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Keywords = rutaecarpine

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15 pages, 6113 KiB  
Article
Computational Docking as a Tool in Guiding the Drug Design of Rutaecarpine Derivatives as Potential SARS-CoV-2 Inhibitors
by Shengying Lin, Xiaoyang Wang, Roy Wai-Lun Tang, Ran Duan, Ka Wing Leung, Tina Ting-Xia Dong, Sarah E. Webb, Andrew L. Miller and Karl Wah-Keung Tsim
Molecules 2024, 29(11), 2636; https://doi.org/10.3390/molecules29112636 - 3 Jun 2024
Viewed by 230
Abstract
COVID-19 continues to spread around the world. This is mainly because new variants of the SARS-CoV-2 virus emerge due to genomic mutations, evade the immune system and result in the effectiveness of current therapeutics being reduced. We previously established a series of detection [...] Read more.
COVID-19 continues to spread around the world. This is mainly because new variants of the SARS-CoV-2 virus emerge due to genomic mutations, evade the immune system and result in the effectiveness of current therapeutics being reduced. We previously established a series of detection platforms, comprising computational docking analysis, S-protein-based ELISA, pseudovirus entry, and 3CL protease activity assays, which allow us to screen a large library of phytochemicals from natural products and to determine their potential in blocking the entry of SARS-CoV-2. In this new screen, rutaecarpine (an alkaloid from Evodia rutaecarpa) was identified as exhibiting anti-SARS-CoV-2 activity. Therefore, we conducted multiple rounds of structure-activity-relationship (SAR) studies around this phytochemical and generated several rutaecarpine analogs that were subjected to in vitro evaluations. Among these derivatives, RU-75 and RU-184 displayed remarkable inhibitory activity when tested in the 3CL protease assay, S-protein-based ELISA, and pseudovirus entry assay (for both wild-type and omicron variants), and they attenuated the inflammatory response induced by SARS-CoV-2. Interestingly, RU-75 and RU-184 both appeared to be more potent than rutaecarpine itself, and this suggests that they might be considered as lead candidates for future pharmacological elaboration. Full article
(This article belongs to the Special Issue Computational Drug Discovery: Methods and Applications)
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14 pages, 4422 KiB  
Article
Rutaecarpine Ameliorates Murine N-Methyl-N’-Nitro-N-Nitrosoguanidine-Induced Chronic Atrophic Gastritis by Sonic Hedgehog Pathway
by Yong He, Hong-Hong Liu, Xue-Lin Zhou, Ting-Ting He, Ao-Zhe Zhang, Xin Wang, Shi-Zhang Wei, Hao-Tian Li, Li-Sheng Chen, Lei Chang, Yan-Ling Zhao and Man-Yi Jing
Molecules 2023, 28(17), 6294; https://doi.org/10.3390/molecules28176294 - 28 Aug 2023
Cited by 3 | Viewed by 1127
Abstract
CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The [...] Read more.
CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The HE and ELISA methods were applied to detect the treatment effects. WB, qRT-PCR, immunohistochemistry, TUNEL, and GES-1 cell flow cytometry approaches were employed to probe the mechanisms. The CAG model was successfully established. The ELISA and HE staining data showed that the RUT treatment effects on CAG rats were reflected by the amelioration of histological damage. The qRT-PCR and WB analyses indicated that the protective effect of RUT is related to the upregulation of the SHH pathway and downregulation of the downstream of apoptosis to improve gastric cellular survival. Our data suggest that RUT induces a gastroprotective effect by upregulating the SHH signaling pathway and stimulating anti-apoptosis downstream. Full article
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14 pages, 43197 KiB  
Communication
Molecular Dynamics Simulation of the Complex of PDE5 and Evodiamine
by Ayame Kobayashi, Motokuni Nakajima, Yoh Noguchi, Ryota Morikawa, Yukiko Matsuo and Masako Takasu
Life 2023, 13(2), 578; https://doi.org/10.3390/life13020578 - 18 Feb 2023
Cited by 2 | Viewed by 1499
Abstract
Alzheimer’s disease is an irreversible neurological disorder for which there are no effective small molecule therapeutics. A phosphodiesterase 5 (PDE5) inhibitor is a candidate medicine for the treatment of Alzheimer’s disease. Rutaecarpine, an indole alkaloid found in Euodiae Fructus, has inhibitory activity [...] Read more.
