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Alves I, Araújo EMQ, Dalgaard LT, Singh S, Børsheim E, Carvalho E. Protective Effects of Sulforaphane Preventing Inflammation and Oxidative Stress to Enhance Metabolic Health: A Narrative Review. Nutrients 2025; 17:428. [PMID: 39940284 PMCID: PMC11821257 DOI: 10.3390/nu17030428] [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: 12/06/2024] [Revised: 01/13/2025] [Accepted: 01/16/2025] [Indexed: 02/14/2025] Open
Abstract
The worldwide obesity epidemic has led to a drastic increase in diabetes and cardiovascular disease in younger generations. Further, maintaining metabolic health during aging is frequently a challenge due to poor diets and decreased mobility. In this setting, bioactive nutrients that are naturally occurring antioxidants, such as sulforaphane (SFN), are of high nutritional interest. SFN, a bioactive compound that is present in cruciferous vegetables, is a molecule that protects cells from cytotoxic damage and mitigates oxidative stress, protecting against disease. It exerts its action through the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Many studies have been performed in animals and humans to evaluate its effects on cancer, brain health, and neurodegenerative disorders. However, fewer clinical studies have been performed to evaluate its effects on insulin resistance and the development of type 2 diabetes mellitus (T2DM) across the lifespan. Given that, in some parts of the world, particularly in Europe, the population is growing older at a significant rate, it is crucial to promote healthy habits (healthy foods, dietary pattern, precision nutrition, and physical activity) from an early stage in life and across the lifespan to avoid debilitating health conditions occurring during adulthood and aging. Thus, in this narrative review, we discuss the protective effects of SFN supplementation on inflammatory and oxidative stress pathways and relate them to metabolic disease.
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Affiliation(s)
- Inês Alves
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal;
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA;
| | - Edilene Maria Queiroz Araújo
- Nutritional Genomics and Metabolic Dysfunctions Research and Extension Center, Department of Life Sciences, State University of Bahia, Salvador 41195001, BA, Brazil;
| | - Louise T. Dalgaard
- Department of Science and Environment, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark;
| | - Sharda Singh
- Division of Hematology & Oncology, Department of Internal Medicine, Texas Tech University Medical Sciences Center, Lubbock, TX 79430, USA;
| | - Elisabet Børsheim
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA;
- Department of Pediatrics & Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Nutrition Center, Little Rock, AR 72202, USA
| | - Eugenia Carvalho
- CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Institute for Interdisciplinar Research, University of Coimbra, 3030-789 Coimbra, Portugal
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Habtemariam S. Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane. Biomedicines 2024; 12:1169. [PMID: 38927376 PMCID: PMC11200786 DOI: 10.3390/biomedicines12061169] [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: 04/23/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Isothiocyanates (ITCs) belong to a group of natural products that possess a highly reactive electrophilic -N=C=S functional group. They are stored in plants as precursor molecules, glucosinolates, which are processed by the tyrosinase enzyme upon plant tissue damage to release ITCs, along with other products. Isolated from broccoli, sulforaphane is by far the most studied antioxidant ITC, acting primarily through the induction of a transcription factor, the nuclear factor erythroid 2-related factor 2 (Nrf2), which upregulates downstream antioxidant genes/proteins. Paradoxically, sulforaphane, as a pro-oxidant compound, can also increase the levels of reactive oxygen species, a mechanism which is attributed to its anticancer effect. Beyond highlighting the common pro-oxidant and antioxidant effects of sulforaphane, the present paper was designed to assess the diverse anti-inflammatory mechanisms reported to date using a variety of in vitro and in vivo experimental models. Sulforaphane downregulates the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, cycloxyhenase-2, and inducible nitric oxide synthase. The signalling pathways of nuclear factor κB, activator protein 1, sirtuins 1, silent information regulator sirtuin 1 and 3, and microRNAs are among those affected by sulforaphane. These anti-inflammatory actions are sometimes due to direct action via interaction with the sulfhydryl structural moiety of cysteine residues in enzymes/proteins. The following are among the topics discussed in this paper: paradoxical signalling pathways such as the immunosuppressant or immunostimulant mechanisms; crosstalk between the oxidative and inflammatory pathways; and effects dependent on health and disease states.
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Affiliation(s)
- Solomon Habtemariam
- Pharmacognosy Research & Herbal Analysis Services UK, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, UK
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Kamal RM, Abdull Razis AF, Mohd Sukri NS, Perimal EK, Ahmad H, Patrick R, Djedaini-Pilard F, Mazzon E, Rigaud S. Beneficial Health Effects of Glucosinolates-Derived Isothiocyanates on Cardiovascular and Neurodegenerative Diseases. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030624. [PMID: 35163897 PMCID: PMC8838317 DOI: 10.3390/molecules27030624] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 12/17/2022]
Abstract
Neurodegenerative diseases (NDDs) and cardiovascular diseases (CVDs) are illnesses that affect the nervous system and heart, all of which are vital to the human body. To maintain health of the human body, vegetable diets serve as a preventive approach and particularly Brassica vegetables have been associated with lower risks of chronic diseases, especially NDDs and CVDs. Interestingly, glucosinolates (GLs) and isothiocyanates (ITCs) are phytochemicals that are mostly found in the Cruciferae family and they have been largely documented as antioxidants contributing to both cardio- and neuroprotective effects. The hydrolytic breakdown of GLs into ITCs such as sulforaphane (SFN), phenylethyl ITC (PEITC), moringin (MG), erucin (ER), and allyl ITC (AITC) has been recognized to exert significant effects with regards to cardio- and neuroprotection. From past in vivo and/or in vitro studies, those phytochemicals have displayed the ability to mitigate the adverse effects of reactive oxidation species (ROS), inflammation, and apoptosis, which are the primary causes of CVDs and NDDs. This review focuses on the protective effects of those GL-derived ITCs, featuring their beneficial effects and the mechanisms behind those effects in CVDs and NDDs.
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Affiliation(s)
- Ramla Muhammad Kamal
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
- Department of Pharmacology, Federal University Dutse, Dutse 720101, Jigawa State, Nigeria
| | - Ahmad Faizal Abdull Razis
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Correspondence:
| | - Nurul Syafuhah Mohd Sukri
- Faculty of Applied Science and Technology, Universiti Tun Hussein Onn Malaysia, Batu Pahat 86400, Johor, Malaysia;
| | - Enoch Kumar Perimal
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Hafandi Ahmad
- Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Rollin Patrick
- Université d’Orléans et CNRS, ICOA, UMR 7311, BP 6759, CEDEX 02, F-45067 Orléans, France;
| | - Florence Djedaini-Pilard
- LG2A UMR 7378, Université de Picardie Jules Verne, 33 rue Saint Leu—UFR des Sciences, F-80000 Amiens, France; (F.D.-P.); (S.R.)
| | - Emanuela Mazzon
- Laboratorio di Neurologia Sperimentale, IRCCS Centro Neurolesi "Bonino Pulejo", 98124 Messina, Italy;
| | - Sébastien Rigaud
- LG2A UMR 7378, Université de Picardie Jules Verne, 33 rue Saint Leu—UFR des Sciences, F-80000 Amiens, France; (F.D.-P.); (S.R.)
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Alonso-Piñeiro JA, Gonzalez-Rovira A, Sánchez-Gomar I, Moreno JA, Durán-Ruiz MC. Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress. Antioxidants (Basel) 2021; 10:1463. [PMID: 34573095 PMCID: PMC8466960 DOI: 10.3390/antiox10091463] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/02/2021] [Accepted: 09/09/2021] [Indexed: 12/19/2022] Open
Abstract
Atherosclerosis remains the underlying process responsible for cardiovascular diseases and the high mortality rates associated. This chronic inflammatory disease progresses with the formation of occlusive atherosclerotic plaques over the inner walls of vascular vessels, with oxidative stress being an important element of this pathology. Oxidation of low-density lipoproteins (ox-LDL) induces endothelial dysfunction, foam cell activation, and inflammatory response, resulting in the formation of fatty streaks in the atherosclerotic wall. With this in mind, different approaches aim to reduce oxidative damage as a strategy to tackle the progression of atherosclerosis. Special attention has been paid in recent years to the transcription factor Nrf2 and its downstream-regulated protein heme oxygenase-1 (HO-1), both known to provide protection against atherosclerotic injury. In the current review, we summarize the involvement of oxidative stress in atherosclerosis, focusing on the role that these antioxidant molecules exert, as well as the potential therapeutic strategies applied to enhance their antioxidant and antiatherogenic properties.
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Affiliation(s)
- Jose Angel Alonso-Piñeiro
- Biomedicine, Biotechnology and Public Health Department, Cádiz University, 11519 Puerto Real, Spain; (J.A.A.-P.); (A.G.-R.); (I.S.-G.)
- Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA), 11001 Cádiz, Spain
| | - Almudena Gonzalez-Rovira
- Biomedicine, Biotechnology and Public Health Department, Cádiz University, 11519 Puerto Real, Spain; (J.A.A.-P.); (A.G.-R.); (I.S.-G.)
- Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA), 11001 Cádiz, Spain
| | - Ismael Sánchez-Gomar
- Biomedicine, Biotechnology and Public Health Department, Cádiz University, 11519 Puerto Real, Spain; (J.A.A.-P.); (A.G.-R.); (I.S.-G.)
- Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA), 11001 Cádiz, Spain
| | - Juan Antonio Moreno
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), UGC Nephrology, Hospital Universitario Reina Sofia, 14004 Cordoba, Spain;
- Department of Cell Biology, Physiology, and Immunology, Agrifood Campus of International Excellence (ceiA3), University of Cordoba, 14014 Cordoba, Spain
| | - Ma Carmen Durán-Ruiz
- Biomedicine, Biotechnology and Public Health Department, Cádiz University, 11519 Puerto Real, Spain; (J.A.A.-P.); (A.G.-R.); (I.S.-G.)
- Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA), 11001 Cádiz, Spain
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Banerjee N, Wang H, Wang G, Boor PJ, Khan MF. Redox-sensitive Nrf2 and MAPK signaling pathways contribute to trichloroethene-mediated autoimmune disease progression. Toxicology 2021; 457:152804. [PMID: 33930529 PMCID: PMC8230612 DOI: 10.1016/j.tox.2021.152804] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/21/2021] [Accepted: 04/23/2021] [Indexed: 12/15/2022]
Abstract
Trichloroethene (TCE) exposure is associated with the induction of autoimmune diseases (ADs). Although oxidative stress plays a major role in TCE-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Dysregulation of redox-sensitive nuclear factor (erythroid-derived 2)-like2 (Nrf2), resulting in uncontrolled antioxidant and cytoprotective genes, and pro-inflammatory MAPK signaling pathways could be critical in TCE-mediated disease progression. This study was, therefore, focused on establishing status and contribution of Nrf2 and MAPK signaling in TCE-mediated inflammatory and autoimmune responses, especially during disease progression. To achieve these objectives, time-response studies were conducted by treating female MRL+/+ mice with TCE (0.5 mg/mL, a dose relevant to human exposure) for 24, 36 and 52 wks. TCE exposure led to reduction in Nrf2 expression, but increased phos-NF-κB (p65) and iNOS along with increased phosphorylation of MAPKs (p38, ERK and JNK) and downstream pro-inflammatory cytokines IL-12, TNF-α and RANTES in the livers in a time-dependent manner. These changes were also associated with time-dependent increases in liver protein carbonyls and induction of serum anti-dsDNA antibodies (marker of systemic lupus erythematosus disease), further supporting the role of oxidative stress and Nrf2/MAPK signaling in TCE-mediated autoimmune response progression. The mechanistic role of MAPK in TCE-mediated autoimmunity was further established by treating MRL+/+ mice with sulforaphane (SFN; 8 mg/kg, i.p., every other day) along with TCE (10 mmol/kg, i.p., every 4th day) for 6 wks using an established protocol, and by in vitro treatment of T cells with dichloroacetyl chloride (a TCE metabolite) with/without p38 MAPK inhibitor. SFN treatment attenuated the TCE-mediated phosphorylation of p38 MAPK. More importantly, treatment with SFN or p38 inhibitor led to suppression of downstream pro-inflammatory cytokines IL-12 and TNF-α. These findings thus support the contribution of Nrf2 and MAPK signaling pathways and help in delineating novel potential therapeutic targets against TCE-mediated autoimmunity.
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Affiliation(s)
- Nivedita Banerjee
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, United States
| | - Hui Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, United States
| | - Gangduo Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, United States
| | - Paul J Boor
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, United States
| | - M Firoze Khan
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, United States.
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Fukunaga N, Kawajiri H, Badiwala MV, Butany J, Li RK, Billia F, Rao V. Protective role of Nrf2 against ischemia reperfusion injury and cardiac allograft vasculopathy. Am J Transplant 2020; 20:1262-1271. [PMID: 31769924 DOI: 10.1111/ajt.15724] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 11/13/2019] [Accepted: 11/18/2019] [Indexed: 01/25/2023]
Abstract
Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.
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Affiliation(s)
- Naoto Fukunaga
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Hiroyuki Kawajiri
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Mitesh V Badiwala
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Jagdish Butany
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Ren-Ke Li
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Filio Billia
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Vivek Rao
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Houghton CA. Sulforaphane: Its "Coming of Age" as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2716870. [PMID: 31737167 PMCID: PMC6815645 DOI: 10.1155/2019/2716870] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 06/24/2019] [Accepted: 09/06/2019] [Indexed: 12/17/2022]
Abstract
A growing awareness of the mechanisms by which phytochemicals can influence upstream endogenous cellular defence processes has led to intensified research into their potential relevance in the prevention and treatment of disease. Pharmaceutical medicine has historically looked to plants as sources of the starting materials for drug development; however, the focus of nutraceutical medicine is to retain the plant bioactive in as close to its native state as possible. As a consequence, the potency of a nutraceutical concentrate or an extract may be lower than required for significant gene expression. The molecular structure of bioactive phytochemicals to a large extent determines the molecule's bioavailability. Polyphenols are abundant in dietary phytochemicals, and extensive in vitro research has established many of the signalling mechanisms involved in favourably modulating human biochemical pathways. Such pathways are associated with core processes such as redox modulation and immune modulation for infection control and for downregulating the synthesis of inflammatory cytokines. Although the relationship between oxidative stress and chronic disease continues to be affirmed, direct-acting antioxidants such as vitamins A, C, and E, beta-carotene, and others have not yielded the expected preventive or therapeutic responses, even though several large meta-analyses have sought to evaluate the potential benefit of such supplements. Because polyphenols exhibit poor bioavailability, few of their impressive in vitro findings have been replicated in vivo. SFN, an aliphatic isothiocyanate, emerges as a phytochemical with comparatively high bioavailability. A number of clinical trials have demonstrated its ability to produce favourable outcomes in conditions for which there are few satisfactory pharmaceutical solutions, foreshadowing the potential for SFN as a clinically relevant nutraceutical. Although myrosinase-inert broccoli sprout extracts are widely available, there now exist myrosinase-active broccoli sprout supplements that yield sufficient SFN to match the doses used in clinical trials.
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Abellán Á, Domínguez-Perles R, Moreno DA, García-Viguera C. Sorting out the Value of Cruciferous Sprouts as Sources of Bioactive Compounds for Nutrition and Health. Nutrients 2019; 11:E429. [PMID: 30791362 PMCID: PMC6412956 DOI: 10.3390/nu11020429] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/13/2019] [Accepted: 02/13/2019] [Indexed: 12/19/2022] Open
Abstract
Edible sprouts with germinating seeds of a few days of age are naturally rich in nutrients and other bioactive compounds. Among them, the cruciferous (Brassicaceae) sprouts stand out due to their high contents of glucosinolates (GLSs) and phenolic compounds. In order to obtain sprouts enriched in these phytochemicals, elicitation is being increasing used as a sustainable practice. Besides, the evidence regarding the bioavailability and the biological activity of these compounds after their dietary intake has also attracted growing interest in recent years, supporting the intake of the natural food instead of enriched ingredients or extracts. Also, there is a growing interest regarding their uses, consumption, and applications for health and wellbeing, in different industrial sectors. In this context, the present review aims to compile and update the available knowledge on the fundamental aspects of production, enrichment in composition, and the benefits upon consumption of diverse edible cruciferous sprouts, which are sources of phenolic compounds and glucosinolates, as well as the evidence on their biological actions in diverse pathophysiological situations and the molecular pathways involved.
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Affiliation(s)
- Ángel Abellán
- Phytochemistry and Healthy Foods Lab, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS (CSIC), Campus Universitario de Espinardo 25, 30100 Murcia, Spain.
| | - Raúl Domínguez-Perles
- Phytochemistry and Healthy Foods Lab, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS (CSIC), Campus Universitario de Espinardo 25, 30100 Murcia, Spain.
| | - Diego A Moreno
- Phytochemistry and Healthy Foods Lab, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS (CSIC), Campus Universitario de Espinardo 25, 30100 Murcia, Spain.
| | - Cristina García-Viguera
- Phytochemistry and Healthy Foods Lab, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS (CSIC), Campus Universitario de Espinardo 25, 30100 Murcia, Spain.
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Cox AG, Gurusinghe S, Abd Rahman R, Leaw B, Chan ST, Mockler JC, Murthi P, Marshall SA, Lim R, Wallace EM. Sulforaphane improves endothelial function and reduces placental oxidative stress in vitro. Pregnancy Hypertens 2019; 16:1-10. [PMID: 31056142 DOI: 10.1016/j.preghy.2019.02.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 01/21/2019] [Accepted: 02/08/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The maternal endothelial dysfunction characteristic of preeclampsia arises, in part, from excessive placental production of anti-angiogenic factors, including soluble Flt-1, soluble endoglin and activin A, inducing oxidative stress. We assessed whether the antioxidant and NRF2-activator sulforaphane could mitigate endothelial and trophoblast dysfunction in vitro. METHODS We induced dysfunction in human umbilical vein endothelial cells (HUVECs) with TNF-α, assessing endothelial activation and dysfunction (endothelin-1, vascular cell adhesion molecule; VCAM1, intracellular adhesion molecule; ICAM1, e-selectin and endothelial permeability) in the presence or absence of sulforaphane. We also assessed the effects of sulforaphane in mitigating hypoxic and hyperoxic injury in term placental explants by measuring secretion of anti-angiogenic factors. To assess the role of NRF2 we silenced NRF2 in HUVECs and primary trophoblast cells. RESULTS Sulforaphane reduced TNF-α mediated HUVEC secretion of endothelin-1, VCAM1, ICAM1 and E-selectin, and prevented increased endothelial permeability. In placental explants, sulforaphane reduced the secretion of soluble Flt-1, soluble endoglin and activin A. Sulforaphane induced activation and nuclear translocation of NRF2 in HUVECs, inducing heme oxygenase 1. NRF2 silencing blocked some but not all of sulforaphane's effects in HUVECs. NRF2 silencing did not prevent sulforaphane's inhibition of trophobast secretion of soluble Flt-1 or activin A. CONCLUSION In reducing placental and endothelial oxidative stress, sulforaphane may offer a new adjuvant therapeutic approach for the treatment of preeclampsia.
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Affiliation(s)
- Annie G Cox
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
| | - Seshini Gurusinghe
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
| | - Rahana Abd Rahman
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
| | - Bryan Leaw
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
| | - Siow T Chan
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
| | - Joanne C Mockler
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
| | - Padma Murthi
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
| | - Sarah A Marshall
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
| | - Rebecca Lim
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
| | - Euan M Wallace
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
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Patel B, Mann GE, Chapple SJ. Concerted redox modulation by sulforaphane alleviates diabetes and cardiometabolic syndrome. Free Radic Biol Med 2018; 122:150-160. [PMID: 29427794 DOI: 10.1016/j.freeradbiomed.2018.02.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 02/01/2018] [Accepted: 02/03/2018] [Indexed: 02/07/2023]
Abstract
Diabetes and cardiometabolic disorders such as hypertension and obesity are major risk factors for the development of cardiovascular disease, with a wealth of evidence suggesting that oxidative stress is linked to the initiation and pathogenesis of these disease processes. With yearly increases in the global incidence of cardiovascular diseases (CVD) and diabetes, numerous studies have focused on characterizing whether upregulating antioxidant defenses through exogenous antioxidants (e.g. vitamin E, vitamin C) or activation of endogenous defenses (e.g. the Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant defense pathway) may be of benefit. The dietary isothiocyanate sulforaphane (SFN) is currently the subject of several clinical trials for a variety of disease states, including the evaluation of its therapeutic potential to ameliorate diabetic and cardiometabolic complications. SFN is a well characterized and potent Nrf2 inducer, however recent studies suggest its protective actions may be in part mediated by its modulation of various pro-inflammatory (e.g. Nuclear factor-kappa B (NFκB)) and metabolic (e.g. Peroxisome Proliferator-Activator Receptor Gamma (PPARγ)) signaling pathways. The focus of this review is to provide a detailed analysis of the known mechanisms by which SFN modulates Nrf2, NFκB and PPARγ signaling and crosstalk and to provide a critical evaluation of the evidence linking these transcriptional pathways with diabetic and cardiometabolic complications and SFN mediated cytoprotection. To allow comparison between rodent and human studies, we discuss the published bioavailability of SFN metabolites achieved in rodents and man in the context of Nrf2, NFκB and PPARγ signaling. Furthermore, we provide an update on the functional outcomes and implicated signaling pathways reported in recent clinical trials with SFN in Type 2 diabetic patients.
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Affiliation(s)
- Bijal Patel
- King's BHF Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Giovanni E Mann
- King's BHF Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Sarah J Chapple
- King's BHF Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
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11
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Li HL, Jin JM, Yang C, Wang P, Huang F, Wu H, Zhang BB, Shi HL, Wu XJ. Isoastragaloside I suppresses LPS-induced tight junction disruption and monocyte adhesion on bEnd.3 cells via an activating Nrf2 antioxidant defense system. RSC Adv 2018. [DOI: 10.1039/c7ra10246a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
ISOI rescued TJs disruption from ROS induced by LPS in bEnd.3 cells. ISOI ameliorated inflammatory response and decreased monocyte adhesion onto bEnd.3 cells induced with LPS. ISOI protected BBB integrity through activating Nrf2 antioxidant pathway.
