Publications by authors named "Mengxi Sun"

21 Publications

  • Page 1 of 1

The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude.

J Exp Med 2021 Jun;218(6)

Department of Pathology, Committees on Immunology and Cancer Biology, The University of Chicago, Chicago, IL.

Gaining a mechanistic understanding of the expansion and maturation program of natural killer (NK) cells will provide opportunities for harnessing their inflammation-inducing and oncolytic capacity for therapeutic purposes. Here, we demonstrated that ID2, a transcriptional regulatory protein constitutively expressed in NK cells, supports NK cell effector maturation by controlling the amplitude and temporal dynamics of the transcription factor TCF1. TCF1 promotes immature NK cell expansion and restrains differentiation. The increased TCF1 expression in ID2-deficient NK cells arrests their maturation and alters cell surface receptor expression. Moreover, TCF1 limits NK cell functions, such as cytokine-induced IFN-γ production and the ability to clear metastatic melanoma in ID2-deficient NK cells. Our data demonstrate that ID2 sets a threshold for TCF1 during NK cell development, thus controlling the balance of immature and terminally differentiated cells that support future NK cell responses.
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http://dx.doi.org/10.1084/jem.20202032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056751PMC
June 2021

Optimizing and Individualizing the Pharmacological Treatment of First-Episode Schizophrenic Patients: Study Protocol for a Multicenter Clinical Trial.

Front Psychiatry 2021 25;12:611070. Epub 2021 Feb 25.

Department of Psychaitry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China.

Affecting ~1% of the world population, schizophrenia is known as one of the costliest and most burdensome diseases worldwide. Antipsychotic medications are the main treatment for schizophrenia to control psychotic symptoms and efficiently prevent new crises. However, due to poor compliance, 74% of patients with schizophrenia discontinue medication within 1.5 years, which severely affects recovery and prognosis. Through research on intra and interindividual variability based on a psychopathology-neuropsychology-neuroimage-genetics-physiology-biochemistry model, our main objective is to investigate an optimized and individualized antipsychotic-treatment regimen and precision treatment for first-episode schizophrenic patients. The study is performed in 20 representative hospitals in China. Three subprojects are included. In subproject 1, 1,800 first-episode patients with schizophrenia are randomized into six different antipsychotic monotherapy groups (olanzapine, risperidone, aripiprazole, ziprasidone, amisulpride, and haloperidol) for an 8-week treatment. By identifying a set of potential biomarkers associated with antipsychotic treatment response, we intend to build a prediction model, which includes neuroimaging, epigenetics, environmental stress, neurocognition, eye movement, electrophysiology, and neurological biochemistry indexes. In subproject 2, apart from verifying the prediction model established in subproject 1 based on an independent cohort of 1,800 first-episode patients with schizophrenia, we recruit patients from a verification cohort who did not get an effective response after an 8-week antipsychotic treatment into a randomized double-blind controlled trial with minocycline (200 mg per day) and sulforaphane (3 tables per day) to explore add-on treatment for patients with schizophrenia. Two hundred forty participants are anticipated to be enrolled for each group. In subproject 3, we tend to carry out one trial to construct an intervention strategy for metabolic syndrome induced by antipsychotic treatment and another one to build a prevention strategy for patients at a high risk of metabolic syndrome, which combines metformin and lifestyle intervention. Two hundred participants are anticipated to be enrolled for each group. The study protocol has been approved by the Medical Ethics committee of the Second Xiangya Hospital of Central South University (No. 2017027). Results will be disseminated in peer-reviewed journals and at international conferences. This trial has been registered on Clinicalrials.gov (NCT03451734). The protocol version is V.1.0 (April 23, 2017).
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http://dx.doi.org/10.3389/fpsyt.2021.611070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947302PMC
February 2021

Runx2 (Runt-Related Transcription Factor 2) Links the DNA Damage Response to Osteogenic Reprogramming and Apoptosis of Vascular Smooth Muscle Cells.

Arterioscler Thromb Vasc Biol 2021 Apr 24;41(4):1339-1357. Epub 2020 Dec 24.

BHF Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, The James Black Centre, United Kingdom (A.M.C., S.Y., R.H., S.A., M.S., C.M.S.).

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http://dx.doi.org/10.1161/ATVBAHA.120.315206DOI Listing
April 2021

Combinatorial ETS1-dependent control of oncogenic NOTCH1 enhancers in T-cell leukemia.

Blood Cancer Discov 2020 Sep;1(2):178-197

Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI.

Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements. Using complementary genetic approaches in mouse models, we show that ablation of Ets1 leads to strong Notch-mediated suppressive effects on T-cell development and leukemogenesis, but milder intestinal effects than pan-Notch inhibitors. Mechanistically, genome-wide chromatin profiling studies demonstrate that Ets1 inactivation impairs recruitment of multiple Notch-associated factors and Notch-dependent activation of transcriptional elements controlling major Notch-driven oncogenic effector pathways. These results uncover previously unrecognized hierarchical heterogeneity of Notch-controlled genes and points to Ets1-mediated enucleation of Notch-Rbpj transcriptional complexes as a target for developing specific anti-Notch therapies in T-ALL that circumvent the barriers of pan-Notch inhibition.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482717PMC
September 2020

Transcriptional regulation of natural killer cell development and maturation.

Adv Immunol 2020 26;146:1-28. Epub 2020 Feb 26.

Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL, United States.

Natural killer cells are lymphocytes that respond rapidly to intracellular pathogens or cancer/stressed cells by producing pro-inflammatory cytokines or chemokines and by killing target cells through direct cytolysis. NK cells are distinct from B and T lymphocytes in that they become activated through a series of broadly expressed germ line encoded activating and inhibitory receptors or through the actions of inflammatory cytokines. They are the founding member of the innate lymphoid cell family, which mirror the functions of T lymphocytes, with NK cells being the innate counterpart to CD8 T lymphocytes. Despite the functional relationship between NK cells and CD8 T cells, the mechanisms controlling their specification, differentiation and maturation are distinct, with NK cells emerging from multipotent lymphoid progenitors in the bone marrow under the control of a unique transcriptional program. Over the past few years, substantial progress has been made in understanding the developmental pathways and the factors involved in generating mature and functional NK cells. NK cells have immense therapeutic potential and understanding how to acquire large numbers of functional cells and how to endow them with potent activity to control hematopoietic and non-hematopoietic malignancies and autoimmunity is a major clinical goal. In this review, we examine basic aspects of conventional NK cell development in mice and humans and discuss multiple transcription factors that are known to guide the development of these cells.
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http://dx.doi.org/10.1016/bs.ai.2020.01.001DOI Listing
February 2020

Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

Department of Surgery, and.

Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients, and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL-17 receptor A (IL-17ra-/-) or pharmacological blockade of IL-17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL-17A positively correlated with the alcohol use in excessive drinkers and was further increased in patients with ALD as compared with healthy individuals. Our data suggest that IL-17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL-17A may provide a novel strategy for treatment of alcohol-induced pathology.
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http://dx.doi.org/10.1172/jci.insight.131277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098802PMC
February 2020

IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease.

J Hepatol 2020 05 31;72(5):946-959. Epub 2019 Dec 31.

Department of Surgery, University of California San Diego, La Jolla, CA, USA. Electronic address:

Background & Aims: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA.

Methods: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens.

Results: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra and major urinary protein-urokinase-type plasminogen activator/Il-17ra mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17ra and Il-17ra mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17ra mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17ra mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17ra mice developed the fewest tumors (compared with Il-17ra mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC.

Conclusions: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.

Lay Summary: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
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http://dx.doi.org/10.1016/j.jhep.2019.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167339PMC
May 2020

Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf.

Cell Rep 2019 10;29(5):1203-1220.e7

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

The basic leucine zipper transcription factor activating transcription factor-like (Batf) contributes to transcriptional programming of multiple effector T cells and is required for T helper 17 (Th17) and T follicular helper (Tfh) cell development. Here, we examine mechanisms by which Batf initiates gene transcription in developing effector CD4 T cells. We find that, in addition to its pioneering function, Batf controls developmentally regulated recruitment of the architectural factor Ctcf to promote chromatin looping that is associated with lineage-specific gene transcription. The chromatin-organizing actions of Batf are largely dependent on Ets1, which appears to be indispensable for the Batf-dependent recruitment of Ctcf. Moreover, most of the Batf-dependent sites to which Ctcf is recruited lie outside of activating protein-1-interferon regulatory factor (Ap-1-Irf) composite elements (AICEs), indicating that direct involvement of Batf-Irf complexes is not required. These results identify a cooperative role for Batf, Ets1, and Ctcf in chromatin reorganization that underpins the transcriptional programming of effector T cells.
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http://dx.doi.org/10.1016/j.celrep.2019.09.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182170PMC
October 2019

Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization.

