Triptolide, an active component of the Chinese herbal remedy <i>Tripterygium wilfordii</i> Hook F, inhibits production of nitric oxide by decreasing inducible nitric oxide synthase gene transcription

Wang, Bin; Ma, Li; Tao, Xiaochun; Lipsky, Peter E.

doi:10.1002/art.20459

Cited by 93 publications

(65 citation statements)

References 38 publications

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“…1A, lane 2). This increase is consistent with previous reports (Meighan-Mantha et al 1999;Zhao et al 2000;B. Wang et al 2004;Chen and Currie 2005).…”

Section: Resultssupporting

confidence: 93%

A general mechanism for transcription regulation by Oct1 and Oct4 in response to genotoxic and oxidative stress

Kang¹,

Gemberling²,

Nakamura³

et al. 2009

Genes Dev.

118

150

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Oct1 and Oct4 are homologous transcription factors with similar DNA-binding specificities. Here we show that Oct1 is dynamically phosphorylated in vivo following exposure of cells to oxidative and genotoxic stress. We further show that stress regulates the selectivity of both proteins for specific DNA sequences. Mutation of conserved phosphorylation target DNA-binding domain residues in Oct1, and Oct4 confirms their role in regulating binding selectivity. Using chromatin immunoprecipitation, we show that association of Oct4 and Oct1 with a distinct group of in vivo targets is inducible by stress, and that Oct1 is essential for a normal post-stress transcriptional response. Finally, using an unbiased Oct1 target screen we identify a large number of genes targeted by Oct1 specifically under conditions of stress, and show that several of these inducible Oct1 targets are also inducibly bound by Oct4 in embryonic stem cells following stress exposure. Oct1 and Oct4 (products of the Pou2f1 and Pou5f1 genes) are members of the POU (Pit-1, Oct1/2, Unc-86) domain transcription factor family (Herr et al. 1988;Ryan and Rosenfeld 1997). This family is defined by the presence of a bipartite DNA-binding domain in which two subdomains, covalently connected by a flexible linker, typically recognize DNA through major groove interactions on opposite sides of the helix (Klemm et al. 1994). The classical DNA recognition sequence is known as an octamer motif (59-ATGCAAAT-39, hereafter called a ''simple'' octamer). However, we demonstrated recently that native binding sites for Oct4 frequently exist in complex paired, overlapping, and nonconsensus configurations (Tantin et al. 2008).Oct4 is a master regulator of the stem cell state and has recently been shown to be one of three proteins sufficient to reprogram differentiated adult mouse and human cells to the embryonic stem (ES) cell lineage (Okita et al. 2007;Takahashi et al. 2007;Nakagawa et al. 2008). The biological function of Oct1 is more enigmatic. Oct1 is known to interact with regulatory sites in interleukin, immunoglobulin, and histone genes (Garrity et al. 1994;Zheng et al. 2003;Ushmorov et al. 2004;Murayama et al. 2006). Oct1 also moderately stimulates gene expression reporter constructs linked to target sequences in transient transfection assays (Sive et al. 1986;LeBowitz et al. 1988). However, we showed that Oct1 is nonessential for native H2B, IgH, and Igk expression (V.E. V.E.H. Wang et al. 2004). Oct1-deficient cells appear morphologically normal in light microscopy and divide at normal rates. Oct1-deficient mice die in mid-late gestation (embryonic days 12,5-18.5 [E12.5-E18.5]) (V.E.H. .We determined previously that Oct1 À/À mouse embryonic fibroblasts (MEFs) are hypersensitive to oxidative and genotoxic stress (Tantin et al. 2005). One explanation for this result is that constitutive products of Oct1-mediated transcription participate in stress response pathways. Support for an alternative hypothesis, namely that Oct1 directly senses cellular stress, comes from the f...

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“…1A, lane 2). This increase is consistent with previous reports (Meighan-Mantha et al 1999;Zhao et al 2000;B. Wang et al 2004;Chen and Currie 2005).…”

Section: Resultssupporting

confidence: 93%

A general mechanism for transcription regulation by Oct1 and Oct4 in response to genotoxic and oxidative stress

Kang¹,

Gemberling²,

Nakamura³

et al. 2009

Genes Dev.