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Affiliation(s)
- Hong-Li Li
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Jin-Mei Jin
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Chun Yang
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Ping Wang
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Fei Huang
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Hui Wu
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Bei-Bei Zhang
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Hai-Lian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
| | - Xiao-Jun Wu
- Shanghai Key Laboratory of Compound Chinese Medicines
- The Ministry of Education (MOE)
- Key Laboratory for Standardization of Chinese Medicines
- Institute of Chinese Materia Medica
- Shanghai University of Traditional Chinese Medicine
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12
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Jang YJ, Park B, Lee HW, Park HJ, Koo HJ, Kim BO, Sohn EH, Um SH, Pyo S. Sinigrin attenuates the progression of atherosclerosis in ApoE -/- mice fed a high-cholesterol diet potentially by inhibiting VCAM-1 expression. Chem Biol Interact 2017; 272:28-36. [PMID: 28483571 DOI: 10.1016/j.cbi.2017.05.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 05/04/2017] [Indexed: 10/19/2022]
Abstract
Atherosclerosis is a complex inflammatory disease associated with elevated levels of atherogenic molecules for leukocyte recruitment. Sinigrin (2-propenylglucosinolate) is found mainly in broccoli, brussels sprouts, and black mustard seeds. Recently, sinigrin has received attention for its role in disease prevention and health promotion. In this study, we examined the effect of sinigrin on development of atherosclerosis in ApoE-/- mice and the expression of adhesion molecules in vascular smooth muscle cells (VSMCs). The serum concentrations of lactate dehydrogenase (LDH), triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), calcium (Ca2+), and pro-inflammatory cytokines were reduced by sinigrin treatment in ApoE-/- mice. In addition, oral administration of sinigrin attenuated the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), C-C motif chemokine ligand 2 (CCL2), and CCL5 on aorta tissues and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), liver X receptor (LXR), sterol regulatory element-binding protein-2 (SREBP-2), and low density lipoprotein receptor (LDLR) on liver tissues in ApoE-/- mice. To provide a potential mechanism underlying the action of sinigrin, we evaluated the in vitro effect of sinigrin on the expression of the VCAM-1 in TNF-α-induced VSMCs. The increased expression of VCAM-1 by TNF-α stimulation was significantly suppressed by the treatment of sinigrin (1-100 μg/ml) and sinigrin inhibited the nuclear translocation of NF-κB and the phosphorylation of p38 MAPK and JNK pathways, suggesting that sinigrin decreases the TNF-α-stimulated VCAM-1 expression through the suppression of NF-κB and MAP kinases signaling pathways. Overall, sinigrin has the potential to be used in reducing the risks of atherosclerosis.
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Affiliation(s)
- Yeon Jeong Jang
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Bongkyun Park
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Hee-Weon Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Hye Jin Park
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Hyun Jung Koo
- Department of Medicinal & Industrial Crops, Korea National College of Agriculture and Fisheries, Jeonju, 54874, Republic of Korea
| | - Byung Oh Kim
- School of Food Sciences & Biotechnology, College of Agriculture & Life Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Eun-Hwa Sohn
- Department of Herbal Medicine Resources, Kangwon National University, Samcheok, 25913, Republic of Korea
| | - Sung Hee Um
- Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Suhkneung Pyo
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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13
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Wojtala M, Pirola L, Balcerczyk A. Modulation of the vascular endothelium functioning by dietary components, the role of epigenetics. Biofactors 2017; 43:5-16. [PMID: 27355807 DOI: 10.1002/biof.1306] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/18/2016] [Accepted: 05/20/2016] [Indexed: 02/06/2023]
Abstract
Rather than being a passive barrier between circulating blood and smooth muscle cells and the underlying tissues, the endothelium is a fundamental functional component of the vasculature, and could be viewed as the largest human endocrine gland/organ, secreting multiple pro-/antiangiogenic factors, cytokines and low-molecular-weight mediators controlling the vascular tone. The location of endothelium, at the interface between the circulation and the tissues, makes this epithelial layer particularly exposed to physical and chemical cues coming from the bloodstream. In response to such stimuli, the endothelium modulates its morphology and functions to maintain vascular homeostasis. Dietary components significantly affect the proper functioning of the endothelium. High-calories and high-fat western diets, in the long term, cause endothelial dysfunction, which is a major contributor to the development of the metabolic syndrome and its pathological consequences, including atherosclerosis, diabetes, and hypertension. On the contrary, plant-derived antioxidant molecules and polyphenols have been shown to exert beneficial effects on endothelial function. Extensive research in the last decade has clearly shown the close relationship between food intake, dietary habits, and gene expression, which is driven by the action of macro- and micronutrients on chromatin regulation. Nutrient-induced chromatin epigenetic modifications via DNA methylation and histone post-translational modifications, especially in the context of the western diet, significantly contribute to the dysregulation of endothelial functioning. Here, we review the current understanding on how dietary components (macronutrients, antioxidants), acting on epigenetic mechanisms, regulate endothelial physiology, and physiopathology. © 2016 BioFactors, 43(1):5-16, 2017.
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Affiliation(s)
- Martyna Wojtala
- Department of Molecular Biophysics, University of Lodz, Pomorska 141/143, Lodz, 90-236, Poland
| | - Luciano Pirola
- Faculty of Medicine Lyon SUD, Carmen Institute, INSERM U1060, Oullins, Cedex, France
| | - Aneta Balcerczyk
- Department of Molecular Biophysics, University of Lodz, Pomorska 141/143, Lodz, 90-236, Poland
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14
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Yamagishi SI, Matsui T. Protective role of sulphoraphane against vascular complications in diabetes. PHARMACEUTICAL BIOLOGY 2016; 54:2329-2339. [PMID: 26841240 DOI: 10.3109/13880209.2016.1138314] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Context Diabetes is a global health challenge. Although large prospective clinical trials have shown that intensive control of blood glucose or blood pressure reduces the risk for development and progression of vascular complications in diabetes, a substantial number of diabetic patients still experience renal failure and cardiovascular events, which could account for disabilities and high mortality rate in these subjects. Objective Sulphoraphane is a naturally occurring isothiocyanate found in widely consumed cruciferous vegetables, such as broccoli, cabbage and Brussels sprouts, and an inducer of phase II antioxidant and detoxification enzymes with anticancer properties. We reviewed here the protective role of sulphoraphane against diabetic vascular complications. Methods In this review, literature searches were undertaken in Medline and in CrossRef. Non-English language articles were excluded. Keywords [sulphoraphane and (diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, diabetic complications, vascular, cardiomyocytes, heart or glycation)] have been used to select the articles. Results There is accumulating evidence that sulphoraphane exerts beneficial effects on vascular damage in both cell culture and diabetic animal models via antioxidative properties. Furthermore, we have recently found that sulphoraphane inhibits in vitro formation of advanced glycation end products (AGEs), suppresses the AGE-induced inflammatory reactions in rat aorta by reducing receptor for AGEs (RAGE) expression and decreases serum levels of AGEs in humans. Conclusion These findings suggest that blockade of oxidative stress and/or the AGE-RAGE axis by sulphoraphane may be a novel therapeutic strategy for preventing vascular complications in diabetes.
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Affiliation(s)
- Sho-Ichi Yamagishi
- a Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications , Kurume University School of Medicine , Kurume , Japan
| | - Takanori Matsui
- a Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications , Kurume University School of Medicine , Kurume , Japan
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15
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Matsui T, Nakamura N, Ojima A, Nishino Y, Yamagishi SI. Sulforaphane reduces advanced glycation end products (AGEs)-induced inflammation in endothelial cells and rat aorta. Nutr Metab Cardiovasc Dis 2016; 26:797-807. [PMID: 27212619 DOI: 10.1016/j.numecd.2016.04.008] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 04/04/2016] [Accepted: 04/12/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Advanced glycation end products (AGEs)-receptor RAGE interaction evokes oxidative stress and inflammatory reactions, thereby being involved in endothelial cell (EC) damage in diabetes. Sulforaphane is generated from glucoraphanin, a naturally occurring isothiocyanate found in widely consumed cruciferous vegetables, by myrosinase. Sulforaphane has been reported to protect against oxidative stress-mediated cell and tissue injury. However, effects of sulforaphane on AGEs-induced vascular damage remain unclear. METHODS AND RESULTS In this study, we investigated whether and how sulforaphane could inhibit inflammation in AGEs-exposed human umbilical vein ECs (HUVECs) and AGEs-injected rat aorta. Sulforaphane treatment for 4 or 24 h dose-dependently inhibited the AGEs-induced increase in RAGE, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecular-1 (VCAM-1) gene expression in HUVECs. AGEs significantly stimulated MCP-1 production by, and THP-1 cell adhesion to, HUVECs, both of which were prevented by 1.6 μM sulforaphane. Sulforaphane significantly suppressed oxidative stress generation and NADPH oxidase activation evoked by AGEs in HUVECs. Furthermore, aortic RAGE, ICAM-1 and VCAM-1 expression in AGEs-injected rats were increased, which were suppressed by simultaneous infusion of sulforaphane. CONCLUSION The present study demonstrated for the first time that sulforaphane could inhibit inflammation in AGEs-exposed HUVECs and AGEs-infused rat aorta partly by suppressing RAGE expression through its anti-oxidative properties. Inhibition of the AGEs-RAGE axis by sulforaphane might be a novel therapeutic target for vascular injury in diabetes.
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Affiliation(s)
- T Matsui
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - N Nakamura
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - A Ojima
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - Y Nishino
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | - S-I Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
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16
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Holloway PM, Gillespie S, Becker F, Vital SA, Nguyen V, Alexander JS, Evans PC, Gavins FNE. Sulforaphane induces neurovascular protection against a systemic inflammatory challenge via both Nrf2-dependent and independent pathways. Vascul Pharmacol 2016; 85:29-38. [PMID: 27401964 DOI: 10.1016/j.vph.2016.07.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 07/01/2016] [Accepted: 07/03/2016] [Indexed: 12/25/2022]
Abstract
Sepsis is often characterized by an acute brain inflammation and dysfunction, which is associated with increased morbidity and mortality worldwide. Preventing cerebral leukocyte recruitment may provide the key to halt progression of systemic inflammation to the brain. Here we investigated the influence of the anti-inflammatory and anti-oxidant compound, sulforaphane (SFN) on lipopolysaccharide (LPS)-induced cellular interactions in the brain. The inflammatory response elicited by LPS was blunted by SFN administration (5 and 50mg/kg i.p.) 24h prior to LPS treatment in WT animals, as visualized and quantified using intravital microscopy. This protective effect of SFN was lost in Nrf2-KO mice at the lower dose tested, however 50mg/kg SFN revealed a partial effect, suggesting SFN works in part independently of Nrf2 activity. In vitro, SFN reduced neutrophil recruitment to human brain endothelial cells via a down regulation of E-selectin and vascular cell adhesion molecule 1 (VCAM-1). Our data confirm a fundamental dose-dependent role of SFN in limiting cerebral inflammation. Furthermore, our data demonstrate that not only is Nrf2 in part essential in mediating these neuroprotective effects, but they occur via down-regulation of E-selectin and VCAM-1. In conclusion, SFN may provide a useful therapeutic drug to reduce cerebral inflammation in sepsis.
