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Zhai J, Kongsberg WH, Pan Y, Hao C, Wang X, Sun J. Caloric restriction induced epigenetic effects on aging. Front Cell Dev Biol 2023; 10:1079920. [PMID: 36712965 PMCID: PMC9880295 DOI: 10.3389/fcell.2022.1079920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/31/2022] [Indexed: 01/15/2023] Open
Abstract
Aging is the subject of many studies, facilitating the discovery of many interventions. Epigenetic influences numerous life processes by regulating gene expression and also plays a crucial role in aging regulation. Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging.
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Affiliation(s)
| | | | | | | | | | - Jie Sun
- *Correspondence: Xiaojing Wang, ; Jie Sun,
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Li D, Yang Y, Wang S, He X, Liu M, Bai B, Tian C, Sun R, Yu T, Chu X. Role of acetylation in doxorubicin-induced cardiotoxicity. Redox Biol 2021; 46:102089. [PMID: 34364220 PMCID: PMC8350499 DOI: 10.1016/j.redox.2021.102089] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/23/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
As a potent chemotherapeutic agent, doxorubicin (DOX) is widely used for the treatment of a variety of cancers However, its clinical utility is limited by dose-dependent cardiotoxicity, and pathogenesis has traditionally been attributed to the formation of reactive oxygen species (ROS). Accordingly, the prevention of DOX-induced cardiotoxicity is an indispensable goal to optimize therapeutic regimens and reduce morbidity. Acetylation is an emerging and important epigenetic modification regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). Despite extensive studies of the molecular basis and biological functions of acetylation, the application of acetylation as a therapeutic target for cardiotoxicity is in the initial stage, and further studies are required to clarify the complex acetylation network and improve the clinical management of cardiotoxicity. In this review, we summarize the pivotal functions of HDACs and HATs in DOX-induced oxidative stress, the underlying mechanisms, the contributions of noncoding RNAs (ncRNAs) and exercise-mediated deacetylases to cardiotoxicity. Furthermore, we describe research progress related to several important SIRT activators and HDAC inhibitors with potential clinical value for chemotherapy and cardiotoxicity. Collectively, a comprehensive understanding of specific roles and recent developments of acetylation in doxorubicin-induced cardiotoxicity will provide a basis for improved treatment outcomes in cancer and cardiovascular diseases.
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Affiliation(s)
- Daisong Li
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Yanyan Yang
- Department of Immunology, Basic Medicine School, Qingdao University, Qingdao, 266071, China
| | - Shizhong Wang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Xiangqin He
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Meixin Liu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Baochen Bai
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Chao Tian
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Ruicong Sun
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Tao Yu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Basic Medicine School, Qingdao University, 38 Deng Zhou Road, Qingdao, 266021, China.
| | - Xianming Chu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; Department of Cardiology, The Affiliated Cardiovascular Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266071, China.
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Carrizzo A, Izzo C, Forte M, Sommella E, Di Pietro P, Venturini E, Ciccarelli M, Galasso G, Rubattu S, Campiglia P, Sciarretta S, Frati G, Vecchione C. A Novel Promising Frontier for Human Health: The Beneficial Effects of Nutraceuticals in Cardiovascular Diseases. Int J Mol Sci 2020; 21:E8706. [PMID: 33218062 PMCID: PMC7698807 DOI: 10.3390/ijms21228706] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/03/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) such as hypertension, atherosclerosis, myocardial infarction, and diabetes are a significant public health problem worldwide. Although several novel pharmacological treatments to reduce the progression of CVDs have been discovered during the last 20 years, the better way to contain the onset of CVDs remains prevention. In this regard, nutraceuticals seem to own a great potential in maintaining human health, exerting important protective cardiovascular effects. In the last years, there has been increased focus on identifying natural compounds with cardiovascular health-promoting effects and also to characterize the molecular mechanisms involved. Although many review articles have focused on the individual natural compound impact on cardiovascular diseases, the aim of this manuscript was to examine the role of the most studied nutraceuticals, such as resveratrol, cocoa, quercetin, curcumin, brassica, berberine and Spirulina platensis, on different CVDs.
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Affiliation(s)
- Albino Carrizzo
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Carmine Izzo
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Maurizio Forte
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
| | - Eduardo Sommella
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy;
| | - Paola Di Pietro
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Eleonora Venturini
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
| | - Michele Ciccarelli
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Gennaro Galasso
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Speranza Rubattu
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S.Andrea, Via di Grottarossa 1035, 00189 Rome, Italy
| | - Petro Campiglia
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Sebastiano Sciarretta
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100 Latina, Italy
| | - Giacomo Frati
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100 Latina, Italy
| | - Carmine Vecchione
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
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Patel C, Pande S, Acharya S. Potentiation of anti-Alzheimer activity of curcumin by probiotic Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory impairment in mice. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1955-1962. [PMID: 32448977 DOI: 10.1007/s00210-020-01904-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 05/10/2020] [Indexed: 12/14/2022]
Abstract
Curcumin, a major component of Indian saffron through clinical studies, revealed its neuroprotective effect in neurodegenerative diseases. However, it has not been utilized alone orally due to its low bioavailability. There are certain strategies to overcome the drawbacks such as poor absorption and low aqueous solubility. Many strategies are utilized to increase the systemic availability of curcumin. Among them, the steady intestinal and liver metabolism of curcumin by a curcumin adjuvant (enzyme inhibitor/inducer) is an important and less engrossed strategy for improving the overall systemic bioavailability of curcumin. Here, we assess the effect of probiotic Lactobacillus rhamnosus as a curcumin adjuvant (potentiate the effect of curcumin) in scopolamine-induced dementia in mice. To induce amnesia, scopolamine was used in a mouse model (1 mg/kg, daily for 10 days i.p.). After execution of behavioural tests (Morris water maze test), brains and liver were isolated for further neurochemical and histopathology examination. Our results showed a significant increase in antioxidant enzyme levels in curcumin with a probiotic group compared with curcumin alone. Besides, histopathology study results showed less neuronal damage of curcumin with probiotics as compared with the curcumin and scopolamine alone groups. Additionally, curcumin with probiotics improved memory and cognitive functions in the behavioural study with the significance of p ≤ 0.0001. In conclusion, curcumin with probiotics has greater activity as compared with curcumin alone and reverses the hallmarks of Alzheimer's disease (AD).
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Affiliation(s)
- Chirag Patel
- Department of Pharmacology, SSR College of Pharmacy, SSR Memorial Trust, Silvassa, Dadra and Nagar Haveli, 396230, India.