Alzheimer’s disease is an irreversible neurological disorder for which there are no effective small molecule therapeutics. A phosphodiesterase 5 (PDE5) inhibitor is a candidate medicine for the treatment of Alzheimer’s disease. Rutaecarpine, an indole alkaloid found in Euodiae Fructus, has inhibitory activity for PDE5. Euodiae Fructus contains more evodiamine than rutaecarpine. Therefore, we performed molecular dynamics simulations of the complex of PDE5 and evodiamine. The results showed that the PDE5 and (−)-evodiamine complexes were placed inside the reaction center compared to the case of PDE5 and (+)-evodiamine complex. The binding of (−)-evodiamine to PDE5 increased the root-mean-square deviation and radius of gyration of PDE5. In the PDE5 with (−)-evodiamine complex, the value of the root-mean-square fluctuation of the M-loop, which is thought to be important for activity, increased. This result suggests that (−)-evodiamine may have inhibitory activity. Full article
(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)
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13 pages, 1985 KiB  
Article
The Ethanol Extract of Evodiae Fructus and Its Ingredient, Rutaecarpine, Inhibit Infection of SARS-CoV-2 and Inflammatory Responses
by Shengying Lin, Xiaoyang Wang, Hongsheng Guo, Niyu Dai, Roy Wai-Lun Tang, Hung Chun Lee, Ka Wing Leung, Tina Ting-Xia Dong, Sarah E. Webb, Andrew L. Miller and Karl Wah-Keung Tsim
Int. J. Mol. Sci. 2023, 24(1), 762; https://doi.org/10.3390/ijms24010762 - 1 Jan 2023
Cited by 3 | Viewed by 2411
Abstract
COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the [...] Read more.
COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the effectiveness of the current vaccines. Thus, there is still an urgent need to develop potent non-vaccine therapeutics against this infectious disease. We recently established a series of detecting platforms to screen a large library of Chinese medicinal herbs and phytochemicals. Here, we reveal that the ethanolic extract of Evodiae Fructus and one of its components, rutaecarpine, showed promising potency in inhibiting the activity of 3C-like (3CL) protease, blocking the entry of the pseudo-typed SARS-CoV-2 (including wild-type and omicron) into cultured cells. In addition, inflammatory responses induced by pseudo-typed SARS-CoV-2 were markedly reduced by Evodiae Fructus extract and rutaecarpine. Together our data indicate that the herbal extract of Evodiae Fructus and rutaecarpine are potent anti-SARS-CoV-2 agents, which might be considered as a treatment against COVID-19 in clinical applications. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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13 pages, 1545 KiB  
Article
Evodiamine and Rutaecarpine as Potential Anticancer Compounds: A Combined Computational Study
by Jingli Liu, Hui Guo, Jing Zhou, Yuwei Wang, Hao Yan, Ruyi Jin and Yuping Tang
Int. J. Mol. Sci. 2022, 23(19), 11513; https://doi.org/10.3390/ijms231911513 - 29 Sep 2022
Cited by 5 | Viewed by 1471
Abstract
Evodiamine (EVO) and rutaecarpine (RUT) are the main active compounds of the traditional Chinese medicinal herb Evodia rutaecarpa. Here, we fully optimized the molecular geometries of EVO and RUT at the B3LYP/6-311++G (d, p) level of density functional theory. The natural [...] Read more.
