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  1. Article ; Online: Targeting cyst initiation in ADPKD.

    Leuenroth, Stephanie J / Crews, Craig M

    Journal of the American Society of Nephrology : JASN

    2009  Volume 20, Issue 1, Page(s) 1–3

    MeSH term(s) Animals ; Calcium Signaling ; Humans ; Polycystic Kidney, Autosomal Dominant/drug therapy ; Polycystic Kidney, Autosomal Dominant/physiopathology ; TRPP Cation Channels/physiology
    Chemical Substances TRPP Cation Channels ; polycystic kidney disease 2 protein
    Language English
    Publishing date 2009-01
    Publishing country United States
    Document type Editorial ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1085942-1
    ISSN 1533-3450 ; 1046-6673
    ISSN (online) 1533-3450
    ISSN 1046-6673
    DOI 10.1681/ASN.2008101118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3344: Show issues Location:
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  2. Article ; Online: Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure.

    Leuenroth, Stephanie J / Crews, Craig M

    Cancer research

    2008  Volume 68, Issue 13, Page(s) 5257–5266

    Abstract: Triptolide, an active component of the medicinal herb lei gong teng, is a potent anticancer and anti-inflammatory therapeutic. It potently inhibits nuclear factor-kappaB transcriptional activation after DNA binding, although a precise mechanism is as yet ...

    Abstract Triptolide, an active component of the medicinal herb lei gong teng, is a potent anticancer and anti-inflammatory therapeutic. It potently inhibits nuclear factor-kappaB transcriptional activation after DNA binding, although a precise mechanism is as yet unknown. Here, we report that triptolide also induces distinct nuclear substructural changes in HeLa cells. These changes in the nucleolus and nuclear speckles are reversible and dependent on both time and concentration. Furthermore, nuclear changes occurred within hours of triptolide treatment and were calcium and caspase independent. Rounding of nuclear speckles, an indication of transcriptional arrest, was evident and was associated with a decrease in RNA polymerase II (RNA Pol II) COOH-terminal domain Ser(2) phosphorylation. Additionally, the nucleolus disassembled and RNA Pol I activity declined after RNA Pol II inhibition. We therefore conclude that triptolide causes global transcriptional arrest as evidenced by inactivity of RNA Pol I and II and the subsequent alteration in nuclear substructure.
    MeSH term(s) Antineoplastic Agents, Alkylating/pharmacology ; Calcium/pharmacology ; Caspases/metabolism ; Caspases/physiology ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cell Nucleus/ultrastructure ; Clone Cells ; Diterpenes/pharmacology ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/physiology ; Epoxy Compounds/pharmacology ; HeLa Cells ; Humans ; Nuclear Proteins/metabolism ; Nucleophosmin ; Phenanthrenes/pharmacology ; Phosphoproteins/metabolism ; Pol1 Transcription Initiation Complex Proteins/metabolism ; RNA Polymerase II/drug effects ; RNA Polymerase II/metabolism ; RNA-Binding Proteins/metabolism ; Time Factors ; Tissue Distribution ; Transcription, Genetic/drug effects ; Nucleolin
    Chemical Substances Antineoplastic Agents, Alkylating ; Diterpenes ; Epoxy Compounds ; Nuclear Proteins ; Phenanthrenes ; Phosphoproteins ; Pol1 Transcription Initiation Complex Proteins ; RNA-Binding Proteins ; transcription factor UBF ; Nucleophosmin (117896-08-9) ; triptolide (19ALD1S53J) ; RNA Polymerase II (EC 2.7.7.-) ; Caspases (EC 3.4.22.-) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2008-07-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-07-6207
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.135/5: Show issues Location:
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  3. Article: Studies on calcium dependence reveal multiple modes of action for triptolide.

    Leuenroth, Stephanie J / Crews, Craig M

    Chemistry & biology

    2005  Volume 12, Issue 12, Page(s) 1259–1268

    Abstract: Triptolide, a diterpene triepoxide isolated from the traditional Chinese medicinal vine Trypterygium wilfordii hook f., has been shown to induce rapid apoptosis in a myriad of cancer cell lines and inhibit NFkappaB transactivation. To understand further ... ...

