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Generating testable hypotheses for schizophrenia and rheumatoid arthritis pathogenesis by integrating epidemiological, genomic, and protein interaction data.

Thu, 2017-06-01 07:59
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Generating testable hypotheses for schizophrenia and rheumatoid arthritis pathogenesis by integrating epidemiological, genomic, and protein interaction data.

NPJ Schizophr. 2017;3:11

Authors: Malavia TA, Chaparala S, Wood J, Chowdari K, Prasad KM, McClain L, Jegga AG, Ganapathiraju MK, Nimgaonkar VL

Abstract
Patients with schizophrenia and their relatives have reduced prevalence of rheumatoid arthritis. Schizophrenia and rheumatoid arthritis genome-wide association studies also indicate negative genetic correlations, suggesting that there may be shared pathogenesis at the DNA level or downstream. A portion of the inverse prevalence could be attributed to pleiotropy, i.e., variants of a single nucleotide polymorphism that could confer differential risk for these disorders. To study the basis for such an interrelationship, we initially compared lists of single nucleotide polymorphisms with significant genetic associations (p < 1(e-8)) for schizophrenia or rheumatoid arthritis, evaluating patterns of linkage disequilibrium and apparent pleiotropic risk profiles. Single nucleotide polymorphisms that conferred risk for both schizophrenia and rheumatoid arthritis were localized solely to the extended HLA region. Among single nucleotide polymorphisms that conferred differential risk for schizophrenia and rheumatoid arthritis, the majority were localized to HLA-B, TNXB, NOTCH4, HLA-C, HCP5, MICB, PSORS1C1, and C6orf10; published functional data indicate that HLA-B and HLA-C have the most plausible pathogenic roles in both disorders. Interactomes of these eight genes were constructed from protein-protein interaction information using publicly available databases and novel computational predictions. The genes harboring apparently pleiotropic single nucleotide polymorphisms are closely connected to rheumatoid arthritis and schizophrenia associated genes through common interacting partners. A separate and independent analysis of the interactomes of rheumatoid arthritis and schizophrenia genes showed a significant overlap between the two interactomes and that they share several common pathways, motivating functional studies suggesting a relationship in the pathogenesis of schizophrenia/rheumatoid arthritis.

PMID: 28560257 [PubMed - in process]

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity.

Sun, 2017-05-28 08:47
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Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity.

J Cardiovasc Transl Res. 2017 May 26;:

Authors: Landis BJ, Schubert JA, Lai D, Jegga AG, Shikany AR, Foroud T, Ware SM, Hinton RB

Abstract
Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies.

PMID: 28550590 [PubMed - as supplied by publisher]

DEK is required for homologous recombination repair of DNA breaks.

Tue, 2017-03-21 10:32
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DEK is required for homologous recombination repair of DNA breaks.

Sci Rep. 2017 Mar 20;7:44662

Authors: Smith EA, Gole B, Willis NA, Soria R, Starnes LM, Krumpelbeck EF, Jegga AG, Ali AM, Guo H, Meetei AR, Andreassen PR, Kappes F, Vinnedge LM, Daniel JA, Scully R, Wiesmüller L, Wells SI

Abstract
DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice. Furthermore, DEK knockout cells were sensitive to apoptosis with NHEJ inhibition. Thus, we hypothesized DEK plays additional roles in homologous recombination (HR). Using episomal and integrated reporters, we demonstrate that HR repair of conventional DSBs is severely compromised in DEK-deficient cells. To define responsible mechanisms, we tested the role of DEK in the HR repair cascade. DEK-deficient cells were impaired for γH2AX phosphorylation and attenuated for RAD51 filament formation. Additionally, DEK formed a complex with RAD51, but not BRCA1, suggesting a potential role regarding RAD51 filament formation, stability, or function. These findings define DEK as an important and multifunctional mediator of HR, and establish a synthetic lethal relationship between DEK loss and NHEJ inhibition.

PMID: 28317934 [PubMed - in process]

Applying systems biology methodology to identify genetic factors possibly associated with recovery after traumatic brain injury.