- SSR College of Pharmacy, SSR Memorial Trust, Sayli Road, Silvassa, Dadra and Nagar Haveli, 396230, India.
| | - Sonal Pande
- Department of Pharmacology, SSR College of Pharmacy, SSR Memorial Trust, Silvassa, Dadra and Nagar Haveli, 396230, India
| | - Sanjeev Acharya
- Department of Pharmacology, SSR College of Pharmacy, SSR Memorial Trust, Silvassa, Dadra and Nagar Haveli, 396230, India
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Agrimi J, Baroni C, Anakor E, Lionetti V. Perioperative Heart-Brain Axis Protection in Obese Surgical Patients: The Nutrigenomic Approach. Curr Med Chem 2020; 27:258-281. [PMID: 30324875 DOI: 10.2174/0929867325666181015145225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/01/2018] [Accepted: 09/25/2018] [Indexed: 02/06/2023]
Abstract
The number of obese patients undergoing cardiac and noncardiac surgery is rapidly increasing because they are more prone to concomitant diseases, such as diabetes, thrombosis, sleep-disordered breathing, cardiovascular and cerebrovascular disorders. Even if guidelines are already available to manage anesthesia and surgery of obese patients, the assessment of the perioperative morbidity and mortality from heart and brain disorders in morbidly obese surgical patients will be challenging in the next years. The present review will recapitulate the new mechanisms underlying the Heart-brain Axis (HBA) vulnerability during the perioperative period in healthy and morbidly obese patients. Finally, we will describe the nutrigenomics approach, an emerging noninvasive dietary tool, to maintain a healthy body weight and to minimize the HBA propensity to injury in obese individuals undergoing all types of surgery by personalized intake of plant compounds that may regulate the switch from health to disease in an epigenetic manner. Our review provides current insights into the mechanisms underlying HBA response in obese surgical patients and how they are modulated by epigenetically active food constituents.
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Affiliation(s)
- Jacopo Agrimi
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Carlotta Baroni
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Ekene Anakor
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Vincenzo Lionetti
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,UOS Anesthesiology, Fondazione Toscana G. Monasterio, Pisa, Italy
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Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation. Nutrients 2019; 11:nu11112702. [PMID: 31717261 PMCID: PMC6893521 DOI: 10.3390/nu11112702] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 12/24/2022] Open
Abstract
The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis of NAFLD, we also characterized the hepatic proteome in MCD diet mice. As a result of two-dimensional proteomic analysis, it was confirmed that thirteen proteins including antioxidant protein were differentially expressed in hepatic steatosis. However, the difference in expression was markedly improved by curcumin treatment. Interestingly, eight of the identified proteins are known to undergo O-GlcNAcylation modification. Thus, we further focused on elucidating how the regulation of O-linked β-N-acetylglucosamine (O-GlcNAc) modification is associated with the progression of hepatic steatosis leading to hepatitis in MCD diet mice. In parallel with lipid accumulation and inflammation, the MCD diet significantly up-regulated hexosamine biosynthetic pathway (HBP) and O-GlcNAc transferase (OGT) via ER stress. Curcumin treatment alleviates the severity of hepatic steatosis by relieving the dependence of O-GlcNAcylation on nuclear factor-κB (NF-κB) in inflammation signaling. Conversely, the expressions of superoxide dismutase 1 (SOD1) and SIRT1 were significantly upregulated by curcumin treatment. In conclusion, curcumin inhibits O-GlcNAcylation pathway, leading to antioxidant responses in non-alcoholic steatohepatitis (NASH) mice. Therefore, curcumin will be a promising therapeutic agent for diseases involving hyper-O-GlcNAcylation, including cancer.
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Abstract
Objective Cisplatin (CDDP) has been known to be an effective antineoplastic drug; however, it has a cardiotoxic effect. Curcumin (CMN) and beta-carotene (BC) have been suggested to protect biological systems against CDDP-induced damage. The current study was conducted to evaluate the possible protective roles of CMN and BC on CDDP-induced cardiotoxicity in rat cardiac tissues. Methods A total of 49 adult female Wistar albino rats were equally divided into seven groups as follows control (no medication), sesame oil (1 mg/kg), CDDP (single dose injection two times as once a week, 5 mg/kg/week), BC (100 mg/kg), CDDP+BC (pretreated BC for 30 min before CDDP injection), CMN (200 mg/kg), and CDDP+CMN (pretreated CMN for 30 min before CDDP injection). These treatments were applied intraperitoneally for CDDP and with gavage for CMN and BC. The oxidative/antioxidant indicators, inflammatory cytokines, and histopathological alterations were examined. Results These alterations included a marked increase in malondialdehyde (MDA) level, significant decrease in catalase (CAT) and superoxide dismutase (SOD) activities, and significant elevation of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interleukin (IL)-6 in the CDDP group compared with the other groups. Histopathologically, CDDP-induced severe myocardial degenerative changes were observed. However, the CDDP-induced disturbances in the above-mentioned parameters significantly improved by treatment with BC and particularly CMN. Conclusion This study indicated that CDDP treatment markedly caused cardiotoxicity; however, treatment with CMN or BC ameliorated this cardiotoxicity in rats. Furthermore, these findings revealed that treatment with CMN has a higher cardioprotective effect than that with BC against CDDP-induced cardiotoxicity in rat cardiac tissues.
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Liu BL, Cheng M, Hu S, Wang S, Wang L, Hu ZQ, Huang CX, Jiang H, Wu G. Effect of the Shensong Yangxin Capsule on Energy Metabolism in Angiotensin II-Induced Cardiac Hypertrophy. Chin Med J (Engl) 2018; 131:2287-2296. [PMID: 30246714 PMCID: PMC6166447 DOI: 10.4103/0366-6999.241819] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Shensong Yangxin Capsule (SSYX), traditional Chinese medicine, has been used to treat arrhythmias, angina, cardiac remodeling, cardiac fibrosis, and so on, but its effect on cardiac energy metabolism is still not clear. The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) II-induced cardiac hypertrophy. Methods We used 2 μl (10-6 mol/L) AngII to treat neonatal rat cardiomyocytes (NRCMs) for 48 h. Myocardial α-actinin staining showed that the myocardial cell volume increased. Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR). Therefore, it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed. Then, NRCMs were treated with 1 μl of different concentrations of SSYX (0.25, 0.5, and 1.0 μg/ml) for another 24 h. To explore the time-depend effect of SSYX on energy metabolism, 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h. Mitochondria was assessed by MitoTracker staining and confocal microscopy. mRNA and protein expression of mitochondrial biogenesis-related genes - Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), energy balance key factor - adenosine monophosphate-activated protein kinase (AMPK), fatty acids oxidation factor - carnitine palmitoyltransferase-1 (CPT-1), and glucose oxidation factor - glucose transporter- 4 (GLUT-4) were measured by PCR and Western blotting analysis. Results With the increase in the concentration of SSYX (from 0.25 to 1.0 μg/ml), an increased mitochondrial density in AngII-induced cardiomyocytes was found compared to that of those treated with AngII only (0.25 μg/ml, 18.3300 ± 0.8895 vs. 24.4900 ± 0.9041, t = 10.240, P < 0.0001; 0.5 μg/ml, 18.3300 ± 0.8895 vs. 25.9800 ± 0.8187, t = 12.710, P < 0.0001; and 1.0 μg/ml, 18.3300 ± 0.8895 vs. 24.2900 ± 1.3120, t = 9.902, P < 0.0001; n = 5 per dosage group). SSYX also increased the mRNA and protein expression of PGC-1α (0.25 μg/ml, 0.8892 ± 0.0848 vs. 1.0970 ± 0.0994, t = 4.319, P = 0.0013; 0.5 μg/ml, 0.8892 ± 0.0848 vs. 1.2330 ± 0.0564, t = 7.150, P < 0.0001; and 1.0 μg/ml, 0.8892 ± 0.0848 vs. 1.1640 ± 0.0755, t = 5.720, P < 0.0001; n = 5 per dosage group), AMPK (0.25 μg/ml, 0.8872 ± 0.0779 vs. 1.1500 ± 0.0507, t = 7.239, P < 0.0001; 0.5 μg/ml, 0.8872 ± 0.0779 vs. 1.2280 ± 0.0623, t = 9.379, P < 0.0001; and 1.0 μg/ml, 0.8872 ± 0.0779 vs. 1.3020 ± 0.0450, t = 11.400, P < 0.0001; n = 5 per dosage group), CPT-1 (1.0 μg/ml, 0.7348 ± 0.0594 vs. 0.9880 ± 0.0851, t = 4.994, P = 0.0007, n = 5), and GLUT-4 (0.5 μg/ml, 1.5640 ± 0.0599 vs. 1.7720 ± 0.0660, t = 3.783, P = 0.0117; 1.0 μg/ml, 1.5640 ± 0.0599 vs. 2.0490 ± 0.1280, t = 8.808, P < 0.0001; n = 5 per dosage group). The effect became more obvious with the increasing concentration of SSYX. When 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h, the expression of AMPK (6 h, 14.6100 ± 0.6205 vs. 16.5200 ± 0.7450, t = 3.456, P = 0.0250; 12 h, 14.6100 ± 0.6205 vs. 18.3200 ± 0.9965, t = 6.720, P < 0.0001; 24 h, 14.6100 ± 0.6205 vs. 21.8800 ± 0.8208, t = 13.160, P < 0.0001; and 48 h, 14.6100 ± 0.6205 vs. 23.7400 ± 1.0970, t = 16.530, P < 0.0001; n = 5 per dosage group), PGC-1α (12 h, 11.4700 ± 0.7252 vs. 16.9000 ± 1.0150, t = 7.910, P < 0.0001; 24 h, 11.4700 ± 0.7252 vs. 20.8800 ± 1.2340, t = 13.710, P < 0.0001; and 48 h, 11.4700 ± 0.7252 vs. 22.0300 ± 1.4180, t = 15.390; n = 5 per dosage group), CPT-1 (24 h, 15.1600 ± 1.0960 vs. 18.5800 ± 0.9049, t = 6.048, P < 0.0001, n = 5), and GLUT-4 (6 h, 10.2100 ± 0.9485 vs. 12.9700 ± 0.8221, t = 4.763, P = 0.0012; 12 h, 10.2100 ± 0.9485 vs. 16.9100 ± 0.8481, t = 11.590, P < 0.0001; 24 h, 10.2100 ± 0.9485 vs. 19.0900 ± 0.9797, t = 15.360, P < 0.0001; and 48 h, 10.2100 ± 0.9485 vs. 14.1900 ± 0.9611, t = 6.877, P < 0.0001; n = 5 per dosage group) mRNA and protein increased gradually with the prolongation of drug action time. Conclusions SSYX could increase myocardial energy metabolism in AngII-induced cardiac hypertrophy. Therefore, SSYX might be considered to be an alternative therapeutic remedy for myocardial hypertrophy.
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Affiliation(s)
- Bei-Lei Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China
| | - Mian Cheng
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Shan Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China
| | - Shun Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China
| | - Le Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China
| | - Zheng-Qing Hu
- Department of Cardiology, Ezhou Hospital, Renmin Hospital of Wuhan University, Ezhou, Hubei 436000, China
| | - Cong-Xin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China
| | - Gang Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060; Department of Cardiology, Ezhou Hospital, Renmin Hospital of Wuhan University, Ezhou, Hubei 436000, China
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Fang G, Chen S, Huang Q, Chen L, Liao D. Curcumin suppresses cardiac fibroblasts activities by regulating the proliferation and cell cycle via the inhibition of the p38 MAPK/ERK signaling pathway. Mol Med Rep 2018; 18:1433-1438. [PMID: 29901190 PMCID: PMC6072161 DOI: 10.3892/mmr.2018.9120] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 05/09/2018] [Indexed: 12/12/2022] Open
Abstract
Cardiac fibrosis is a deleterious effect of many cardiovascular diseases. Previous studies have shown that curcumin has exhibited protective effects on cardiovascular diseases. The aim of the present study was to evaluate the effects of curcumin on the activity of human cardiac fibroblasts (CFs) and to elucidate the underlying mechanisms involved. Human CFs were incubated with or without curcumin (20 µmol/l) and transforming growth factor β1 (TGF‑β1; 10 ng/ml), and the expression of α‑smooth muscle actin (α‑SMA), collagen type Iα (COLA)‑1 and COLA3 was evaluated using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Cell proliferation was evaluated by Cell Counting Kit‑8 analysis, and phases of the cell cycle were studied by flow cytometry. Western blot analysis was performed to evaluate the expression of cyclin‑dependent kinase 1 (CDK1), Cyclin B, phosphorylation (p)‑mothers against decapentaplegic homolog 2/3 (p‑smad2/3), p‑P38, and p‑extracellular regulated protein kinases (ERK). Curcumin significantly reduced mRNA and protein levels of α‑SMA, COLA1, and COLA3 in CFs stimulated with TGF‑β1. However, in the absence of TGF‑β1, curcumin did not have any effects on CFs, suggesting that curcumin inhibited TGF‑β1‑mediated CF activities, including differentiation and collagen deposition. Additionally, curcumin inhibited the proliferation of TGF‑β1‑treated CFs, and promoted G2/M phase cell cycle arrest. Curcumin reduced cell cycle protein expression by inhibiting smad2/3, p38 mitogen‑activated protein kinase, and ERK phosphorylation in TGF‑β1‑treated CFs. Thus, these results indicated that curcumin may be a potential anti‑fibrotic drug to treat cardiac fibrosis.
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Affiliation(s)
- Guanhua Fang
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Shaoqin Chen
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Qiuyu Huang
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Liangwan Chen
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Dongshan Liao
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
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Kangarlou S, Ramezanpour S, Balalaie S, Roudbar Mohammadi S, Haririan I. Curcumin-loaded nanoliposomes linked to homing peptides for integrin targeting and neuropilin-1-mediated internalization. PHARMACEUTICAL BIOLOGY 2017; 55:277-285. [PMID: 27937055 PMCID: PMC6130459 DOI: 10.1080/13880209.2016.1261301] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 08/17/2016] [Accepted: 11/07/2016] [Indexed: 06/06/2023]
Abstract
CONTEXT Curcumin, a naturally occurring polyphenol, has been extensively studied for its broad-spectrum anticancer effects. The potential benefits are, however, limited due to its poor water solubility and rapid degradation which result in low bioavailability on administration. OBJECTIVES This study encapsulates curcumin in nanoliposomes including an integrin-homing peptide combined with a C end R neuropilin-1 targeting motif for targeted delivery and receptor-mediated internalization, respectively. MATERIALS AND METHODS The linear GHHNGR (Glycine-Histidine-Histidine-Asparagine-Glycine-Arginine) was synthesized through F-moc chemistry on 2-chlorotrityl chloride resin and conjugated to oleic acid. The lipoyl-peptide units were then co-assembled with lecithin and 0-75 mole % Tween-80 into liposomes. Curcumin was passively entrapped using a film hydration technique and its degradation profile was examined within seven consecutive days. The cytotoxic effects of the curcumin-loaded liposomes were studied on MCF-7 and MDA-MB-468, during 24 h exposure in MTT assay. RESULTS The maximum curcumin entrapment (15.5% W/W) and minimum degradation (< 23%) were obtained in a pH switch loading method from 5.7 to 8, in nanoliposomes (< 50 nm) containing oleyl-peptide, lecithin and Tween-80 (1:1:0.75 mole ratio). The oleyl-peptide did not prove any haemolytic activity (< 1.5%) up to 10-fold of its experimental concentration. The curcumin-loaded liposomes displayed significant reduction in the viabilities of MCF-7 (IC50 3.8 μM) and MDA-MB-468 (IC50 5.4 μM). DISCUSSION AND CONCLUSION This study indicated potential advantages of the peptide-conjugated liposomes in drug transport to the cancer cells. This feature might be an outcome of probable interactions between the targeted nanoliposomes with the integrin and neuropilin-1 receptors.
