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Mahmood NMS, Mahmud AMR, Maulood IM. Vascular actions of Ang 1-7 and Ang 1-8 through EDRFs and EDHFs in non-diabetes and diabetes mellitus. Nitric Oxide 2025; 156:9-26. [PMID: 40032212 DOI: 10.1016/j.niox.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/23/2025] [Accepted: 02/27/2025] [Indexed: 03/05/2025]
Abstract
The renin-angiotensin system (RAS) plays a pivotal role in regulating vascular homeostasis, while angiotensin 1-8 (Ang 1-8) traditionally dominates as a vasoconstrictor factor. However, the discovery of angiotensin 1-7 (Ang 1-7) and Ang 1-8 has revealed counter-regulatory mechanisms mediated through endothelial-derived relaxing factors (EDRFs) and endothelial-derived hyperpolarizing factors (EDHFs). This review delves into the vascular actions of Ang 1-7 and Ang 1-8 in both non-diabetes mellitus (non-DM) and diabetes mellitus (DM) conditions, highlighting their effects on vascular endothelial cell (VECs) function as well. In a non-DM vasculature context, Ang 1-8 demonstrate dual effect including vasoconstriction and vasodilation, respectively. Additionally, Ang 1-7 induces vasodilation upon nitric oxide (NO) production as a prominent EDRFs in distinct mechanisms. Further research elucidating the precise mechanisms underlying the vascular actions of Ang 1-7 and Ang 1-8 in DM will facilitate the development of tailored therapeutic interventions aimed at preserving vascular health and preventing cardiovascular complications.
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Affiliation(s)
- Nazar M Shareef Mahmood
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq.
| | - Almas M R Mahmud
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Ismail M Maulood
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
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Cheng R, Cheng X, Jiang D, Xiong J, Ding Y, Liu J, Zhao H, Feng H, Wu D, Zhang W. Spectrum-effect relationship of the cardiovascular-protective effect of with Chrysanthemi Flos by UPLC-MS/MS and component knock-out method. Food Chem Toxicol 2025; 200:115372. [PMID: 40054725 DOI: 10.1016/j.fct.2025.115372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/25/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
Chrysanthemi Flos (CF), as one of the important 'dual-use' plants, possesses great pharmacological research and development potential. This work aimed to find the pharmacodynamic material basis of CF in cardiovascular-protection by spectrum-effect relationship and component knock-out method. The fingerprint was established by ultra-high performance liquid chromatography and 25 peaks were picked out as common peaks. The common peaks were identified by ultra-performance liquid chromatography-quadrupole-orbitrap-mass spectrometry including twelve flavonoids, nine phenylpropanoids, three organic acids, and one nucleoside. The cardiovascular-protective effect of CF was determined by angiotensin II-induced injury model of human umbilical vein endothelial cells. Grey relation analysis, partial least squares regression analysis and Pearson's correlation analysis were performed to assess the relationship between the cardiovascular-protective effect and ingredients. Spectrum-effect relationship and component knock-out method revealed that P11 (luteolin-7-O-β-D-glucoside), P14 (3,4-O-dicaffeoylquinic acid), P16 (1,5-O-dicaffeoylquinic acid), and P17 (3,5-O-dicaffeoylquinic acid) were the pharmacological material basis for the cardiovascular-protective effect of CF. This work preliminarily elucidated the pharmacodynamic material basis of cardiovascular-protective effect of CF, which could be used to considerable methods and insight for the fundamental research of the pharmacodynamic material basis of Traditional Chinese Medicine.
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Affiliation(s)
- Ranran Cheng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Xiang Cheng
- Bozhou Vocational and Technical College, Bozhou, 236800, China.
| | - Dongliang Jiang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Junwei Xiong
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Yangfei Ding
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Juan Liu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Hongsu Zhao
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Hangmin Feng
- Anhui Provincial Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Hefei, 230012, China.
| | - Deling Wu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Provincial Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Hefei, 230012, China; MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, China.
| | - Wei Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Provincial Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Hefei, 230012, China; MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, China; Joint Research Center for Chinese Herbal Medicine of Anhui of IHM, Hefei, Anhui University of Chinese Medicine, Hefei, 230012, China.
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Guerrero-Becerra L, Morimoto S, Arrellano-Ordoñez E, Morales-Miranda A, Guevara-Gonzalez RG, Feregrino-Pérez AA, Lomas-Soria C. Polyphenolic Compounds in Fabaceous Plants with Antidiabetic Potential. Pharmaceuticals (Basel) 2025; 18:69. [PMID: 39861134 PMCID: PMC11768933 DOI: 10.3390/ph18010069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/21/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Diabetes mellitus (DM) is a chronic non-communicable disease with an increasing prevalence in Latin America and worldwide, impacting various social and economic areas. It causes numerous complications for those affected. Current treatments for diabetes include oral hypoglycemic drugs, which can lead to adverse effects and health complications. Other natural alternatives for DM treatment have been studied as adjunct therapies that could reduce or eliminate the need for antidiabetic medications. Several natural supplements may offer an alternative way to improve the quality of life for patients with DM, and they may have other nutraceutical applications. Due to their phenolic compound content, some leguminous substances have been proposed as these alternatives. Phenolic compounds, with their high antioxidant activity, have shown promising potential in insulin synthesis, secretion, and the functionality of the endocrine pancreas. This review provides valuable information on various leguminous plants with anti-diabetic properties, including antioxidant, hypoglycemic, anti-fat-induced damage, and anti-apoptotic properties in vitro and in vivo, attributed to the high content of phenolic compounds in their seeds. Natural products with antidiabetic and pharmacological treatment potential improve diabetes management by offering more effective and complementary alternatives. To integrate these herbal remedies into modern medicine, further research on phenolic compound type, doses, efficacy, and safety in the human population is needed.
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Affiliation(s)
- Lucia Guerrero-Becerra
- Center of Applied Research in Biosystems (CARB-CIAB), School of Engineering, Autonomous University of Querétaro-Campus Amazcala, Carr. Amazacala-Chichimequillas km 1.0, El Marqués, Querétaro 76265, Mexico; (L.G.-B.); (E.A.-O.); (R.G.G.-G.)
- Research and Postgraduate Division, School of Engineering, Universidad Autónoma de Querétaro, Campus Amazcala, Carretera a Chichimequillas Km 1 s/n, Amazcala, El Marqués, Querétaro 76265, Mexico
| | - Sumiko Morimoto
- Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México 14080, Mexico; (S.M.); (A.M.-M.)
| | - Estefania Arrellano-Ordoñez
- Center of Applied Research in Biosystems (CARB-CIAB), School of Engineering, Autonomous University of Querétaro-Campus Amazcala, Carr. Amazacala-Chichimequillas km 1.0, El Marqués, Querétaro 76265, Mexico; (L.G.-B.); (E.A.-O.); (R.G.G.-G.)
| | - Angélica Morales-Miranda
- Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México 14080, Mexico; (S.M.); (A.M.-M.)
| | - Ramón G. Guevara-Gonzalez
- Center of Applied Research in Biosystems (CARB-CIAB), School of Engineering, Autonomous University of Querétaro-Campus Amazcala, Carr. Amazacala-Chichimequillas km 1.0, El Marqués, Querétaro 76265, Mexico; (L.G.-B.); (E.A.-O.); (R.G.G.-G.)
| | - Ana Angélica Feregrino-Pérez
- Research and Postgraduate Division, School of Engineering, Universidad Autónoma de Querétaro, Campus Amazcala, Carretera a Chichimequillas Km 1 s/n, Amazcala, El Marqués, Querétaro 76265, Mexico
| | - Consuelo Lomas-Soria
- Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México 14080, Mexico; (S.M.); (A.M.-M.)