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Affiliation(s)
- Paul M Holloway
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Scarlett Gillespie
- Division of Brain Sciences, Imperial College London, London, United Kingdom
| | - Felix Becker
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA; Department for General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
| | - Shantel A Vital
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Victoria Nguyen
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - J Steven Alexander
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Paul C Evans
- Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom
| | - Felicity N E Gavins
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA; Division of Brain Sciences, Imperial College London, London, United Kingdom.
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17
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Sulforaphane improves dysregulated metabolic profile and inhibits leptin-induced VSMC proliferation: Implications toward suppression of neointima formation after arterial injury in western diet-fed obese mice. J Nutr Biochem 2016; 32:73-84. [PMID: 27142739 DOI: 10.1016/j.jnutbio.2016.01.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 01/19/2016] [Accepted: 01/28/2016] [Indexed: 12/24/2022]
Abstract
Sulforaphane (SFN), a dietary phase-2 enzyme inducer that mitigates cellular oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) activation, is known to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. In particular, SFN attenuates the mitogenic and pro-inflammatory actions of platelet-derived growth factor (PDGF) and tumor necrosis factor-α (TNFα), respectively, in VSMCs. Nevertheless, the vasoprotective role of SFN has not been examined in the setting of obesity characterized by hyperleptinemia and insulin resistance. Using the mouse model of western diet-induced obesity, the present study demonstrates for the first time that subcutaneous delivery of SFN (0.5mg/Kg/day) for~3weeks significantly attenuates neointima formation in the injured femoral artery [↓ (decrease) neointima/media ratio by~60%; n=5-8]. This was associated with significant improvements in metabolic parameters, including ↓ weight gain by~52%, ↓ plasma leptin by~42%, ↓ plasma insulin by~63%, insulin resistance [↓ homeostasis model assessment of insulin resistance (HOMA-IR) index by~73%], glucose tolerance (↓ AUCGTT by~24%), and plasma lipid profile (e.g., ↓ triglycerides). Under in vitro conditions, SFN significantly decreased leptin-induced VSMC proliferation by~23% (n=5) with associated diminutions in leptin-induced cyclin D1 expression and the phosphorylation of p70S6kinase and ribosomal S6 protein (n=3-4). The present findings reveal that, in addition to improving systemic metabolic parameters, SFN inhibits leptin-induced VSMC proliferative signaling that may contribute in part to the suppression of injury-induced neointima formation in diet-induced obesity.
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18
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Inhibition of VCAM-1 expression on mouse vascular smooth muscle cells by lobastin via downregulation of p38, ERK 1/2 and NF-κB signaling pathways. Arch Pharm Res 2015; 39:83-93. [DOI: 10.1007/s12272-015-0687-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 11/18/2015] [Indexed: 10/22/2022]
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Mimura J, Itoh K. Role of Nrf2 in the pathogenesis of atherosclerosis. Free Radic Biol Med 2015; 88:221-232. [PMID: 26117321 DOI: 10.1016/j.freeradbiomed.2015.06.019] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Revised: 06/03/2015] [Accepted: 06/06/2015] [Indexed: 01/01/2023]
Abstract
Atherosclerosis is a chronic inflammatory disease of the vascular arterial walls. A number of studies have revealed the biological and genetic bases of atherosclerosis, and over 100 genes influence atherosclerosis development. Nrf2 plays an important role in oxidative stress response and drug metabolism, but the Nrf2 signaling pathway is closely associated with atherosclerosis development. During atherosclerosis progression, Nrf2 signaling modulates many physiological and pathophysiological processes, such as lipid homeostasis regulation, foam cell formation, macrophage polarization, redox regulation and inflammation. Interestingly, Nrf2 exhibits both pro- and anti-atherogenic effects in experimental animal models. These observations make the Nrf2 pathway a promising target to prevent atherosclerosis.
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Affiliation(s)
- Junsei Mimura
- Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
| | - Ken Itoh
- Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
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20
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Sulforaphane Protects against Cardiovascular Disease via Nrf2 Activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:407580. [PMID: 26583056 PMCID: PMC4637098 DOI: 10.1155/2015/407580] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Revised: 04/20/2015] [Accepted: 04/28/2015] [Indexed: 01/18/2023]
Abstract
Cardiovascular disease (CVD) causes an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Oxidative stress plays a major role in the pathophysiology of cardiac disorders. Several studies have highlighted the cardinal role played by the overproduction of reactive oxygen or nitrogen species in the pathogenesis of ischemic myocardial damage and consequent cardiac dysfunction. Isothiocyanates (ITC) are sulfur-containing compounds that are broadly distributed among cruciferous vegetables. Sulforaphane (SFN) is an ITC shown to possess anticancer activities by both in vivo and epidemiological studies. Recent data have indicated that the beneficial effects of SFN in CVD are due to its antioxidant and anti-inflammatory properties. SFN activates NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than a hundred cytoprotective proteins, including antioxidants and phase II detoxifying enzymes. This review will summarize the evidence from clinical studies and animal experiments relating to the potential mechanisms by which SFN modulates Nrf2 activation and protects against CVD.
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Shehatou GSG, Suddek GM. Sulforaphane attenuates the development of atherosclerosis and improves endothelial dysfunction in hypercholesterolemic rabbits. Exp Biol Med (Maywood) 2015; 241:426-36. [PMID: 26490346 DOI: 10.1177/1535370215609695] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 09/02/2015] [Indexed: 01/17/2023] Open
Abstract
The aim of the present work was to explore possible protective effects of sulforaphane (SFN) against atherosclerosis development and endothelial dysfunction in hypercholesterolemic rabbits. Rabbits were assigned to three groups of five: group I fed normal chow diet for four weeks, group II fed 1% high cholesterol diet (HCD) and group III fed HCD + SFN (0.25 mg/kg/day). Blood samples were collected for measurement of serum triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), lactate dehydrogenase (LDH) and C-reactive protein (CRP). Aortic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and total nitrite/nitrate (NOx) were measured. Vascular reactivity and intima/media (I/M) ratio were analyzed. Nuclear factor-kappa B (NF-κB) activation in aortic endothelial cells was identified immunohistochemically. HCD induced significant increases in serum TGs, TC, LDL-C, LDH, and CRP, and aortic MDA and SOD. Moreover, HCD caused significant reductions in serum HDL-C, aortic GSH and NOx. SFN administration significantly decreased HCD-induced elevations in serum TC, LDL-C, CRP, and LDH. while significantly increased HDL-C and GSH levels and normalized aortic SOD and NOx. Additionally, SFN significantly improved rabbit aortic endothelium-dependent relaxation to acetylcholine. Moreover, SFN significantly reduced the elevation in I/M ratio. This effect was confirmed by aortic histopathologic examination. The expression of NF-κB in aortic tissue showed a marked reduction upon treatment with SFN. In conclusion, this study reveals that SFN has the ability to ameliorate HCD-induced atherosclerotic lesions progression and vascular dysfunction, possibly via its lipid-lowering and antioxidant effects and suppression of NF-κB-mediated inflammation.
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Affiliation(s)
- George S G Shehatou
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Ghada M Suddek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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22
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Brown RH, Reynolds C, Brooker A, Talalay P, Fahey JW. Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways. Respir Res 2015; 16:106. [PMID: 26369337 PMCID: PMC4570035 DOI: 10.1186/s12931-015-0253-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 07/21/2015] [Indexed: 01/16/2023] Open
Abstract
Background It is widely recognized that deep inspiration (DI), either before methacholine (MCh) challenge (Bronchoprotection, BP) or after MCh challenge (Bronchodilation, BD) protects against this challenge in healthy individuals, but not in asthmatics. Sulforaphane, a dietary antioxidant and antiinflammatory phytochemical derived from broccoli, may affect the pulmonary bronchoconstrictor responses to MCh and the responses to DI in asthmatic patients. Methods Forty-five moderate asthmatics were administered sulforaphane (100 μmol daily for 14 days), BP, BD, lung volumes by body-plethsmography, and airway morphology by computed tomography (CT) were measured pre- and post sulforaphane consumption. Results Sulforaphane ameliorated the bronchoconstrictor effects of MCh on FEV1 significantly (on average by 21 %; p = 0.01) in 60 % of these asthmatics. Interestingly, in 20 % of the asthmatics, sulforaphane aggravated the bronchoconstrictor effects of MCh and in a similar number was without effect, documenting the great heterogeneity of the responsiveness of these individuals to sulforaphane. Moreover, in individuals in whom the FEV1 response to MCh challenge decreased after sulforaphane administration, i.e., sulforaphane was protective, the activities of Nrf2-regulated antioxidant and anti-inflammatory genes decreased. In contrast, individuals in whom sulforaphane treatment enhanced the FEV1 response to MCh, had increased expression of the activities of these genes. High resolution CT scans disclosed that in asthmatics sulforaphane treatment resulted in a significant reduction in specific airway resistance and also increased small airway luminal area and airway trapping modestly but significantly. Conclusion These findings suggest the potential value of blocking the bronchoconstrictor hyperresponsiveness in some types of asthmatics by phytochemicals such as sulforaphane.
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Affiliation(s)
- Robert H Brown
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,Division of Pulmonary Medicine and Critical Care, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Room E7614, 615 N. Wolfe Street, Baltimore, MD, 21205, USA.
| | - Curt Reynolds
- Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Room E7614, 615 N. Wolfe Street, Baltimore, MD, 21205, USA
| | - Allison Brooker
- Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Room E7614, 615 N. Wolfe Street, Baltimore, MD, 21205, USA
| | - Paul Talalay
- Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Center for Human Nutrition, Department of International Health, Johns Hopkins University School of Public Health, Baltimore, MD, USA
| | - Jed W Fahey
- Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Center for Human Nutrition, Department of International Health, Johns Hopkins University School of Public Health, Baltimore, MD, USA
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Park B, Yim JH, Lee HK, Kim BO, Pyo S. Ramalin inhibits VCAM-1 expression and adhesion of monocyte to vascular smooth muscle cells through MAPK and PADI4-dependent NF-kB and AP-1 pathways. Biosci Biotechnol Biochem 2014; 79:539-52. [PMID: 25494680 DOI: 10.1080/09168451.2014.991681] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Cell adhesion molecules play a critical role in inflammatory processes and atherosclerosis. In this study, we investigated the effect of ramalin, a chemical compound from the Antarctic lichen Ramalina terebrata, on vascular cell adhesion molecule-1 (VCAM-1) expression induced by TNF-α in vascular smooth muscular cells (VSMCs). Pretreatment of VSMCs with ramalin (0.1-10 μg/mL) concentration-dependently inhibited TNF-α-induced VCAM-1 expression. Additionally, ramalin inhibited THP-1 (human acute monocytic leukemia cell line) cell adhesion to TNF-α-stimulated VSMCs. Ramalin suppressed TNF-α-induced production of reactive oxygen species (ROS), PADI4 expression, and phosphorylation of p38, ERK, and JNK. Moreover, ramalin inhibited TNF-α-induced translocation of NF-κB and AP-1. Inhibition of PADI4 expression by small interfering RNA or the PADI4-specific inhibitor markedly attenuated TNF-α-induced activation of NF-κB and AP-1 and VCAM-1 expression in VSMCs. Our study provides insight into the mechanisms underlying ramalin activity and suggests that ramalin may be a potential therapeutic agent to modulate inflammation within atherosclerosis.
