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  1. Article ; Online: Gene therapy for alpha 1-antitrypsin deficiency with an oxidant-resistant human alpha 1-antitrypsin.

    Sosulski, Meredith L / Stiles, Katie M / Frenk, Esther Z / Hart, Fiona M / Matsumura, Yuki / De, Bishnu P / Kaminsky, Stephen M / Crystal, Ronald G

    JCI insight

    2020  Volume 5, Issue 15

    Abstract: ... and M358 with leucine (L) on a normal M1 alanine (A) 213 background provided maximum antiprotease ...

    Abstract Alpha 1-antitrypsin (AAT) deficiency, a hereditary disorder characterized by low serum levels of functional AAT, is associated with early development of panacinar emphysema. AAT inhibits serine proteases, including neutrophil elastase, protecting the lung from proteolytic destruction. Cigarette smoke, pollution, and inflammatory cell-mediated oxidation of methionine (M) 351 and 358 inactivates AAT, limiting lung protection. In vitro studies using amino acid substitutions demonstrated that replacing M351 with valine (V) and M358 with leucine (L) on a normal M1 alanine (A) 213 background provided maximum antiprotease protection despite oxidant stress. We hypothesized that a onetime administration of a serotype 8 adeno-associated virus (AAV8) gene transfer vector coding for the oxidation-resistant variant AAT (A213/V351/L358; 8/AVL) would maintain antiprotease activity under oxidant stress compared with normal AAT (A213/M351/M358; 8/AMM). 8/AVL was administered via intravenous (IV) and intrapleural (IPL) routes to C57BL/6 mice. High, dose-dependent AAT levels were found in the serum and lung epithelial lining fluid (ELF) of mice administered 8/AVL or 8/AMM by IV or IPL. 8/AVL serum and ELF retained serine protease-inhibitory activity despite oxidant stress while 8/AMM function was abolished. 8/AVL represents a second-generation gene therapy for AAT deficiency providing effective antiprotease protection even with oxidant stress.
    MeSH term(s) Animals ; Dependovirus/genetics ; Female ; Genetic Therapy/methods ; Genetic Vectors/administration & dosage ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Oxidants ; Oxidative Stress ; Transgenes ; alpha 1-Antitrypsin/administration & dosage ; alpha 1-Antitrypsin/genetics ; alpha 1-Antitrypsin Deficiency/genetics ; alpha 1-Antitrypsin Deficiency/pathology ; alpha 1-Antitrypsin Deficiency/therapy
    Chemical Substances Oxidants ; SERPINA1 protein, human ; alpha 1-Antitrypsin
    Language English
    Publishing date 2020-08-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.135951
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Regulation of transforming growth factor-beta1 (TGF-β1)-induced pro-fibrotic activities by circadian clock gene BMAL1.

    Dong, Chunmin / Gongora, Rafael / Sosulski, Meredith L / Luo, Fayong / Sanchez, Cecilia G

    Respiratory research

    2016  Volume 17, Page(s) 4

    Abstract: Background: BMAL1 is a transcriptional activator of the molecular clock feedback network. Besides its role in generating circadian rhythms, it has also been shown to be involved in the modulation of cell proliferation, autophagy and cancer cell invasion. ...

