Yan Li
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Publication
Journal: Nature
April/25/2005
Abstract
Brain-derived neurotrophic factor (BDNF) is known to promote neuronal survival and differentiation and to guide axon extension both in vitro and in vivo. The BDNF-induced chemo-attraction of axonal growth cones requires Ca2+ signalling, but how Ca2+ is regulated by BDNF at the growth cone remains largely unclear. Extracellular application of BDNF triggers membrane currents resembling those through TRPC (transient receptor potential canonical) channels in rat pontine neurons and in Xenopus spinal neurons. Here, we report that in cultured cerebellar granule cells, TRPC channels contribute to the BDNF-induced elevation of Ca2+ at the growth cone and are required for BDNF-induced chemo-attractive turning. Several members of the TRPC family are highly expressed in these neurons, and both Ca2+ elevation and growth-cone turning induced by BDNF are abolished by pharmacological inhibition of TRPC channels, overexpression of a dominant-negative form of TRPC3 or TRPC6, or downregulation of TRPC3 expression via short interfering RNA. Thus, TRPC channel activity is essential for nerve-growth-cone guidance by BDNF.
Publication
Journal: BMC Neuroscience
November/13/2006
Abstract
BACKGROUND
Glaucoma is a chronic neurodegenerative disease of the retina, characterized by the degeneration of axons in the optic nerve and retinal ganglion cell apoptosis. DBA/2J inbred mice develop chronic hereditary glaucoma and are an important model system to study the molecular mechanisms underlying this disease and novel therapeutic interventions designed to attenuate the loss of retinal ganglion cells. Although the genetics of this disease in these mice are well characterized, the etiology of its progression, particularly with respect to retinal degeneration, is not. We have used two separate labeling techniques, post-mortem DiI labeling of axons and ganglion cell-specific expression of the betaGeo reporter gene, to evaluate the time course of optic nerve degeneration and ganglion cell loss, respectively, in aging mice.
RESULTS
Optic nerve degeneration, characterized by axon loss and gliosis is first apparent in mice between 8 and 9 months of age. Degeneration appears to follow a retrograde course with axons dying from their proximal ends toward the globe. Although nerve damage is typically bilateral, the progression of disease is asymmetric between the eyes of individual mice. Some nerves also exhibit focal preservation of tracts of axons generally in the nasal peripheral region. Ganglion cell loss, as a function of the loss of betaGeo expression, is evident in some mice between 8 and 10 months of age and is prevalent in the majority of mice older than 10.5 months. Most eyes display a uniform loss of ganglion cells throughout the retina, but many younger mice exhibit focal loss of cells in sectors extending from the optic nerve head to the retinal periphery. Similar to what we observe in the optic nerves, ganglion cell loss is often asymmetric between the eyes of the same animal.
CONCLUSIONS
A comparison of the data collected from the two cohorts of mice used for this study suggests that the initial site of damage in this disease is to the axons in the optic nerve, followed by the subsequent death of the ganglion cell soma.
Publication
Journal: Cancer Letters
September/4/2017
Abstract
Circular RNAs (circRNAs) comprise a novel class of widespread non-coding RNAs that may regulate gene expression in eukaryotes. However, the characterization and function of circRNAs in human cancer remain elusive. Here we identified at least 5500 distinct circRNA candidates and a series of circRNAs that are differentially expressed in gastric cancer (GC) tissues compared with matched normal tissues. We further characterized one circRNA derived from the PVT1 gene and termed it as circPVT1. The expression of circPVT1 is often upregulated in GC tissues due to the amplification of its genomic locus. circPVT1 may promote cell proliferation by acting as a sponge for members of the miR-125 family. The level of circPVT1 was observed as an independent prognostic marker for overall survival and disease-free survival of patients with GC. Our findings suggest that circPVT1 is a novel proliferative factor and prognostic marker in GC.
Publication
Journal: Nature Medicine
September/7/2018
Abstract
Although programmed death-ligand 1-programmed death 1 (PD-L1-PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.