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Affiliation(s)
- Bongkyun Park
- a School of Pharmacy , Sungkyunkwan University , Suwon , Republic of Korea
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Byrne MM, Murphy RT, Ryan AW. Epigenetic modulation in the treatment of atherosclerotic disease. Front Genet 2014; 5:364. [PMID: 25389432 PMCID: PMC4211541 DOI: 10.3389/fgene.2014.00364] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 09/29/2014] [Indexed: 12/14/2022] Open
Abstract
Cardiovascular disease is the single largest cause of death in the western world and its incidence is on the rise globally. Atherosclerosis, characterized by the development of atheromatus plaque, can trigger luminal narrowing and upon rupture result in myocardial infarction or ischemic stroke. Epigenetic phenomena are a focus of considerable research interest due to the role they play in gene regulation. Epigenetic mechanisms such as DNA methylation and histone acetylation have been identified as potential drug targets in the treatment of cardiovascular disease. miRNAs are known to play a role in gene silencing, which has been widely investigated in cancer. In comparison, the role they play in cardiovascular disease and plaque rupture is not well understood. Nutritional epigenetic modifiers from dietary components, for instance sulforaphane found in broccoli, have been shown to suppress the pro-inflammatory response through transcription factor activation. This review will discuss current and potential epigenetic therapeutics for the treatment of cardiovascular disease, focusing on the use of miRNAs and dietary supplements such as sulforaphane and protocatechuic aldehyde.
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Affiliation(s)
- Mikaela M. Byrne
- Department of Clinical Medicine and Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James’s HospitalDublin, Ireland
| | - Ross T. Murphy
- Department of Cardiology, St. James’s HospitalDublin, Ireland
| | - Anthony W. Ryan
- Department of Clinical Medicine and Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James’s HospitalDublin, Ireland
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Uitz E, Bahadori B, McCarty MF, Moghadasian MH. Practical strategies for modulating foam cell formation and behavior. World J Clin Cases 2014; 2:497-506. [PMID: 25325059 PMCID: PMC4198401 DOI: 10.12998/wjcc.v2.i10.497] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 08/05/2014] [Accepted: 08/29/2014] [Indexed: 02/05/2023] Open
Abstract
Although high density lipoprotein (HDL)-mediated reverse cholesterol transport is crucial to the prevention and reversal of atheroma, a recent meta-analysis makes evident that current pharmaceutical strategies for modulating HDL cholesterol levels lower cardiovascular risk only to the extent that they concurrently decrease low density lipoprotein (LDL) cholesterol. This corresponds well with findings of a recent Mendelian randomization analysis, in which genetic polymorphisms associated with HDL cholesterol but no other known cardiovascular risk factors failed to predict risk for myocardial infarction. Although it is still seems appropriate to search for therapies that could improve the efficiency with which HDL particles induce reverse cholesterol transport, targeting HDL cholesterol levels per se with current measures appears to be futile. It may therefore be more promising to promote reverse cholesterol transport with agents that directly target foam cells. Macrophage expression of the cholesterol transport proteins adenosine triphosphate binding cassette transporter A1, adenosine triphosphate binding cassette transporter G1, and scavenger receptor class B member 1 is transcriptionally up-regulated by activated liver X receptors (LXR), whereas nuclear factor (NF)-kappaB antagonizes their expression. Taurine, which inhibits atherogenesis in rodent studies, has just been discovered to act as a weak agonist for LXRalpha. Conversely, it may be possible to oppose NF-kappaB activation in macrophages with a range of measures. Induction of heme oxygenase-1, which can be attained with phase 2 inducer phytochemicals such as lipoic acid and green tea catechins, promotes reverse cholesterol transport in macrophages and inhibits atherogenesis in rodents, likely due to, in large part, NF-kappaB antagonism. Inhibition of macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity with the spirulina-derived bilirubin-mimetic phycocyanobilin may also oppose NF-kappaB activation, and salicylic acid similarly should be useful for this purpose. The 5' adenosine monophosphate-activated protein kinase activator berberine promotes macrophage reverse cholesterol transport in cell culture; metformin probably shares this property. Many of these measures could also be expected to promote plaque stability by suppressing foam cell production of inflammatory cytokines and matrix metalloproteinases, and to reduce intimal monocyte infiltration by anti-inflammatory effects on vascular endothelium. Direct targeting of foam cells with agents such as phase 2 inducers, spirulina, salicylate, taurine, and berberine or metformin, may hence have considerable potential for preventing and reversing atheroma, and for preventing the plaque rupture that triggers vascular thrombosis.
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Hung CN, Huang HP, Wang CJ, Liu KL, Lii CK. Sulforaphane inhibits TNF-α-induced adhesion molecule expression through the Rho A/ROCK/NF-κB signaling pathway. J Med Food 2014; 17:1095-102. [PMID: 25238321 DOI: 10.1089/jmf.2013.2901] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Endothelial dysfunction is an early indicator of cardiovascular diseases. Increased stimulation of tumor necrosis factor-α (TNF-α) triggers the inflammatory mediator secretion of endothelial cells, leading to atherosclerotic risk. In this study, we investigated whether sulforaphane (SFN) affected the expression of intracellular adhesion molecule-1 (ICAM-1) in TNF-α-induced ECV 304 endothelial cells. Our data showed that SFN attenuated TNF-α-induced expression of ICAM-1 in ECV 304 cells. Pretreatment of ECV 304 cells with SFN inhibited dose-dependently the secretion of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and IL-8. SFN inhibited TNF-α-induced nuclear factor-κB (NF-κB) DNA binding activity. Furthermore, SFN decreased TNF-α-mediated phosphorylation of IκB kinase (IKK) and IκBα, Rho A, ROCK, ERK1/2, and plasminogen activator inhibitor-1 (PAI-1) levels. Collectively, SFN inhibited the NF-κB DNA binding activity and downregulated the TNF-α-mediated induction of ICAM-1 in endothelial cells by inhibiting the Rho A/ROCK/NF-κB signaling pathway, suggesting the beneficial effects of SFN on suppression of inflammation within the atherosclerotic lesion.
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Affiliation(s)
- Chi-Nan Hung
- 1 Department of Holistic Wellness, Ming Dao University , ChangHua, Taiwan
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Schrottmaier WC, Oskolkova OV, Schabbauer G, Afonyushkin T. MicroRNA miR-320a modulates induction of HO-1, GCLM and OKL38 by oxidized phospholipids in endothelial cells. Atherosclerosis 2014; 235:1-8. [PMID: 24786516 DOI: 10.1016/j.atherosclerosis.2014.03.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 03/02/2014] [Accepted: 03/26/2014] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Oxidized phospholipids (OxPLs), which are highly abundant in atherosclerotic lesions, are known to induce electrophilic stress response (ESR). ESR induces cytoprotective genes via the NF-E2-related factor 2 (NRF2) transcription factor. In order to get further insight into the mechanisms of ESR, we studied the role of microRNA (miR)-320a in induction of NRF2-dependent genes by OxPLs. METHODS Microarray profiling and qRT-PCR methods were used for measurements of mRNA and miRNA levels. miR-320a levels were changed by transfection with synthetic oligonucleotides. Protein analysis was performed by Western blotting. The functional activity of NRF2 was measured by DNA-binding ELISA. RESULTS Oxidized palmitoyl-arachidonoyl-phosphatidylcholine (OxPAPC) induced miR-320a in endothelial cells. Induction of HO-1, OKL38 and GCLM mRNAs by OxPAPC and sulforaphane was attenuated upon knockdown of miR-320a. In contrast, transfection of ECs with miR-320a mimic oligonucleotide potentiated the effects of OxPAPC and sulforaphane on induction of HO-1, OKL38 and GCLM mRNAs. OxPAPC-induced p38 activation, levels of NRF2 protein and its ability to bind to consensus NRF2 DNA binding site were elevated in ECs transfected with miR-320a mimic. miR-320a positively regulated induction of VEGF mRNA by OxPAPC. Levels of miR-320a and HO-1 and OKL38 mRNAs were elevated in aortas of ApoE knockout mice fed with high fat diet. Manipulation of miR-320a level in ECs did not affect ability of OxPAPC to induce IL-8, COX-2 and MCP-1. CONCLUSION miR-320a plays important role in induction of expression of HO-1, GCLM and OKL38 upon ESR induced either by OxPAPC or sulforaphane. These observations propose a general role of miR-320a in control of ESR induced by different electrophilic agents.
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Affiliation(s)
- Waltraud C Schrottmaier
- Institute for Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Olga V Oskolkova
- Department of Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Gernot Schabbauer
- Institute for Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
| | - Taras Afonyushkin
- Department of Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
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Nguyen B, Luong L, Naase H, Vives M, Jakaj G, Finch J, Boyle J, Mulholland JW, Kwak JH, Pyo S, de Luca A, Athanasiou T, Angelini G, Anderson J, Haskard DO, Evans PC. Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass. J Thorac Cardiovasc Surg 2014; 148:690-697.e3. [PMID: 24521949 DOI: 10.1016/j.jtcvs.2013.12.048] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 12/10/2013] [Accepted: 12/20/2013] [Indexed: 01/23/2023]
Abstract
OBJECTIVES Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood. METHODS A porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells. RESULTS Surgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury. CONCLUSIONS Systemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury.