    Abstract Triptolide, a diterpene triepoxide isolated from the traditional Chinese medicinal vine Trypterygium wilfordii hook f., has been shown to induce rapid apoptosis in a myriad of cancer cell lines and inhibit NFkappaB transactivation. To understand further the general cellular mechanisms for this therapeutically relevant natural product, binding and biological activities were assessed. Studies showed that triptolide binding was saturable, reversible, and primarily localized to cell membranes. Depletion of calcium enhanced overall binding while differentially modulating biological function. Furthermore, triptolide's structural moieties demonstrated variability in the regulation of cell death versus inhibition of NFkappaB transactivation. These results implicate triptolide in the manipulation of at least two distinct cellular pathways with differing requirements for calcium and effective triptolide concentration in order to elicit each particular biological function.
    MeSH term(s) Antineoplastic Agents, Alkylating/chemistry ; Antineoplastic Agents, Alkylating/metabolism ; Antineoplastic Agents, Alkylating/pharmacology ; Antineoplastic Agents, Phytogenic/chemistry ; Antineoplastic Agents, Phytogenic/metabolism ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Binding, Competitive/drug effects ; Calcium/pharmacology ; Calcium/physiology ; Calcium-Binding Proteins/metabolism ; Cell Line, Tumor ; Cell Membrane/metabolism ; Diterpenes/chemistry ; Diterpenes/metabolism ; Diterpenes/pharmacology ; Epoxy Compounds ; HeLa Cells ; Humans ; NF-kappa B/metabolism ; Phenanthrenes/chemistry ; Phenanthrenes/metabolism ; Phenanthrenes/pharmacology ; Transcriptional Activation
    Chemical Substances Antineoplastic Agents, Alkylating ; Antineoplastic Agents, Phytogenic ; Calcium-Binding Proteins ; Diterpenes ; Epoxy Compounds ; NF-kappa B ; Phenanthrenes ; triptolide (19ALD1S53J) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2005-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 917827-2
    ISSN 1879-1301 ; 1074-5521
    ISSN (online) 1879-1301
    ISSN 1074-5521
    DOI 10.1016/j.chembiol.2005.09.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4429: Show issues Location:
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  4. Article ; Online: Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD.

    Leuenroth, Stephanie J / Bencivenga, Natasha / Chahboune, Halima / Hyder, Fahmeed / Crews, Craig M

    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

    2010  Volume 25, Issue 7, Page(s) 2187–2194

    Abstract: Background: Autosomal dominant polycystic kidney disease (ADPKD), a major cause of end-stage renal failure, results from genetic mutation of either polycystin-1 (Pkd1) or polycystin-2 (Pkd2). In order to develop novel therapies to treat the advancement ... ...