Publication
Journal: Science
January/29/2009
Abstract
The Vibrio parahaemolyticus type III effector VopS is implicated in cell rounding and the collapse of the actin cytoskeleton by inhibiting Rho guanosine triphosphatases (GTPases). We found that VopS could act to covalently modify a conserved threonine residue on Rho, Rac, and Cdc42 with adenosine 5'-monophosphate (AMP). The resulting AMPylation prevented the interaction of Rho GTPases with downstream effectors, thereby inhibiting actin assembly in the infected cell. Eukaryotic proteins were also directly modified with AMP, potentially expanding the repertoire of posttranslational modifications for molecular signaling.
Publication
Journal: Genes and Development
December/10/2006
Abstract
MicroRNAs (miRNAs) have been implicated in regulating various aspects of animal development, but their functions in neurogenesis are largely unknown. Here we report that loss of miR-9a function in the Drosophila peripheral nervous system leads to ectopic production of sensory organ precursors (SOPs), whereas overexpression of miR-9a results in a severe loss of SOPs. We further demonstrate a strong genetic interaction between miR-9a and senseless (sens) in controlling the formation of SOPs in the adult wing imaginal disc. Moreover, miR-9a suppresses Sens expression through its 3' untranslated region. miR-9a is expressed in epithelial cells, including those adjacent to SOPs within proneural clusters, suggesting that miR-9a normally inhibits neuronal fate in non-SOP cells by down-regulating Sens expression. These results indicate that miR-9a ensures the generation of the precise number of neuronal precursor cells during development.
Publication
Journal: Blood
June/4/2007
Abstract
Bone homeostasis is regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclastogenesis is controlled by the ratio of receptor activator of NF-kappaB ligand (RANKL) relative to its decoy receptor, osteoprotegerin (OPG). The source of OPG has historically been attributed to osteoblasts (OBs). While activated lymphocytes play established roles in pathological bone destruction, no role for lymphocytes in basal bone homeostasis in vivo has been described. Using immunomagnetic isolation of bone marrow (BM) B cells and B-cell precursor populations and quantitation of their OPG production by enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), cells of the B lineage were found to be responsible for 64% of total BM OPG production, with 45% derived from mature B cells. Consistently B-cell knockout (KO) mice were found to be osteoporotic and deficient in BM OPG, phenomena rescued by B-cell reconstitution. Furthermore, T cells, through CD40 ligand (CD40L) to CD40 costimulation, promote OPG production by B cells in vivo. Consequently, T-cell-deficient nude mice, CD40 KO mice, and CD40L KO mice display osteoporosis and diminished BM OPG production. Our data suggest that lymphocytes are essential stabilizers of basal bone turnover and critical regulators of peak bone mass in vivo.
Publication
Journal: Journal of the American Society of Nephrology : JASN
October/26/2010
Abstract
Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1β and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1β, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3(-/-) mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1β and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.
Publication
Journal: New England Journal of Medicine
November/26/2012
Abstract
BACKGROUND
Despite advances in resuscitation care in recent years, it is not clear whether survival and neurologic function after in-hospital cardiac arrest have improved over time.
METHODS
We identified all adults who had an in-hospital cardiac arrest at 374 hospitals in the Get with the Guidelines-Resuscitation registry between 2000 and 2009. Using multivariable regression, we examined temporal trends in risk-adjusted rates of survival to discharge. Additional analyses explored whether trends were due to improved survival during acute resuscitation or postresuscitation care and whether they occurred at the expense of greater neurologic disability in survivors.