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Affiliation(s)
- Bao Nguyen
- BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Le Luong
- Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom
| | - Hatam Naase
- BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Marc Vives
- Department of Anaesthesia, Toronto General Hospital, Toronto, Ontario, Canada
| | - Gentjan Jakaj
- BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Jonathan Finch
- BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Joseph Boyle
- BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - John W Mulholland
- Department of Clinical Perfusion Science, Hammersmith Hospital, London, United Kingdom
| | - Jong-hwan Kwak
- School of Pharmacy, Sungkyunkwan University, Seoul, Republic of Korea
| | - Suhkneung Pyo
- School of Pharmacy, Sungkyunkwan University, Seoul, Republic of Korea
| | - Amalia de Luca
- BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Thanos Athanasiou
- Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Gianni Angelini
- Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Jon Anderson
- Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Dorian O Haskard
- BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Paul C Evans
- Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
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Ishikado A, Sono Y, Matsumoto M, Robida-Stubbs S, Okuno A, Goto M, King GL, Keith Blackwell T, Makino T. Willow bark extract increases antioxidant enzymes and reduces oxidative stress through activation of Nrf2 in vascular endothelial cells and Caenorhabditis elegans. Free Radic Biol Med 2013; 65:1506-1515. [PMID: 23277146 PMCID: PMC3800243 DOI: 10.1016/j.freeradbiomed.2012.12.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 12/02/2012] [Accepted: 12/09/2012] [Indexed: 12/30/2022]
Abstract
Willow bark extract (WBE) is listed in the European Pharmacopoeia and has been traditionally used for treating fever, pain, and inflammation. Recent studies have demonstrated its clinical usefulness. This study investigated the antioxidative effects of WBE in human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans. WBE prevented oxidative-stress-induced cytotoxicity of HUVECs and death of C. elegans. WBE dose-dependently increased mRNA and protein expression levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) target genes heme oxygenase-1, γ-glutamylcysteine ligase modifier and catalytic subunits, and p62 and intracellular glutathione (GSH) in HUVECs. In the nematode C. elegans, WBE increased the expression of the gcs-1::green fluorescent protein reporter, a well-characterized target of the Nrf2 ortholog SKN-1, in a manner that was SKN-1-dependent. WBE increased intranuclear expression and DNA binding of Nrf2 and the activity of an antioxidant response element (ARE) reporter plasmid in HUVECs. WBE-induced expression of Nrf2-regulated genes and increased GSH levels in HUVECs were reduced by Nrf2 and p38 small interfering (si) RNAs and by the p38-specific inhibitor SB203580. Nrf2 siRNA reduced the cytoprotective effect of WBE against oxidative stress in HUVECs. Salicin, a major anti-inflammatory ingredient of WBE, failed to activate ARE-luciferase activity, whereas a salicin-free WBE fraction showed intensive activity. WBE induced antioxidant enzymes and prevented oxidative stress through activation of Nrf2 independent of salicin, providing a new potential explanation for the clinical usefulness of WBE.
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Affiliation(s)
| | - Yoko Sono
- R&D Department, Sunstar Inc., Osaka 569-1195, Japan
| | | | - Stacey Robida-Stubbs
- Section on Islet Cell & Regenerative Biology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Aya Okuno
- R&D Department, Sunstar Inc., Osaka 569-1195, Japan
| | - Masashi Goto
- R&D Department, Sunstar Inc., Osaka 569-1195, Japan
| | - George L King
- Section on Vascular Cell Biology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - T Keith Blackwell
- Section on Islet Cell & Regenerative Biology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
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30
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Jiao Z, Zhang Q, Chang J, Nie D, Li M, Zhu Y, Wang C, Wang Y, Liu F. A protective role of sulforaphane on alveolar epithelial cells exposed to cigarette smoke extract. Exp Lung Res 2013; 39:379-86. [PMID: 24117145 DOI: 10.3109/01902148.2013.830162] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Sulforaphane (SFN) is an excellent antioxidant agent, few of the studies focus on the possible protective role of SFN from cigarette smoke-induced injury on alveolar epithelial cells. OBJECTIVES the aim of the study is to observe the possible protective role of SFN, as well as the function of insulin-like growth factor binding protein-3 (IGFBP-3) in the process. METHODS MTT assay was used to evaluate cell viability after cigarette smoke extract (CSE) and/or SFN exposure, cell cycle was analyzed using flow cytometry, intracellular reactive oxygen species (ROS) level was detected by staining with fluorescent indicator 2', 7'-dichlorofluorescin diacetate (DCFH-DA), finally both real-time quantitative RT-PCR and western blot were employed to observe mRNA and protein levels of IGFBP-3. RESULTS SFN could restore the viability of A549 cells, attenuate G1 block of the cell cycle, and significantly reduce the proportion of sub-G1 cells; at the same time, CSE-induced accumulation of intracellular ROS was decreased by SFN. Interestingly, high expression of IGFBP-3 was found at both transcriptional and translational levels, however by pre-incubation with SFN, the expression of IGFBP-3 was not stimulated by CSE exposure. CONCLUSIONS SFN can antagonize CSE-induced growth arrest of alveolar epithelial cells and IGFBP-3 probably plays an important role in the process.
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Affiliation(s)
- Zongxian Jiao
- Research Institute of Pathology, School of Basic Medical Sciences, Lanzhou University , Lanzhou, Gansu , P.R. China
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31
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Lee YR, Noh EM, Han JH, Kim JM, Hwang BM, Kim BS, Lee SH, Jung SH, Youn HJ, Chung EY, Kim JS. Sulforaphane controls TPA-induced MMP-9 expression through the NF-κB signaling pathway, but not AP-1, in MCF-7 breast cancer cells. BMB Rep 2013; 46:201-6. [PMID: 23615261 PMCID: PMC4133889 DOI: 10.5483/bmbrep.2013.46.4.160] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)-butane] is an isothiocyanate found in some cruciferous vegetables, especially broccoli. Sulforaphane has been shown to display anti-cancer properties against various cancer cell lines. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM), plays an important role in cancer cell invasion. In this study, we investigated the effect of sulforaphane on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. TPA-induced MMP-9 expression and cell invasion were decreased by sulforaphane treatment. TPA substantially increased NF-κB and AP-1 DNA binding activity. Pre-treatment with sulforaphane inhibited TPA-stimulated NF-κB binding activity, but not AP-1 binding activity. In addition, we found that sulforaphane suppressed NF-κB activation, by inhibiting phosphorylation of IκB in TPA-treated MCF-7 cells. In this study, we demonstrated that the inhibition of TPA-induced MMP-9 expression and cell invasion by sulforaphane was mediated by the suppression of the NF-κB pathway in MCF-7 cells. [BMB Reports 2013; 46(4): 201-206]
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Affiliation(s)
- Young-Rae Lee
- Department of Anesthesiology and Pain Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon 420-717, Korea.
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Huang CS, Lin AH, Liu CT, Tsai CW, Chang IS, Chen HW, Lii CK. Isothiocyanates protect against oxidized LDL-induced endothelial dysfunction by upregulating Nrf2-dependent antioxidation and suppressing NFκB activation. Mol Nutr Food Res 2013; 57:1918-30. [PMID: 23836589 DOI: 10.1002/mnfr.201300063] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 04/16/2013] [Accepted: 04/21/2013] [Indexed: 12/30/2022]
Abstract
SCOPE Oxidative stress plays a pivotal role in the pathophysiology of cardiovascular diseases. Oxidized low-density lipoprotein (oxLDL) is a key contributor to atherogenesis through multiple mechanisms. In this study, we investigated the protection by three structurally related isothiocyanates, i.e., sulforaphane (SFN), benzyl isothiocyanate (BITC), and phenethyl isocyanate (PEITC), against oxLDL-induced leukocyte adhesion to vascular endothelium and the mechanism involved. METHODS AND RESULTS The protection against oxLDL-induced endothelial dysfunction by isothiocyanates was studied in human umbilical vein endothelial cells (HUVECs). oxLDL increased reactive oxygen species (ROS) production, stimulated nuclear factor-kappaB (NFκB) activation, and enhanced intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin expression in HUVECs, which led to promotion of monocyte adhesion to HUVECs. Treatment with SFN, BITC, and PEITC (0-10 μM) dose-dependently induced heme oxygenase (HO)-1, glutamate cysteine ligase (GCL) catalytic and modifier subunit expression, intracellular glutathione content, and antioxidant response element (ARE)-luciferase reporter activity. SFN, BITC, and PEITC pretreatment reversed oxLDL-induced ROS production, NFκB nuclear translocation, κB-reporter activity, ICAM-1, VCAM-1, and E-selectin expression, and monocyte adhesion to endothelial cells. Both heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown attenuated the isothiocyanate inhibition of oxLDL-induced ROS production, κB-reporter activity, and adhesion molecule expression. CONCLUSION SFN, BITC, and PEITC protect against oxLDL-induced endothelial damage by upregulating Nrf2-dependent HO-1 and GCL expression, which leads to inhibition of NFκB activation and ICAM-1, VCAM-1, and E-selectin expression.
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Affiliation(s)
- Chin-Shiu Huang
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
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Wang Y, Liu X, Wang W, Song W, Chen L, Fang Q, Yan X. The Expression of Inflammatory Cytokines on the Aorta Endothelia Are Up-regulated in Pinealectomized Rats. Inflammation 2013; 36:1363-73. [PMID: 23824598 DOI: 10.1007/s10753-013-9676-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Blum NM, Mueller K, Lippmann D, Metges CC, Linn T, Pallauf J, Mueller AS. Feeding of selenium alone or in combination with glucoraphanin differentially affects intestinal and hepatic antioxidant and phase II enzymes in growing rats. Biol Trace Elem Res 2013; 151:384-99. [PMID: 23271678 DOI: 10.1007/s12011-012-9567-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 11/28/2012] [Indexed: 12/14/2022]
Abstract
The anti-carcinogenic effects of sulforaphane (SFN) are based on the up-regulation of antioxidant enzymes (AE) and phase II enzymes (PIIE) through the transcription factor Nrf2. Current knowledge on the roles of the SFN precursor glucoraphanin (GRA) on these processes is limited. Anti-carcinogenic effects of Se depending on glutathione peroxidase (GPx) activity have also been reported. We studied effects and possible synergisms of Se and GRA on the expression and activity of a broad spectrum of AE and PIIE in jejunum, colon and the liver of rats fed diets differing in Se and GRA concentration. In all organs, GPx1 mRNA expression was 70 % to 90 % lower in Se deficiency than in Se sufficiency. GPx2 expression increased in jejunum and liver under Se deficiency and decreased in the colon. Se deficiency increased most colonic AE and PIIE compared to Se adequacy. Adequate and in particular supranutritive Se combined with GRA increased colonic AE and PIIE expression up to 3.72-fold. In the liver Se deficiency raised the expression of AE and PIIE up to 4.49-fold. GRA attenuated liver AE and PIIE response in Se deficiency. Expression- and correlation analyses revealed that Keap1 mRNA better reflects AE and PIIE gene expression than Nrf2 mRNA. We conclude that: (1) GPx1 sensitively indicates Se deficiency; (2) the influence of Se and Nrf2/Keap1 on GPx2 expression depends on the organ; (3) GRA combined with supranutritive Se may effectively protect against inflammation and colon cancer; (4) future investigations on AE and PIIE expression should consider the role of Keap1 to a higher extent.