Sat, 2017-03-18 08:57
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Applying systems biology methodology to identify genetic factors possibly associated with recovery after traumatic brain injury.

J Neurotrauma. 2017 Mar 16;:

Authors: Kurowski BG, Treble-Barna A, Pitzer AJ, Wade SL, Martin LJ, Chima RS, Jegga A

Abstract
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacking. Current genetic studies related to TBI have focused on specific candidate genes. The objectives of this study were to use a system biology-based approach to identify biologic processes over-represented with genetic variants previously implicated in clinical outcomes after TBI and identify unique genes potentially related to recovery after TBI. After performing a systematic review to identify genes in the literature associated with clinical outcomes, we used the genes identified to perform a systems biology-based integrative computational analysis to ascertain the interactions between molecular components and to develop models for regulation and function of genes involved in TBI recovery. The analysis identified over-representation of genetic variants primarily in two biologic processes: response to injury (cell proliferation, cell death, inflammatory response, cellular metabolism) and neurocognitive and behavioral reserve (brain development, cognition, and behavior). Overall this study demonstrates the use of a systems biology-based approach to identify unique/novel genes or sets of genes important to the recovery process. Findings from this systems biology-based approach provide additional insight into the potential impact of genetic variants on the underlying complex biological processes important to TBI recovery and may inform the development of empirical genetic-related studies for TBI. Future studies that combine systems biology methodology and genomic, proteomic, and epigenetic approaches are needed in TBI.

PMID: 28301983 [PubMed - as supplied by publisher]

Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model.

Thu, 2017-03-09 06:17
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Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model.

Physiol Rep. 2017 Mar;5(5):

Authors: Munjal C, Jegga AG, Opoka AM, Stoilov I, Norris RA, Thomas CJ, Smith JM, Mecham RP, Bressan GM, Hinton RB

Abstract
Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1-deficient mouse (Emilin1(-/-) ) is a model of latent AVD, characterized by activated TGFβ/MEK/p-Erk signaling and upregulated elastase activity. Emilin1(-/-) aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12-14 months) Emilin1(-/-) mice were treated with refametinib (RDEA-119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6-31 (anti-VEGF-A mouse antibody) for 4 weeks. Refametinib- and doxycycline-treated Emilin1(-/-) mice markedly reduced MEK/p-Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP-2, and MMP-9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1(-/-) aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1(-/-) and age-matched wild-type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p-Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression.

PMID: 28270590 [PubMed - in process]

Hsp90 regulation of fibroblast activation in pulmonary fibrosis.

Tue, 2017-02-28 06:26
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Hsp90 regulation of fibroblast activation in pulmonary fibrosis.

JCI Insight. 2017 Feb 23;2(4):e91454

Authors: Sontake V, Wang Y, Kasam RK, Sinner D, Reddy GB, Naren AP, McCormack FX, White ES, Jegga AG, Madala SK

Abstract
Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix (ECM) production. To identify inhibitors that can attenuate fibroblast activation, we queried IPF gene signatures against a library of small-molecule-induced gene-expression profiles and identified Hsp90 inhibitors as potential therapeutic agents that can suppress fibroblast activation in IPF. Although Hsp90 is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in IPF. Here, we found elevated Hsp90 staining in lung biopsies of patients with IPF. Notably, fibroblasts isolated from fibrotic lesions showed heightened Hsp90 ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a small-molecule inhibitor of Hsp90 ATPase activity, attenuated fibroblast activation and also TGF-β-driven effects on fibroblast to myofibroblast transformation. The loss of the Hsp90AB, but not the Hsp90AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of pulmonary fibrosis, suggesting that targeting Hsp90 represents an effective strategy for the treatment of fibrotic lung disease.

PMID: 28239659 [PubMed - in process]

Correction: IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

Tue, 2017-01-24 06:21

Correction: IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

PLoS One. 2017;12(1):e0170446

Authors: Singh B, Jegga AG, Shanmukhappa KS, Edukulla R, Khurana Hershey GK, Medvedovic M, Dillon SR, Madala SK

Abstract
[This corrects the article DOI: 10.1371/journal.pone.0161877.].