    Abstract Background: BMAL1 is a transcriptional activator of the molecular clock feedback network. Besides its role in generating circadian rhythms, it has also been shown to be involved in the modulation of cell proliferation, autophagy and cancer cell invasion. However, the role of BMAL1 in pulmonary fibrogenesis is still largely unknown. In this study, we investigated the crosstalk between BMAL1 and the signaling transduction and cellular activities of TGF-β1, a key player in lung fibrogenesis.
    Methods: Lungs from wild type and TGF-β1-adenovirus-infected mice were harvested and homogenized for isolation of RNA and protein. RT-PCR and Western Blotting were employed to measure the expression level of clock genes and TGF-β1-induced downstream target genes. siRNA against human BMAL1 gene was transfected by using lipofectamine RNAiMAX to knockdown the endogenous BMAL1 in both lung epithelial cells and fibroblasts.
    Results: Our results showed that TGF-β1 is able to up-regulate BMAL1 expression in both lung epithelial cells and normal lung fibroblasts. In animal models of pulmonary fibrosis, BMAL1 expression was also significantly higher in adenovirus-TGF-β1-infected mice than in the control group. Interestingly, BMAL1 was mostly found in a deacetylated form in the presence of TGF-β1. Importantly, siRNA-mediated knockdown of BMAL1 significantly attenuated the canonical TGF-β1 signaling pathway and altered TGF-β1-induced epithelial-mesenchymal transition and MMP9 production in lung epithelial cells. In addition, BMAL1 knockdown inhibited the fibroblast to myofibroblast differentiation of normal human lung fibroblasts.
    Conclusions: Our results indicate that activation of TGF-β1 promotes the transcriptional induction of BMAL1. Furthermore, BMAL1 is required for the TGF-β1-induced signaling transduction and pro-fibrotic activities in the lung.
    MeSH term(s) ARNTL Transcription Factors/metabolism ; Animals ; Circadian Clocks ; Circadian Rhythm Signaling Peptides and Proteins/metabolism ; Female ; Gene Expression Regulation ; Idiopathic Pulmonary Fibrosis/metabolism ; Idiopathic Pulmonary Fibrosis/pathology ; Lung/metabolism ; Lung/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Transforming Growth Factor beta1
    Chemical Substances ARNTL Transcription Factors ; Bmal1 protein, mouse ; Circadian Rhythm Signaling Peptides and Proteins ; Transforming Growth Factor beta1
    Language English
    Publishing date 2016-01-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2041675-1
    ISSN 1465-993X ; 1465-993X
    ISSN (online) 1465-993X
    ISSN 1465-993X
    DOI 10.1186/s12931-016-0320-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Sirtuin 3 Deregulation Promotes Pulmonary Fibrosis.

    Sosulski, Meredith L / Gongora, Rafael / Feghali-Bostwick, Carol / Lasky, Joseph A / Sanchez, Cecilia G

    The journals of gerontology. Series A, Biological sciences and medical sciences

    2016  Volume 72, Issue 5, Page(s) 595–602

    Abstract: Oxidative stress leads to alveolar epithelial cell injury and fibroblast-myofibroblast differentiation (FMD), key events in the pathobiology of pulmonary fibrosis (PF). Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase regulator of antioxidant ... ...

    Abstract Oxidative stress leads to alveolar epithelial cell injury and fibroblast-myofibroblast differentiation (FMD), key events in the pathobiology of pulmonary fibrosis (PF). Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase regulator of antioxidant response and mitochondrial homeostasis. Here, we demonstrate reduced SIRT3 expression in the lungs of old mice compared to young mice, as well as in two murine models of PF. The analysis of the pattern of SIRT3 expression in the lungs of patients with PF revealed low SIRT3 staining within the fibrotic regions. We also demonstrated, using murine models of PF and human lung fibroblasts, that reduced SIRT3 expression in response to transforming growth factor beta 1 (TGFβ1) promotes acetylation (inactivation) of major oxidative stress response regulators, such as SOD2 and isocitrate dehydrogenase 2. Reduction of SIRT3 in human lung fibroblasts promoted FMD. By contrast, overexpression of SIRT3 attenuated TGFβ1-mediated FMD and significantly reduced the levels of SMAD family member 3 (SMAD3). Resveratrol induced SIRT3 expression and ameliorated acetylation changes induced by TGFβ1. We demonstrated that SIRT3-deficient mice are more susceptible to PF compared to control mice, and concomitantly exhibit enhanced SMAD3 expression. Collectively, these data define a SIRT3/TGFβ1 interaction during aging that may play a significant role in the pathobiology of PF.
    MeSH term(s) Aging/metabolism ; Animals ; Cell Differentiation ; Disease Models, Animal ; Down-Regulation ; Fibroblasts/metabolism ; Humans ; Isocitrate Dehydrogenase/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Pulmonary Fibrosis/pathology ; Resveratrol ; Sirtuin 3/metabolism ; Smad3 Protein/metabolism ; Stilbenes/pharmacology ; Superoxide Dismutase/metabolism ; Transforming Growth Factor beta1/metabolism
    Chemical Substances Smad3 Protein ; Stilbenes ; Transforming Growth Factor beta1 ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; isocitrate dehydrogenase 2, mouse (EC 1.1.1.41) ; Superoxide Dismutase (EC 1.15.1.1) ; Sirtuin 3 (EC 3.5.1.-) ; Resveratrol (Q369O8926L)
    Language English
    Publishing date 2016-08-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1223643-3
    ISSN 1758-535X ; 1079-5006
    ISSN (online) 1758-535X
    ISSN 1079-5006
    DOI 10.1093/gerona/glw151
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.242/A: Show issues Location:
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  4. Article ; Online: Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFβ1.

