1 or ICAM-1 in myeloma cells repressed macrophages’ ability to protect myeloma cells. Interaction of macrophages and myeloma cells via these molecules activated Src and Erk1/2 kinases and c-myc pathways and suppressed caspase activation induced by chemotherapy drugs. Thus, our study sheds new light on the mechanism of drug resistance in MM and provides novel targets for improving the efficacy of chemotherapy in patients.
doi:10.1038/leu.2012.272
PMCID: PMC3652581  PMID: 22996336
macrophage; multidrug resistance; multiple myeloma; PSGL-1
18.  D-ribosylation induces cognitive impairment through RAGE-dependent astrocytic inflammation 
Han, C | Lu, Y | Wei, Y | Wu, B | Liu, Y | He, R
Cell Death & Disease  2014;5(3):e1117-.
Non-enzymatic glycation of proteins by reducing saccharides for instance D-glucose is an important post-translational modification regulating protein function. Already two centuries ago, D-glucose (Glc) was identified in the urine of diabetic patients. Recently, abnormally high level of D-ribose (Rib) in the urine of type 2 diabetics has been discovered, which is highly active in protein glycation, resulting in the production of advanced glycation end products (AGEs). Accumulation of AGEs leads to altered cellular function, for example AGE accumulation in the nervous system impairs cognitive ability, yet the mechanisms mediating this process for Rib are unknown. Here we found that treatment with Rib accelerated AGE formation in U251 and U87MG astrocytoma cells and in mouse brain, inducing upregulation of receptor for AGEs (RAGE). Astrocytoma cells with elevated levels of RAGE displayed enhanced activity of the proinflammatory nuclear transcription factor kappaB and increased expression of tumor necrosis factor alpha and glial fibrillary acidic protein. Moreover, injection of Rib induced astrocyte activation in mouse hippocampus and impaired spatial learning and memory abilities. These results indicate that mouse spatial cognitive impairment caused by Rib-derived AGEs is correlated with activation of an astrocyte-mediated, RAGE-dependent inflammatory response. This study may provide insights into the mechanism of Rib-involved cognitive impairments and diabetic encephalopathy.
doi:10.1038/cddis.2014.89
PMCID: PMC3973213  PMID: 24625976
advanced glycation end products; astrocyte activation; D-ribose; inflammatory response; RAGE; type 2 diabetes mellitus
19.  Significance of and Risk Factors for the Development of Central Airway Stenosis after Lung Transplantation 
Central airways stenosis (CAS) after lung transplant is a poorly understood complication. Objectives of this study were to determine if CAS was associated with chronic rejection or worse survival after transplant as well as to identify factors associated with CAS in a large cohort of lung transplant recipients. Lung transplant recipients transplanted at a single center were retrospectively reviewed for the development of CAS requiring airway dilation. 467 subjects met inclusion criteria with 60 (13%) of these developing CAS requiring intervention. Of these 60 recipients, 22 (37%) had resolution of CAS with bronchoplasty alone, while 32 (53%) ultimately required stent placement. CAS that required intervention was not a risk factor for the development of bronchiolitis obliterans syndrome or worse overall survival. Significant risk factors for the subsequent development of CAS in a time-dependant multivariable model were pulmonary fungal infections and the need for post-operative tracheostomy. While CAS was not associated with BOS or worse survival, it remains an important complication after lung transplant with potentially preventable risk factors.
doi:10.1111/ajt.12017
PMCID: PMC3558605  PMID: 23279590
lung transplantation; stenosis; stent; infection
20.  MiRNA-210 modulates a nickel-induced cellular energy metabolism shift by repressing the iron–sulfur cluster assembly proteins ISCU1/2 in Neuro-2a cells 
He, M | Lu, Y | Xu, S | Mao, L | Zhang, L | Duan, W | Liu, C | Pi, H | Zhang, Y | Zhong, M | Yu, Z | Zhou, Z
Cell Death & Disease  2014;5(2):e1090-.