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Affiliation(s)
- Sogol Kangarlou
- Department of Pharmaceutical Biomaterials School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Sorour Ramezanpour
- Peptide Chemistry Research Center, K.N. Toosi University of Technology, Tehran, Iran
| | - Saeed Balalaie
- Peptide Chemistry Research Center, K.N. Toosi University of Technology, Tehran, Iran
| | - Shahla Roudbar Mohammadi
- Department of Medical Mycology School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ismaeil Haririan
- Department of Pharmaceutical Biomaterials School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Medical Biomaterials Research Center, Tehran University of Medical Sciences, Tehran, Iran
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11
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Gera M, Sharma N, Ghosh M, Huynh DL, Lee SJ, Min T, Kwon T, Jeong DK. Nanoformulations of curcumin: an emerging paradigm for improved remedial application. Oncotarget 2017; 8:66680-66698. [PMID: 29029547 PMCID: PMC5630447 DOI: 10.18632/oncotarget.19164] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 06/29/2017] [Indexed: 12/26/2022] Open
Abstract
Curcumin is a natural polyphenol and essential curcuminoid derived from the rhizome of the medicinal plant Curcuma longa (L.) is universally acknowledged as “Wonder drug of life”. It is a vital consumable and restorative herb, commonly keened for several ailments such as cancer, arthritis, pain, bruises, gastrointestinal quandaries, swelling and much more. Despite its enormous curative potential, the poor aqueous solubility and consequently, minimal systemic bioavailability with rapid degradation are some of the major factors which restrict the utilization of curcumin at medical perspective. However, to improve its clinically relevant parameters, nanoformulation of curcumin is emerging as a novel substitute for their superior therapeutic modality. It enhances its aqueous solubility and targeted delivery to the tissue of interest that prompts to enhance the bioavailability, better drug conveyance, and more expeditious treatment. Subsequent investigations are endeavored to enhance the bio-distribution of native curcumin by modifying with felicitous nano-carriers for encapsulation. In this review, we specifically focus on the recent nanotechnology based implementations applied for overcoming the innate constraints of native curcumin and additionally the associated challenges which restrict its potential therapeutic applications both in vivo and in-vitro studies, as well as their detailed mechanism of action, have additionally been discussed.
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Affiliation(s)
- Meeta Gera
- Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea
| | - Neelesh Sharma
- Division of Veterinary Medicine, Faculty of Veterinary Science and Animal Husbandry, Sher-e-Kashmi University of Agricultural Sciences and Technology, R.S. Pura, Jammu, India
| | - Mrinmoy Ghosh
- Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea
| | - Do Luong Huynh
- Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea
| | - Sung Jin Lee
- Department of Animal Biotechnology, College of Animal Bioscience and Technology, Kangwon National University, Gangwon-do, Republic of Korea
| | - Taesun Min
- Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea
| | - Taeho Kwon
- Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.,Laboratory of Animal Genetic Engineering and Stem Cell Biology, Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju, Republic of Korea
| | - Dong Kee Jeong
- Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.,Laboratory of Animal Genetic Engineering and Stem Cell Biology, Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju, Republic of Korea
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12
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The Impact of Environmental Factors in Influencing Epigenetics Related to Oxidative States in the Cardiovascular System. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2712751. [PMID: 28607629 PMCID: PMC5457758 DOI: 10.1155/2017/2712751] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 04/03/2017] [Accepted: 04/12/2017] [Indexed: 12/14/2022]
Abstract
Oxidative states exert a significant influence on a wide range of biological and molecular processes and functions. When their balance is shifted towards enhanced amounts of free radicals, pathological phenomena can occur, as the generation of reactive oxygen species (ROS) in tissue microenvironment or in the systemic circulation can be detrimental. Epidemic chronic diseases of western societies, such as cardiovascular disease, obesity, and diabetes correlate with the imbalance of redox homeostasis. Current advances in our understanding of epigenetics have revealed a parallel scenario showing the influence of oxidative stress as a major regulator of epigenetic gene regulation via modification of DNA methylation, histones, and microRNAs. This has provided both the biological link and a potential molecular explanation between oxidative stress and cardiovascular/metabolic phenomena. Accordingly, in this review, we will provide current insights on the physiological and pathological impact of changes in oxidative states on cardiovascular disorders, by specifically focusing on the influence of epigenetic regulation. A special emphasis will highlight the effect on epigenetic regulation of human's current life habits, external and environmental factors, including food intake, tobacco, air pollution, and antioxidant-based approaches. Additionally, the strategy to quantify oxidative states in humans in order to determine which biological marker could best match a subject's profile will be discussed.
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13
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He Y, Deng Z, Alghamdi M, Lu L, Fear MW, He L. From genetics to epigenetics: new insights into keloid scarring. Cell Prolif 2017; 50. [PMID: 28054407 DOI: 10.1111/cpr.12326] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 11/16/2016] [Indexed: 12/16/2022] Open
Abstract
Keloid scarring is a dermal fibroproliferative response characterized by excessive and progressive deposition of collagen; aetiology and molecular pathology underlying keloid formation and progression remain unclear. Genetic predisposition is important in the pathogenic processes of keloid formation, however, environmental factors and epigenetic mechanisms may also play pivotal roles. Epigenetic modification is a recent area of investigation in understanding the molecular pathogenesis of keloid scarring and there is increasing evidence that epigenetic changes may play a role in induction and persistent activation of fibroblasts in keloid scars. Here we have reviewed three epigenetic mechanisms: DNA methylation, histone modification and the role of non-coding RNAs. We also review the evidence that these mechanisms may play a role in keloid formation - in future, it may be possible that epigenetic markers may be used instead of prognostic or diagnostic markers here. However, there is a significant amount of work required to increase our current understanding of the role of epigenetic modification in keloid disease.