    Sosulski, Meredith L / Gongora, Rafael / Danchuk, Svitlana / Dong, Chunmin / Luo, Fayong / Sanchez, Cecilia G

    Aging cell

    2015  Volume 14, Issue 5, Page(s) 774–783

    Abstract: Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis (IPF) is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may ... ...

    Abstract Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis (IPF) is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to pulmonary fibrosis. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy (mitophagy). Fibroblast to myofibroblast differentiation (FMD) is an important feature of pulmonary fibrosis in which the profibrotic cytokine TGFβ1 plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by TGFβ1 is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a TGFβ1-adenoviral model of lung fibrosis. PINK1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of pulmonary fibrosis. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.
    MeSH term(s) Aging ; Animals ; Autophagy ; Cell Differentiation ; Cells, Cultured ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Humans ; Lung/cytology ; Lung/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Oxidative Stress ; Pulmonary Fibrosis/genetics ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/pathology ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism
    Chemical Substances Reactive Oxygen Species ; Transforming Growth Factor beta1
    Language English
    Publishing date 2015-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2113083-8
    ISSN 1474-9726 ; 1474-9718
    ISSN (online) 1474-9726
    ISSN 1474-9718
    DOI 10.1111/acel.12357
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6581: Show issues Location:
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  5. Article ; Online: Co-treatment with arsenic trioxide and ganciclovir reduces tumor volume in a murine xenograft model of nasopharyngeal carcinoma.

    Sides, Mark D / Sosulski, Meredith L / Luo, Fayong / Lin, Zhen / Flemington, Erik K / Lasky, Joseph A

    Virology journal

    2013  Volume 10, Page(s) 152

    Abstract: We have previously shown that disruption of promyelocytic leukemia nuclear bodies (PML NBs) is sufficient to activate the EBV lytic cycle thus making infected cells susceptible to ganciclovir (GCV) mediated killing in vitro. Here we show that co- ... ...

    Abstract We have previously shown that disruption of promyelocytic leukemia nuclear bodies (PML NBs) is sufficient to activate the EBV lytic cycle thus making infected cells susceptible to ganciclovir (GCV) mediated killing in vitro. Here we show that co-administration of GCV and arsenic trioxide (ATO), a PML NB disruptor, reduces tumor volume in a xenograft model of nasopharyngeal carcinoma utilizing CNE1 cells. When administered at pharmacologic levels, both GCV and ATO reduced tumor growth while co-treatment with GCV + ATO resulted in a diminution of tumor volume. Treatment with GCV or ATO individually resulted in an increased number of apoptotic cells while co-treatment with GCV + ATO synergistically induced apoptosis. Treatment with ATO or co-treatment with GCV + ATO resulted in expression of EBV lytic proteins. These data suggest that co-treatment with GCV + ATO may provide an effective treatment for nasopharyngeal carcinoma patients.
    MeSH term(s) Animals ; Antineoplastic Agents/administration & dosage ; Antiviral Agents/administration & dosage ; Arsenic Trioxide ; Arsenicals/administration & dosage ; Carcinoma ; Disease Models, Animal ; Drug Therapy, Combination/methods ; Ganciclovir/administration & dosage ; Heterografts/drug effects ; Humans ; Mice ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/drug therapy ; Oxides/administration & dosage ; Treatment Outcome ; Tumor Burden/drug effects
    Chemical Substances Antineoplastic Agents ; Antiviral Agents ; Arsenicals ; Oxides ; Ganciclovir (P9G3CKZ4P5) ; Arsenic Trioxide (S7V92P67HO)
    Language English
    Publishing date 2013-05-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1743-422X
    ISSN (online) 1743-422X
    DOI 10.1186/1743-422X-10-152
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Mice with a "monoclonal nose": perturbations in an olfactory map impair odor discrimination.

