The first cyclomegastigmane rhododendroside A from Rhododendron brachycarpum alleviates HMGB1-induced sepsis

Zhou, Wei; Oh, Joonseok; Lee, Wonhwa; Kwak, Soyoung; Li, Wei; Chittiboyina, Amar G.; Ferreira, Daneel; Hamann, Mark T.; Lee, Seung Ho; Bae, Jong‐Sup; Na, MinKyun

doi:10.1016/j.bbagen.2014.02.016

Cited by 22 publications

(11 citation statements)

References 20 publications

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“…In continuing attempts to identify plant-derived drug prototypes for the treatment of cardiovascular dysfunctions and complications, − the current study elaborates the identification of six new cucurbitane-type triterpenoids from the fruits of M. charantia . These cucurbitanes were also evaluated for their inhibitory activity against PDGF-induced VSMC proliferation to determine whether these major constituents can be developed into practical chemotypes alleviating cardiovascular disorders and their complications.…”

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confidence: 99%

Inhibition of Proliferation of Vascular Smooth Muscle Cells by Cucurbitanes from Momordica charantia

Tuấn¹,

Lee²,

et al. 2017

J. Nat. Prod.

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The cucurbitaceous plant Momordica charantia L., named "bitter melon", inhabits Asia, Africa, and South America and has been used as a traditional medicine. The atypical proliferation of vascular smooth muscle cells (VSMCs) plays an important role in triggering the pathogenesis of cardiovascular diseases. Platelet-derived growth factor (PDGF) is regarded as the most powerful growth factor in promoting the intimal accumulation of VSMCs. The current study features the identification of six new cucurbitane-type triterpenoids (1-6) from the fruits of M. charantia, utilizing diverse chromatographic and spectroscopic techniques. In particular, the 2D structure of 1 was confirmed utilizing the long-range HSQMBC NMR pulse, capable of measuring heteronuclear long-range correlations (J). The cucurbitanes were also assessed for their inhibitory activity against PDGF-induced VSMC proliferation. This current study may constitute a basis for developing those chemotypes into sensible pharmacophores alleviating cardiovascular disorders.

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confidence: 99%

Inhibition of Proliferation of Vascular Smooth Muscle Cells by Cucurbitanes from Momordica charantia

Tuấn¹,

Lee²,

et al. 2017

J. Nat. Prod.

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“…As part of a continuous endeavor to probe potential nature-derived drug templates for the treatment of cardiovascular disorders and related complications, ,− the current study delineates the isolation of nine new arborinane triterpenoids ( 1 – 9 ) from R. philippinensis in the first chemical investigation of this underutilized plant resource. These compounds were evaluated for their inhibitory potential against PDGF-induced VSMC proliferation and migration to assess whether these relatively rare triterpenoids may serve as prototypes for the development of cardiovascular drug leads.…”

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confidence: 99%

Arborinane Triterpenoids from Rubia philippinensis Inhibit Proliferation and Migration of Vascular Smooth Muscle Cells Induced by the Platelet-Derived Growth Factor

Quan

Park²,

et al. 2016

J. Nat. Prod.

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The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are associated with cardiovascular diseases and related complications. Such deleterious proliferation and migration events are triggered by cytokines and growth factors, and among them, platelet-derived growth factor (PDGF) is recognized as the most potent inducer. Despite the genus Rubia being researched to identify valuable commercial and medicinal virtues, Rubia philippinensis has rarely been investigated. Nine arborinane-type triterpenoids (1-9) were identified from this underutilized plant species. In particular, 4 was identified as the first arborinane derivative carrying a ketocarbonyl motif at C-19. The presence of the cyclopentanone moiety and the associated configurational assignment were determined by utilizing NOE and coupling constant analysis. These compounds were assessed for their inhibitory potential on PDGF-induced proliferation and the migration of VSMCs. Treatment with 5 μM compound 5 (62.6 ± 10.7%) and compound 9 (41.1 ± 4.7%) impeded PDGF-stimulated proliferation without exerting cytotoxicity. Compound 7 exhibited antimigration activity in a dose-dependent manner (38.5 ± 3.0% at 10 μM, 57.6 ± 3.2% at 30 μM). These results suggest that the arborinane-type triterpenoids may be a pertinent starting point for the development of cardiovascular drugs capable of preventing the intimal accumulation of VSMCs.

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“…p38 is an important downstream signal triggered by HMGB1-RAGE binding (34,35). HMGB1 is known to induce hyperpermeability by promoting phosphorylation of p38 (34,36), and our recent studies have shown that HMGB1 application causes the activation of p38 and subsequently increases permeability in HUVECs (37)(38)(39). Because the threonine phosphorylation of moesin proteins has also been shown to be related to MAPK activation (11), it is reasonable to estimate that HMGB1-induced phosphorylation of moesin is mediated by MAPKs.…”

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Role of moesin in HMGB1-stimulated severe inflammatory responses

Lee¹,

Kwon²,

Han³

et al. 2015

Thromb Haemost

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Sepsis is a life-threatening condition that arises when the body's response to infection causes systemic inflammation. High-mobility group box 1 (HMGB1), as a late mediator of sepsis, enhances hyperpermeability, and it is therefore a therapeutic target. Despite extensive research into the underlying mechanisms of sepsis, the target molecules controlling vascular leakage remain largely unknown. Moesin is a cytoskeletal protein involved in cytoskeletal changes and paracellular gap formation. The objectives of this study were to determine the roles of moesin in HMGB1-mediated vascular hyperpermeability and inflammatory responses and to investigate the mechanisms of action underlying these responses. Using siRNA knockdown of moesin expression in primary human umbilical vein endothelial cells (HUVECs), moesin was found to be required in HMGB1-induced F-actin rearrangement, hyperpermeability, and inflammatory responses. The mechanisms involved in moesin phosphorylation were analysed by blocking the binding of the HMGB1 receptor (RAGE) and inhibiting the Rho and MAPK pathways. HMGB1-treated HUVECs exhibited an increase in Thr558 phosphorylation of moesin. Circulating levels of moesin were measured in patients admitted to the intensive care unit with sepsis, severe sepsis, and septic shock; these patients showed significantly higher levels of moesin than healthy controls, which was strongly correlated with disease severity. High blood moesin levels were also observed in cecal ligation and puncture (CLP)-induced sepsis in mice. Administration of blocking moesin antibodies attenuated CLP-induced septic death. Collectively, our findings demonstrate that the HMGB1-RAGE-moesin axis can elicit severe inflammatory responses, suggesting it to be a potential target for the development of diagnostics and therapeutics for sepsis.

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The first cyclomegastigmane rhododendroside A from Rhododendron brachycarpum alleviates HMGB1-induced sepsis

Cited by 22 publications

References 20 publications

Inhibition of Proliferation of Vascular Smooth Muscle Cells by Cucurbitanes from Momordica charantia

Inhibition of Proliferation of Vascular Smooth Muscle Cells by Cucurbitanes from Momordica charantia

Arborinane Triterpenoids from Rubia philippinensis Inhibit Proliferation and Migration of Vascular Smooth Muscle Cells Induced by the Platelet-Derived Growth Factor

Role of moesin in HMGB1-stimulated severe inflammatory responses

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