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Affiliation(s)
- Yongjing He
- Department of Plastic Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhenjun Deng
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China.,Department of Physiology, Kunming Medical University, Kunming, China
| | - Mansour Alghamdi
- Burn Injury Research Unit, School of Surgery, University of Western Australia, Crawley, WA, Australia.,Department of Human Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Lechun Lu
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China.,Department of Physiology, Kunming Medical University, Kunming, China
| | - Mark W Fear
- Burn Injury Research Unit, School of Surgery, University of Western Australia, Crawley, WA, Australia
| | - Li He
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China
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14
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Syed AA, Lahiri S, Mohan D, Valicherla GR, Gupta AP, Kumar S, Maurya R, Bora HK, Hanif K, Gayen JR. Cardioprotective Effect of Ulmus wallichiana Planchon in β-Adrenergic Agonist Induced Cardiac Hypertrophy. Front Pharmacol 2016; 7:510. [PMID: 28066255 PMCID: PMC5174112 DOI: 10.3389/fphar.2016.00510] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 12/09/2016] [Indexed: 01/01/2023] Open
Abstract
Ulmus wallichiana Planchon (Family: Ulmaceae), a traditional medicinal plant, was used in fracture healing in the folk tradition of Uttarakhand, Himalaya, India. The present study investigated the cardioprotective effect of ethanolic extract (EE) and butanolic fraction (BF) of U. wallichiana in isoprenaline (ISO) induced cardiac hypertrophy in Wistar rats. Cardiac hypertrophy was induced by ISO (5 mg/kg/day, subcutaneously) in rats. Treatment was performed by oral administration of EE and BF of U. wallichiana (500 and 50 mg/kg/day). The blood pressure (BP) and heart rate (HR) were measured by non-invasive blood pressure measurement technique. Plasma renin, Ang II, NO, and cGMP level were estimated using an ELISA kit. Angiotensin converting enzyme activity was estimated. BP and HR were significantly increased in ISO group (130.33 ± 1.67 mmHg vs. 111.78 ± 1.62 mmHg, p < 0.001 and 450.51 ± 4.90 beats/min vs. 347.82 ± 6.91 beats/min, respectively, p < 0.001). The BP and HR were significantly reduced (EE: 117.53 ± 2.27 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001, BF: 119.74 ± 3.32 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001); HR: (EE: 390.22 ± 8.24 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001, BF: 345.38 ± 6.79 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001) after the treatment of EE and BF of U. wallichiana, respectively. Plasma renin, Ang II, ACE activity was decreased and NO, cGMP level were increased. The EE and BF of U. wallichiana down regulated the expression of ANP, BNP, TNF-α, IL-6, MMP9, β1-AR, TGFβ1 and up regulated NOS3, ACE2 and Mas expression level, respectively. Thus, this study demonstrated that U. wallichiana has cardioprotective effect against ISO induced cardiac hypertrophy.
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Affiliation(s)
- Anees A Syed
- Division of Pharmacokinetics and Metabolism, Council of Scientific and Industrial Research-Central Drug Research Institute Lucknow, India
| | - Shibani Lahiri
- Division of Pharmacokinetics and Metabolism, Council of Scientific and Industrial Research-Central Drug Research Institute Lucknow, India
| | - Divya Mohan
- Division of Pharmacology, Council of Scientific and Industrial Research-Central Drug Research Institute Lucknow, India
| | - Guru R Valicherla
- Division of Pharmacokinetics and Metabolism, Council of Scientific and Industrial Research-Central Drug Research InstituteLucknow, India; Academy of Scientific and Innovative ResearchNew Delhi, India
| | - Anand P Gupta
- Division of Pharmacokinetics and Metabolism, Council of Scientific and Industrial Research-Central Drug Research Institute Lucknow, India
| | - Sudhir Kumar
- Division of Medicinal and Process Chemistry, Council of Scientific and Industrial Research-Central Drug Research Institute Lucknow, India
| | - Rakesh Maurya
- Academy of Scientific and Innovative ResearchNew Delhi, India; Division of Medicinal and Process Chemistry, Council of Scientific and Industrial Research-Central Drug Research InstituteLucknow, India
| | - Himanshu K Bora
- Division of Laboratory Animals, Council of Scientific and Industrial Research-Central Drug Research Institute Lucknow, India
| | - Kashif Hanif
- Division of Pharmacology, Council of Scientific and Industrial Research-Central Drug Research InstituteLucknow, India; Academy of Scientific and Innovative ResearchNew Delhi, India
| | - Jiaur R Gayen
- Division of Pharmacokinetics and Metabolism, Council of Scientific and Industrial Research-Central Drug Research InstituteLucknow, India; Academy of Scientific and Innovative ResearchNew Delhi, India
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15
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Shankar E, Kanwal R, Candamo M, Gupta S. Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol 2016; 40-41:82-99. [PMID: 27117759 DOI: 10.1016/j.semcancer.2016.04.002] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 04/08/2016] [Accepted: 04/18/2016] [Indexed: 12/21/2022]
Abstract
The influence of diet and environment on human health has been known since ages. Plant-derived natural bioactive compounds (phytochemicals) have acquired an important role in human diet as potent antioxidants and cancer chemopreventive agents. In past few decades, the role of epigenetic alterations such as DNA methylation, histone modifications and non-coding RNAs in the regulation of mammalian genome have been comprehensively addressed. Although the effects of dietary phytochemicals on gene expression and signaling pathways have been widely studied in cancer, the impact of these dietary compounds on mammalian epigenome is rapidly emerging. The present review outlines the role of different epigenetic mechanisms in the regulation and maintenance of mammalian genome and focuses on the role of dietary phytochemicals as epigenetic modifiers in cancer. Above all, the review focuses on summarizing the progress made thus far in cancer chemoprevention with dietary phytochemicals, the heightened interest and challenges in the future.
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Affiliation(s)
- Eswar Shankar
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Rajnee Kanwal
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Mario Candamo
- Department of Biology, School of Undergraduate Studies, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Sanjay Gupta
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA; Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA; Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
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16
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Voelter-Mahlknecht S. Epigenetic associations in relation to cardiovascular prevention and therapeutics. Clin Epigenetics 2016; 8:4. [PMID: 26779291 PMCID: PMC4714496 DOI: 10.1186/s13148-016-0170-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/06/2016] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases (CVD) increasingly burden societies with vast financial and health care problems. Therefore, the importance of improving preventive and therapeutic measures against cardiovascular diseases is continually growing. To accomplish such improvements, research must focus particularly on understanding the underlying mechanisms of such diseases, as in the field of epigenetics, and pay more attention to strengthening primary prevention. To date, preliminary research has found a connection between DNA methylation, histone modifications, RNA-based mechanisms and the development of CVD like atherosclerosis, cardiac hypertrophy, myocardial infarction, and heart failure. Several therapeutic agents based on the findings of such research projects are currently being tested for use in clinical practice. Although these tests have produced promising data so far, no epigenetically active agents or drugs targeting histone acetylation and/or methylation have actually entered clinical trials for CVDs, nor have they been approved by the FDA. To ensure the most effective prevention and treatment possible, further studies are required to understand the complex relationship between epigenetic regulation and the development of CVD. Similarly, several classes of RNA therapeutics are currently under development. The use of miRNAs and their targets as diagnostic or prognostic markers for CVDs is promising, but has not yet been realized. Further studies are necessary to improve our understanding of the involvement of lncRNA in regulating gene expression changes underlying heart failure. Through the data obtained from such studies, specific therapeutic strategies to avoid heart failure based on interference with incRNA pathways could be developed. Together, research and testing findings raise hope for enhancing the therapeutic armamentarium. This review presents the currently available data concerning epigenetic mechanisms and compounds involved in cardiovascular diseases, as well as preventive and therapeutic approaches against them.