RESULTS
Among 84,625 hospitalized patients with cardiac arrest, 79.3% had an initial rhythm of asystole or pulseless electrical activity, and 20.7% had ventricular fibrillation or pulseless ventricular tachycardia. The proportion of cardiac arrests due to asystole or pulseless electrical activity increased over time (P<0.001 for trend). Risk-adjusted rates of survival to discharge increased from 13.7% in 2000 to 22.3% in 2009 (adjusted rate ratio per year, 1.04; 95% confidence interval [CI], 1.03 to 1.06; P<0.001 for trend). Survival improvement was similar in the two rhythm groups and was due to improvement in both acute resuscitation survival and postresuscitation survival. Rates of clinically significant neurologic disability among survivors decreased over time, with a risk-adjusted rate of 32.9% in 2000 and 28.1% in 2009 (adjusted rate ratio per year, 0.98; 95% CI, 0.97 to 1.00; P=0.02 for trend).
CONCLUSIONS
Both survival and neurologic outcomes after in-hospital cardiac arrest have improved during the past decade at hospitals participating in a large national quality-improvement registry. (Funded by the American Heart Association.).
Publication
Journal: Physiological Reviews
December/7/2014
Abstract
Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.
Publication
Journal: Annals of Surgical Oncology
August/29/2011
Abstract
BACKGROUND
This randomized phase III study was to evaluate the efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis (PC) from gastric cancer.
METHODS
Sixty-eight gastric PC patients were randomized into CRS alone (n = 34) or CRS + HIPEC (n = 34) receiving cisplatin 120 mg and mitomycin C 30 mg each in 6000 ml of normal saline at 43 ± 0.5°C for 60-90 min. The primary end point was overall survival, and the secondary end points were safety profiles.
RESULTS
Major clinicopathological characteristics were balanced between the 2 groups. The PC index was 2-36 (median 15) in the CRS + HIPEC and 3-23 (median 15) in the CRS groups (P = 0.489). The completeness of CRS score (CC 0-1) was 58.8% (20 of 34) in the CRS and 58.8% (20 of 34) in the CRS + HIPEC groups (P = 1.000). At a median follow-up of 32 months (7.5-83.5 months), death occurred in 33 of 34 (97.1%) cases in the CRS group and 29 of 34 (85.3%) cases of the CRS + HIPEC group. The median survival was 6.5 months (95% confidence interval 4.8-8.2 months) in CRS and 11.0 months (95% confidence interval 10.0-11.9 months) in the CRS + HIPEC groups (P = 0.046). Four patients (11.7%) in the CRS group and 5 (14.7%) patients in the CRS + HIPEC group developed serious adverse events (P = 0.839). Multivariate analysis found CRS + HIPEC, synchronous PC, CC 0-1, systemic chemotherapy ≥ 6 cycles, and no serious adverse events were independent predictors for better survival.
CONCLUSIONS
For synchronous gastric PC, CRS + HIPEC with mitomycin C 30 mg and cisplatin 120 mg may improve survival with acceptable morbidity.
Publication
Journal: The Lancet
October/10/2007
Abstract
BACKGROUND
Few studies have formally compared the predictive value of the blood pressure at night over and beyond the daytime value. We investigated the prognostic significance of the ambulatory blood pressure during night and day and of the night-to-day blood pressure ratio.
METHODS
We did 24-h blood pressure monitoring in 7458 people (mean age 56.8 years [SD 13.9]) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We calculated multivariate-adjusted hazard ratios for daytime and night-time blood pressure and the systolic night-to-day ratio, while adjusting for cohort and cardiovascular risk factors.
RESULTS
Median follow-up was 9.6 years (5th to 95th percentile 2.5-13.7). Adjusted for daytime blood pressure, night-time blood pressure predicted total (n=983; p<0.0001), cardiovascular (n=387; p<0.01), and non-cardiovascular (n=560; p<0.001) mortality. Conversely, adjusted for night-time blood pressure, daytime blood pressure predicted only non-cardiovascular mortality (p<0.05), with lower blood pressure levels being associated with increased risk. Both daytime and night-time blood pressure consistently predicted all cardiovascular events (n=943; p<0.05) and stroke (n=420; p<0.01). Adjusted for night-time blood pressure, daytime blood pressure lost prognostic significance only for cardiac events (n=525; p> or =0.07). Adjusted for the 24-h blood pressure, night-to-day ratio predicted mortality, but not fatal combined with non-fatal events. Antihypertensive drug treatment removed the significant association between cardiovascular events and the daytime blood pressure. Participants with systolic night-to-day ratio value of 1 or more were older, at higher risk of death, and died at an older age than those whose night-to-day ratio was normal >> or =0.80 to <0.90).