PMID: 28114322 [PubMed - in process]

Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation.

Thu, 2016-12-15 16:05
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Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation.

J Mol Cell Cardiol. 2016 Dec 09;:

Authors: Lynch TL, Ismahil MA, Jegga AG, Zilliox MJ, Troidl C, Prabhu SD, Sadayappan S

Abstract
Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C((t/t)) mouse model of DCM at 3months of age. Compared to wild type (WT) mice, DCM mice exhibited significantly decreased fractional shortening (36.4±2% vs. 15.5±1.0%, p<0.0001) and significantly increased spleen weight (5.3±0.3% vs. 7.2±0.4mm/mg, p=0.002). Intriguingly, flow cytometry analysis revealed a significant increase in total (CD45(+)CD11b(+)Ly6C(-)MHCII(+)F480(+)) macrophages (6.5±1.4% vs. 14.8±1.4%, p=0.002) and classically activated (CD45(+)CD11b(+)Ly6C(-)MHCII(+)F480(+)CD206(-)) proinflammatory (M1) macrophages (3.4±0.8% vs. 10.3±1.2%, p=0.0009) in DCM hearts as compared with WT hearts. These results were further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b(+)Ly6C(+)MHCII(low)F480(hi)) macrophages were significantly elevated (2.4±0.1% vs. 1.3±0.1%, p=0.0001) in DCM compared to WT animals. Serum cytokine analysis in DCM animals exhibited a significant increase (0.65±0.2 vs. 2.175±0.5pg/mL, p=0.02) in interleukin (IL)-6 compared to WT animals. Furthermore, RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction.

PMID: 27955979 [PubMed - as supplied by publisher]

Pharmacogenomics and chemical library screens reveal a novel SCF(SKP2) inhibitor that overcomes bortezomib resistance in multiple myeloma.

Fri, 2016-09-30 07:02

Pharmacogenomics and chemical library screens reveal a novel SCF(SKP2) inhibitor that overcomes bortezomib resistance in multiple myeloma.

Leukemia. 2016 Sep 28;

Authors: Malek E, Abdel-Malek MA, Jagannathan S, Vad N, Karns R, Jegga AG, Broyl A, van Duin M, Sonneveld P, Cottini F, Anderson KC, Driscoll JJ

Abstract
While clinical benefit of the proteasome inhibitor (PI) bortezomib for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin (Ub) ligase Skp1-Cullin-1-Skp2 (SCF(Skp2)) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF(Skp2) activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here, we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138(+) cells isolated from bortezomib-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138(+) cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCF(Skp2) complex, stabilized p27 and increased the number of annexin-V positive cells after bortezomib treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced bortezomib-induced apoptosis. DT204 co-treatment with bortezomib overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof-of-concept for rationally-designed drug combinations that incorporate SCF(Skp2) inhibitors to treat bortezomib resistant disease.Leukemia accepted article preview online, 28 September 2016. doi:10.1038/leu.2016.258.

PMID: 27677741 [PubMed - as supplied by publisher]

IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

Thu, 2016-08-25 07:02

IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

PLoS One. 2016;11(8):e0161877

Authors: Singh B, Jegga AG, Shanmukhappa KS, Edukulla R, Khurana GH, Medvedovic M, Dillon SR, Madala SK

Abstract
Interleukin-31 (IL-31) is a type 2 helper T-cell-derived cytokine that has recently been shown to cause severe inflammation and tissue remodeling in multiple chronic diseases of the skin and lungs. IL-31 is upregulated in allergic and inflammatory diseases, including atopic dermatitis, asthma, cutaneous T-cell lymphomas, and allergic rhinitis, as well as autoimmune diseases such as systemic erythematosus. Overexpression of IL-31 in T cells causes severe inflammation, with histological features similar to skin lesions of patients with atopic dermatitis. However, the molecular mechanisms involved in IL31-driven pathological remodeling in skin diseases remain largely unknown. Here, we studied the role of IL-31 in skin damage as a result of intradermal administration of recombinant IL-31 into mice. Notably, IL-31 was sufficient to increase epidermal basal-cell proliferation and thickening of the epidermal skin layer. Our findings demonstrate a progressive increase in transepidermal water loss with chronic administration of IL-31 into the skin. Further, analysis of the skin transcriptome indicates a significant increase in the transcripts involved in epidermal-cell proliferation, epidermal thickening, and mechanical integrity. In summary, our findings demonstrate an important role for IL-31 signaling in epidermal cell proliferation and thickening that together may lead to impaired skin-barrier function in pathological remodeling of the skin.