Cell Rep 2019 06;27(11):3124-3138.e13

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address:

Biomineralization of the extracellular matrix is an essential, regulated process. Inappropriate mineralization of bone and the vasculature has devastating effects on patient health, yet an integrated understanding of the chemical and cell biological processes that lead to mineral nucleation remains elusive. Here, we report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADP-ribose) polymerases in response to oxidative and/or DNA damage. We use ultrastructural methods to show poly(ADP-ribose) can form both calcified spherical particles, reminiscent of those found in vascular calcification, and biomimetically calcified collagen fibrils similar to bone. Importantly, inhibition of poly(ADP-ribose) biosynthesis in vitro and in vivo inhibits biomineralization, suggesting a therapeutic route for the treatment of vascular calcifications. We conclude that poly(ADP-ribose) plays a central chemical role in both pathological and physiological extracellular matrix calcification.
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http://dx.doi.org/10.1016/j.celrep.2019.05.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581741PMC
June 2019

Effect of Betahistine and Metformin on Antipsychotic-Induced Weight Gain: An Analysis of Two Clinical Trials.

Front Psychiatry 2018 27;9:620. Epub 2018 Nov 27.

Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.

Antipsychotic-induced weight gain is one of the most common adverse effects of antipsychotic treatment. However, there are no well-established interventions for the weight gain yet. In this study, we pooled the data from two clinical trials, which were originally examining the efficacy of betahistine and the efficacy of metformin in treating antipsychotic-induced weight gain and insulin resistance. A total of 67 people with schizophrenia or bipolar disorder treated with antipsychotics were assigned to 36 mg day betahistine ( = 13) or 1,000 mg day metformin ( = 25) or placebo ( = 29) treatment for 12 weeks, with evaluation at baseline and week 12. The primary outcome was the body mass index (BMI). After treatment, metformin group had a mean decrease in BMI of 1.46 ± 0.14 ( < 0.001) and insulin resistance index (IRI) of 4.30 ± 2.02 ( < 0.001). The betahistine group had no significant alteration in BMI or IRI. However, placebo group had a mean increase in BMI of 1.27 ± 0.77 ( < 0.001) and IRI of 0.45 ± 0.86 ( < 0.001). Between the two treatment groups, metformin significantly decreased weight, BMI, fasting glucose, insulin level, and IRI but not waist circumference when compared with betahistine. Moreover, metformin significantly decreased weight, BMI, waist circumference, fasting glucose, insulin level, and IRI when compared with placebo, whereas betahistine significantly decreased body weight, waist circumference, BMI, insulin level, and IRI but not fasting glucose when compared with placebo. In this study, we found that both metformin treatment and betahistine treatment were efficacious in improving antipsychotic-induced weight gain and insulin resistance, and metformin was more efficacious in preventing and revising the weight gain induced by antipsychotics. www.ClinicalTrials.gov, NCT00451399(Study 1), NCT00709202(Study 2).
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http://dx.doi.org/10.3389/fpsyt.2018.00620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277778PMC
November 2018

The role of human cytochrome P450 2E1 in liver inflammation and fibrosis.

Hepatol Commun 2017 12 30;1(10):1043-1057. Epub 2017 Oct 30.

Department of Medicine University of California San Diego La Jolla CA.

Cytochrome P450 2E1 () plays an important role in alcohol and toxin metabolism by catalyzing the conversion of substrates into more polar metabolites and producing reactive oxygen species. Reactive oxygen species-induced oxidative stress promotes hepatocyte injury and death, which in turn induces inflammation, activation of hepatic stellate cells, and liver fibrosis. Here, we analyzed mice expressing only the human gene (hCYP2E1) to determine differences in hCYP2E1 versus endogenous mouse Cyp2e1 function with different liver injuries. After intragastric alcohol feeding, expression was induced in both hCYP2E1 and wild-type (Wt) mice. hCYP2E1 mice had greater inflammation, fibrosis, and lipid peroxidation but less hepatic steatosis. In addition, hCYP2E1 mice demonstrated increased expression of fibrogenic and proinflammatory genes but decreased expression of lipogenic genes compared to Wt mice. Lipidomics of free fatty acid, triacylglycerol, diacylglycerol, and cholesterol ester species and proinflammatory prostaglandins support these conclusions. Carbon tetrachloride-induced injury suppressed expression of both mouse and human , but again hCYP2E1 mice exhibited greater hepatic stellate cell activation and fibrosis than Wt controls with comparable expression of proinflammatory genes. By contrast, 14-day bile duct ligation induced comparable cholestatic injury and fibrosis in both genotypes. : Alcohol-induced liver fibrosis but not hepatic steatosis is more severe in the hCYP2E1 mouse than in the Wt mouse, demonstrating the use of this model to provide insight into the pathogenesis of alcoholic liver disease. ( 2017;1:1043-1057).
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http://dx.doi.org/10.1002/hep4.1115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721400PMC
December 2017

Lnc'ing Id2 to ILC1.