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Sirotkin AV, Harrath AH. Apigenin as a Promising Agent for Enhancing Female Reproductive Function and Treating Associated Disorders. Biomedicines 2024; 12:2405. [PMID: 39457717 PMCID: PMC11504338 DOI: 10.3390/biomedicines12102405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/13/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Apigenin is an organic flavonoid abundant in some plants such as parsley, chamomile, or celery. Recently, it has been investigated for several of its pharmacological characteristics, such as its ability to act as an antioxidant, reduce inflammation, and inhibit the growth of cancer cells. The purpose of this review is to provide a summary of the existing knowledge regarding the effects of apigenin on female reproductive systems and its dysfunctions. Apigenin can influence reproductive processes by regulating multiple biological events, including oxidative processes, cell proliferation, apoptosis, cell renewal and viability, ovarian blood supply, and the release of reproductive hormones. It could stimulate ovarian folliculogenesis, as well as ovarian and embryonal cell proliferation and viability, which can lead to an increase in fertility and influence the release of reproductive hormones, which may exert its effects on female reproductive health. Furthermore, apigenin could inhibit the activities of ovarian cancer cells and alleviate the pathological changes in the female reproductive system caused by environmental pollutants, harmful medications, cancer, polycystic ovarian syndrome, ischemia, as well as endometriosis. Therefore, apigenin may have potential as a biostimulator for female reproductive processes and as a therapeutic agent for certain reproductive diseases.
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Affiliation(s)
- Alexander V. Sirotkin
- Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia;
| | - Abdel Halim Harrath
- Zoology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
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Shin S, Park J, Choi HY, Bu Y, Lee K. Antihypertensive Effects of Lindera erythrocarpa Makino via NO/cGMP Pathway and Ca 2+ and K + Channels. Nutrients 2024; 16:3003. [PMID: 39275318 PMCID: PMC11397354 DOI: 10.3390/nu16173003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/01/2024] [Accepted: 09/03/2024] [Indexed: 09/16/2024] Open
Abstract
Studies have demonstrated the therapeutic effects of Lindera plants. This study was undertaken to reveal the antihypertensive properties of Lindera erythrocarpa leaf ethanolic extract (LEL). Aorta segments of Sprague-Dawley rats were used to study the vasodilatory effect of LEL, and the mechanisms involved were evaluated by treating specific inhibitors or activators that affect the contractility of blood vessels. Our results revealed that LEL promotes a vasorelaxant effect through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, blocking the Ca2+ channels, opening the K+ channels, and inhibiting the vasoconstrictive action of angiotensin II. In addition, the effects of LEL on blood pressure were investigated in spontaneously hypertensive rats by the tail-cuff method. LEL (300 or 1000 mg/kg) was orally administered to the rats, and 1000 mg/kg of LEL significantly lowered the blood pressure. Systolic blood pressure decreased by -20.06 ± 4.87%, and diastolic blood pressure also lowered by -30.58 ± 5.92% at 4 h in the 1000 mg/kg LEL group. Overall, our results suggest that LEL may be useful to treat hypertensive diseases, considering its vasorelaxing and hypotensive effects.
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Affiliation(s)
- Sujin Shin
- Department of Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Junkyu Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Ho-Young Choi
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Youngmin Bu
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyungjin Lee
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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Chen HT, Tung CH, Yu BH, Chen YC. Sixteen prescribed Chinese herbal medicines provide time-dependent cardiorenal and survival benefits in patients with overall and advanced diabetic kidney disease: a real-world study in Taiwan. Front Pharmacol 2024; 15:1297854. [PMID: 39239654 PMCID: PMC11374620 DOI: 10.3389/fphar.2024.1297854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 08/05/2024] [Indexed: 09/07/2024] Open
Abstract
Background A causal connection between oxidative stress and inflammation in diabetes, along with its associated renal and cardiovascular complications, has been established. Sixteen prescribed potentially renoprotective Chinese herbal medicines for diabetic kidney disease (PRCHMDKD), which are scientific Chinese medicine (botanical drug) and categorized into five classes (clearing heat, nourishing yin, dampness dispelling, tonifying qi, and harmonizing formulas), exhibit shared antioxidative properties and target multiple oxidative stress pathways. However, the time-response, cumulative effects, and safety (hyperkalemia risk) of these sixteen PRCHMDKD on cardiorenal and survival outcomes in patients with overall and advanced DKD remain unresolved. Methods This retrospective cohort study analyzed national health insurance claims data in 2000-2017. Four statistical methods, including Cox proportional hazards models, complementary restricted mean survival time (RMST), propensity score matching, and competing risk analysis for end-stage renal disease (ESRD), were employed to investigate this relationship. The study included 43,480 PRCHMDKD users and an equal number of matched nonusers within the overall DKD patient population. For advanced DKD patients, the cohort comprised 1,422 PRCHMDKD users and an equivalent number of matched nonusers. Results PRCHMDKD use in overall and advanced, respectively, DKD patients was associated with time-dependent reductions in adjusted hazard ratios for ESRD (0.66; 95% CI, 0.61-0.70 vs. 0.81; 0.65-0.99), all-cause mortality (0.48; 0.47-0.49 vs. 0.59; 0.50-0.70), and cardiovascular mortality (0.50; 0.48-0.53 vs. 0.61; 0.45-0.82). Significant differences in RMST were observed in overall and advanced, respectively, DKD patients, favoring PRCHMDKD use: 0.31 years (95% CI, 0.24-0.38) vs. 0.61 years (0.13-1.10) for ESRD, 2.71 years (2.60-2.82) vs. 1.50 years (1.03-1.98) for all-cause mortality, and 1.18 years (1.09-1.28) vs. 0.59 years (0.22-0.95) for cardiovascular mortality. Additionally, hyperkalemia risk did not increase. These findings remained consistent despite multiple sensitivity analyses. Notably, the cumulative effects of utilizing at least four or five classes and multiple botanical drugs from the sixteen PRCHMDKD provided enhanced renoprotection for patients with both overall and advanced DKD. This suggests that there is involvement of multiple targets within the oxidative stress pathways associated with DKD. Conclusion This real-world study suggests that using these sixteen PRCHMDKD provides time-dependent cardiorenal and survival benefits while ensuring safety for DKD patients.
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Affiliation(s)
- Hsiao-Tien Chen
- Department of Chinese Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Chien-Hsueh Tung
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Ben-Hui Yu
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Yi-Chun Chen
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
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Demirel S. Vasorelaxant effects of biochemical constituents of various medicinal plants and their benefits in diabetes. World J Diabetes 2024; 15:1122-1141. [PMID: 38983824 PMCID: PMC11229960 DOI: 10.4239/wjd.v15.i6.1122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 03/07/2024] [Accepted: 05/06/2024] [Indexed: 06/11/2024] Open
Abstract
Endothelial function plays a pivotal role in cardiovascular health, and dysfunction in this context diminishes vasorelaxation concomitant with endothelial activity. The nitric oxide-cyclic guanosine monophosphate pathway, prostacyclin-cyclic adenosine monophosphate pathway, inhibition of phosphodiesterase, and the opening of potassium channels, coupled with the reduction of calcium levels in the cell, constitute critical mechanisms governing vasorelaxation. Cardiovascular disease stands as a significant contributor to morbidity and mortality among individuals with diabetes, with adults afflicted by diabetes exhibiting a heightened cardiovascular risk compared to their non-diabetic counterparts. A plethora of medicinal plants, characterized by potent pharmacological effects and minimal side effects, holds promise in addressing these concerns. In this review, we delineate various medicinal plants and their respective biochemical constituents, showcasing concurrent vasorelaxant and anti-diabetic activities.