The cellular energy metabolism shift, characterized by the inhibition of oxidative phosphorylation (OXPHOS) and enhancement of glycolysis, is involved in nickel-induced neurotoxicity. MicroRNA-210 (miR-210) is regulated by hypoxia-inducible transcription factor-1α (HIF-1α) under hypoxic conditions and controls mitochondrial energy metabolism by repressing the iron–sulfur cluster assembly protein (ISCU1/2). ISCU1/2 facilitates the assembly of iron–sulfur clusters (ISCs), the prosthetic groups that are critical for mitochondrial oxidation-reduction reactions. This study aimed to investigate whether miR-210 modulates alterations in energy metabolism after nickel exposure through suppressing ISCU1/2 and inactivating ISCs-containing metabolic enzymes. We determined that NiCl2 exposure leads to a significant accumulation of HIF-1α, rather than HIF-1β, in Neuro-2a cells. The miR-210 overexpression and ISCU1/2 downregulation was observed in a dose- and time-dependent manner. The gain-of-function and loss-of-dysfunction assays revealed that miR-210 mediated the ISCU1/2 suppression, energy metabolism alterations, and ISC-containing metabolic enzyme inactivation after nickel exposure. In addition, the impact of miR-210 on ISC-containing metabolic enzymes was independent from cellular iron regulation. Overall, these data suggest that repression of miR-210 on ISCU1/2 may contribute to HIF-1α-triggered alterations in energy metabolism after nickel exposure. A better understanding of how nickel impacts cellular energy metabolism may facilitate the elucidation of the mechanisms by which nickel affects the human health.
doi:10.1038/cddis.2014.60
PMCID: PMC3944272  PMID: 24577088
nickel; energy metabolism shift; miR-210; ISCU1/2; glycolysis
21.  GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis 
Cell Death & Disease  2014;5(1):e1028-.
Abnormal Sonic Hedgehog signalling leads to increased transcriptional activation of its downstream effector, glioma 2 (GLI2), which is implicated in the pathogenesis of a variety of human cancers. However, the mechanisms underlying the tumorigenic role of GLI2 remain elusive. We demonstrate that overexpression of GLI2-β isoform, which lacks the N-terminal repressor domain (GLI2ΔN) in human keratinocytes is sufficient to induce numerical and structural chromosomal aberrations, including tetraploidy/aneuploidy and chromosomal translocations. This is coupled with suppression of cell cycle regulators p21WAF1/CIP1 and 14-3-3σ, and strong induction of anti-apoptotic signalling, resulting in a reduction in the ability to eliminate genomically abnormal cells. Overexpression of GLI2ΔN also rendered human keratinocytes resistant to UVB-mediated apoptosis, whereas inhibition of B-cell lymphoma 2 (BCL-2) restored endogenous (genomic instability (GIN)) and exogenous (UVB) DNA damage-induced apoptosis. Thus, we propose that ectopic expression of GLI2 profoundly affects the genomic integrity of human epithelial cells and contributes to the survival of progenies with genomic alterations by deregulating cell cycle proteins and disabling the apoptotic mechanisms responsible for their elimination. This study reveals a novel role for GLI2 in promoting GIN, a hallmark of human tumors, and identifies potential mechanisms that may provide new opportunities for the design of novel forms of cancer therapeutic strategies.
doi:10.1038/cddis.2013.535
PMCID: PMC4040660  PMID: 24481442
genomic instability; GLI2; BCC; aneuploidy; apoptosis; Bcl-2
22.  Calcineurin suppresses AMPK-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress 
He, H | Liu, X | Lv, L | Liang, H | Leng, B | Zhao, D | Zhang, Y | Du, Z | Chen, X | Li, S | Lu, Y | Shan, H
Cell Death & Disease  2014;5(1):e997-.
Calcineurin signalling plays a critical role in the pathogenesis of many cardiovascular diseases. Calcineurin has been proven to affect a series of signalling pathways and to exert a proapoptotic effect in cardiomyocytes. However, whether it is able to regulate autophagy remains largely unknown. Here, we report that prolonged oxidative stress-induced activation of calcineurin contributes to the attenuation of adaptive AMP-activated protein kinase (AMPK) signalling and inhibits autophagy in cardiomyocytes. Primary cardiomyocytes exhibited rapid formation of autophagosomes, microtubule-associated protein 1 light chain 3 (LC3) expression and phosphorylation of AMPK in response to hydrogen peroxide (H2O2) treatment. However, prolonged (12 h) H2O2 treatment attenuated these effects and was accompanied by a significant increase in calcineurin activity and apoptosis. Inhibition of calcineurin by FK506 restored AMPK function and LC3 expression, and decreased the extent of apoptosis caused by prolonged oxidative stress. In contrast, overexpression of the constitutively active form of calcineurin markedly attenuated the increase in LC3 induced by short-term (3 h) H2O2 treatment and sensitised cells to apoptosis. In addition, FK506 failed to induce autophagy and alleviate apoptosis in cardiomyocytes expressing a kinase-dead K45R AMPK mutant. Furthermore, inhibition of autophagy by 3-methylanine (3-MA) or by knockdown of the essential autophagy-related gene ATG7 abrogated the protective effect of FK506. These findings suggest a novel role of calcineurin in suppressing adaptive autophagy during oxidative stress by downregulating the AMPK signalling pathway. The results also provide insight into how altered calcineurin and autophagic signalling is integrated to control cell survival during oxidative stress and may guide strategies to prevent cardiac oxidative damage.
doi:10.1038/cddis.2013.533
PMCID: PMC4040710  PMID: 24434520
oxidative stress; cardiomyocyte; autophagy; calcineurin; AMPK
23.  Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers 
Clinical pharmacology and therapeutics  2012;91(5):10.1038/clpt.2011.323.
Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AUC0–24) and maximum concentration (Cmax) were similar in the 15- and 20-mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time-dependent, accumulation occurred with daily dosing. The mean AUC0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01). Changes in the oral clearance of MDZ did not vary by RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose-proportional, and its CYP3A induction was robust.
doi:10.1038/clpt.2011.323
PMCID: PMC3837382  PMID: 22472995
24.  Contrasting Effects of Cyclosporine and Rapamycin in De Novo Generation of Alloantigen-Specific Regulatory T Cells 
The outcome of T-cell-mediated responses, immunity or tolerance, critically depends on the balance of cytopathic versus regulatory T (Treg) cells. In the creation of stable tolerance to MHC incompatible allografts, reducing the unusually large mass of donorreactive cytopathic T effector (Teff) cells via apoptosis is often required. Cyclosporine (CsA) blocks activation-induced cell death (AICD) of Teff cells, and is detrimental to tolerance induction by costimulation blockade, whereas Rapamycin (RPM) preserves AICD, and augments the potential of costimulation blockade to create tolerance. While differences between CsA and RPM in influencing apoptosis of activated graft-destructive Teff cells are apparent, their effects on graft-protective Treg cells remain enigmatic. Moreover, it is unclear whether tolerizing regimens foster conversion of naïve peripheral T cells into alloantigen-specific Treg cells for graft protection. Here we show, using reporter mice for Treg marker Foxp3, that RPM promotes de novo conversion of alloantigen-specific Treg cells, whereas CsA completely inhibits this process. Upon transfer, in vivo converted Treg cells potently suppress the rejection of donor but not third party skin grafts. Thus, the differential effects of RPM and CsA on Teff and Treg cells favor the use of RPM in shifting the balance of aggressive to protective type alloimmunity.
doi:10.1111/j.1600-6143.2007.01842.x
PMCID: PMC3831357  PMID: 17511761
Antigen specific; cyclosporine; de novo generation; Foxp3; Rapamycin; regulatory T cells; tolerance
25.  Influence of health insurance, hospital factors and physician volume on receipt of immediate post-mastectomy reconstruction in women with invasive and non-invasive breast cancer 
For women with breast cancer who undergo mastectomy, immediate breast reconstruction (IR) offers a cosmetic and psychological advantage. We evaluated the association between demographic, hospital, surgeon and insurance factors and receipt of IR. We conducted a retrospective hospital-based analysis with the Perspective database. Women who underwent a mastectomy for invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS) from 2000 to 2010 were included. Logistic regression analysis was used to determine factors predictive of IR. Analyses were stratified by age (<50 vs. ≥50) and IBC versus DCIS. Of the 108,992 women with IBC who underwent mastectomy, 30,859 (28.3 %) underwent IR, as compared to 6,501 (44.2 %) of the 14,710 women with DCIS who underwent mastectomy underwent IR. In a multivariable model for IBC, increasing age, black race, being married, rural location, and increased comorbidities were associated with decreased IR. Odds ratios (OR) of IR increased with commercial insurance (OR 3.38) and Medicare (OR 1.66) insurance (vs. self-pay), high surgeon-volume (OR 1.19), high hospital-volume (OR 2.24), and large hospital size (OR 1.20). The results were identical for DCIS, and by age category. The absolute difference between the proportion of patients who received IR with commercial insurance compared to other insurance, increased over time. Immediate in-hospital complication rates were higher for flap reconstruction compared to implant or no reconstruction (15.2, 4.0, and 6.1 %, respectively, P <.0001). IR has increased significantly over time; however, modifiable factors such as insurance status, hospital size, hospital location, and physician volume strongly predict IR. Public policy should ensure that access to reconstructive surgery is universally available.
doi:10.1007/s10549-012-2273-4
PMCID: PMC3651032  PMID: 23053659
Breast reconstruction; Insurance; Hospital volume

Results 1-25 (137)