Evodiamine (EVO) and rutaecarpine (RUT) are the main active compounds of the traditional Chinese medicinal herb Evodia rutaecarpa. Here, we fully optimized the molecular geometries of EVO and RUT at the B3LYP/6-311++G (d, p) level of density functional theory. The natural population analysis (NPA) charges, frontier molecular orbitals, molecular electrostatic potentials, and the chemical reactivity descriptors for EVO and RUT were also investigated. Furthermore, molecular docking, molecular dynamics simulations, and the analysis of the binding free energies of EVO and RUT were carried out against the anticancer target topoisomerase 1 (TOP1) to clarify their anticancer mechanisms. The docking results indicated that they could inhibit TOP1 by intercalating into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, suggesting that they may be potential TOP1 inhibitors. Molecular dynamics (MD) simulations evaluated the binding stability of the TOP1–DNA–ligand ternary complex. The calculation of binding free energy showed that the binding ability of EVO with TOP1 was stronger than that of RUT. These results elucidated the structure–activity relationship and the antitumor mechanism of EVO and RUT at the molecular level. It is suggested that EVO and RUT may be potential compounds for the development of new anticancer drugs. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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13 pages, 3577 KiB  
Article
Anti-Inflammatory Mechanism of An Alkaloid Rutaecarpine in LTA-Stimulated RAW 264.7 Cells: Pivotal Role on NF-κB and ERK/p38 Signaling Molecules
by Thanasekaran Jayakumar, Chun-Ming Yang, Ting-Lin Yen, Chia-Yuan Hsu, Joen-Rong Sheu, Chih-Wei Hsia, Manjunath Manubolu, Wei-Chieh Huang, Cheng-Ying Hsieh and Chih-Hsuan Hsia
Int. J. Mol. Sci. 2022, 23(11), 5889; https://doi.org/10.3390/ijms23115889 - 24 May 2022
Cited by 12 | Viewed by 2202
Abstract
Lipoteichoic acid (LTA) is a key cell wall component and virulence factor of Gram-positive bacteria. LTA contributes a major role in infection and it mediates inflammatory responses in the host. Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from Evodia rutaecarpa, has shown a variety of [...] Read more.
Lipoteichoic acid (LTA) is a key cell wall component and virulence factor of Gram-positive bacteria. LTA contributes a major role in infection and it mediates inflammatory responses in the host. Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from Evodia rutaecarpa, has shown a variety of fascinating biological properties such as anti-thrombotic, anticancer, anti-obesity and thermoregulatory, vasorelaxing activity. It has also potent effects on the cardiovascular and endocrine systems. Herein, we investigated rutaecarpine’s (Rut) anti-inflammatory effects in LTA-stimulated RAW macrophage cells. The Western blot and spectrophotometric results revealed that Rut inhibited the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-1β in the LTA-induced macrophage cells. Successively, our mechanistic studies publicized that Rut inhibited LTA-induced phosphorylation of mitogen-activated protein kinase (MAPK) including the extracellular signal-regulated kinase (ERK), and p38, but not c-Jun NH2-terminal kinase (JNK). In addition, the respective Western blot and confocal image analyses exhibited that Rut reserved nuclear transcription factor kappa-B (NF-κB) by hindering inhibitor of nuclear factor κB-α (IκBα) and NF-κB p65 phosphorylation and p65 nuclear translocation. These results indicate that Rut exhibits its anti-inflammatory effects mainly through attenuating NF-κB and ERK/p38 signaling pathways. Overall, this result suggests that Rut could be a potential therapeutic agent for the treatment of Gram-positive bacteria induced inflammatory diseases. Full article
(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)
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18 pages, 4342 KiB  
Article
Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway
by Dandan Chen, Yanan Duan, Shuxiang Yu, Xinwen Zhang, Ni Li and Jingya Li
Pharmaceuticals 2022, 15(4), 469; https://doi.org/10.3390/ph15040469 - 13 Apr 2022
Cited by 3 | Viewed by 2615
Abstract
Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, [...] Read more.
Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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15 pages, 2586 KiB  
Article
The Anti-Proliferative and Apoptotic Effects of Rutaecarpine on Human Esophageal Squamous Cell Carcinoma Cell Line CE81T/VGH In Vitro and In Vivo
by Li-Yu Wang, Shu-Lan Yeh, Shih-Tien Hsu, Chao-Hsiang Chen, Chien-Chih Chen and Cheng-Hung Chuang
Int. J. Mol. Sci. 2022, 23(5), 2843; https://doi.org/10.3390/ijms23052843 - 5 Mar 2022
Cited by 4 | Viewed by 1913
Abstract
The overall five-year survival rate for patients with esophageal cancer is low (15 to 25%) because of the poor prognosis at earlier stages. Rutaecarpine (RTP) is a bioalkaloid found in the traditional Chinese herb Evodia rutaecarpa and has been shown to exhibit anti-proliferative [...] Read more.