PMID: 27556734 [PubMed - as supplied by publisher]

Data mining differential clinical outcomes associated with drug regimens using adverse event reporting data.

Wed, 2016-07-13 06:47

Data mining differential clinical outcomes associated with drug regimens using adverse event reporting data.

Nat Biotechnol. 2016 Jul 12;34(7):697-700

Authors: Sarangdhar M, Tabar S, Schmidt C, Kushwaha A, Shah K, Dahlquist JE, Jegga AG, Aronow BJ

PMID: 27404875 [PubMed - as supplied by publisher]

Canonical genetic signatures of the adult human brain.

Wed, 2016-06-01 21:27
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Canonical genetic signatures of the adult human brain.

Nat Neurosci. 2015 Dec;18(12):1832-44

Authors: Hawrylycz M, Miller JA, Menon V, Feng D, Dolbeare T, Guillozet-Bongaarts AL, Jegga AG, Aronow BJ, Lee CK, Bernard A, Glasser MF, Dierker DL, Menche J, Szafer A, Collman F, Grange P, Berman KA, Mihalas S, Yao Z, Stewart L, Barabási AL, Schulkin J, Phillips J, Ng L, Dang C, Haynor DR, Jones A, Van Essen DC, Koch C, Lein E

Abstract
The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure and function. We applied a correlation-based metric called differential stability to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization. The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations. Using genes with high differential stability, we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely patterned genes displayed marked shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry.

PMID: 26571460 [PubMed - indexed for MEDLINE]

IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival.

Wed, 2016-06-01 21:27
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IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival.

Oncotarget. 2015 Dec 22;6(41):43395-407

Authors: Adams AK, Bolanos LC, Dexheimer PJ, Karns RA, Aronow BJ, Komurov K, Jegga AG, Casper KA, Patil YJ, Wilson KM, Starczynowski DT, Wells SI

Abstract
The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.

PMID: 26527316 [PubMed - in process]

Concept Modeling-based Drug Repositioning.

Wed, 2016-06-01 21:27
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Concept Modeling-based Drug Repositioning.

AMIA Jt Summits Transl Sci Proc. 2015;2015:222-6

Authors: Patchala J, Jegga AG

Abstract
Our hypothesis is that drugs and diseases sharing similar biomedical and genomic concepts are likely to be related, and thus repositioning opportunities can be identified by ranking drugs based on the incidence of shared similar concepts with diseases and vice versa. To test this, we constructed a probabilistic topic model based on the Unified Medical Language System (UMLS) concepts that appear in the disease and drug related abstracts in MEDLINE. The resulting probabilistic topic associations were used to measure the similarity between disease and drugs. The success of the proposed model is evaluated using a set of repositioned drugs, and comparing a drug's ranking based on its similarity to the original and new indication. We then applied the model to rare disorders and compared them to all approved drugs to facilitate "systematically serendipitous" discovery of relationships between rare diseases and existing drugs, some of which could be potential repositioning candidates.

PMID: 26306277 [PubMed]

Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice.

Wed, 2016-06-01 21:27
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Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice.