    Abstract Background: Autosomal dominant polycystic kidney disease (ADPKD), a major cause of end-stage renal failure, results from genetic mutation of either polycystin-1 (Pkd1) or polycystin-2 (Pkd2). In order to develop novel therapies to treat the advancement of disease progression, numerous rodent models of different genetic backgrounds are available to study cyst development.
    Methods: Here, a Pkd1-floxed inducible mouse model using the interferon responsive Mx1Cre-recombinase was utilized to test the effect of the small molecule triptolide. Relative to other Pkd1 inactivation models, cyst progression in this neonatal to adult transition model is attenuated. Following the characterization of inducible cyst formation in these mice, the development of kidney cysts from triptolide or vehicle-treated animals was analysed.
    Results: Although Pkd1 deletion on postnatal Days P10 and P12 resulted in numerous cysts by P35, daily injections with triptolide beginning on Day P16 significantly reduced the total number of cysts per kidney, with a pronounced effect on the number of microcysts and the overall cystic burden. Additionally, renal function as assessed by blood urea nitrogen levels was also improved in triptolide-treated mice at both the P22 and P35 time points. As the Pkd1(flox/flox);Mx1Cre model has not been previously used for drug development studies, the feasibility of a 6-month adult Pkd1 inactivation study was also tested. While kidney cyst formation was minimal and focal in nature, livers of these Pkd1-deficient mice were severely cystic, enlarged and pale.
    Conclusions: These results suggest that the Pkd1(flox/flox);Mx1Cre model of ADPKD is amenable to short-term kidney cyst formation drug studies; however, it may be problematic for long-term therapeutic research where widespread liver cysts and fibrosis could compromise drug metabolism.
    MeSH term(s) Aging/pathology ; Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Antineoplastic Agents, Alkylating/therapeutic use ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Disease Models, Animal ; Disease Progression ; Diterpenes/pharmacology ; Diterpenes/therapeutic use ; Epoxy Compounds/pharmacology ; Epoxy Compounds/therapeutic use ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Integrases/genetics ; Integrases/metabolism ; Kidney/drug effects ; Kidney/metabolism ; Kidney/pathology ; Mice ; Mice, Mutant Strains ; Mutation/genetics ; Myxovirus Resistance Proteins ; Phenanthrenes/pharmacology ; Phenanthrenes/therapeutic use ; Polycystic Kidney, Autosomal Dominant/genetics ; Polycystic Kidney, Autosomal Dominant/physiopathology ; Polycystic Kidney, Autosomal Dominant/prevention & control ; TRPP Cation Channels/genetics ; TRPP Cation Channels/metabolism ; Time Factors
    Chemical Substances Antineoplastic Agents, Alkylating ; Cyclin-Dependent Kinase Inhibitor p21 ; Diterpenes ; Epoxy Compounds ; Myxovirus Resistance Proteins ; Phenanthrenes ; TRPP Cation Channels ; polycystic kidney disease 1 protein ; triptolide (19ALD1S53J) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-) ; GTP-Binding Proteins (EC 3.6.1.-)
    Language English
    Publishing date 2010-02-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 90594-x
    ISSN 1460-2385 ; 0931-0509
    ISSN (online) 1460-2385
    ISSN 0931-0509
    DOI 10.1093/ndt/gfp777
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2198: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
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    Zs.MO 329: Show issues

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  5. Article ; Online: Triptolide reduces cystogenesis in a model of ADPKD.

    Leuenroth, Stephanie J / Bencivenga, Natasha / Igarashi, Peter / Somlo, Stefan / Crews, Craig M

    Journal of the American Society of Nephrology : JASN

    2008  Volume 19, Issue 9, Page(s) 1659–1662

    Abstract: Mutations in PKD1 result in autosomal dominant polycystic kidney disease, which is characterized by increased proliferation of tubule cells leading to cyst initiation and subsequent expansion. Given the cell proliferation associated with cyst growth, an ... ...

    Abstract Mutations in PKD1 result in autosomal dominant polycystic kidney disease, which is characterized by increased proliferation of tubule cells leading to cyst initiation and subsequent expansion. Given the cell proliferation associated with cyst growth, an attractive therapeutic strategy has been to target the hyperproliferative nature of the disease. We previously demonstrated that the small molecule triptolide induces cellular calcium release through a polycystin-2-dependent pathway, arrests Pkd1(-/-) cell growth, and reduces cystic burden in Pkd1(-/-) embryonic mice. To assess cyst progression in neonates, we used the kidney-specific Pkd1(flox/-);Ksp-Cre mouse model of autosomal dominant polycystic kidney disease, in which the burden of cysts is negligible at birth but then progresses rapidly over days. The number, size, and proliferation rate of cysts were examined. Treatment with triptolide significantly improved renal function at postnatal day 8 by inhibition of the early phases of cyst growth. Because the proliferative index of kidney epithelium in neonates versus adults is significantly different, future studies will need to address whether triptolide delays or reduces cyst progression in the Pkd1 adult model.
    MeSH term(s) Animals ; Animals, Newborn ; Antineoplastic Agents, Alkylating/therapeutic use ; Diterpenes/therapeutic use ; Epoxy Compounds/therapeutic use ; Mice ; Mice, Transgenic ; Phenanthrenes/therapeutic use ; Polycystic Kidney, Autosomal Dominant/drug therapy
    Chemical Substances Antineoplastic Agents, Alkylating ; Diterpenes ; Epoxy Compounds ; Phenanthrenes ; triptolide (19ALD1S53J)
    Language English
    Publishing date 2008-07-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1085942-1
    ISSN 1533-3450 ; 1046-6673
    ISSN (online) 1533-3450
    ISSN 1046-6673
    DOI 10.1681/ASN.2008030259
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3344: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    ab Jg. 2022: Lesesaal (EG)

