Dual-targeting Rutaecarpine-NO donor hybrids as novel anti-hypertensive agents by promoting release of CGRP

Ma, Jinfei; Cui, Lan; Fan, Jinbao; Cao, Wei; Zeng, Gu-Qing; Wang, Yajing; Li, Yuan‐Jian; Zhou, Yingjun; Deng, Xu

doi:10.1016/j.ejmech.2019.02.037

Cited by 32 publications

(13 citation statements)

References 30 publications

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“…There is plenty of evidence that Rut plays a positive role in the treatment of cardiovascular disease 8. Rut stimulates the synthesis and release of CGRP by activating TRPV1 and plays an effective role in vasodilation and hypertension 23. Besides, Xue et al found that Rut (1.1 mg/mL) could reduce the myocardial infarction size of myocardial I/R injury, improve the disorder of fatty acid and glucose metabolism, and increase the content of ATP 24.…”

Section: Discussionmentioning

confidence: 99%

<p>Rutaecarpine may improve neuronal injury, inhibits apoptosis, inflammation and oxidative stress by regulating the expression of ERK1/2 and Nrf2/HO-1 pathway in rats with cerebral ischemia-reperfusion injury</p>

Han¹,

Hu²,

Chen³

2019

DDDT

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BackgroundCerebral ischemia-reperfusion (CI/R) injury is a more serious brain injury caused by the recovery of blood supply after cerebral ischemia for a certain period of time. Rutaecarpine (Rut) is an alkaloid isolated from Evodia officinalis with various biological activities. Previous studies have shown that Rut has a certain protective effect on ischemic brain injury, but the specific molecular mechanism is still unknown.MethodsIn this study, a rat model of CI/R was established to explore the effects and potential molecular mechanisms of Rut on CI/R injury in rats.ResultsThe results showed that Rut alleviated neuronal injury induced by CI/R in a dose-dependent manner. Besides, Rut inhibited neuronal apoptosis by inhibiting the activation of caspase 3 and the expression of Bax. In addition, Rut alleviated the inflammatory response and oxidative stress caused by CI/R through inhibiting the production of pro-inflammatory factors (IL-6 and IL-1β), lactate dehydrogenase (LDH), malondialdehyde (MDA) and ROS, and increased the levels of anti-inflammatory factors (IL-4 and IL-10) and superoxide dismutase (SOD). Biochemically, Western blot analyses showed that Rut inhibited the phosphorylation of ERK1/2 and promoted the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway-related proteins (Nrf2, heme oxygenase 1 (HO-1) and NAD (P) H-quinone oxidoreductase 1) in a dose-dependent manner. These results show that Rut may alleviate brain injury induced by CI/R by regulating the expression of ERK1/2 and the activation of Nrf2/HO-1 pathway.ConclusionIn conclusion, these results suggest that Rut may be used as an effective therapeutic agent for damage caused by CI/R.

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Section: Discussionmentioning

confidence: 99%

<p>Rutaecarpine may improve neuronal injury, inhibits apoptosis, inflammation and oxidative stress by regulating the expression of ERK1/2 and Nrf2/HO-1 pathway in rats with cerebral ischemia-reperfusion injury</p>

Han¹,

Hu²,

Chen³

2019

DDDT

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“…Several in vitro studies acknowledged positive effect of RUT in peritoneal resident macrophages (Li et al, 2019), monocytes (Liu et al, 2016), osteoclast (Fukuma et al, 2018), HepG2 cells (Jin et al, 2017;Surbala et al, 2020) and Hepa-1c1c7 cells (Lee et al, 2012). Meanwhile, RUT has shown versatile beneficial effects on several experimental models, such as colitis (Zhang et al, 2020), atherosclerosis (Luo et al, 2020, cerebral ischemia-reperfusion (Han et al, 2019), hypertension (Ma et al, 2019), Acute kidney injury (Liu et al, 2020a;Liu et al, 2020b), type 2 diabetic (Surbala et al, 2020), Alzheimer's disease (Ahmad et al, 2020;Huang et al, 2020) and so on. Notably, RUT exerted definite anti-inflammatory, anti-oxidation and anti-apoptosis effects in several experimental pathology with the signaling of NF-κB, Nrf2/HO-1, Bcl-2/Bax pathways (Jin et al, 2017;Li et al, 2019a;Li et al, 2019b;Han et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Rutaecarpine Ameliorates Ethanol-Induced Gastric Mucosal Injury in Mice by Modulating Genes Related to Inflammation, Oxidative Stress and Apoptosis

Ren

Wei

et al. 2020

Front. Pharmacol.