Immunity 2017 09;47(3):389-390

Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA. Electronic address:

The transcriptional repressor Id2 is constitutively expressed in all innate lymphoid cells (ILCs) and is required for their development. In this issue of Immunity, Mowel et al. (2017) demonstrate that Id2 expression is regulated by a cell type-specific cis-regulatory element in group 1 ILCs that is demarcated by a long non-coding RNA.
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http://dx.doi.org/10.1016/j.immuni.2017.08.019DOI Listing
September 2017

Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis.

J Clin Invest 2017 Apr 13;127(4):1254-1270. Epub 2017 Mar 13.

Cholestatic liver fibrosis is caused by obstruction of the biliary tract and is associated with early activation of portal fibroblasts (PFs) that express Thy-1, fibulin 2, and the recently identified marker mesothelin (MSLN). Here, we have demonstrated that activated PFs (aPFs) and myofibroblasts play a critical role in the pathogenesis of liver fibrosis induced by bile duct ligation (BDL). Conditional ablation of MSLN+ aPFs in BDL-injured mice attenuated liver fibrosis by approximately 50%. Similar results were observed in MSLN-deficient mice (Msln-/- mice) or mice deficient in the MSLN ligand mucin 16 (Muc16-/- mice). In vitro analysis revealed that MSLN regulates TGF-β1-inducible activation of WT PFs by disrupting the formation of an inhibitory Thy-1-TGFβRI complex. MSLN also facilitated the FGF-mediated proliferation of WT aPFs. Therapeutic administration of anti-MSLN-blocking Abs attenuated BDL-induced fibrosis in WT mice. Liver specimens from patients with cholestatic liver fibrosis had increased numbers of MSLN+ aPFs/myofibroblasts, suggesting that MSLN may be a potential target for antifibrotic therapy.
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http://dx.doi.org/10.1172/JCI88845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373891PMC
April 2017

Murine thymic NK cells are distinct from ILC1s and have unique transcription factor requirements.

Eur J Immunol 2017 05 13;47(5):800-805. Epub 2017 Apr 13.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Group 1 innate lymphoid cells include natural killer (NK) cells and ILC1s, which mediate the response to intracellular pathogens. Thymic NK (tNK) cells were described with hybrid features of immature NK cells and ILC1 but whether these cells are related to NK cells or ILC1 has not been fully investigated. We report that murine tNK cells expressed the NK-cell associated transcription factor EOMES and developed independent of the essential ILC1 factor TBET, confirming their placement within the NK lineage. Moreover, tNK cells resemble NK cells rather than ILC1 in their requirements for the E protein transcription factor inhibitor ID2. We provide further insight into the mechanisms governing tNK-cell development by showing that the transcription factor ETS1 prevented tNK cell acquisition of the conventional NK-cell maturation markers CD11b and KLRG1. Our data reveal few ILC1 in the thymus and clarify the identity and developmental requirements of tNK cells.
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http://dx.doi.org/10.1002/eji.201646871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662841PMC
May 2017

A SUMO-acetyl switch in PXR biology.

Biochim Biophys Acta 2016 09 12;1859(9):1170-1182. Epub 2016 Feb 12.

Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States. Electronic address:

Post-translational modification (PTM) of nuclear receptor superfamily members regulates various aspects of their biology to include sub-cellular localization, the repertoire of protein-binding partners, as well as their stability and mode of degradation. The nuclear receptor pregnane X receptor (PXR, NR1I2) is a master-regulator of the drug-inducible gene expression in liver and intestine. The PXR-mediated gene activation program is primarily recognized to increase drug metabolism, drug transport, and drug efflux pathways in these tissues. The activation of PXR also has important implications in significant human diseases including inflammatory bowel disease and cancer. Our recent investigations reveal that PXR is modified by multiple PTMs to include phosphorylation, SUMOylation, and ubiquitination. Using both primary cultures of hepatocytes and cell-based assays, we show here that PXR is modified through acetylation on lysine residues. Further, we show that increased acetylation of PXR stimulates its increased SUMO-modification to support active transcriptional suppression. Pharmacologic inhibition of lysine de-acetylation using trichostatin A (TSA) alters the sub-cellular localization of PXR in cultured hepatocytes, and also has a profound impact upon PXR transactivation capacity. Both the acetylation and SUMOylation status of the PXR protein is affected by its ability to associate with the lysine de-acetylating enzyme histone de-acetylase (HDAC)3 in a complex with silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Taken together, our data support a model in which a SUMO-acetyl 'switch' occurs such that acetylation of PXR likely stimulates SUMO-modification of PXR to promote the active repression of PXR-target gene expression. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
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http://dx.doi.org/10.1016/j.bbagrm.2016.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975675PMC
September 2016