118

150

View full text Add to dashboard Cite

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“…Natural products of several types, including lignans (Hwang et al, 2003), sesquiterpene esters (Jin et al, 2002) and sesquiterpene lactones Schorr et al, 2002), have been found to interfere with various steps in NF-κB release and activation of DNA transcription (Lee et al, 2002a). Genes involved in inflammation can also be activated by other transcription factors, such as activator protein-1 (AP-1), nuclear factor of activated T cells (NFAT), and Oct-1, and by the p38 mitogen-activated protein (MAP) kinase pathway (Barnes and Karin, 1997;Diehl et al, 2004;Pinna et al, 2004;Wang et al, 2004a).…”

Section: Proinflammatory Enzymes-nitric Oxide Synthase (Nos) Catalyzementioning

confidence: 99%

“…Whether any components of the Tripterygium extract interfere with AP-1 activity remains controversial (Maekawa et al, 1999;Sylvester et al, 2001;Wang et al, 2004a). Pure triptolide (1) did not affect DNA binding of NF-κB; rather, it inhibited the transcription of proinflammatory genes by blocking the transactivation of NF-κB, which occurs after its binding to promoter regions of these genes Lee et al, 2002a).…”

Section: Proinflammatory Enzymes-nitric Oxide Synthase (Nos) Catalyzementioning

confidence: 99%

“…Pure triptolide (1) did not affect DNA binding of NF-κB; rather, it inhibited the transcription of proinflammatory genes by blocking the transactivation of NF-κB, which occurs after its binding to promoter regions of these genes Lee et al, 2002a). Triptolide (1) also inhibited transactivation by NFAT and upregulation of the nucleotide-binding activity of Oct-1 Wang et al, 2004a).…”

Section: Proinflammatory Enzymes-nitric Oxide Synthase (Nos) Catalyzementioning

confidence: 99%

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Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

et al. 2007

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Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook. f., have a long history of use in traditional Chinese medicine. In recent years there has been considerable interest in the use of Tripterygium extracts and of the main bioactive constituent, the diterpene triepoxide triptolide (1), to treat a variety of autoimmune and inflammation-related conditions. The main mode of action of the Tripterygium extracts and triptolide (1) is the inhibition of expression of proinflammatory genes such as those for interleukin-2 (IL-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interferon-gamma (IFN-γ). The efficacy and safety of certain types of Tripterygium extracts were confirmed in human clinical trials in the US and abroad. Over 300 compounds have been identified in the genus Tripterygium, and many of these have been evaluated for biological activity. The overall activity of the extract is based on the interaction between its components. Therefore, the safety and efficacy of the extract cannot be fully mimicked by any individual constituent. This review discusses the biochemical composition and biological and pharmacological activities of Tripterygium extracts, and their main bioactive components.

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“…Meanwhile, many studies have been dedicated to elucidating the potential molecular mechanisms underlying the anti-inflammatory and immunosuppressive effects of TEs [18], including the inhibition of platelet activation [20], the induction of nitric oxide [21], and prostaglandin E 2 [22] production. Based on studies both in vitro and in vivo , it is easy to speculate that TEs are likely to be types of herbal DMARDs, which differ from synthetic DMARDs.…”

Section: Introductionmentioning

confidence: 99%

Extracts ofTripterygium wilfordiiHook F in the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis of Randomised Controlled Trials

Liu

Gao

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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Clinical trials have reported the effects of Tripterygium wilfordii Hook F (TwHF) extracts (TEs) in the treatment of rheumatoid arthritis (RA); however, the results have been inconsistent. This meta-analysis is aimed to assess the safety of TEs and their effects on the treatment of RA. Randomised controlled trials (RCTs) comparing the effects of TEs and placebo (PBO) or disease-modifying antirheumatic drugs (DMARDs) in patients with RA were included. Weighted mean differences (MDs) were calculated for net changes by employing fixed-effect or random-effects models. After filtering, ten RCTs (involving 733 participants) were included in this study. The methodological quality of these studies was generally low. Compared with DMARDs, TEs alone produced a mild increase in grip strength (GS) (P = 0.02; standard mean difference (SMD) = 0.81; 95% confidence interval (CI): 0.14 to 1.48). The most common adverse effects (AEs) of TEs were gastrointestinal discomfort, menstruation disorders, and amenorrhea. In conclusion, TEs, as a sort of “herbal DMARD,” could be as effective as synthetic DMARDs in the treatment of RA. However, the efficacy of TEs in treating RA should be further estimated with better designed, fully powered, confirmatory RCTs that apply the American College of Rheumatology (ACR) improvement criteria to evaluate their outcomes.

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Triptolide, an active component of the Chinese herbal remedy Tripterygium wilfordii Hook F, inhibits production of nitric oxide by decreasing inducible nitric oxide synthase gene transcription

Cited by 93 publications

References 38 publications

A general mechanism for transcription regulation by Oct1 and Oct4 in response to genotoxic and oxidative stress

A general mechanism for transcription regulation by Oct1 and Oct4 in response to genotoxic and oxidative stress

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

Extracts ofTripterygium wilfordiiHook F in the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis of Randomised Controlled Trials

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