The overall five-year survival rate for patients with esophageal cancer is low (15 to 25%) because of the poor prognosis at earlier stages. Rutaecarpine (RTP) is a bioalkaloid found in the traditional Chinese herb Evodia rutaecarpa and has been shown to exhibit anti-proliferative effect on tumor cells. However, the mechanisms by which RTP confer these effects and its importance in esophageal squamous cell carcinoma treatment remain unclear. Thus, in the present study, we first incubated human esophageal squamous cell carcinoma cell line, CE81T/VGH, with RTP to evaluate RTP’s effects on tumor cell growth and apoptosis. We also performed a xenograft study to confirm the in vitro findings. Furthermore, we determined the expression of p53, Bax, bcl-2, caspase-3, caspase-9, and PCNA in CE81T/VGH cells or the tumor tissues to investigate the possible mechanisms. All the effects of TRP were compared with that of cisplatin. The results showed that RTP significantly inhibits CE81T/VGH cell growth, promotes arrest of cells in the G2/M phase, and induces apoptosis. Consistently, the in vivo study showed that tumor size, tumor weight, and proliferating cell nuclear antigen protein expression in tumor tissue are significantly reduced in the high-dose RTP treatment group. Furthermore, the in vitro and in vivo studies showed that RTP increases the expression of p53 and Bax proteins, while inhibiting the expression of Bcl-2 in cancer cells. In addition, RTP significantly increases the expression of cleaved caspase-9 and cleaved caspase-3 proteins in tumor tissues in mice. These results suggest that RTP may trigger the apoptosis and inhibit growth in CE81T/VGH cells by the mechanisms associated with the regulation of the expression of p53, Bax, Bcl-2, as well as caspase-9 and caspase-3. Full article
(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products)
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14 pages, 17058 KiB  
Article
Decreased Human Platelet Activation and Mouse Pulmonary Thrombosis by Rutaecarpine and Comparison of the Relative Effectiveness with BAY11-7082: Crucial Signals of p38-NF-κB
by Wei-Chieh Huang, Shaw-Min Hou, Ming-Ping Wu, Chih-Wei Hsia, Thanasekaran Jayakumar, Chih-Hsuan Hsia, Periyakali Saravana Bhavan, Chi-Li Chung and Joen-Rong Sheu
Molecules 2022, 27(2), 476; https://doi.org/10.3390/molecules27020476 - 12 Jan 2022
Cited by 5 | Viewed by 2130
Abstract
Platelets play a critical role in arterial thrombosis. Rutaecarpine (RUT) was purified from Tetradium ruticarpum, a well-known Chinese medicine. This study examined the relative activity of RUT with NF-κB inhibitors in human platelets. BAY11-7082 (an inhibitor of IκB kinase [IKK]), Ro106-9920 (an [...] Read more.
Platelets play a critical role in arterial thrombosis. Rutaecarpine (RUT) was purified from Tetradium ruticarpum, a well-known Chinese medicine. This study examined the relative activity of RUT with NF-κB inhibitors in human platelets. BAY11-7082 (an inhibitor of IκB kinase [IKK]), Ro106-9920 (an inhibitor of proteasomes), and RUT concentration-dependently (1–6 μM) inhibited platelet aggregation and P-selectin expression. RUT was found to have a similar effect to that of BAY11-7082; however, it exhibits more effectiveness than Ro106-9920. RUT suppresses the NF-κB pathway as it inhibits IKK, IκBα, and p65 phosphorylation and reverses IκBα degradation in activated platelets. This study also investigated the role of p38 and NF-κB in cell signaling events and found that SB203580 (an inhibitor of p38) markedly reduced p38, IKK, and p65 phosphorylation and reversed IκBα degradation as well as p65 activation in a confocal microscope, whereas BAY11-7082 had no effects in p38 phosphorylation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay shows that RUT and BAY11-7082 did not exhibit free radical scavenging activity. In the in vivo study, compared with BAY11-7082, RUT more effectively reduced mortality in adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism without affecting the bleeding time. In conclusion, a distinctive pathway of p38-mediated NF-κB activation may involve RUT-mediated antiplatelet activation, and RUT could act as a strong prophylactic or therapeutic drug for cardiovascular diseases. Full article
(This article belongs to the Special Issue The Pharmacological Properties and Therapeutic Use of Natural Products)
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15 pages, 3050 KiB  
Article
Targeting MAPK/NF-κB Pathways in Anti-Inflammatory Potential of Rutaecarpine: Impact on Src/FAK-Mediated Macrophage Migration
by Thanasekaran Jayakumar, Kao-Chang Lin, Chao-Chien Chang, Chih-Wei Hsia, Manjunath Manubolu, Wei-Chieh Huang, Joen-Rong Sheu and Chih-Hsuan Hsia
Int. J. Mol. Sci. 2022, 23(1), 92; https://doi.org/10.3390/ijms23010092 - 22 Dec 2021
Cited by 20 | Viewed by 2871
Abstract
Studies have discovered that different extracts of Evodia rutaecarpa and its phytochemicals show a variety of biological activities associated with inflammation. Although rutaecarpine, an alkaloid isolated from the unripe fruit of E. rutaecarpa, has been exposed to have anti-inflammatory properties, the mechanism [...] Read more.