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Affiliation(s)
- Susanne Voelter-Mahlknecht
- University Hospital of Tuebingen, Institute of Occupational and Social Medicine and Health Services Research, Wilhelmstr. 27, 72074 Tuebingen, Germany
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17
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Liu H, Liu A, Shi C, Li B. Curcumin suppresses transforming growth factor-β1-induced cardiac fibroblast differentiation via inhibition of Smad-2 and p38 MAPK signaling pathways. Exp Ther Med 2016; 11:998-1004. [PMID: 26998027 DOI: 10.3892/etm.2016.2969] [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: 11/16/2014] [Accepted: 12/10/2015] [Indexed: 02/06/2023] Open
Abstract
The differentiation of cardiac fibroblasts (CFs) into myofibroblasts and the subsequent deposition of the extracellular matrix is associated with myocardial fibrosis following various types of myocardial injury. In the present study, the effect of curcumin, which is a pharmacologically-safe natural compound from the Curcuma longa herb, on transforming growth factor (TGF)-β1-induced CFs was investigated, and the underlying molecular mechanisms were examined. The expression levels of α-smooth muscle actin (SMA) stress fibers were investigated using western blotting and immunofluorescence in cultured neonatal rat CFs. Protein and mRNA expression levels of α-SMA and collagen type I (ColI) were determined by western blotting and reverse transcription-quantitative polymerase chain reaction. In addition, the activation of Smad2 and p38 was examined using western blotting. Curcumin, SB431542 (a TGF-βR-Smad2 inhibitor) and SB203580 (a p38 inhibitor) were used to inhibit the stimulation by TGF-β1. The results demonstrated that the TGF-β1-induced expression of α-SMA and ColI was suppressed by curcumin at the mRNA and protein levels, while SB431542 and SB203580 induced similar effects. Furthermore, phosphorylated Smad-2 and p38 were upregulated in TGF-β1-induced CFs, and these effects were substantially inhibited by curcumin administration. In conclusion, the results of the present study demonstrated that treatment with curcumin effectively suppresses TGF-β1-induced CF differentiation via Smad-2 and p38 signaling pathways. Thus, curcumin may be a potential therapeutic agent for the treatment of cardiac fibrosis.
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Affiliation(s)
- Huzi Liu
- Department of Cardiac Surgery, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi 030024, P.R. China
| | - Aijun Liu
- Pediatric Heart Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Chunli Shi
- Outpatient Department, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi 030024, P.R. China
| | - Bao Li
- Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi 030024, P.R. China
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18
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Koizume S, Miyagi Y. Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets. World J Clin Oncol 2014; 5:908-920. [PMID: 25493229 PMCID: PMC4259953 DOI: 10.5306/wjco.v5.i5.908] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 03/31/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is a leading cause of cancer death in women, worldwide. Fortunately, breast cancer is relatively chemosensitive, with recent advances leading to the development of effective therapeutic strategies, significantly increasing disease cure rate. However, disease recurrence and treatment of cases lacking therapeutic molecular targets, such as epidermal growth factor receptor 2 and hormone receptors, referred to as triple-negative breast cancers, still pose major hurdles in the treatment of breast cancer. Thus, novel therapeutic approaches to treat aggressive breast cancers are essential. Blood coagulation factor VII (fVII) is produced in the liver and secreted into the blood stream. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. TF is overexpressed in breast cancer tissues. The TF-fVII complex may be formed in the absence of injury, because fVII potentially exists in the tissue fluid within cancer tissues. The active form of this complex (TF-fVIIa) may stimulate the expression of numerous malignant phenotypes in breast cancer cells. Thus, the TF-fVII pathway is a potentially attractive target for breast cancer treatment. To date, a number of studies investigating the mechanisms by which TF-fVII signaling contributes to breast cancer progression, have been conducted. In this review, we summarize the mechanisms controlling TF and fVII synthesis and regulation in breast cancer cells. Our current understanding of the TF-fVII pathway as a mediator of breast cancer progression will be also described. Finally, we will discuss how this knowledge can be applied to the design of future therapeutic strategies.
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19
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Abstract
Acute kidney injury (AKI) is a risk factor for chronic kidney disease and death. Despite progress made in understanding the cellular and molecular basis of AKI pathogenesis there has been no improvement in the high mortality rate from this disease in decades. Epigenetics is one of the most intensively studied fields of biology today and represents a new paradigm for understanding the pathophysiology of disease. Although epigenetics of AKI is a nascent field, the available information already is providing compelling evidence that chromatin biology plays a critical role in this disease. In this article we explore what is known about the contribution of epigenetic mechanisms to the pathophysiology of AKI and how this knowledge already is guiding the development of new diagnostic tools and epigenetic therapies.
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20
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Curcumin attenuation of lipopolysaccharide induced cardiac hypertrophy in rodents. ISRN INFLAMMATION 2013; 2013:539305. [PMID: 24236240 PMCID: PMC3819047 DOI: 10.1155/2013/539305] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/04/2013] [Indexed: 11/17/2022]
Abstract
To study the ameliorating effects of curcumin in lipopolysaccharide (LPS) induced cardiac hypertrophy, mice were assigned to 4 groups (3 males and 3 females in each group): (A) control, (B) curcumin: 100 μ g/kg of body weight by intraperitoneal route (IP), (C) LPS: 60 mg/kg (IP), and (D) LPS + curcumin: both at previously stated concentrations by IP route. All mice were sacrificed as 12 hr and 24 hrs groups accordingly after LPS injection. The hearts were collected, photographed for cardiomegaly, and weighed to compare heart weight/brain weight (HW/BW) in mg/mg. For immunohistochemistry, the tissue sections were exposed to histone H3, H4 and acetylated histone H3, H4 antibody. LPS induced a significant increase in histone acetylation as shown by intense staining. In curcumin + LPS treated mice nuclear staining was similar to the control group indicating that curcumin traversed the histone acetylation activity of the LPS. To further check the mechanism of action of curcumin, p300 protein acetylation levels were analyzed. This study suggests that the probable mechanism of action of curcumin is via the reduction of p300 HAT activity.
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21
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Bhullar KS, Jha A, Youssef D, Rupasinghe HPV. Curcumin and its carbocyclic analogs: structure-activity in relation to antioxidant and selected biological properties. Molecules 2013; 18:5389-404. [PMID: 23666006 PMCID: PMC6270194 DOI: 10.3390/molecules18055389] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 04/24/2013] [Accepted: 05/07/2013] [Indexed: 11/16/2022] Open
Abstract
Curcumin is the major phenolic compound present in turmeric (Curcuma longa L.). Curcumin and 15 novel analogs were investigated for their antioxidant and selected biological activities. Strong relationships between the structure and evaluated activity revealed that the compounds with specific functional groups and carbon skeleton had specific biological profiles. Among the compounds tested, the derivatives (E)-2-(3,4-dimethoxybenzylidene)-5-((E)-3-(3,4-dimethoxyphenyl)acryloyl)cyclopentanone (3e), and (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)-cyclopentanone (3d) and the parent compound curcumin exhibited the strongest free radical scavenging and antioxidant capacity. Concerning the other biological activities studied the compound (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxy-phenyl)-acryloyl)cyclopentanone (3d) was the most potent angiotensin converting enzyme (ACE) inhibitor, while the derivatives (E)-2-(4-hydroxybenzylidene)-6-((E)-3-(4-hydroxyphenyl)acryloyl)cyclohexanone (2b), (E)-2-(3,4-dimethoxybenzylidene)-6-((E)-3-(3,4-dimethoxyphenyl)acryloyl)cyclohexanone (2e) and (E)-2-(3,4-dimethoxybenzylidene)-5-((E)-3-(3,4-dimethoxyphenyl)acryloyl)cyclopentanone (3e) exhibited strong tyrosinase inhibition. Moreover, (E)-2-(3,4-dimethoxybenzylidene)-6-((E)-3-(3,4-dimethoxyphenyl)-acryloyl)cyclohexanone (2e) was also found to be the strongest human HIV-1 protease inhibitor in vitro among the tested compounds. Cytotoxicity studies using normal human lung cells revealed that the novel curcumin as well as its carbocyclic analogs are not toxic.