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Affiliation(s)
- Sadettin Demirel
- Medicine School, Physiology Department, Bursa Uludag University, Bursa 16059, Türkiye
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Liga S, Paul C. Puerarin-A Promising Flavonoid: Biosynthesis, Extraction Methods, Analytical Techniques, and Biological Effects. Int J Mol Sci 2024; 25:5222. [PMID: 38791264 PMCID: PMC11121215 DOI: 10.3390/ijms25105222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/26/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Flavonoids, a variety of plant secondary metabolites, are known for their diverse biological activities. Isoflavones are a subgroup of flavonoids that have gained attention for their potential health benefits. Puerarin is one of the bioactive isoflavones found in the Kudzu root and Pueraria genus, which is widely used in alternative Chinese medicine, and has been found to be effective in treating chronic conditions like cardiovascular diseases, liver diseases, gastric diseases, respiratory diseases, diabetes, Alzheimer's disease, and cancer. Puerarin has been extensively researched and used in both scientific and clinical studies over the past few years. The purpose of this review is to provide an up-to-date exploration of puerarin biosynthesis, the most common extraction methods, analytical techniques, and biological effects, which have the potential to provide a new perspective for medical and pharmaceutical research and development.
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Affiliation(s)
| | - Cristina Paul
- Biocatalysis Group, Department of Applied Chemistry and Engineering of Organic and Natural Compounds, Faculty of Industrial Chemistry and Environmental Engineering, Politehnica University Timisoara, Vasile Pârvan No. 6, 300223 Timisoara, Romania;
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Isla KKY, Tanae MM, de Lima-Landman MTR, de Magalhães PM, Lapa AJ, Souccar C. Vasorelaxant effects of ellagitannins isolated from Cuphea carthagenensis. PLANTA MEDICA 2024; 90:276-285. [PMID: 38272038 DOI: 10.1055/a-2240-7372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
Cuphea carthagenensis (Jacq.) J. F. Macbr. is a popular plant in Brazilian folk medicine owing to its hypotensive and central nervous system depressant effects. This study aimed to validate the hypotensive effect of the plant's aqueous extract (AE) in rats and examine the vascular actions of three hydrolyzable tannins, oenothein B, woodfordin C, and eucalbanin B, isolated from AE. Systolic blood pressure in unanesthetized rats was determined using the non-invasive tail-cuff method. Oral treatment of normotensive rats with 0.5 and 1.0 g/kg/day AE induced a dose-related hypotensive effect after 1 week. In rat aortic rings pre-contracted with noradrenaline, all ellagitannins (20 - 180 µM) induced a concentration-related vasorelaxation. This effect was blocked by either removing the endothelium or pre-incubating with NG-nitro-l-arginine methyl ester (10 µM), an inhibitor of nitric oxide (NO) synthase. In KCl-depolarized rat portal vein preparations, the investigated compounds did not affect significantly the maximal contractile responses and pD2 values of the concentration-response curves to CaCl2. Our results demonstrated the hypotensive effect of C. carthagenensis AE in unanesthetized rats. All isolated ellagitannins induced vasorelaxation in vitro via activating NO synthesis/NO release from endothelial cells, without altering the Ca2+ influx in vascular smooth muscle preparations. Considering the low oral bioavailability of ellagitannins, the determined in vitro actions of these compounds are unlikely to account for the hypotensive effect of AE in vivo. It remains to be determined the role of the bioactive ellagitannin-derived metabolites in the hypotensive effect observed after oral treatment of unanesthetized rats with the plant extract.
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Affiliation(s)
- Kaori Katiuska Yamaguchi Isla
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Mirtes Midori Tanae
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | - Pedro Melillo de Magalhães
- Multidisciplinary Center for Chemical, Biological and Agricultural Research, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil
| | - Antônio José Lapa
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Caden Souccar
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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Xie W, Chen S, Wang W, Qin X, Kong C, Wang D. Nuciferine reduces vascular leakage and improves cardiac function in acute myocardial infarction by regulating the PI3K/AKT pathway. Sci Rep 2024; 14:7086. [PMID: 38528077 PMCID: PMC10963720 DOI: 10.1038/s41598-024-57595-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/20/2024] [Indexed: 03/27/2024] Open
Abstract
The destruction of the microvascular structure and function can seriously affect the survival and prognosis of patients with acute myocardial infarction (AMI). Nuciferine has a potentially beneficial effect in the treatment of cardiovascular disease, albeit its role in microvascular structure and function during AMI remains unclear. This study aimed to investigate the protective effect and the related mechanisms of nuciferine in microvascular injury during AMI. Cardiac functions and pathological examination were conducted in vivo to investigate the effect of nuciferine on AMI. The effect of nuciferine on permeability and adherens junctions in endothelial cells was evaluated in vitro, and the phosphorylation level of the PI3K/AKT pathway (in the presence or absence of PI3K inhibitors) was also analyzed. In vivo results indicated that nuciferine inhibited ischemia-induced cardiomyocyte damage and vascular leakage and improved cardiac function. In addition, the in vitro results revealed that nuciferine could effectively inhibit oxygen-glucose deprivation (OGD) stimulated breakdown of the structure and function of human coronary microvascular endothelial cells (HCMECs). Moreover, nuciferine could significantly increase the phosphorylation level of the PI3K/AKT pathway. Finally, the inhibitor wortmannin could reverse the protective effect of nuciferine on HCMECs. Nuciferine inhibited AMI-induced microvascular injury by regulating the PI3K/AKT pathway and protecting the endothelial barrier function in mice.
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Affiliation(s)
- Wei Xie
- Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
- Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, Jiangsu, China
| | - Shumin Chen
- Department of Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenzhe Wang
- Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
- Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, Jiangsu, China
| | - Xichun Qin
- Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
- Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, Jiangsu, China
| | - Chuiyu Kong
- Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.
- Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, Jiangsu, China.
| | - Dongjin Wang
- Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.
- Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, Jiangsu, China.
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Shin S, Park J, Choi HY, Bu Y, Lee K. Sakuranetin as a Potential Regulator of Blood Pressure in Spontaneously Hypertensive Rats by Promoting Vasorelaxation through Calcium Channel Blockade. Biomedicines 2024; 12:346. [PMID: 38397948 PMCID: PMC10887318 DOI: 10.3390/biomedicines12020346] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Natural compounds, known for diverse pharmacological properties, have attracted attention as potential sources for hypertension treatment. Previous studies have revealed the hypotensive effect and vascular relaxation of prunetin, a natural compound derived from Prunus yedoensis. However, the potential blood pressure-lowering and vasorelaxant effects of sakuranetin, another representative compound found in plants belonging to the genus Prunus, have remained unexplored. We aimed to fill this gap by investigating the hypotensive and vasorelaxant effects of sakuranetin in rats. Results indicated that sakuranetin, particularly in the sakuranetin 20 mg/kg group, led to significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by -14.53 ± 5.64% and -19.83 ± 6.56% at 4 h after administration. In the sakuranetin 50 mg/kg group, the SBP and DBP decreased by -13.27 ± 6.86% and -16.62 ± 10.01% at 2 h and by -21.61 ± 4.49% and -30.45 ± 5.21% at 4 h after administration. In addition, we identified the vasorelaxant effects of sakuranetin, attributing its mechanisms to the inhibition of calcium influx and the modulation of angiotensin II. Considering its hypotensive and vasorelaxant effects, sakuranetin could potentially serve as an antihypertensive agent. However, further research is required to evaluate the safety and long-term efficacy.