Reversibility of liver fibrosis.

Clin Res Hepatol Gastroenterol 2015 Sep 20;39 Suppl 1:S60-3. Epub 2015 Jul 20.

Department of Surgery, University of California, San Diego, La Jolla, 92093 California, United States. Electronic address:

Liver fibrosis is a serious health problem worldwide, which can be induced by a wide spectrum of chronic liver injuries. However, until today, there is no effective therapy available for liver fibrosis except the removal of underlying etiology or liver transplantation. Recent studies indicate that liver fibrosis is reversible when the causative agent(s) is removed. Understanding of mechanisms of liver fibrosis regression will lead to the identification of new therapeutic targets for liver fibrosis. This review summarizes recent research progress on mechanisms of reversibility of liver fibrosis. While most of the research has been focused on HSCs/myofibroblasts and inflammatory pathways, the crosstalk between different organs, various cell types and multiple signaling pathways should not be overlooked. Future studies that lead to fully understanding of the crosstalk between different cell types and the molecular mechanism underlying the reversibility of liver fibrosis will definitely give rise to new therapeutic strategies to treat liver fibrosis.
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http://dx.doi.org/10.1016/j.clinre.2015.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636085PMC
September 2015

SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes.

Drug Metab Dispos 2015 Sep 10;43(9):1316-25. Epub 2015 Jun 10.

Departments of Pharmacology and Toxicology (W.C., J.L.S.), Mass Spectrometry Laboratory (N.G., T.D.W.), and Molecular Biosciences, University of Kansas, Lawrence, Kansas (Y.A.); and Department of Medicine, University of California, San Diego, La Jolla, California (M.S.)

Several nuclear receptor (NR) superfamily members are known to be the molecular target of either the small ubiquitin-related modifier (SUMO) or ubiquitin-signaling pathways. However, little is currently known regarding how these two post-translational modifications interact to control NR biology. We show that SUMO and ubiquitin circuitry coordinately modifies the pregnane X receptor (PXR, NR1I2) to play a key role in regulating PXR protein stability, transactivation capacity, and transcriptional repression. The SUMOylation and ubiquitylation of PXR is increased in a ligand- and tumor necrosis factor alpha -: dependent manner in hepatocytes. The SUMO-E3 ligase enzymes protein inhibitor of activated signal transducer and activator of transcription-1 (STAT1) STAT-1 (PIAS1) and protein inhibitor of activated STAT Y (PIASy) drive high levels of PXR SUMOylation. Expression of protein inhibitor of activated stat 1 selectively increases SUMO(3)ylation as well as PXR-mediated induction of cytochrome P450, family 3, subfamily A and the xenobiotic response. The PIASy-mediated SUMO(1)ylation imparts a transcriptionally repressive function by ameliorating interaction of PXR with coactivator protein peroxisome proliferator-activated receptor gamma coactivator-1-alpha. The SUMO modification of PXR is effectively antagonized by the SUMO protease sentrin protease (SENP) 2, whereas SENP3 and SENP6 proteases are highly active in the removal of SUMO2/3 chains. The PIASy-mediated SUMO(1)ylation of PXR inhibits ubiquitin-mediated degradation of this important liver-enriched NR by the 26S proteasome. Our data reveal a working model that delineates the interactive role that these two post-translational modifications play in reconciling PXR-mediated gene activation of the xenobiotic response versus transcriptional repression of the proinflammatory response in hepatocytes. Taken together, our data reveal that the SUMOylation and ubiquitylation of the PXR interface in a fundamental manner directs its biologic function in the liver in response to xenobiotic or inflammatory stress.
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http://dx.doi.org/10.1124/dmd.115.065201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538856PMC
September 2015

Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes.