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Affiliation(s)
- Nicole M Blum
- Institute of Agricultural and Nutritional Sciences, Preventive Nutrition Group, Martin Luther University Halle Wittenberg, Von Danckelmann Platz 2, 06120, Halle (Saale), Germany
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Kwon JS, Joung H, Kim YS, Shim YS, Ahn Y, Jeong MH, Kee HJ. Sulforaphane inhibits restenosis by suppressing inflammation and the proliferation of vascular smooth muscle cells. Atherosclerosis 2012; 225:41-9. [DOI: 10.1016/j.atherosclerosis.2012.07.040] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 06/28/2012] [Accepted: 07/27/2012] [Indexed: 10/28/2022]
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Wang J, Liu Y, Zhang A, Li C, Dong J. Inhibitory CpG sequences reduced ischemia/reperfusion-induced hepatic metastases of liver tumor in a murine model. J Surg Res 2012; 178:248-54. [PMID: 22502906 DOI: 10.1016/j.jss.2012.01.057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2011] [Revised: 01/09/2012] [Accepted: 01/31/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND It is reported that hepatic ischemia/reperfusion (I/R) during hepatectomy accelerates liver tumor growth. Hepatic I/R induces inflammation cytokines, which can accelerate the outgrowth of liver tumor. Inhibitory CpG sequence (iCpG) is an inhibitor of TLR9, which plays an important role in hepatic I/R. The aim of this study was to examine whether iCpG could prevent hepatic I/R-induced metastases of the liver tumor. MATERIALS AND METHODS A murine tumor model that underwent partial hepatic I/R or sham operation was treated with iCpG or control DNA sequence (Ctrl ODN). Tumor growth and metastases were observed on day 14 after surgery; Endothelial leukocyte adhesion molecules such as E-selectin and intracellular adhesion molecule-1 (ICAM-1) protein expression were measured 24 h after reperfusion by Western blotting; E-selectin and ICAM-1 mRNA expression in hepatic tissue was measured 2 h after reperfusion by RT-PCR; NF-κB activity in hepatic tissue was measured 2 h after reperfusion by electrophoretic gel mobility shift assay. RESULTS The tumor growth in the mice subjected to hepatic I/R was remarkably stimulated when compared with the mice subjected to laparotomy alone. The iCpG had no significant inhibitory effect on tumor growth in sham-operated mice subjected to tumor. However, iCpG could reduce the tumor growth and inhibit the activation of NF-κB and downregulate the E-selectin and ICAM-1 mRNA and protein in the mice with tumor subjected to I/R. CONCLUSIONS ICpG might reduce I/R-induced hepatic metastases of liver tumor cells by inhibiting NF-κB expression and downregulating the adhesive molecules, such as E-selectin and ICAM-1.
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Affiliation(s)
- Jin Wang
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China
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Murakami A, Ohnishi K. Target molecules of food phytochemicals: food science bound for the next dimension. Food Funct 2012; 3:462-76. [PMID: 22377900 DOI: 10.1039/c2fo10274a] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Phytochemicals are generally defined as secondary metabolites in plants that play crucial roles in their adaptation to a variety of environmental stressors. There is a great body of compelling evidence showing that these metabolites have pronounced potentials for regulating and modulating human health and disease onset, as shown by both experimental and epidemiological approaches. Concurrently, enormous efforts have been made to elucidate the mechanism of actions underlying their biological and physiological functions. For example, the pioneering work of Tachibana et al. uncovered the receptor for (-)-epigallocatechin-3-gallate (EGCg) as the 67 kDa laminin receptor, which was shown to partially mediate the functions of EGCg, such as anti-inflammatory, anti-allergic, and anti-proliferative activities. Thereafter, several protein kinases were identified as binding proteins of flavonoids, including myricetin, quercetin, and kaempferol. Isothiocyanates, sulfur-containing phytochemicals present in cruciferous plants, are well known to target Keap1 for activating the transcription factor Nrf2 for inducing self-defensive and anti-oxidative gene expression. In addition, we recently identified CD36 as a cell surface receptor for ursolic acid, a triterpenoid ubiquitously occurring in plants. Importantly, the above mentioned target proteins are indispensable for phytochemicals to exhibit, at least in part, their bioactivities. Nevertheless, it is reasonable to assume that some of the activities and potential toxicities of metabolites are exerted via their interactions with unidentified, off-target proteins. This notion may be supported by the fact that even rationally designed drugs occasionally display off-target effects and induce unexpected outcomes, including toxicity. Here we update the current status and future directions of research related to target molecules of food phytochemicals.
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Affiliation(s)
- Akira Murakami
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
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Ghosh K, Kanapathipillai M, Korin N, McCarthy JR, Ingber DE. Polymeric nanomaterials for islet targeting and immunotherapeutic delivery. NANO LETTERS 2012; 12:203-8. [PMID: 22196766 PMCID: PMC3280082 DOI: 10.1021/nl203334c] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Here we report a proof-of-concept for development of pancreatic islet-targeting nanoparticles for immunomodulatory therapy of autoimmune type 1 diabetes. Modified with a unique islet-homing peptide, these polymeric nanomaterials exhibit 3-fold greater binding to islet endothelial cells and a 200-fold greater anti-inflammatory effect through targeted islet endothelial cell delivery of an immunosuppressant drug. Our findings also underscore the need to carefully tailor drug loading and nanoparticle dosage to achieve maximal vascular targeting and immunosuppression.
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Affiliation(s)
- Kaustabh Ghosh
- Vascular Biology Program, Departments of Pathology & Surgery, Children’s Hospital and Harvard Medical School, Boston, MA, USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA
| | | | - Netanel Korin
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA
| | - Jason R. McCarthy
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Donald E. Ingber
- Vascular Biology Program, Departments of Pathology & Surgery, Children’s Hospital and Harvard Medical School, Boston, MA, USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA
- School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
- To whom correspondence should be sent ()
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Fimognari C, Turrini E, Ferruzzi L, Lenzi M, Hrelia P. Natural isothiocyanates: genotoxic potential versus chemoprevention. Mutat Res 2011; 750:107-131. [PMID: 22178957 DOI: 10.1016/j.mrrev.2011.12.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 12/01/2011] [Accepted: 12/02/2011] [Indexed: 12/12/2022]
Abstract
Isothiocyanates, occurring in many dietary cruciferous vegetables, show interesting chemopreventive activities against several chronic-degenerative diseases, including cancer, cardiovascular diseases, neurodegeneration, diabetes. The electrophilic carbon residue in the isothiocyanate moiety reacts with biological nucleophiles and modification of proteins is recognized as a key mechanism underlying the biological activity of isothiocyanates. The nuclear factor-erythroid-2-related factor 2 system, which orchestrates the expression of a wide array of antioxidant genes, plays a role in the protective effect of isothiocyanates against almost all the pathological conditions reported above. Recent emerging findings suggest a further common mechanism. Chronic inflammation plays a central role in many human diseases and isothiocyanates inhibit the activity of many inflammation components, suppress cyclooxygenase 2, and irreversibly inactivate the macrophage migration inhibitory factor. Due to their electrophilic reactivity, some isothiocyanates are able to form adducts with DNA and induce gene mutations and chromosomal aberrations. DNA damage has been demonstrated to be involved in the pathogenesis of various chronic-degenerative diseases of epidemiological relevance. Thus, the genotoxicity of the isothiocyanates should be carefully considered. In addition, the dose-response relationship for genotoxic compounds does not suggest evidence of a threshold. Thus, chemicals that are genotoxic pose a greater potential risk to humans than non-genotoxic compounds. Dietary consumption levels of isothiocyanates appear to be several orders of magnitude lower than the doses used in the genotoxicity studies and thus it is highly unlikely that such toxicities would occur in humans. However, the beneficial properties of isothiocyanates stimulated an increase of dietary supplements and functional foods with highly enriched isothiocyanate concentrations on the market. Whether such concentrations may exert a potential health risk cannot be excluded with certainty and an accurate evaluation of the toxicological profile of isothiocyanates should be prompted before any major increase in their consumption be recommended or their clinical use suggested.
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Affiliation(s)
- Carmela Fimognari
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
| | - Eleonora Turrini
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
| | - Lorenzo Ferruzzi
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
| | - Monia Lenzi
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
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Sulforaphane suppresses vascular adhesion molecule-1 expression in TNF-α-stimulated mouse vascular smooth muscle cells: involvement of the MAPK, NF-κB and AP-1 signaling pathways. Vascul Pharmacol 2011; 56:131-41. [PMID: 22155163 DOI: 10.1016/j.vph.2011.11.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Revised: 10/04/2011] [Accepted: 11/28/2011] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is a long-term inflammatory disease of the arterial wall. Increased expression of the cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) is associated with increased proliferation of vascular smooth muscle cells (VSMCs), leading to increased neointima or atherosclerotic lesion formation. Therefore, the functional inhibition of adhesion molecules could be a critical therapeutic target of inflammatory disease. In the present study, we investigate the effect of sulforaphane on the expression of VCAM-1 induced by TNF-α in cultured mouse vascular smooth muscle cell lines. Pretreatment of VSMCs for 2h with sulforaphane (1-5μg/ml) dose-dependently inhibited TNF-α-induced adhesion of THP-1 monocytic cells and protein expression of VCAM-1. Sulforaphane also suppressed TNF-α-induced production of intracellular reactive oxygen species (ROS) and activation of p38, ERK and JNK. Furthermore, sulforaphane inhibited NK-κB and AP-1 activation induced by TNF-α. Sulforaphane inhibited TNF-α-induced ΙκΒ kinase activation, subsequent degradation of ΙκΒα and nuclear translocation of p65 NF-κB and decreased c-Jun and c-Fos protein level. This study suggests that sulforaphane inhibits the adhesive capacity of VSMC and downregulates the TNF-α-mediated induction of VCAM-1 in VSMC by inhibiting the MAPK, NF-κB and AP-1 signaling pathways and intracellular ROS production. Thus, sulforaphane may have beneficial effects to suppress inflammation within the atherosclerotic lesion.
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Chen Z, Jiang H, Wan Y, Bi C, Yuan Y. H(2)O (2)-induced secretion of tumor necrosis factor-α evokes apoptosis of cardiac myocytes through reactive oxygen species-dependent activation of p38 MAPK. Cytotechnology 2011; 64:65-73. [PMID: 22002864 DOI: 10.1007/s10616-011-9392-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 08/30/2011] [Indexed: 12/20/2022] Open
Abstract
P38 mitogen-activated protein kinases (p38 MAPK) and tumor necrosis factor-α (TNF-α) play important roles in oxidative stress-induced apoptosis in cardiac myocytes. However, the regulation and functional role of cross-talk between p38 MAPK and TNF-α pathways have not yet been fully characterized in cardiac myocytes. In this study, we found that inhibition of p38 MAPK with SB-203580 (SB) reduced H(2)O(2)-stimulated secretion of TNF-α, whereas pre-activation of p38 MAPK with sodium arsenite (SA) enhanced H(2)O(2)-stimulated secretion of TNF-α. In addition, pretreatment of cells with TNF-α increased basal and H(2)O(2)-stimulated p38 MAPK and apoptosis of cardiac myocytes, and p38 MAPK-associated apoptosis of cardiac myocytes induced by TNF-α was blocked by inhibition of p38 MAPK with SB. Finally, H(2)O(2)-induced apoptosis was attenuated by the inhibitors of p38 MAPK or reactive oxygen species (ROS), whereas it was enhanced by p38 MAPK agonist SA. These results suggest that H(2)O(2)-induced secretion of TNF-α increases apoptosis of cardiac myocytes through ROS-dependent activation of p38 MAPK. This may represent a novel mechanism that TNF-α partly interplays with p38 MAPK pathways during oxidative stress-modulated apoptosis in cardiac myocytes.