CONCLUSIONS
In contrast to commonly held views, daytime blood pressure adjusted for night-time blood pressure predicts fatal combined with non-fatal cardiovascular events, except in treated patients, in whom antihypertensive drugs might reduce blood pressure during the day, but not at night. The increased mortality in patients with higher night-time than daytime blood pressure probably indicates reverse causality. Our findings support recording the ambulatory blood pressure during the whole day.
Publication
Journal: Current Biology
March/26/2008
Abstract
Plants use receptor kinases, such as FLS2 and EFR, to perceive bacterial pathogens and initiate innate immunity. This immunity is often suppressed by bacterial effectors, allowing pathogen propagation. To counteract, plants have evolved disease resistance genes that detect the bacterial effectors and reinstate resistance. The Pseudomonas syringae effector AvrPto promotes infection in susceptible plants but triggers resistance in plants carrying the protein kinase Pto and the associated resistance protein Prf. Here we show that AvrPto binds receptor kinases, including Arabidopsis FLS2 and EFR and tomato LeFLS2, to block plant immune responses in the plant cell. The ability to target receptor kinases is required for the virulence function of AvrPto in plants. The FLS2-AvrPto interaction and Pto-AvrPto interaction appear to share similar sequence requirements, and Pto competes with FLS2 for AvrPto binding. The results suggest that the mechanism by which AvrPto recognizes virulence targets is linked to the evolution of Pto, which, in association with Prf, recognizes the bacterium and triggers strong resistance.
Publication
Journal: Emerging Infectious Diseases
February/17/2005
Abstract
Avian influenza that infects poultry in close proximity to humans is a concern because of its pandemic potential. In 2004, an outbreak of highly pathogenic avian influenza H7N3 occurred in poultry in British Columbia, Canada. Surveillance identified two persons with confirmed avian influenza infection. Symptoms included conjunctivitis and mild influenzalike illness.
Publication
Journal: Cell
November/23/2008
Abstract
Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.
Publication
Journal: Nature Biotechnology
March/9/2010
Abstract
Replicate mass spectrometry (MS) measurements and the use of multiple analytical methods can greatly expand the comprehensiveness of shotgun proteomic profiling of biological samples. However, the inherent biases and variations in such data create computational and statistical challenges for quantitative comparative analysis. We developed and tested a normalized, label-free quantitative method termed the normalized spectral index (SI(N)), which combines three MS abundance features: peptide count, spectral count and fragment-ion (tandem MS or MS/MS) intensity. SI(N) largely eliminated variances between replicate MS measurements, permitting quantitative reproducibility and highly significant quantification of thousands of proteins detected in replicate MS measurements of the same and distinct samples. It accurately predicts protein abundance more often than the five other methods we tested. Comparative immunoblotting and densitometry further validate our method. Comparative quantification of complex data sets from multiple shotgun proteomics measurements is relevant for systems biology and biomarker discovery.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
May/9/2010
Abstract
Neuropathology involving TAR DNA binding protein-43 (TDP-43) has been identified in a wide spectrum of neurodegenerative diseases collectively named as TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). To test whether increased expression of wide-type human TDP-43 (hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressing hTDP-43 in various neuronal subpopulations. Expression in the fly eyes of the full-length hTDP-43, but not a mutant lacking its amino-terminal domain, led to progressive loss of ommatidia with remarkable signs of neurodegeneration. Expressing hTDP-43 in mushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expression in motor neurons led to axon swelling, reduction in axon branches and bouton numbers, and motor neuron loss together with functional deficits. Thus, our transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP-43 proteinopathy, providing a powerful animal model for this group of devastating diseases. Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy.