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Affiliation(s)
- Sujin Shin
- Department of Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Junkyu Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Ho-Young Choi
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Youngmin Bu
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyungjin Lee
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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12
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Kim GD. Induction of Hepatocellular Carcinoma Cell Cycle Arrest and Apoptosis by Dendropanax morbifera Leveille Leaf Extract via the PI3K/AKT/mTOR Pathway. J Cancer Prev 2023; 28:185-193. [PMID: 38205361 PMCID: PMC10774480 DOI: 10.15430/jcp.2023.28.4.185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 01/12/2024] Open
Abstract
Liver cancer is prevalent worldwide and associated with a high mortality rate. Therefore, developing novel drugs derived from natural products to reduce the side effects of chemotherapy is urgently needed. In this study, the inhibitory effect of Dendropanax morbifera Leveille extract (DME) on growth of hepatocellular carcinoma (HCC) cells and its underlying mechanisms were investigated. DME suppressed the growth, migration, and invasion of SK-Hep1 human HCC cells. It also reduced the expression of the G0/G1 phase regulator proteins cyclin-dependent kinase (CDK) 4, cyclin D, CDK2, and cyclin E, thereby inducing G0/G1 arrest. Moreover, DME treatment reduced the expression of antiapoptotic proteins, including caspase-9, caspase-3, PARP, and Bcl-2 and increased the expression of the proapoptotic protein, Bax. DME also increased reactive oxygen species production and reduced the cellular uptake of rhodamine 123. DME treatment increased the levels of p-p38 and p-FOXO3a in a dose-dependent manner and decreased those of p-PI3K, p-AKT, p-mTOR, and p-p70 in SK-Hep1 cells. In addition, combined treatment with DME and LY294002, an AKT inhibitor, significantly reduced p-AKT levels. In summary, these results show that the PI3K/AKT/mTOR signaling pathway is involved in DME-mediated inhibition of proliferation, migration, and invasiveness, and induction of apoptosis of HCC cells.
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Affiliation(s)
- Gi Dae Kim
- Department of Food and Nutrition, Kyungnam University, Changwon, Korea
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13
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Tang F, Liu D, Zhang L, Xu LY, Zhang JN, Zhao XL, Ao H, Peng C. Targeting endothelial cells with golden spice curcumin: A promising therapy for cardiometabolic multimorbidity. Pharmacol Res 2023; 197:106953. [PMID: 37804925 DOI: 10.1016/j.phrs.2023.106953] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 09/20/2023] [Accepted: 10/04/2023] [Indexed: 10/09/2023]
Abstract
Cardiometabolic multimorbidity (CMM) is an increasingly significant global public health concern. It encompasses the coexistence of multiple cardiometabolic diseases, including hypertension, stroke, heart disease, atherosclerosis, and T2DM. A crucial component to the development of CMM is the disruption of endothelial homeostasis. Therefore, therapies targeting endothelial cells through multi-targeted and multi-pathway approaches hold promise for preventing and treatment of CMM. Curcumin, a widely used dietary supplement derived from the golden spice Carcuma longa, has demonstrated remarkable potential in treatment of CMM through its interaction with endothelial cells. Numerous studies have identified various molecular targets of curcumin (such as NF-κB/PI3K/AKT, MAPK/NF-κB/IL-1β, HO-1, NOs, VEGF, ICAM-1 and ROS). These findings highlight the efficacy of curcumin as a therapeutic agent against CMM through the regulation of endothelial function. It is worth noting that there is a close relationship between the progression of CMM and endothelial damage, characterized by oxidative stress, inflammation, abnormal NO bioavailability and cell adhesion. This paper provides a comprehensive review of curcumin, including its availability, pharmacokinetics, pharmaceutics, and therapeutic application in treatment of CMM, as well as the challenges and future prospects for its clinical translation. In summary, curcumin shows promise as a potential treatment option for CMM, particularly due to its ability to target endothelial cells. It represents a novel and natural lead compound that may offer significant therapeutic benefits in the management of CMM.
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Affiliation(s)
- Fei Tang
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Dong Liu
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Li Zhang
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Li-Yue Xu
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Jing-Nan Zhang
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Xiao-Lan Zhao
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Hui Ao
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Cheng Peng
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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14
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Jung J, Shin S, Park J, Lee K, Choi HY. Hypotensive and Vasorelaxant Effects of Sanguisorbae Radix Ethanol Extract in Spontaneously Hypertensive and Sprague Dawley Rats. Nutrients 2023; 15:4510. [PMID: 37960162 PMCID: PMC10647409 DOI: 10.3390/nu15214510] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Hypertension requires proper management because of the increased risk of cardiovascular disease and death. For this purpose, functional foods containing tannins have been considered an effective treatment. Sanguisorbae radix (SR) also contains various tannins; however, there have been no studies on its vasorelaxant or antihypertensive effects. In this study, the vasorelaxant effect of the ethanol extract of SR (SRE) was investigated in the thoracic aorta of Sprague Dawley rats. SRE (1, 3, 10, 30, and 100 μg/mL) showed this effect in a dose-dependent manner, and its mechanisms were related to the NO/cGMP pathway and voltage-gated K+ channels. Concentrations of 300 and 1000 μg/mL blocked the influx of extracellular Ca2+ and inhibited vasoconstriction. Moreover, 100 μg/mL of SRE showed a relaxing effect on blood vessels constricted by angiotensin II. The hypotensive effect of SRE was investigated in spontaneously hypertensive rats (SHR) using the tail-cuff method. Blood pressure significantly decreased 4 and 8 h after 1000 mg/kg of SRE administration. Considering these hypotensive effects and the vasorelaxant mechanisms of SRE, our findings suggests that SRE can be used as a functional food to prevent and treat hypertension. Further studies are needed for identifying the active components and determining the optimal dosage.
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Affiliation(s)
- Jaesung Jung
- Department of Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.S.)
| | - Sujin Shin
- Department of Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.S.)
| | - Junkyu Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Kyungjin Lee
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Ho-Young Choi
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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Chen AP, Zhang ZJ, Li JZ, Zuo L, Cheng YX, Deng D, Li XL, Ma XY, Man D, Zheng MH, Chen J, Wen B, Wang J, Zhou JG, Zhao HH. Mechanism of Wuweijiangyasan in the Treatment of Spontaneous Hypertension based on Network Pharmacology. WORLD JOURNAL OF TRADITIONAL CHINESE MEDICINE 2023; 9:355-368. [DOI: 10.4103/2311-8571.351793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background:
Hypertension affects over 1 billion people globally and is the top risk factor of cardiovascular morbidity and mortality. Wuweijiangyasan (WWJYS), as an empirical prescription, has stable depressurization effects. This study investigated the chemical composition and pharmacodynamic effects of WWJYS in regulating the blood pressure (BP), emotion, and blood lipid of spontaneous hypertensive rats, and further explored the depressurization mechanism of WWJYS.
Materials and Methods:
This study used network pharmacology to identify the origins and predict targets of WWJYS, and artificial intelligence-based molecular docking is used to further predict targets and mechanisms. The chemical constituents of WWJYS were analyzed and identified by ultra high-performance liquid chromatography–mass spectrometry (MS)/MS.