Studies have discovered that different extracts of Evodia rutaecarpa and its phytochemicals show a variety of biological activities associated with inflammation. Although rutaecarpine, an alkaloid isolated from the unripe fruit of E. rutaecarpa, has been exposed to have anti-inflammatory properties, the mechanism of action has not been well studied. Thus, this study investigated the molecular mechanisms of rutaecarpine (RUT) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. RUT reserved the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukin (IL)-1β in the LPS-induced macrophages. RUT showed an inhibitory effect on the mitogen-activated protein kinases (MAPKs), and it also inhibited nuclear transcription factor kappa-B (NF-κB) by hindering IκBα and NF-κB p65 phosphorylation and p65 nuclear translocation. The phospho-PI3K and Akt was concentration-dependently suppressed by RUT. However, RUT not only suggestively reduced the migratory ability of macrophages and their numbers induced by LPS but also inhibited the phospho-Src, and FAK. Taken together, these results indicate that RUT participates a vital role in the inhibition of LPS-induced inflammatory processes in RAW 264.7 macrophages and that the mechanisms involve PI3K/Akt and MAPK-mediated downregulation of NF-κB signaling pathways. Notably, reducing the migration and number of cells induced by LPS via inhibiting of Src/FAK pathway was also included to the anti-inflammatory mechanism of RUT. Therefore, RUT may have potential benefits as a therapeutic agent against chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)
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16 pages, 23361 KiB  
Article
Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β  Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism
by Chun-Jen Huang, Wei-Chieh Huang, Wei-Ting Lin, Lan-Hsin Shu, Joen-Rong Sheu, Oanh-Thi Tran, Chih-Wei Hsia, Thanasekaran Jayakumar, Periyakali Saravana Bhavan, Cheng-Ying Hsieh and Chao-Chien Chang
Int. J. Mol. Sci. 2021, 22(20), 11109; https://doi.org/10.3390/ijms222011109 - 15 Oct 2021
Cited by 16 | Viewed by 2936
Abstract
The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial [...] Read more.
The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1–5 μM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3β pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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22 pages, 10451 KiB  
Article
Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation
by Tingting Zou, Cheng Zeng, Junyan Qu, Xiaohua Yan and Zhenghong Lin
Biomedicines 2021, 9(9), 1143; https://doi.org/10.3390/biomedicines9091143 - 2 Sep 2021
Cited by 12 | Viewed by 2590
Abstract
The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it [...] Read more.
The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect. Full article
(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)
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12 pages, 2588 KiB  
Article
Rutaecarpine Increases Nitric Oxide Synthesis via eNOS Phosphorylation by TRPV1-Dependent CaMKII and CaMKKβ/AMPK Signaling Pathway in Human Endothelial Cells
by Gi Ho Lee, Chae Yeon Kim, Chuanfeng Zheng, Sun Woo Jin, Ji Yeon Kim, Seung Yeon Lee, Mi Yeon Kim, Eun Hee Han, Yong Pil Hwang and Hye Gwang Jeong
Int. J. Mol. Sci. 2021, 22(17), 9407; https://doi.org/10.3390/ijms22179407 - 30 Aug 2021
Cited by 17 | Viewed by 2633
Abstract
Rutaecarpine (RUT) is a bioactive alkaloid isolated from the fruit of Evodia rutaecarpa that exerts a cellular protective effect. However, its protective effects on endothelial cells and its mechanism of action are still unclear. In this study, we demonstrated the effects of RUT [...] Read more.