Publication
Journal: Nature Medicine
April/1/2010
Abstract
Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy.
Publication
Journal: International Journal of Molecular Sciences
September/7/2015
Abstract
Orally administered drugs must overcome several barriers before reaching their target site. Such barriers depend largely upon specific membrane transport systems and intracellular drug-metabolizing enzymes. For the first time, the P-glycoprotein (P-gp) and cytochrome P450s, the main line of defense by limiting the oral bioavailability (OB) of drugs, were brought into construction of QSAR modeling for human OB based on 805 structurally diverse drug and drug-like molecules. The linear (multiple linear regression: MLR, and partial least squares regression: PLS) and nonlinear (support-vector machine regression: SVR) methods are used to construct the models with their predictivity verified with five-fold cross-validation and independent external tests. The performance of SVR is slightly better than that of MLR and PLS, as indicated by its determination coefficient (R(2)) of 0.80 and standard error of estimate (SEE) of 0.31 for test sets. For the MLR and PLS, they are relatively weak, showing prediction abilities of 0.60 and 0.64 for the training set with SEE of 0.40 and 0.31, respectively. Our study indicates that the MLR, PLS and SVR-based in silico models have good potential in facilitating the prediction of oral bioavailability and can be applied in future drug design.
Publication
Journal: PLoS Genetics
May/2/2010
Abstract
The population structure of an organism reflects its evolutionary history and influences its evolutionary trajectory. It constrains the combination of genetic diversity and reveals patterns of past gene flow. Understanding it is a prerequisite for detecting genomic regions under selection, predicting the effect of population disturbances, or modeling gene flow. This paper examines the detailed global population structure of Arabidopsis thaliana. Using a set of 5,707 plants collected from around the globe and genotyped at 149 SNPs, we show that while A. thaliana as a species self-fertilizes 97% of the time, there is considerable variation among local groups. This level of outcrossing greatly limits observed heterozygosity but is sufficient to generate considerable local haplotypic diversity. We also find that in its native Eurasian range A. thaliana exhibits continuous isolation by distance at every geographic scale without natural breaks corresponding to classical notions of populations. By contrast, in North America, where it exists as an exotic species, A. thaliana exhibits little or no population structure at a continental scale but local isolation by distance that extends hundreds of km. This suggests a pattern for the development of isolation by distance that can establish itself shortly after an organism fills a new habitat range. It also raises questions about the general applicability of many standard population genetics models. Any model based on discrete clusters of interchangeable individuals will be an uneasy fit to organisms like A. thaliana which exhibit continuous isolation by distance on many scales.
Publication
Journal: Nature Medicine
April/16/2013
Abstract
A better understanding of human hepatocellular carcinoma (HCC) pathogenesis at the molecular level will facilitate the discovery of tumor-initiating events. Transcriptome sequencing revealed that adenosine-to-inosine (A→I) RNA editing of AZIN1 (encoding antizyme inhibitor 1) is increased in HCC specimens. A→I editing of AZIN1 transcripts, specifically regulated by ADAR1 (encoding adenosine deaminase acting on RNA-1), results in a serine-to-glycine substitution at residue 367 of AZIN1, located in β-strand 15 (β15) and predicted to cause a conformational change, induced a cytoplasmic-to-nuclear translocation and conferred gain-of-function phenotypes that were manifested by augmented tumor-initiating potential and more aggressive behavior. Compared with wild-type AZIN1 protein, the edited form has a stronger affinity to antizyme, and the resultant higher AZIN1 protein stability promotes cell proliferation through the neutralization of antizyme-mediated degradation of ornithine decarboxylase (ODC) and cyclin D1 (CCND1). Collectively, A→I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.