Results:
In the WWJYS group, the systolic BP level significantly was decreased, and the HR was stable. The irritability became stable after the 5-week treatment compared with the model group (P < 0.05). Rats' rotation tolerance time increased after 2-weeks stabilization. Compared with the model group, angiotensin-converting enzyme 2 protein and mRNA of the WWJYS group increased significantly (P < 0.05). Network pharmacology collected 64 compounds and identified 22 potential targets of WWJYS for antihypertensive activity. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that WWJYS might regulate smooth muscle cells, affect inflammatory response and improve endothelial function through multiple pathways. The molecular docking study further supported that the target proteins have good combinations with the main active components of WWJYS.
Conclusions:
The data indicated that WWJYS had significant depressurization, analgesic, and sedative, as well as lipid-lowering effects, and the depressurization mechanism of WWJYS may function in multiple signal pathways, especially in improving blood vessel function and intervening inflammation.
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Nainu F, Frediansyah A, Mamada SS, Permana AD, Salampe M, Chandran D, Emran TB, Simal-Gandara J. Natural products targeting inflammation-related metabolic disorders: A comprehensive review. Heliyon 2023; 9:e16919. [PMID: 37346355 PMCID: PMC10279840 DOI: 10.1016/j.heliyon.2023.e16919] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/23/2023] Open
Abstract
Currently, the incidence of metabolic disorders is increasing, setting a challenge to global health. With major advancement in the diagnostic tools and clinical procedures, much has been known in the etiology of metabolic disorders and their corresponding pathophysiologies. In addition, the use of in vitro and in vivo experimental models prior to clinical studies has promoted numerous biomedical breakthroughs, including in the discovery and development of drug candidates to treat metabolic disorders. Indeed, chemicals isolated from natural products have been extensively studied as prospective drug candidates to manage diabetes, obesity, heart-related diseases, and cancer, partly due to their antioxidant and anti-inflammatory properties. Continuous efforts have been made in parallel to improve their bioactivity and bioavailability using selected drug delivery approaches. Here, we provide insights on recent progress in the role of inflammatory-mediated responses on the initiation of metabolic disorders, with particular reference to diabetes mellitus, obesity, heart-related diseases, and cancer. In addition, we discussed the prospective role of natural products in the management of diabetes, obesity, heart-related diseases, and cancers and provide lists of potential biological targets for high throughput screening in drug discovery and development. Lastly, we discussed findings observed in the preclinical and clinical studies prior to identifying suitable approaches on the phytochemical drug delivery systems that are potential to be used in the treatment of metabolic disorders.
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Affiliation(s)
- Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | - Andri Frediansyah
- Research Center for Food Technology and Processing (PRTPP), National Research and Innovation Agency (BRIN), Yogyakarta 55861, Indonesia
| | - Sukamto S. Mamada
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | - Andi Dian Permana
- Department of Pharmaceutical Science and Technology, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | | | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Talha Bin Emran
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Jesus Simal-Gandara
- Universidade de Vigo, Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, E32004 Ourense, Spain
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17
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Chen HT, Yu BH, Yeh MH, Hung SK, Chen YC. Dose- and time-dependent renoprotection of Angelica sinensis in patients with chronic kidney disease: A longitudinal cohort study. Front Pharmacol 2023; 14:1153583. [PMID: 37180720 PMCID: PMC10166798 DOI: 10.3389/fphar.2023.1153583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 04/05/2023] [Indexed: 05/16/2023] Open
Abstract
Background: Based on their anti-oxidative and anti-fibrotic properties, Angelica sinensis (Oliv.) Diels roots [Apiaceae; Radix Angelicae sinensis] (Danggui [abbreviated as S in the context]), Astragalus membranaceus (Fisch.) Bunge [Fabaceae; Astragalus membranaceus] (Huangqi [A]), Rheum palmatum L. [Polygonaceae; Rheum palmatum] (Dahuang [R]), and Salvia miltiorrhiza Bunge [Lamiaceae; Salvia miltiorrhiza Bunge radix et rhizoma] (Danshen [D]) are potential renoprotective Chinese herbal medicines (CHMs). Renoprotection using ARD alone for the treatment of chronic kidney disease (CKD) has been documented in pre-clinical, clinical, and meta-analysis research; however, only pre-clinical data are available for the use of S alone. Moreover, with an increasing number of CKD patients taking prescribed CHMs, hyperkalemia risk remains unclear. Methods: This study retrospectively analyzed national health insurance claims data in 2001-2017. Propensity score matching was used to analyze renal and survival outcomes and the dose-response effects of S without ARD use in 18,348 new S users, 9,174 new ARD users, and 36,696 non-users. Cox proportional hazard regression was used to investigate adjusted hazard ratios (aHRs) for end-stage renal disease (ESRD) in the presence of competing mortality and death. The additive effect of the S herb in single form to compounds was also analyzed. Additionally, to analyze hyperkalemia risk, an exact match on each covariate was used to include 42,265 new CHM users and non-users, while Poisson regression was used to estimate adjusted incidence rate ratios (aIRRs) of hyperkalemia of prescribed CHMs. Results: S users and ARD users were associated with aHRs of 0.77 (95% confidence interval; 0.69-0.86) and 1.04 (0.91-1.19), respectively, for ESRD and 0.55 (0.53-0.57) and 0.71 (0.67-0.75), respectively, for death. The renal and survival benefits of S use were consistent in several sensitivity analyses. The dose- and time-dependent renoprotection and dose-dependent survival benefits were observed for S use. The top two additive renoprotective collocations of the S herb in compounds were Xue-Fu-Zhu-Yu-Tang and Shen-Tong-Zhu-Yu-Tang, followed by Shu-Jing-Huo-Xue-Tang and Shen-Tong-Zhu-Yu-Tang. Moreover, CHM users were associated with aIRRs of 0.34 (0.31-0.37) for hyperkalemia. Conclusion: This study suggests dose- and time-dependent renoprotection and dose-dependent survival benefits of the S herb in compounds and no increased hyperkalemia risk of the prescribed CHMs in CKD patients.
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Affiliation(s)
- Hsiao-Tien Chen
- Department of Chinese Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Ben-Hui Yu
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Ming-Hsien Yeh
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
| | - Shih-Kai Hung
- Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Yi-Chun Chen
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
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Ramos LC, Palacios J, Barrientos RE, Gómez J, Castagnini JM, Barba FJ, Tapia A, Paredes A, Cifuentes F, Simirgiotis MJ. UHPLC-MS Phenolic Fingerprinting, Aorta Endothelium Relaxation Effect, Antioxidant, and Enzyme Inhibition Activities of Azara dentata Ruiz & Pav Berries. Foods 2023; 12:foods12030643. [PMID: 36766170 PMCID: PMC9914855 DOI: 10.3390/foods12030643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/18/2022] [Accepted: 01/21/2023] [Indexed: 02/05/2023] Open
Abstract
Azara dentata Ruiz & Pav. is a small Chilean native plant from Patagonia, a producer of small white reddish berries. For the first time, the proximal analysis of the fruits, phenolic fingerprinting, the antioxidant activity, and the enzymatic inhibition and relaxation effects in rat aorta induced by the ethanolic extract of these fruits were investigated. The proximal composition and the mineral (Ca: 2434 ± 40 mg/kg; Mg: 702 ± 13 mg/kg; Fe: 117.1 ± 1.6 mg/kg; Zn: 16.1 ± 0.4 mg/kg) and heavy metal (As: 121 ± 11 µg/kg; Cd: 152 ± 5 µg/kg; Hg: 7.7 ± 1.3 µg/kg; Pb 294 ± 4 µg/kg) contents were analyzed. Anthocyanins, flavonoids, phenolic acids, and coumarins were identified using UHPLC-PDA-QTOF-MS. The ethanolic extracts showed a total phenolic content of 23.50 ± 0.93 mg GAE/g extract. In addition, the antioxidant activity was assessed using both DPPH and TEAC (28.64 ± 1.87 and 34.72 ± 2.33 mg Trolox/g of dry fruit, respectively), FRAP (25.32 ± 0.23 mg Trolox equivalent/g dry fruit), and ORAC (64.95 ± 1.23 mg Trolox equivalents/g dry fruit). The inhibition of enzymatic activities (acetylcholinesterase IC50: 2.87 + 0.23 µg extract/mL, butyrylcholinesterase IC50: 6.73 + 0.07 µg extract/mL, amylase IC50: 5.6 ± 0.0 µg extract/mL, lipase IC50: 30.8 ± 0.0 µg extract/mL, and tyrosinase IC50: 9.25 ± 0.15 µg extract/mL) was also assessed. The extract showed 50-60% relaxation in rat aorta (intact), mediated thorough the release of endothelial nitric oxide. Our results suggest that A. dentata is a good source of compounds with the capacity to inhibit important enzymes, can be hypotensive, and can thus have good potentiality as supplements in the amelioration of neurodegenerative diseases and could also have potential to be used to develop new functional foods. The study highlights the benefits of these neglected small fruits and could boost their consumption.
