Triptolide increases transcript and protein levels of survival motor neurons in human SMA fibroblasts and improves survival in SMA-like mice.
Background and Purpose: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease. Since disease severity is related to the amount of survival motor neuron (SMN) protein, up-regulated functional SMN protein levels from the SMN2 gene are considered a major SMA drug-discovery strategy. In t...
| Publicado en: | British Journal of Pharmacology Vol. 166; no. 3; pp. 1114 - 1127 |
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| Autores principales: | , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Wiley-Blackwell
Jun2012
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104303519&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104303519 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00071188 DZ6 jtl: British Journal of Pharmacology issn: 00071188 maglogo: Y pubinfo: dt: Jun2012 vid: 166 iid: 3 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 104303519 NLM22220673 2011902707 10.1111/j.1476-5381.2012.01829.x NLM22220673 PMC3417433 104303519 ppf: 1114 ppct: 13 formats: tig: atl: Triptolide increases transcript and protein levels of survival motor neurons in human SMA fibroblasts and improves survival in SMA-like mice. aug: au: Hsu YY Jong YJ Tsai HH Tseng YT An LM Lo YC Hsu, Ya-Yun Jong, Yuh-Jyh Tsai, Hsin-Hung Tseng, Yu-Ting An, Li-Mei Lo, Yi-Ching affil: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan sug: subj: Carrier Proteins Fibroblasts Drug Effects Hydrocarbons Therapeutic Use Motor Neurons Drug Effects Muscular Atrophy, Spinal Drug Therapy Neuroprotective Agents Therapeutic Use RNA Drug Effects Animal Studies Apoptosis Drug Effects Biochemical Phenomena Blotting, Western Body Weight Drug Effects Cell Culture Techniques Cell Nucleus Drug Effects Cell Nucleus Metabolism Cell Physiology Drug Effects Cells Dose-Response Relationship, Drug Ethers Ethers Administration and Dosage Ethers Pharmacodynamics Ethers Therapeutic Use Fibroblasts Metabolism Fibroblasts Pathology Human Hydrocarbons Hydrocarbons Administration and Dosage Hydrocarbons Pharmacodynamics Kaplan-Meier Estimator Mice Models, Biological Molecular Structure Motor Neurons Metabolism Muscular Atrophy, Spinal Metabolism Muscular Atrophy, Spinal Pathology Neuroprotective Agents Neuroprotective Agents Administration and Dosage Neuroprotective Agents Pharmacodynamics Plants Polymerase Chain Reaction ab: Background and Purpose: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease. Since disease severity is related to the amount of survival motor neuron (SMN) protein, up-regulated functional SMN protein levels from the SMN2 gene are considered a major SMA drug-discovery strategy. In this study, we investigated the possible effects of triptolide, a diterpene triepoxide purified from Tripterygium wilfordii Hook. F., as a new compound for increasing SMN protein.Experimental Approach: The effects and mechanisms of triptolide on the production of SMA protein were determined by cell-based assays using the motor neuronal cell line NSC34 and skin fibroblasts from SMA patients. Wild-type (Smn(+/+) SMN2(-/-) , C57BL/6) and SMA-like (Smn(-/-) SMN2) mice were injected with triptolide (0.01 or 0.1 mg·kg(-1) ·day(-1) , i.p.) and their survival rate and level of change in SMN protein in neurons and muscle tissue measured.Key Results: In NSC34 cells and human SMA fibroblasts, pM concentrations of triptolide significantly increased SMN protein expression and the levels of SMN complex component (Gemin2 and Gemin3). In human SMA fibroblasts, triptolide increased SMN-containing nuclear gems and the ratio of full-length transcripts (FL-SMN2) to SMN2 transcripts lacking exon 7 (SMN2Δ7). Furthermore, in SMA-like mice, triptolide significantly increased SMN protein levels in the brain, spinal cord and gastrocnemius muscle. Furthermore, triptolide treatment increased survival and reduced weight loss in SMA-like mice.Conclusion and Implications: Triptolide enhanced SMN protein production by promoting SMN2 activation, exon 7 inclusion and increasing nuclear gems, and increased survival in SMA mice, which suggests triptolide might be a potential candidate for SMA therapy. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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