Publication
Journal: Journal of Biological Chemistry
November/9/2008
Abstract
Nuclear factor kappa-B (NF-kappaB)-regulated inflammatory genes, such as TNF-alpha (tumor necrosis factor-alpha), play key roles in the pathogenesis of inflammatory diseases, including diabetes and the metabolic syndrome. However, the nuclear chromatin mechanisms are unclear. We report here that the chromatin histone H3-lysine 4 methyltransferase, SET7/9, is a novel coactivator of NF-kappaB. Gene silencing of SET7/9 with small interfering RNAs in monocytes significantly inhibited TNF-alpha-induced inflammatory genes and histone H3-lysine 4 methylation on these promoters, as well as monocyte adhesion to endothelial or smooth muscle cells. Chromatin immunoprecipitation revealed that SET7/9 small interfering RNA could reduce TNF-alpha-induced recruitment of NF-kappaB p65 to inflammatory gene promoters. Inflammatory gene induction by ligands of the receptor for advanced glycation end products was also attenuated in SET7/9 knockdown monocytes. In addition, we also observed increased inflammatory gene expression and SET7/9 recruitment in macrophages from diabetic mice. Microarray profiling revealed that, in TNF-alpha-stimulated monocytes, the induction of 25% NF-kappaB downstream genes, including the histone H3-lysine 27 demethylase JMJD3, was attenuated by SET7/9 depletion. These results demonstrate a novel role for SET7/9 in inflammation and diabetes.
Publication
Journal: Inflammatory Bowel Diseases
September/12/2011
Abstract
BACKGROUND
Attenuated innate immune responses to the intestinal microbiota have been linked to the pathogenesis of Crohn's disease (CD). Recent genetic studies have revealed that hypofunctional mutations of NLRP3, a member of the NOD-like receptor (NLR) superfamily, are associated with an increased risk of developing CD. NLRP3 is a key component of the inflammasome, an intracellular danger sensor of the innate immune system. When activated, the inflammasome triggers caspase-1-dependent processing of inflammatory mediators, such as IL-1β and IL-18.
METHODS
In the current study we sought to assess the role of the NLRP3 inflammasome in the maintenance of intestinal homeostasis through its regulation of innate protective processes. To investigate this role, Nlrp3(-/-) and wildtype mice were assessed in the dextran sulfate sodium and 2,4,6-trinitrobenzenesulfonic acid models of experimental colitis.
RESULTS
Nlrp3(-/-) mice were found to be more susceptible to experimental colitis, an observation that was associated with reduced IL-1β, reduced antiinflammatory cytokine IL-10, and reduced protective growth factor TGF-β. Macrophages isolated from Nlrp3(-/-) mice failed to respond to bacterial muramyl dipeptide. Furthermore, Nlrp3-deficient neutrophils exhibited reduced chemotaxis and enhanced spontaneous apoptosis, but no change in oxidative burst. Lastly, Nlrp3(-/-) mice displayed altered colonic β-defensin expression, reduced colonic antimicrobial secretions, and a unique intestinal microbiota.
CONCLUSIONS
Our data confirm an essential role for the NLRP3 inflammasome in the regulation of intestinal homeostasis and provide biological insight into disease mechanisms associated with increased risk of CD in individuals with NLRP3 mutations.
Publication
Journal: Nature
June/16/2004
Abstract
The molecular complexity of tissues and the inaccessibility of most cells within a tissue limit the discovery of key targets for tissue-specific delivery of therapeutic and imaging agents in vivo. Here, we describe a hypothesis-driven, systems biology approach to identifying a small subset of proteins induced at the tissue-blood interface that are inherently accessible to antibodies injected intravenously. We use subcellular fractionation, subtractive proteomics and bioinformatics to identify endothelial cell surface proteins exhibiting restricted tissue distribution and apparent tissue modulation. Expression profiling and gamma-scintigraphic imaging with antibodies establishes two of these proteins, aminopeptidase-P and annexin A1, as selective in vivo targets for antibodies in lungs and solid tumours, respectively. Radio-immunotherapy to annexin A1 destroys tumours and increases animal survival. This analytical strategy can map tissue- and disease-specific expression of endothelial cell surface proteins to uncover novel accessible targets useful for imaging and therapy.
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