Hepatology. 2016 Feb;63(2):512-23

Authors: Miethke AG, Zhang W, Simmons J, Taylor AE, Shi T, Shanmukhappa SK, Karns R, White S, Jegga AG, Lages CS, Nkinin S, Keller BT, Setchell KD

Abstract
UNLABELLED: Deficiency of multidrug resistance 2 (mdr2), a canalicular phospholipid floppase, leads to excretion of low-phospholipid "toxic" bile causing progressive cholestasis. We hypothesize that pharmacological inhibition of the ileal, apical sodium-dependent bile acid transporter (ASBT), blocks progression of sclerosing cholangitis in mdr2(-/-) mice. Thirty-day-old, female mdr2(-/-) mice were fed high-fat chow containing 0.006% SC-435, a minimally absorbed, potent inhibitor of ASBT, providing, on average, 11 mg/kg/day of compound. Bile acids (BAs) and phospholipids were measured by mass spectrometry. Compared with untreated mdr2(-/-) mice, SC-435 treatment for 14 days increased fecal BA excretion by 8-fold, lowered total BA concentration in liver by 65%, reduced total BA and individual hydrophobic BA concentrations in serum by >98%, and decreased plasma alanine aminotransferase, total bilirubin, and serum alkaline phosphatase levels by 86%, 93%, and 55%, respectively. Liver histology of sclerosing cholangitis improved, and extent of fibrosis decreased concomitant with reduction of hepatic profibrogenic gene expression. Biliary BA concentrations significantly decreased and phospholipids remained low and unchanged with treatment. The phosphatidylcholine (PC)/BA ratio in treated mice corrected toward a ratio of 0.28 found in wild-type mice, indicating decreased bile toxicity. Hepatic RNA sequencing studies revealed up-regulation of putative anti-inflammatory and antifibrogenic genes, including Ppara and Igf1, and down-regulation of several proinflammatory genes, including Ccl2 and Lcn2, implicated in leukocyte recruitment. Flow cytometric analysis revealed significant reduction of frequencies of hepatic CD11b(+) F4/80(+) Kupffer cells and CD11b(+) Gr1(+) neutrophils, accompanied by expansion of anti-inflammatory Ly6C(-) monocytes in treated mdr2(-/-) mice.
CONCLUSION: Inhibition of ASBT reduces BA pool size and retention of hydrophobic BA, favorably alters the biliary PC/BA ratio, profoundly changes the hepatic transcriptome, attenuates recruitment of leukocytes, and abrogates progression of murine sclerosing cholangitis.

PMID: 26172874 [PubMed - in process]

Polycomb repressive complex 1 controls uterine decidualization.

Wed, 2016-05-18 16:52
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Polycomb repressive complex 1 controls uterine decidualization.

Sci Rep. 2016;6:26061

Authors: Bian F, Gao F, Kartashov AV, Jegga AG, Barski A, Das SK

Abstract
Uterine stromal cell decidualization is an essential part of the reproductive process. Decidual tissue development requires a highly regulated control of the extracellular tissue remodeling; however the mechanism of this regulation remains unknown. Through systematic expression studies, we detected that Cbx4/2, Rybp, and Ring1B [components of polycomb repressive complex 1 (PRC1)] are predominantly utilized in antimesometrial decidualization with polyploidy. Immunofluorescence analyses revealed that PRC1 members are co-localized with its functional histone modifier H2AK119ub1 (mono ubiquitination of histone-H2A at lysine-119) in polyploid cell. A potent small-molecule inhibitor of Ring1A/B E3-ubiquitin ligase or siRNA-mediated suppression of Cbx4 caused inhibition of H2AK119ub1, in conjunction with perturbation of decidualization and polyploidy development, suggesting a role for Cbx4/Ring1B-containing PRC1 in these processes. Analyses of genetic signatures by RNA-seq studies showed that the inhibition of PRC1 function affects 238 genes (154 up and 84 down) during decidualization. Functional enrichment analyses identified that about 38% genes primarily involved in extracellular processes are specifically targeted by PRC1. Furthermore, ~15% of upregulated genes exhibited a significant overlap with the upregulated Bmp2 null-induced genes in mice. Overall, Cbx4/Ring1B-containing PRC1 controls decidualization via regulation of extracellular gene remodeling functions and sheds new insights into underlying molecular mechanism(s) through transcriptional repression regulation.

PMID: 27181215 [PubMed - in process]