    Fleischmann, Alexander / Shykind, Benjamin M / Sosulski, Dara L / Franks, Kevin M / Glinka, Meredith E / Mei, Dan Feng / Sun, Yonghua / Kirkland, Jennifer / Mendelsohn, Monica / Albers, Mark W / Axel, Richard

    Neuron

    2008  Volume 60, Issue 6, Page(s) 1068–1081

    Abstract: We have altered the neural representation of odors in the brain by generating a mouse with a "monoclonal nose" in which greater than 95% of the sensory neurons express a single odorant receptor, M71. As a consequence, the frequency of sensory neurons ... ...

    Abstract We have altered the neural representation of odors in the brain by generating a mouse with a "monoclonal nose" in which greater than 95% of the sensory neurons express a single odorant receptor, M71. As a consequence, the frequency of sensory neurons expressing endogenous receptor genes is reduced 20-fold. We observe that these mice can smell, but odor discrimination and performance in associative olfactory learning tasks are impaired. However, these mice cannot detect the M71 ligand acetophenone despite the observation that virtually all sensory neurons and glomeruli are activated by this odor. The M71 transgenic mice readily detect other odors in the presence of acetophenone. These observations have implications for how receptor activation in the periphery is represented in the brain and how these representations encode odors.
    MeSH term(s) Aggression/physiology ; Animals ; Brain Mapping ; Discrimination, Psychological/physiology ; Evoked Potentials/physiology ; Male ; Mice ; Mice, Transgenic ; Nose/physiology ; Odorants ; Olfaction Disorders/genetics ; Olfaction Disorders/metabolism ; Olfaction Disorders/pathology ; Olfactory Bulb/cytology ; Olfactory Bulb/physiology ; Olfactory Pathways/cytology ; Olfactory Pathways/metabolism ; Olfactory Receptor Neurons/metabolism ; Receptors, Odorant/genetics ; Sexual Behavior, Animal/physiology
    Chemical Substances Olfr151 protein, mouse ; Receptors, Odorant
    Language English
    Publishing date 2008-12-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2008.10.046
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2496: Show issues Location:
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    Zs.MG 92: Show issues

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  7. Article: Co-treatment with arsenic trioxide and ganciclovir reduces tumor volume in a murine xenograft model of nasopharyngeal carcinoma

    Sides, Mark D / Sosulski, Meredith L / Luo, Fayong / Lin, Zhen / Flemington, Erik K / Lasky, Joseph A

    Virology journal

    Volume v. 10,, Issue no. 1

    Abstract: We have previously shown that disruption of promyelocytic leukemia nuclear bodies (PML NBs) is sufficient to activate the EBV lytic cycle thus making infected cells susceptible to ganciclovir (GCV) mediated killing in vitro. Here we show that co- ... ...

    Abstract We have previously shown that disruption of promyelocytic leukemia nuclear bodies (PML NBs) is sufficient to activate the EBV lytic cycle thus making infected cells susceptible to ganciclovir (GCV) mediated killing in vitro. Here we show that co-administration of GCV and arsenic trioxide (ATO), a PML NB disruptor, reduces tumor volume in a xenograft model of nasopharyngeal carcinoma utilizing CNE1 cells. When administered at pharmacologic levels, both GCV and ATO reduced tumor growth while co-treatment with GCV + ATO resulted in a diminution of tumor volume. Treatment with GCV or ATO individually resulted in an increased number of apoptotic cells while co-treatment with GCV + ATO synergistically induced apoptosis. Treatment with ATO or co-treatment with GCV + ATO resulted in expression of EBV lytic proteins. These data suggest that co-treatment with GCV + ATO may provide an effective treatment for nasopharyngeal carcinoma patients.
    Keywords models ; mice ; patients ; apoptosis ; leukemia ; arsenic ; proteins ; carcinoma
    Language English
    Document type Article
    ISSN 1743-422X
    Database AGRIS - International Information System for the Agricultural Sciences and Technology

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