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Affiliation(s)
- Lucia Cuesta Ramos
- Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy, Universitat de València, Burjassot, 46100 València, Spain
| | - Javier Palacios
- Laboratorio de Bioquímica Aplicada, Química y Farmacia, Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique 1110939, Chile
| | - Ruth E. Barrientos
- Instituto de Farmacia, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Jessica Gómez
- Instituto de Biotecnología-Instituto de Ciencias Básicas, Universidad Nacional de San Juan, Av. Libertador General San Martín 1109 (O), San Juan CP 5400, Argentina
| | - Juan Manuel Castagnini
- Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy, Universitat de València, Burjassot, 46100 València, Spain
- Correspondence: (J.M.C.); (M.J.S.); Tel.: +56-63-63233257 (M.J.S.)
| | - Francisco J. Barba
- Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy, Universitat de València, Burjassot, 46100 València, Spain
| | - Alejandro Tapia
- Instituto de Biotecnología-Instituto de Ciencias Básicas, Universidad Nacional de San Juan, Av. Libertador General San Martín 1109 (O), San Juan CP 5400, Argentina
| | - Adrián Paredes
- Laboratorio de Productos Naturales, Departamento de Química, Facultad de Ciencias Básicas, Universidad de Antofagasta, Antofagasta 1270300, Chile
| | - Fredi Cifuentes
- Laboratorio de Fisiología Experimental, Instituto Antofagasta, Universidad de Antofagasta, Antofagasta 1270300, Chile
| | - Mario J. Simirgiotis
- Instituto de Farmacia, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile
- Correspondence: (J.M.C.); (M.J.S.); Tel.: +56-63-63233257 (M.J.S.)
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19
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Chen G, Zhang L, Van Schepdael A, Wang X. Recent Advances in Activation of Endothelial Nitric Oxide Synthase by Natural Products: An Effects and Mechanisms Review. FOOD REVIEWS INTERNATIONAL 2023. [DOI: 10.1080/87559129.2023.2166061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Guangxuan Chen
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, China
| | - Le Zhang
- Department of Chemistry, University of Missouri, Columbia, Missouri, USA
| | - Ann Van Schepdael
- Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven - University of Leuven, Leuven, Belgium
| | - Xu Wang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, China
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Identification of prototype compounds and their metabolites in rats' serum from Xuefu Zhuyu Decoction by UPLC-Q-TOF/MS. CHINESE HERBAL MEDICINES 2023; 15:139-150. [PMID: 36875444 PMCID: PMC9975640 DOI: 10.1016/j.chmed.2022.08.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/13/2022] [Accepted: 08/10/2022] [Indexed: 11/24/2022] Open
Abstract
Objective As a classic prescription in traditional Chinese medicine, Xuefu Zhuyu Decoction (XFZYD) has been widely used in the clinical treatment of cardiovascular and cerebrovascular diseases. In order to unveil the potentially effective compounds, a rapid ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method was established to identify prototype compounds and their metabolites from XFZYD in rats' serum. Methods The serum from rats after intragastric administration of XFZYD aqueous extract was analyzed by UPLC-Q-TOF/MS method. The prototype compounds and their metabolites were identified by comparison with the reference standards and tentatively characterized by comprehensively analyzing the retention time, MS data, characteristic MS fragmentation pattern and retrieving literatures. Results A total of 175 compounds (24 prototype compounds and 151 metabolites) were identified and tentatively characterized. The metabolic pathways of prototype compounds in vivo were also summarized, including glucuronidation, hydrolyzation, sulfation, demethylation, and hydroxylation, and so on. Conclusion In this study, a UPLC-Q-TOF/MS technique was developed to analyze prototype compounds and their metabolites from XFZYD in serum, which would provide the evidence for further studying the effective compounds of XFZYD.
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Wang D, Bu T, Li Y, He Y, Yang F, Zou L. Pharmacological Activity, Pharmacokinetics, and Clinical Research Progress of Puerarin. Antioxidants (Basel) 2022; 11:2121. [PMID: 36358493 PMCID: PMC9686758 DOI: 10.3390/antiox11112121] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/22/2022] [Accepted: 10/26/2022] [Indexed: 09/01/2023] Open
Abstract
As a kind of medicine and food homologous plant, kudzu root (Pueraria lobata (Willd.) Ohwi) is called an "official medicine" in Chinese folk medicine. Puerarin is the main active component extracted from kudzu root, and its structural formula is 8-β-D-grapes pyranose-4, 7-dihydroxy isoflavone, with a white needle crystal; it is slightly soluble in water, and its aqueous solution is colorless or light yellow. Puerarin is a natural antioxidant with high health value and has a series of biological activities such as antioxidation, anti-inflammation, anti-tumor effects, immunity improvement, and cardio-cerebrovascular and nerve cell protection. In particular, for the past few years, it has also been extensively used in clinical study. This review focuses on the antioxidant activity of puerarin, the therapy of diverse types of inflammatory diseases, various new drug delivery systems of puerarin, the "structure-activity relationship" of puerarin and its derivatives, and pharmacokinetic and clinical studies, which can provide a new perspective for the puerarin-related drug research and development, clinical application, and further development and utilization.
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Affiliation(s)
- Di Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tong Bu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yangqian Li
- Asset and Laboratory Management Department, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yueyue He
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Fan Yang
- Academic Affairs Office, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu 610106, China
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22
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Carullo G, Saponara S, Ahmed A, Gorelli B, Mazzotta S, Trezza A, Gianibbi B, Campiani G, Fusi F, Aiello F. Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits Ca V1.2 and Stimulates K Ca1.1 Channels. Mar Drugs 2022; 20:md20080515. [PMID: 36005518 PMCID: PMC9410420 DOI: 10.3390/md20080515] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 07/30/2022] [Accepted: 08/11/2022] [Indexed: 11/26/2022] Open
Abstract
Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.