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Affiliation(s)
- Zhilong Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, 99 Zi Yang Road, Wuhan, 430060, Hubei, China
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Bongard RD, Krenz GS, Gastonguay AJ, Williams CL, Lindemer BJ, Merker MP. Characterization of the threshold for NAD(P)H:quinone oxidoreductase activity in intact sulforaphane-treated pulmonary arterial endothelial cells. Free Radic Biol Med 2011; 50:953-62. [PMID: 21238579 PMCID: PMC3851029 DOI: 10.1016/j.freeradbiomed.2011.01.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Revised: 01/03/2011] [Accepted: 01/06/2011] [Indexed: 12/22/2022]
Abstract
Treatment of bovine pulmonary arterial endothelial cells in culture with the phase II enzyme inducer sulforaphane (5μM, 24h; sulf-treated) increased cell-lysate NAD(P)H:quinone oxidoreductase (NQO1) activity by 5.7 ± 0.6 (mean ± SEM)-fold, but intact-cell NQO1 activity by only 2.8 ± 0.1-fold compared to control cells. To evaluate the hypothesis that the threshold for sulforaphane-induced intact-cell NQO1 activity reflects a limitation in the capacity to supply NADPH at a sufficient rate to drive all the induced NQO1 to its maximum activity, total KOH-extractable pyridine nucleotides were measured in cells treated with duroquinone to stimulate maximal NQO1 activity. NQO1 activation increased NADP(+) in control and sulf-treated cells, with the effect more pronounced in the sulf-treated cells, in which the NADPH was also decreased. Glucose-6-phosphate dehydrogenase (G-6-PDH) inhibition partially blocked NQO1 activity in control and sulf-treated cells, but G-6-PDH overexpression via transient transfection with the human cDNA alleviated neither the restriction on intact sulf-treated cell NQO1 activity nor the impact on the NADPH/NADP(+) ratios. Intracellular ATP levels were not affected by NQO1 activation in control or sulf-treated cells. An increased dependence on extracellular glucose and a rightward shift in the K(m) for extracellular glucose were observed in NQO1-stimulated sulf-treated vs control cells. The data suggest that glucose transport in the sulf-treated cells may be insufficient to support the increased metabolic demand for pentose phosphate pathway-generated NADPH as an explanation for the NQO1 threshold.
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Affiliation(s)
- Robert D Bongard
- Department of Pulmonary Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Evans PC. The influence of sulforaphane on vascular health and its relevance to nutritional approaches to prevent cardiovascular disease. EPMA J 2011. [PMID: 23199123 PMCID: PMC3405367 DOI: 10.1007/s13167-011-0064-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Oxidation of low-density lipoproteins (LDL) promotes atherosclerosis by enhancing vascular inflammation and foam cell formation. The corollary is that diets that stimulate endogenous anti-oxidants may protect against atherosclerosis. This review focuses on sulforaphane, an isothiocyanate derived from green vegetables, which induces multiple anti-oxidant enzymes via activation of a transcription factor called Nrf2. Although studies of cultured cells and experimental animals revealed that sulforaphane can suppress inflammatory activation of vascular cells, the potential beneficial effects of sulforaphane in atherosclerosis have not been studied directly. A deeper understanding of vascular responses to sulforaphane may inform nutritional approaches to prevent vascular inflammation and atherosclerosis.
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Affiliation(s)
- Paul C Evans
- British Heart Foundation, Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN UK
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van Horssen J, Witte ME, Schreibelt G, de Vries HE. Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta Mol Basis Dis 2011; 1812:141-50. [DOI: 10.1016/j.bbadis.2010.06.011] [Citation(s) in RCA: 225] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Revised: 06/08/2010] [Accepted: 06/16/2010] [Indexed: 12/20/2022]
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Choi KW, Park HJ, Jung D, Kim TW, Park YM, Kim BO, Sohn EH, Moon EY, Um SH, Rhee DK, Pyo S. Inhibition of TNF-α-induced adhesion molecule expression by diosgenin in mouse vascular smooth muscle cells via downregulation of the MAPK, Akt and NF-κB signaling pathways. Vascul Pharmacol 2010; 53:273-80. [DOI: 10.1016/j.vph.2010.09.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Revised: 09/25/2010] [Accepted: 09/28/2010] [Indexed: 01/23/2023]
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Vazquez-Prieto MA, Miatello RM. Organosulfur compounds and cardiovascular disease. Mol Aspects Med 2010; 31:540-5. [PMID: 20940019 DOI: 10.1016/j.mam.2010.09.009] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Revised: 09/14/2010] [Accepted: 09/14/2010] [Indexed: 11/17/2022]
Abstract
Epidemiological studies have shown an inverse relationship between consumption of fruits and vegetables and the risk of cardiovascular disease. Phytochemicals are non-nutritional chemical compounds found in small quantities in fruits and vegetables with known health benefits. Among them, organosulfides are present mainly in garlic and onion characterized by their antioxidant and anti-inflammatory properties, and isothiocyanates in cruciferous vegetables have anticarcinogenic effects in experimental models. In this review, we are focusing on the main biological studies regarding the beneficial effect of organosulfur compounds on their protection against cardiovascular disease.
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Affiliation(s)
- Marcela A Vazquez-Prieto
- Laboratory of Cardiovascular Pathophysiology, Department of Pathology, School of Medicine, National University of Cuyo and Institute for Experimental Medical and Biological Research (IMBECU), National Council of Research (CONICET), Mendoza, Argentina
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Song H, Zhao H, Qu Y, Sun Q, Zhang F, Du Z, Liang W, Qi Y, Yang P. Carbon monoxide releasing molecule-3 inhibits concurrent tumor necrosis factor-α- and interleukin-1β-induced expression of adhesion molecules on human gingival fibroblasts. J Periodontal Res 2010; 46:48-57. [PMID: 20860588 DOI: 10.1111/j.1600-0765.2010.01307.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND OBJECTIVE Carbon monoxide releasing molecule-3 (CORM-3) is a newly reported compound that has shown anti-inflammatory effects in a number of cells. In this study, we aimed to investigate the influence of CORM-3 on concurrent tumor necrosis factor-α (TNF-α)- and interleukin (IL)-1β-induced expression of adhesion molecules on human gingival fibroblasts (HGF). MATERIAL AND METHODS HGF were cultured from the explants of normal gingival tissues. Cells were costimulated with TNF-α and IL-1β in the presence or absence of CORM-3 for different periods of time. The expression of adhesion molecules, nuclear factor-kappaB (NF-κB) and phosphorylated p38 was studied using western blotting. RT-PCR was applied to check the expression of the adhesion molecules at the mRNA level. The activity of NF-κB was analysed using a reporter gene assay. RESULTS CORM-3 inhibited the up-regulation of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and endothelial leukocyte adhesion molecule in HGF after costimulation with TNF-α and IL-1β, which resulted in the decreased adhesion of peripheral blood mononuclear cells to these cells. Sustained activation of the NF-κB pathway by costimulation with TNF-α and IL-1β was suppressed by CORM-3, which was reflected by a reduced NF-κB response element-dependent luciferase activity and decreased nuclear NF-κB-p65 expression. CORM-3 inhibited MAPK p38 phosphorylation in response to stimulation with proinflammatory cytokines. CONCLUSION The results of this study bode well for the application of CORM-3 as an anti-inflammatory agent to inhibit NF-κB activity and to suppress the expression of adhesion molecules on HGF, which suggests a promising potential for CORM-3 in the treatment of inflammatory periodontal disease.
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Affiliation(s)
- H Song
- School of Dentistry, Shangdong University, Shandong Provincial Key Laboratory of Oral Biomedicine, Jinan, China
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Butters D, Whitehouse M. Beyond conventional DMARDs: extending TNF-regulant therapies to the vast majority/less privileged who do need them. Int J Rheum Dis 2010; 12:299-306. [PMID: 20374366 DOI: 10.1111/j.1756-185x.2009.01427.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
This article is a plea to find (better) ways to extend the benefits of anti-cytokine therapies to ensure they will become available as widely as possible. Pessimistically, this will probably involve substituting more affordable, although somewhat less specific, non-biological agents for present target-specific bio-DMARDs (disease-modifying antirheumatic drugs) to ensure far wider distribution of benefits. Optimistically, new developments in technology and bio-engineering might dramatically reduce costs of present 'biological' therapies. (The antibiotics we now take for granted were once also horrendously expensive.). Pragmatically, one goal for this mission should include seriously pursuing more research and pilot clinical trials of non-protein combination therapies able to control: (i) TNF or other pro-inflammatory cytokines; and also (ii) other mediators sustaining chronic inflammation (-->pain, effusion, fibrosis, porosis, etc.). This can be immediately facilitated by drawing upon the immense resources of non-prescription Asia-Pacific traditional therapies--particularly when these have already been shown to either reduce TNF synthesis or control TNF-induced responses in preclinical studies. Could this be a major goal for the next decade, helping rectify some of the omissions of the current Bone & Joint Decade 2000-2010?
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Affiliation(s)
- Desley Butters
- Therapeutics Research Unit, Department of Medicine, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia
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Menshikova EB, Tkachev VO, Zenkov NK. Redox-dependent signaling system Nrf2/ARE in inflammation. Mol Biol 2010. [DOI: 10.1134/s0026893310030015] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Zakkar M, Van der Heiden K, Luong LA, Chaudhury H, Cuhlmann S, Hamdulay SS, Krams R, Edirisinghe I, Rahman I, Carlsen H, Haskard DO, Mason JC, Evans PC. Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. Arterioscler Thromb Vasc Biol 2009; 29:1851-7. [PMID: 19729611 DOI: 10.1161/atvbaha.109.193375] [Citation(s) in RCA: 194] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Proinflammatory mediators influence atherosclerosis by inducing adhesion molecules (eg, VCAM-1) on endothelial cells (ECs) via signaling intermediaries including p38 MAP kinase. Regions of arteries exposed to high shear stress are protected from inflammation and atherosclerosis, whereas low-shear regions are susceptible. Here we investigated whether the transcription factor Nrf2 regulates EC activation in arteries. METHODS AND RESULTS En face staining revealed that Nrf2 was activated in ECs at an atheroprotected region of the murine aorta where it negatively regulated p38-VCAM-1 signaling, but was expressed in an inactive form in ECs at an atherosusceptible site. Treatment with sulforaphane, a dietary antioxidant, activated Nrf2 and suppressed p38-VCAM-1 signaling at the susceptible site in wild-type but not Nrf2(-/-) animals, indicating that it suppresses EC activation via Nrf2. Studies of cultured ECs revealed that Nrf2 inactivates p38 by suppressing an upstream activator MKK3/6 and by enhancing the activity of the negative regulator MKP-1. CONCLUSIONS Nrf2 prevents ECs at the atheroprotected site from exhibiting a proinflammatory state via the suppression of p38-VCAM-1 signaling. Pharmacological activation of Nrf2 reduces EC activation at atherosusceptible sites and may provide a novel therapeutic strategy to prevent or reduce atherosclerosis.
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Affiliation(s)
- Mustafa Zakkar
- British Heart Foundation Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, UK
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