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Affiliation(s)
- Khushwant S. Bhullar
- Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, B2N 5E3, Canada
| | - Amitabh Jha
- Department of Chemistry, Acadia University, Wolfville, Nova Scotia, B4P 2R6, Canada
| | - Dani Youssef
- Department of Chemistry, Acadia University, Wolfville, Nova Scotia, B4P 2R6, Canada
- Département des Science, Université Sainte Anne, Church Point, Nova Scotia, B0W 1M0, Canada
| | - H. P. Vasantha Rupasinghe
- Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, B2N 5E3, Canada
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Aziz MTA, El Ibrashy IN, Mikhailidis DP, Rezq AM, Wassef MAA, Fouad HH, Ahmed HH, Sabry DA, Shawky HM, Hussein RE. Signaling mechanisms of a water soluble curcumin derivative in experimental type 1 diabetes with cardiomyopathy. Diabetol Metab Syndr 2013; 5:13. [PMID: 23497378 PMCID: PMC3602235 DOI: 10.1186/1758-5996-5-13] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 02/20/2013] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Curcumin exhibits anti-diabetic activities, induces heme-oxygenase-1 (HO-1) and is an inhibitor of transcriptional co-activator p300. A novel water soluble curcumin derivative (NCD) has been developed to overcome low invivo bioavailability of curcumin. We evaluated the effect of the NCD on signaling mechanisms involved in cardiomyocyte hypertrophy and studied whether its action is mediated via inducible HO-1. MATERIALS AND METHODS Rats were divided into controls, controls receiving NCD, diabetic, diabetic receiving NCD, diabetic receiving pure curcumin, diabetic receiving HO inhibitor, zinc protoporphyrin IX (ZnPP IX) and diabetic receiving NCD and ZnPP IX. NCD and curcumin were given orally. After 45 days, cardiac physiologic parameters, plasma glucose, insulin, glycated hemoglobin (GHb), HO-1 gene expression and HO activity in pancreas and cardiac tissues were assessed. Gene expression of p300, atrial natriuretic peptide (ANP) and myocyte enhancer factor 2 (MEF2A and MEF2C) were studied. RESULTS NCD and curcumin decreased plasma glucose, GHb and increased insulin levels significantly in diabetic rats. This action may be partially mediated by induction of HO-1 gene. HO-1 gene expression and HO activity were significantly increased in diabetic heart and pancreas. Diabetes upregulated the expression of ANP, MEF2A, MEF2C and p300. NCD and curcumin prevented diabetes-induced upregulation of these parameters and improved left ventricular function. The effect of the NCD was better than the same dose of curcumin.
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Affiliation(s)
- Mohamed Talaat Abdel Aziz
- Unit of Biochemistry and Molecular Biology, Medical Biochemistry Department, Faculty of Medicine, Cairo University, Kasr El Aini, Cairo, Egypt
| | | | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital campus, University College London Medical School, University College London (UCL), London, UK
| | - Ameen Mahmoud Rezq
- Unit of Biochemistry and Molecular Biology, Medical Biochemistry Department, Faculty of Medicine, Cairo University, Kasr El Aini, Cairo, Egypt
| | - Mohamed Abdel Aziz Wassef
- Unit of Biochemistry and Molecular Biology, Medical Biochemistry Department, Faculty of Medicine, Cairo University, Kasr El Aini, Cairo, Egypt
| | - Hanan Hassan Fouad
- Unit of Biochemistry and Molecular Biology, Medical Biochemistry Department, Faculty of Medicine, Cairo University, Kasr El Aini, Cairo, Egypt
| | - Hanan Hosni Ahmed
- Unit of Biochemistry and Molecular Biology, Medical Biochemistry Department, Faculty of Medicine, Cairo University, Kasr El Aini, Cairo, Egypt
| | - Dina A Sabry
- Unit of Biochemistry and Molecular Biology, Medical Biochemistry Department, Faculty of Medicine, Cairo University, Kasr El Aini, Cairo, Egypt
| | | | - Rania Elsayed Hussein
- Unit of Biochemistry and Molecular Biology, Medical Biochemistry Department, Faculty of Medicine, Cairo University, Kasr El Aini, Cairo, Egypt
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Su ZY, Shu L, Khor TO, Lee JH, Fuentes F, Tony Kong AN. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem (Cham) 2013; 329:133-62. [PMID: 22836898 PMCID: PMC3924422 DOI: 10.1007/128_2012_340] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Oxidative stress is caused by an imbalance of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the antioxidative stress defense systems in cells. ROS/RNS or carcinogen metabolites can attack intracellular proteins, lipids, and nucleic acids, which can result in genetic mutations, carcinogenesis, and other diseases. Nrf2 plays a critical role in the regulation of many antioxidative stress/antioxidant and detoxification enzyme genes, such as glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1), UDP-glucuronyl transferases (UGTs), and heme oxygenase-1 (HO-1), directly via the antioxidant response element (ARE). Recently, many studies have shown that dietary phytochemicals possess cancer chemopreventive potential through the induction of Nrf2-mediated antioxidant/detoxification enzymes and anti-inflammatory signaling pathways to protect organisms against cellular damage caused by oxidative stress. In addition, carcinogenesis can be caused by epigenetic alterations such as DNA methylation and histone modifications in tumor-suppressor genes and oncogenes. Interestingly, recent studies have shown that several naturally occurring dietary phytochemicals can epigenetically modify the chromatin, including reactivating Nrf2 via demethylation of CpG islands and the inhibition of histone deacetylases (HDACs) and/or histone acetyltransferases (HATs). The advancement and development of dietary phytochemicals in cancer chemoprevention research requires the integration of the known, and as-yet-unknown, compounds with the Nrf2-mediated antioxidant, detoxification, and anti-inflammatory systems and their in vitro and in vivo epigenetic mechanisms; human clinical efficacy studies must also be performed.
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Affiliation(s)
- Zheng-Yuan Su
- Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Limin Shu
- Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Tin Oo Khor
- Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Jong Hun Lee
- Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Francisco Fuentes
- Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA, Departamento de Agricultura del Desierto y Biotecnología, Universidad Arturo Prat, Casilla 121, Iquique, Chile
| | - Ah-Ng Tony Kong
- Department of Pharmaceutics, Center for Cancer Prevention Research, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
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Yao QY, Xu BL, Wang JY, Liu HC, Zhang SC, Tu CT. Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats. Altern Ther Health Med 2012; 12:156. [PMID: 22978413 PMCID: PMC3495222 DOI: 10.1186/1472-6882-12-156] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 09/08/2012] [Indexed: 12/20/2022]
Abstract
Background At present there is no effective and accepted therapy for hepatic fibrosis. Transforming growth factor (TGF)-β1 signaling pathway contributes greatly to hepatic fibrosis. Reducing TGF-β synthesis or inhibiting components of its complex signaling pathway represent important therapeutic targets. The aim of the study was to investigate the effect of curcumin on liver fibrosis and whether curcumin attenuates the TGF-β1 signaling pathway. Methods Sprague–Dawley rat was induced liver fibrosis by carbon tetrachloride (CCl4) for six weeks together with or without curcumin, and hepatic histopathology and collagen content were employed to quantify liver necro-inflammation and fibrosis. Moreover, the mRNA and protein expression levels of TGF-β1, Smad2, phosphorylated Smad2, Smad3, Smad7 and connective tissue growth factor (CTGF) were determined by quantitative real time-PCR, Western blot, or immunohistochemistry. Results Rats treated with curcumin improved liver necro-inflammation, and reduced liver fibrosis in association with decreased α-smooth muscle actin expression, and decreased collagen deposition. Furthermore, curcumin significantly attenuated expressions of TGFβ1, Smad2, phosphorylated Smad2, Smad3, and CTGF and induced expression of the Smad7. Conclusions Curcumin significantly attenuated the severity of CCl4-induced liver inflammation and fibrosis through inhibition of TGF-β1/Smad signalling pathway and CTGF expression. These data suggest that curcumin might be an effective antifibrotic drug in the prevention of liver disease progression.