Drug Metab Dispos 2015 Mar 19;43(3):335-43. Epub 2014 Dec 19.

Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas

Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs). Preactivation of PXR for 24 hours in PCHs isolated from wild-type mice suppressed the subsequent LPS-inducible expression of the key inflammatory mediators interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) but not in PCHs isolated from Pxr-null (PXR-knockout [KO]) mice. Basal expression of key inflammatory cytokines was elevated in PCHs from PXR-KO mice. Stimulation of PCHs from PXR-KO mice with LPS alone produced enhanced levels of IL-1β when compared with wild-type mice. Experiments performed using PCHs from both humanized-PXR transgenic mice as well as human donors indicate that prolonged activation of PXR produces an increased secretion of IL1-Ra from cells through time. Our data reveal a working model that describes a pivotal role for PXR in both inhibiting as well as in resolving the inflammatory response in hepatocytes. Understanding the molecular details of how PXR is converted from a positive regulator of drug-metabolizing enzymes into a transcriptional suppressor of inflammation in liver will provide new pharmacologic strategies for modulating inflammatory-related diseases in the liver and intestine.
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http://dx.doi.org/10.1124/dmd.114.062307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352581PMC
March 2015

Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas.

Sci China Life Sci 2014 Mar 16;57(3):315-326. Epub 2014 Feb 16.

Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, 410013, China.

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC) tumorigenesis. However, the mechanism(s) connecting EBV infection and NPC remain unclear. Recently, a new class of EBV microRNAs (miRNAs) has been described. To determine how EBV miRNAs control the expression of host genes, and to understand their potential role in NPC tumorigenesis, we profiled the expression of 44 mature EBV miRNAs and potential host genes in NPC and non-tumor nasopharyngeal epithelial tissues. We found that 40 EBV miRNAs from the BART transcript were highly expressed in NPC. Analysis of potential BART miRNA target genes revealed that 3140 genes and several important pathways might be involved in the carcinogenesis of NPC. A total of 105 genes with potential EBV miRNA binding sites were significantly downregulated, suggesting that EBV miRNAs may regulate these genes and contribute to NPC carcinogenesis. An EBV miRNA and host gene regulation network was generated to provide useful clues for validating of EBV miRNA functions in NPC tumorigenesis.
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http://dx.doi.org/10.1007/s11427-013-4577-yDOI Listing
March 2014

Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver.

Drug Metab Rev 2013 Feb;45(1):48-59

Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, USA.

Adverse drug events (ADEs) are a common cause of patient morbidity and mortality and are classically thought to result, in part, from variation in expression and activity of hepatic enzymes of drug metabolism. It is now known that alterations in the expression of genes that encode drug- and bile-acid-transporter proteins in both the gut and liver play a previously unrecognized role in determining patient drug response and eventual clinical outcome. Four nuclear receptor (NR) superfamily members, including pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (NR1I3), farnesoid X receptor (NR1H4), and vitamin D receptor (NR1I1), play pivotal roles in drug- and bile-acid-activated programs of gene expression to coordinately regulate drug- and bile-acid transport activity in the intestine and liver. This review focuses on the NR-mediated gene activation of drug and bile-acid transporters in these tissues as well as the possible underlying molecular mechanisms.
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http://dx.doi.org/10.3109/03602532.2012.748793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557796PMC
February 2013

Preparation and antibacterial activities of polyaniline/Cu0.05Zn0.95O nanocomposites.

Dalton Trans 2012 Mar 17;41(9):2804-11. Epub 2012 Jan 17.

Zhejiang Key Laboratory for Reactive Chemistry on Solid Surface, Department of Chemistry, Zhejiang Normal University, Jinhua, China.

Polyaniline/Cu(0.05)Zn(0.95)O (PANI/CZO) nanocomposites were prepared by in situ inverse microemulsion method. Based on the characterization of the crystal structure, chemical composition, and morphology of the samples, it was confirmed that CZO nanoparticles were incorporated into the polyaniline matrix. Studies of the antimicrobial activities of the samples against Staphylococcus aureus, Escherichia coli and Candida albicans were carried out using powder inhibition zone, minimum inhibitory concentration and minimal bactericidal concentrations methods. The results showed clearly that, as an antibacterial agent, PANI/CZO nanocomposites exhibited excellent antibacterial activity against the growth of microorganisms. Furthermore, the antibacterial mechanism of the samples was also deduced in this paper.
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http://dx.doi.org/10.1039/c2dt11823hDOI Listing
March 2012