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Background: Rutaecarpine (RUT), a major quinazolino carboline alkaloid compound from the dry unripe fruit Tetradium ruticarpum (A. Juss.) T. G. Hartley, has various pharmacological effects. The aim of this present study was to investigate the potential gastroprotective effect of rutaecarpine on ethanol-induced acute gastric mucosal injury in mice and associated molecular mechanisms, such as activating Nrf2 and Bcl-2 via PI3K/AKT signaling pathway and inhibiting NF-κB.Methods: Gastric ulcer index and histopathology was carried out to determine the efficacy of RUT in gastric ulceration, and the content of SOD, GSH in serum and CAT, MDA, MPO, TNF-α, IL-6, IL-1β in tissue were measured by kits. Besides, in order to illustrate the potential inflammatory, oxidative, and apoptotic perturbations, the mRNA levels of NF-κB p65, PI3K, AKT, Nrf2, Nqo1, HO-1, Bcl-2 and Bax were analyzed. In addition, the protein expression of NF-κB p65 and Nrf2 in cytoplasm and nucleus, AKT, p-AKT, Bcl-2 Bax and Caspase 3 were analyzed for further verification. Finally, immunofluorescence analysis was performed to further verify nuclear translocation of NF-κB p65.Results: Current data strongly demonstrated that RUT alleviated the gross gastric damage, ulcer index and the histopathology damage caused by ethanol. RUT inhibited the expression and nuclear translocation of NF-κB p65 and the expression of its downstream signals, such as TNF-α, IL-6, IL-1β and MPO. Immunofluorescence analysis also verifies the result. In the context of oxidative stress, RUT improved the antioxidant milieu by remarkably upregulating the expression Nqo1 and HO-1 with activating Nrf2, and could remarkably upregulate antioxidant SOD, GSH, CAT and downregulate levels of MDA. Additionally, RUT activate the expression of Bcl-2 and inhibited the expression of downstream signals Bax and Caspase 3 to promote gastric cellular survival. These were confirmed by RUT activation of the PI3K/AKT pathway manifested by enhanced expression of PI3K and promotion of AKT phosphorylation.Conclusion: Taken together, these results strongly demonstrated that RUT exerted a gastroprotective effect against gastric mucosal injury induced by ethanol. The underlying mechanism might be associated with the improvement of anti-inflammatory, anti-oxidation and anti-apoptosis system.

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“…Rutaecarpine is a quinazolinocarboline-type alkaloid which is a major bioactive constituent in Evodiae Fructus prescribed for treatment of hypertension in traditional Chinese medicine. Molecular hybridization of this alkaloid with a furoxan subunit resulted in a more potent vasodilator and antihypertensive effect of the prepared hybrids at various dosages (20–40 mg/kg) in vivo in rats compared to parent medication [ 96 ].…”

Section: Furoxansmentioning

confidence: 99%

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

Ферштат

Zhilin

2021

Molecules

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Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses. A wide number of vascular diseases as well as various immune and neurodegenerative disorders were found to be directly associated with a disruption of NO production in living organisms. These issues justify a constant search of novel NO-donors with improved pharmacokinetic profiles and prolonged action. In a series of known structural classes capable of NO release, heterocyclic NO-donors are of special importance due to their increased hydrolytic stability and low toxicity. It is no wonder that synthetic and biochemical investigations of heterocyclic NO-donors have emerged significantly in recent years. In this review, we summarized recent advances in the synthesis, reactivity and biomedical applications of promising heterocyclic NO-donors (furoxans, sydnone imines, pyridazine dioxides, azasydnones). The synthetic potential of each heterocyclic system along with biochemical mechanisms of action are emphasized.

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Dual-targeting Rutaecarpine-NO donor hybrids as novel anti-hypertensive agents by promoting release of CGRP

Cited by 32 publications

References 30 publications

<p>Rutaecarpine may improve neuronal injury, inhibits apoptosis, inflammation and oxidative stress by regulating the expression of ERK1/2 and Nrf2/HO-1 pathway in rats with cerebral ischemia-reperfusion injury</p>

<p>Rutaecarpine may improve neuronal injury, inhibits apoptosis, inflammation and oxidative stress by regulating the expression of ERK1/2 and Nrf2/HO-1 pathway in rats with cerebral ischemia-reperfusion injury</p>

Rutaecarpine Ameliorates Ethanol-Induced Gastric Mucosal Injury in Mice by Modulating Genes Related to Inflammation, Oxidative Stress and Apoptosis

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

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