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  6. Article: Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease

    Leuenroth, Stephanie J / Okuhara, Dayne / Shotwell, Joseph D / Markowitz, Glen S / Yu, Zhiheng / Somlo, Stefan / Crews, Craig M

    Proceedings of the National Academy of Sciences of the United States of America. 2007 Mar. 13, v. 104, no. 11

    2007  

    Abstract: During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca²⁺) channel polycystin-2 (PC2), ... ...

    Abstract During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca²⁺) channel polycystin-2 (PC2), resulting in a calcium flux-mediated cell cycle arrest. Loss or mutation of either PC2 or its regulatory protein polycystin-1 (PC1) results in autosomal dominant polycystic kidney disease (ADPKD), characterized by cyst formation and growth and often leading to renal failure and death. Here we show that triptolide, the active diterpene in the traditional Chinese medicine Lei Gong Teng, induces Ca²⁺ release by a PC2-dependent mechanism. Furthermore, in a murine model of ADPKD, triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca²⁺ signaling in these cells. We anticipate that small molecule induction of PC2-dependent calcium release is likely to be a valid therapeutic strategy for ADPKD.
    Keywords cysts (pathology) ; Tripterygium wilfordii ; medicinal plants ; herbal medicines ; Oriental traditional medicine ; diterpenoids ; calcium ; ion transport ; medicinal properties ; signal transduction ; cell proliferation ; kidney diseases ; regulatory proteins ; humans
    Language English
    Dates of publication 2007-0313
    Size p. 4389-4394.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    Database NAL-Catalogue (AGRICOLA)

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  7. Article: Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease.

    Leuenroth, Stephanie J / Okuhara, Dayne / Shotwell, Joseph D / Markowitz, Glen S / Yu, Zhiheng / Somlo, Stefan / Crews, Craig M

    Proceedings of the National Academy of Sciences of the United States of America

    2007  Volume 104, Issue 11, Page(s) 4389–4394

    Abstract: During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca(2+)) channel polycystin-2 (PC2), ... ...

    Abstract During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca(2+)) channel polycystin-2 (PC2), resulting in a calcium flux-mediated cell cycle arrest. Loss or mutation of either PC2 or its regulatory protein polycystin-1 (PC1) results in autosomal dominant polycystic kidney disease (ADPKD), characterized by cyst formation and growth and often leading to renal failure and death. Here we show that triptolide, the active diterpene in the traditional Chinese medicine Lei Gong Teng, induces Ca(2+) release by a PC2-dependent mechanism. Furthermore, in a murine model of ADPKD, triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca(2+) signaling in these cells. We anticipate that small molecule induction of PC2-dependent calcium release is likely to be a valid therapeutic strategy for ADPKD.
    MeSH term(s) Animals ; Calcium/metabolism ; Calcium Channels/metabolism ; Diterpenes/pharmacology ; Epithelial Cells/cytology ; Epoxy Compounds/pharmacology ; Immunosuppressive Agents/pharmacology ; Kidney/metabolism ; Medicine, Chinese Traditional ; Mice ; Mice, Transgenic ; Phenanthrenes/pharmacology ; Polycystic Kidney Diseases/drug therapy ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; TRPP Cation Channels/metabolism ; Transgenes ; p21-Activated Kinases
    Chemical Substances Calcium Channels ; Diterpenes ; Epoxy Compounds ; Immunosuppressive Agents ; Phenanthrenes ; TRPP Cation Channels ; polycystic kidney disease 1 protein ; triptolide (19ALD1S53J) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2007-03-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0700499104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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