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Affiliation(s)
- Gabriele Carullo
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Simona Saponara
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Amer Ahmed
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Beatrice Gorelli
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Sarah Mazzotta
- Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
| | - Alfonso Trezza
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Beatrice Gianibbi
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Giuseppe Campiani
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Fabio Fusi
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
- Correspondence: (F.F.); (F.A.)
| | - Francesca Aiello
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edif. Polifunzionale, 87036 Arcavacata di Rende, Italy
- Correspondence: (F.F.); (F.A.)
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23
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Xia B, Li Q, Wu J, Yuan X, Wang F, Lu X, Huang C, Zheng K, Yang R, Yin L, Liu K, You Q. Sinomenine Confers Protection Against Myocardial Ischemia Reperfusion Injury by Preventing Oxidative Stress, Cellular Apoptosis, and Inflammation. Front Pharmacol 2022; 13:922484. [PMID: 35837272 PMCID: PMC9274168 DOI: 10.3389/fphar.2022.922484] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/09/2022] [Indexed: 11/23/2022] Open
Abstract
Sinomenine (SIN), an alkaloid extracted from the root of S. acutum. sinomenine, has been shown to have antiarrhythmic, antioxidant, and anti-inflammatory effects in myocardial ischemia-reperfusion injury (MIRI) ex vivo. In this study, we investigated the cardioprotective effects of SIN in an in vivo mouse model of MIRI. Adult male C57BL/6J mice received SIN (80 mg/kg) for 5 days and underwent 30 min of percutaneous occlusion of the left anterior descending artery (LAD) followed by 24 h of reperfusion. Results showed that pretreatment with SIN significantly reduced myocardial infarct size and concentrations of markers of cardiac injury and improved left ventricular ejection fraction (EF) and shortening fraction (FS) in MIRI mice. The SIN pretreatment prevented the MIRI-induced decrease in the expression levels of Bcl-2, increase in the expression levels of caspase-3, caspase-9, and Bax, and increase in the number of TUNEL-positive cells in ischemic heart tissue. It was also found that pretreatment with SIN prevented the MIRI-induced oxidative stress imbalance in ischemic heart tissue, as shown by the increase in total antioxidant capacity (T-AOC) and glutathione (GSH) and the decrease in malondialdehyde (MDA), reactive oxygen species (ROS), and dihydroethidium (DHE) density. Further studies showed that the stimulus of cardiac ischemia/reperfusion caused a remarkable increase in the expression levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) mRNA in ischemic heart tissue, which was effectively prevented by pretreatment with SIN. These results demonstrate that SIN can attenuate MIRI-induced cardiac injury in vivo by preventing oxidative stress, inflammation, and apoptosis.
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Affiliation(s)
- Boyu Xia
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Qi Li
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Jingjing Wu
- Department of Cardiology, Suzhou Kowloon Hospital of Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - Xiaomei Yuan
- Department of Cardiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Fei Wang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xu Lu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China
| | - Koulong Zheng
- Department of Cardiology, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Rongrong Yang
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Le Yin
- Department of Cardiology, Tongzhou People’s Hospital, Nantong, China
| | - Kun Liu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- *Correspondence: Kun Liu, ; Qingsheng You,
| | - Qingsheng You
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- *Correspondence: Kun Liu, ; Qingsheng You,
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Li M, Han B, Zhao H, Xu C, Xu D, Sieniawska E, Lin X, Kai G. Biological active ingredients of Astragali Radix and its mechanisms in treating cardiovascular and cerebrovascular diseases. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 98:153918. [PMID: 35104756 DOI: 10.1016/j.phymed.2021.153918] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 12/12/2021] [Accepted: 12/30/2021] [Indexed: 05/13/2023]
Abstract
BACKGROUND With the rising age of the global population, the incidence rate of cardiovascular and cerebrovascular diseases (CCVDs) is increasing, which causes serious public health burden. The efforts for new therapeutic approaches are still being sought since the treatment effects of existing therapies are not quite satisfactory. Chinese traditional medicine proved to be very efficient in the treatment of CCVDs. Well described and established in Chinese medicine, Astragali Radix, has been commonly administered in the prophylaxis and cure of CCVDs for thousands of years. PURPOSE This review summarized the action mode and mechanisms of Astragali Radix phytochemicals on CCVDs, hoping to provide valuable information for the future application, development and improvement of Astragali Radix as well as CCVDs treatment. METHODS A plenty of literature on biological active ingredients of Astragali Radix used for CCVDs treatment were retrieved from online electronic PubMed and Web of Science databases. RESULTS This review highlighted the effects of five main active components in Astragali Radix including astragaloside Ⅳ, cycloastragenol, astragalus polysaccharide, calycosin-7-O-β-d-glucoside, and calycosin on CCVDs. The mechanisms mainly involved anti-oxidative damage, anti-inflammatory, and antiapoptotic through signaling pathways such as PI3K/Akt, Nrf2/HO-1, and TLR4/NF-κB pathway. In addition, the majority active constituents in AR have no obvious toxic side effects. CONCLUSION The main active components of Astragali Radix, especially AS-IV, have been extensively summarized. It has been proved that Astragali Radix has obvious therapeutic effects on various CCVDs, including myocardial and cerebral ischemia, hypertension, atherosclerosis, cardiac hypertrophy, chronic heart failure. CAG possesses anti-ischemia activity without toxicity, indicating a worthy of further development. However, high-quality clinical and pharmacokinetic studies are required to validate the current studies.
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Affiliation(s)
- Man Li
- Laboratory for Core Technology of TCM Quality Improvement and Transformation, The Third Affiliated Hospital, School of Pharmaceutical Sciences, Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Bing Han
- Laboratory for Core Technology of TCM Quality Improvement and Transformation, The Third Affiliated Hospital, School of Pharmaceutical Sciences, Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Huan Zhao
- Laboratory for Core Technology of TCM Quality Improvement and Transformation, The Third Affiliated Hospital, School of Pharmaceutical Sciences, Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Chongyi Xu
- Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Taizhou, Zhejiang, 317500, China
| | - Daokun Xu
- Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Taizhou, Zhejiang, 317500, China
| | - Elwira Sieniawska
- Department of Natural Products Chemistry, Medical University of Lublin, Chodzki 1, 20-093 Lublin, Poland
| | - Xianming Lin
- Laboratory for Core Technology of TCM Quality Improvement and Transformation, The Third Affiliated Hospital, School of Pharmaceutical Sciences, Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Guoyin Kai
- Laboratory for Core Technology of TCM Quality Improvement and Transformation, The Third Affiliated Hospital, School of Pharmaceutical Sciences, Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
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25
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Xu JF, Xia J, Wan Y, Yang Y, Wu JJ, Peng C, Ao H. Vasorelaxant Activities and its Underlying Mechanisms of Magnolia Volatile Oil on Rat Thoracic Aorta Based on Network Pharmacology. Front Pharmacol 2022; 13:812716. [PMID: 35308213 PMCID: PMC8926352 DOI: 10.3389/fphar.2022.812716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Objective: Magnolia volatile oil (MVO) is a mixture mainly containing eudesmol and its isomers. This study was to investigate the vasorelaxant effects and the underlying mechanism of MVO in rat thoracic aortas. Method: The present study combined gas chromatography–mass spectrometry (GC-MS) and network pharmacology analysis with in vitro experiments to clarify the mechanisms of MVO against vessel contraction. A compound–target network, compound–target–disease network, protein–protein interaction network, compound–target–pathway network, gene ontology, and pathway enrichment for hypertension were applied to identify the potential active compounds, drug targets, and pathways. Additionally, the thoracic aortic rings with or without endothelium were prepared to explore the underlying mechanisms. The roles of the PI3K-Akt-NO pathways, neuroreceptors, K+ channels, and Ca2+ channels on the vasorelaxant effects of MVO were evaluated through the rat thoracic aortic rings. Results: A total of 29 compounds were found in MVO, which were identified by GC-MS, of which 21 compounds with a content of more than 0.1% were selected for further analysis. The network pharmacology research predicted that beta-caryophyllene, palmitic acid, and (+)-β-selinene might act as the effective ingredients of MVO for the treatment of hypertension. Several hot targets, mainly involving TNF, CHRM1, ACE, IL10, PTGS2, REN, and F2, and pivotal pathways, such as the neuroactive ligand–receptor interaction, the calcium signaling pathway, and the PI3K-Akt signaling, were responsible for the vasorelaxant effect of MVO. As expected, MVO exerted a vasorelaxant effect on the aortic rings pre-contracted by KCl and phenylephrine in an endothelium-dependent and non-endothelium-dependent manner. Importantly, a pre-incubation with indomethacin (Indo), N-nitro-L-arginine methyl ester, methylene blue, wortmannin, and atropine sulfate as well as 4-aminopyridione diminished MVO-induced vasorelaxation, suggesting that the activation of the PI3K-Akt-NO pathway and KV channel were involved in the vasorelaxant effect of MVO, which was consistent with the results of the Kyoto Encyclopedia of Genes and the Genomes. Additionally, MVO could significantly inhibit Ca2+ influx resulting in the contraction of aortic rings, revealing that the inhibition of the calcium signaling pathway exactly participated in the vasorelaxant activity of MVO as predicted by network pharmacology. Conclusion: MVO might be a potent treatment of diseases with vascular dysfunction like hypertension. The underlying mechanisms were related to the PI3K-Akt-NO pathway, KV pathway, as well as Ca2+ channel, which were predicted by the network pharmacology and verified by the experiments in vitro. This study based on network pharmacology provided experimental support for the clinical application of MVO in the treatment of hypertension and afforded a novel research method to explore the activity and mechanism of traditional Chinese medicine.