Rutaecarpine (RUT) is a bioactive alkaloid isolated from the fruit of Evodia rutaecarpa that exerts a cellular protective effect. However, its protective effects on endothelial cells and its mechanism of action are still unclear. In this study, we demonstrated the effects of RUT on nitric oxide (NO) synthesis via endothelial nitric oxide synthase (eNOS) phosphorylation in endothelial cells and the underlying molecular mechanisms. RUT treatment promoted NO generation by increasing eNOS phosphorylation. Additionally, RUT induced an increase in intracellular Ca2+ concentration and phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of transient receptor potential vanilloid type 1 (TRPV1) attenuated RUT-induced intracellular Ca2+ concentration and phosphorylation of CaMKII, CaMKKβ, AMPK, and eNOS. Treatment with KN-62 (a CaMKII inhibitor), Compound C (an AMPK inhibitor), and STO-609 (a CaMKKβ inhibitor) suppressed RUT-induced eNOS phosphorylation and NO generation. Interestingly, RUT attenuated the expression of ICAM-1 and VCAM-1 induced by TNF-α and inhibited the inflammation-related NF-κB signaling pathway. Taken together, these results suggest that RUT promotes NO synthesis and eNOS phosphorylation via the Ca2+/CaMKII and CaM/CaMKKβ/AMPK signaling pathways through TRPV1. These findings provide evidence that RUT prevents endothelial dysfunction and benefit cardiovascular health. Full article
(This article belongs to the Special Issue Quantitative Identification and Action-Mechanisms of Anti-cancer and Anti-inflammatory Natural Compounds 2.0)
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11 pages, 3214 KiB  
Article
Rutaecarpine Protects against Acetaminophen-Induced Acute Liver Injury in Mice by Activating Antioxidant Enzymes
by Jae Ho Choi, Sun Woo Jin, Gi Ho Lee, Eun Hee Han, Yong Pil Hwang and Hye Gwang Jeong
Antioxidants 2021, 10(1), 86; https://doi.org/10.3390/antiox10010086 - 10 Jan 2021
Cited by 16 | Viewed by 3047
Abstract
Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is used to treat hypertension, postpartum hemorrhage, dysentery, and amenorrhea as a traditional medicine in Asia. We investigated the effect of rutaecarpine on acetaminophen-induced hepatotoxicity in mice. Rutaecarpine was administered [...] Read more.
Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is used to treat hypertension, postpartum hemorrhage, dysentery, and amenorrhea as a traditional medicine in Asia. We investigated the effect of rutaecarpine on acetaminophen-induced hepatotoxicity in mice. Rutaecarpine was administered orally daily for seven consecutive days, followed by intraperitoneal injection of acetaminophen in mice on day seven to induce hepatotoxicity. Rutaecarpine pretreatment significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) activities and hepatic malondialdehyde content and prevented acetaminophen-induced hepatic glutathione depletion. Furthermore, CYP2E1 expression was decreased by rutaecarpine pretreatment in a dose-dependent manner. Rutaecarpine pretreatment inhibited acetaminophen-induced expression of inflammatory cytokines by inhibiting NF-κB activation by JNK1/2. Also, rutaecarpine pretreatment promoted Nrf2-mediated activation of the antioxidant enzymes GCLC, HO-1, and NQO1. This indicates that the protective effect of rutaecarpine during acetaminophen-induced acute liver injury is mediated by the activation of antioxidant enzymes. Therefore, rutaecarpine has a protective effect of APAP-induced liver damage. Full article
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
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9 pages, 3491 KiB  
Article
Study of Caspase 8 Inhibition for the Management of Alzheimer’s Disease: A Molecular Docking and Dynamics Simulation
by Syed Sayeed Ahmad, Meetali Sinha, Khurshid Ahmad, Mohammad Khalid and Inho Choi
Molecules 2020, 25(9), 2071; https://doi.org/10.3390/molecules25092071 - 29 Apr 2020
Cited by 35 | Viewed by 4773
Abstract
Alzheimer’s disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in [...] Read more.
Alzheimer’s disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in the context of AD. In the present study, we performed a virtual screening of 200 natural compounds by molecular docking with respect to their abilities to bind with caspase 8. Among them, rutaecarpine was found to have the highest (negative) binding energy (−6.5 kcal/mol) and was further subjected to molecular dynamics (MD) simulation analysis. Caspase 8 was determined to interact with rutaecarpine through five amino acid residues, specifically Thr337, Lys353, Val354, Phe355, and Phe356, and two hydrogen bonds (ligand: H35-A: LYS353:O and A:PHE355: N-ligand: N5). Furthermore, a 50 ns MD simulation was conducted to optimize the interaction, to predict complex flexibility, and to investigate the stability of the caspase 8–rutaecarpine complex, which appeared to be quite stable. The obtained results propose that rutaecarpine could be a lead compound that bears remarkable anti-Alzheimer’s potential against caspase 8. Full article
(This article belongs to the Section Medicinal Chemistry)
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