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Affiliation(s)
- Jin-Feng Xu
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia Xia
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yan Wan
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Yang
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiao-Jiao Wu
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Cheng Peng, ; Hui Ao,
| | - Hui Ao
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Cheng Peng, ; Hui Ao,
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Vasorelaxant-Mediated Antihypertensive Effect of the Leaf Aqueous Extract from Stephania abyssinica (Dillon & A. Rich) Walp (Menispermaceae) in Rat. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4730341. [PMID: 34660790 PMCID: PMC8519676 DOI: 10.1155/2021/4730341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/17/2021] [Indexed: 11/21/2022]
Abstract
Stephania abyssinica is a medicinal plant used in Cameroon alternative medicine to treat arterial hypertension (AHT). Previous in vitro studies demonstrated the endothelium nitric oxide-independent vasorelaxant property of the aqueous extract from Stephania abyssinica (AESA). But its effect on AHT is unknown. The present study was undertaken to explore other vasorelaxant mechanisms and to determine the antihypertensive effects of AESA in male Wistar rats. Phytochemical analysis of AESA was carried out using the liquid chromatography-mass spectrometry (LC-MS) method. The vasorelaxant effects of AESA (1-1000 μg/mL) were studied on rat isolated thoracic aorta rings, in the absence or presence of indomethacin (10 μM) or methylene blue (10 μM). The inhibitory effect of AESA on phenylephrine (PE, 10 μM) or KCl- (60 mM) induced contraction as well as the intracellular calcium release was also evaluated. The in vivo antihypertensive activity of AESA (43, 86, or 172 mg/kg/day) or captopril (20 mg/kg/day) administered orally was assessed in L-NAME- (40 mg/kg/day) treated rats. Blood pressure and heart rate (HR) were measured at the end of each week while serum or urinary nitric oxide (NO), creatinine, and glomerular filtration rate (GFR) were determined at the end of the 6 weeks of treatment, as well as histological analysis of the heart and the kidney. The LC-MS profiling of AESA identified 9 compounds including 7 alkaloids. AESA produced a concentration-dependent relaxation on contraction induced either by PE and KCl, which was significantly reduced in endothelium-denuded vessels, as well as in vessels pretreated with indomethacin and methylene blue. Moreover, AESA inhibited the intracellular Ca2+ release-induced contraction. In vivo, AESA reduced the AHT, heart rate (HR), and ventricular hypertrophy and increased serum NO, urine creatinine, and GFR. AESA also ameliorated heart and kidney lesions as compared to the L-NAME group. These findings supported the use of AESA as a potential antihypertensive drug.
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27
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Abdallah HM, Timraz NZ, Ibrahim SRM, El-Halawany AM, Malebari AM, Shehata IA, El-Bassossy HM. Nitric-Oxide-Mediated Vasodilation of Bioactive Compounds Isolated from Hypericum revolutum in Rat Aorta. BIOLOGY 2021; 10:biology10060541. [PMID: 34204229 PMCID: PMC8234642 DOI: 10.3390/biology10060541] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/04/2021] [Accepted: 06/15/2021] [Indexed: 11/23/2022]
Abstract
Simple Summary Hypericum revolutum (HR) is reported to produce vasodilating activity in phenylephrine-precontracted aortae, where the chloroform fraction is the most potent. Chemical investigation of this fraction yielded two new compounds, revolutin (1) and hyperevolutin C (2), along with three known metabolites, β-sitosterol (3), euxanthone (4), and 2,3,4-tirmethoxy xanthone (5). Isolated compounds 1, 2, 3, and 5 produce vasodilation activities that are dependent on endothelial nitric oxide release. Abstract Vasodilators are an important class in the management of hypertension and related cardiovascular disorders. In this regard, the chloroform fraction of Hypericum revolutum (HR) has been reported to produce vasodilating activity in phenylephrine-precontracted aortae. The current work aims to identify the active metabolites in the chloroform fraction of HR and illustrate the possible mechanism of action. The vasodilation activities were investigated using the isolated artery technique. NO vascular release was assessed by utilizing the NO-sensitive fluorescent probe DAF-FM. Free radical scavenging capacity was assessed utilizing DPPH. Chemical investigation of this fraction yielded two new compounds, revolutin (1) and hyperevolutin C (2), along with three known metabolites, β-sitosterol (3), euxanthone (4), and 2,3,4-tirmethoxy xanthone (5). Compounds 1, 2, 3, and 5 showed significant vasodilation activities that were blocked by either endothelial denudation or L-NAME (nitric oxide synthase inhibitor), pointing towards a role of endothelial nitric oxide in their activities. In confirmation of this role, compounds 1–3 showed a significant release of NO from isolated vessels, as indicated by DAF-FM. On the other hand, only compound 5 showed free radical scavenging activities, as indicated by DPPH. In conclusion, isolated compounds 1, 2, 3, and 5 produce vasodilation activities that are dependent on endothelial nitric oxide release.
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Affiliation(s)
- Hossam M. Abdallah
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.Z.T.); (I.A.S.)
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;
- Correspondence: ; Tel.: +966-54-4733-110
| | - Noha Z. Timraz
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.Z.T.); (I.A.S.)
| | - Sabrin R. M. Ibrahim
- Batterjee Medical College, North Obhur, Abdullah Al-Faisal Street, Jeddah 21442, Saudi Arabia;
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Ali M. El-Halawany
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;
| | - Azizah M. Malebari
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Ibrahim A. Shehata
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.Z.T.); (I.A.S.)
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;
| | - Hany M. El-Bassossy
- Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
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