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Hou J, Kang YJ. Regression of pathological cardiac hypertrophy: signaling pathways and therapeutic targets. Pharmacol Ther 2012; 135:337-54. [PMID: 22750195 DOI: 10.1016/j.pharmthera.2012.06.006] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Accepted: 06/12/2012] [Indexed: 02/05/2023]
Abstract
Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming.
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Affiliation(s)
- Jianglong Hou
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
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26
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Shah S, Prasad S, Knudsen KE. Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression. Cancer Res 2012. [PMID: 22258452 DOI: 10.1158/0008-5472.can-11-0943, 10.1158/1538-7445.am2012-1248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function. Curcumin reduced the association of histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression. Histone deacetylase inhibitors reversed the effects of curcumin on AR activity, further underscoring the impact of curcumin on altering the chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of ligand-dependent and ligand-independent AR residence on chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of tumors. Biological relevance was further identified using in vivo xenograft models mimicking disease progression. Curcumin cooperated in vivo with androgen deprivation as indicated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results show the combinatorial impact of targeting AR and histone modification in prostate cancer, thus setting the stage for further development of curcumin as a novel agent to target AR signaling.
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Affiliation(s)
- Supriya Shah
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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Shah S, Prasad S, Knudsen KE. Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression. Cancer Res 2012; 72:1248-59. [PMID: 22258452 DOI: 10.1158/0008-5472.can-11-0943] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function. Curcumin reduced the association of histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression. Histone deacetylase inhibitors reversed the effects of curcumin on AR activity, further underscoring the impact of curcumin on altering the chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of ligand-dependent and ligand-independent AR residence on chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of tumors. Biological relevance was further identified using in vivo xenograft models mimicking disease progression. Curcumin cooperated in vivo with androgen deprivation as indicated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results show the combinatorial impact of targeting AR and histone modification in prostate cancer, thus setting the stage for further development of curcumin as a novel agent to target AR signaling.
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Affiliation(s)
- Supriya Shah
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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28
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Bishopric NH. The virtue of just enough stress: a molecular model. TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION 2012; 123:175-192. [PMID: 23303984 PMCID: PMC3540631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Molecular biology emphasizes the study of all-or-nothing phenomena and molecular events with a large dynamic range. However, many important physiologic parameters in the clinical setting are tightly constrained (e.g., serum sodium concentration, body mass, venous oxygen saturation, sleep duration). Stress responses exhibit both a wide dynamic range and a potential for important effects at a "just-enough" threshold activation level. Stress responses occur in a number of body systems (e.g., neuropsychiatric, immune, cardiovascular) and are essential for short-term damage control, but also must be tightly constrained in range and duration to permit the organism to walk the narrow homeostatic path to long-term survival. Using an example of a newly appreciated stress-responsive molecule in the heart, acetyltransferase p300, as well as examples from the literature, this article discusses the advantages of self-limited stress, the adverse effects of sustained stress, and the built-in mechanisms that feed back on and terminate stress signals, and advances a hypothesis regarding stress as a pharmacological target in the heart.
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Affiliation(s)
- Nanette H Bishopric
- University of Miami Miller School of Medicine, PO Box 016189 (R-189), RMSB 6026, Miami, FL 33101, USA.
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29
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Kosanovic D, Kojonazarov B, Luitel H, Dahal BK, Sydykov A, Cornitescu T, Janssen W, Brandes RP, Davie N, Ghofrani HA, Weissmann N, Grimminger F, Seeger W, Schermuly RT. Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension. Respir Res 2011; 12:87. [PMID: 21699729 PMCID: PMC3141422 DOI: 10.1186/1465-9921-12-87] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2011] [Accepted: 06/23/2011] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats. METHODS Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed. RESULTS The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling. CONCLUSION The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
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MESH Headings
- Administration, Oral
- Animals
- Antihypertensive Agents/administration & dosage
- Antihypertensive Agents/pharmacology
- Disease Models, Animal
- Echocardiography, Doppler
- Endothelin A Receptor Antagonists
- Fibrosis
- Hemodynamics/drug effects
- Hypertension, Pulmonary/chemically induced
- Hypertension, Pulmonary/diagnostic imaging
- Hypertension, Pulmonary/drug therapy
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/physiopathology
- Hypertrophy, Right Ventricular/diagnostic imaging
- Hypertrophy, Right Ventricular/drug therapy
- Hypertrophy, Right Ventricular/metabolism
- Hypertrophy, Right Ventricular/physiopathology
- Isoxazoles/administration & dosage
- Isoxazoles/pharmacology
- Male
- Monocrotaline
- Pulmonary Artery/drug effects
- Pulmonary Artery/physiopathology
- Rats
- Rats, Sprague-Dawley
- Receptor, Endothelin A/metabolism
- Sulfones/administration & dosage
- Sulfones/pharmacology
- Time Factors
- Ventricular Function, Right/drug effects
- Ventricular Remodeling/drug effects
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Abstract
Chromatin regulation provides an important means for controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease.
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Affiliation(s)
- Pei Han
- CCSR Building, Room 3115-C, 269 Campus Dr, Stanford, CA 94305-5169, USA
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31
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Aggarwal BB. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu Rev Nutr 2010; 30:173-99. [PMID: 20420526 DOI: 10.1146/annurev.nutr.012809.104755] [Citation(s) in RCA: 285] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Extensive research within the past two decades has revealed that obesity, a major risk factor for type 2 diabetes, atherosclerosis, cancer, and other chronic diseases, is a proinflammatory disease. Several spices have been shown to exhibit activity against obesity through antioxidant and anti-inflammatory mechanisms. Among them, curcumin, a yellow pigment derived from the spice turmeric (an essential component of curry powder), has been investigated most extensively as a treatment for obesity and obesity-related metabolic diseases. Curcumin directly interacts with adipocytes, pancreatic cells, hepatic stellate cells, macrophages, and muscle cells. There, it suppresses the proinflammatory transcription factors nuclear factor-kappa B, signal transducer and activators of transcription-3, and Wnt/beta-catenin, and it activates peroxisome proliferator-activated receptor-gamma and Nrf2 cell-signaling pathways, thus leading to the downregulation of adipokines, including tumor necrosis factor, interleukin-6, resistin, leptin, and monocyte chemotactic protein-1, and the upregulation of adiponectin and other gene products. These curcumin-induced alterations reverse insulin resistance, hyperglycemia, hyperlipidemia, and other symptoms linked to obesity. Other structurally homologous nutraceuticals, derived from red chili, cinnamon, cloves, black pepper, and ginger, also exhibit effects against obesity and insulin resistance.
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Affiliation(s)
- Bharat B Aggarwal
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Meeran SM, Ahmed A, Tollefsbol TO. Epigenetic targets of bioactive dietary components for cancer prevention and therapy. Clin Epigenetics 2010; 1:101-116. [PMID: 21258631 PMCID: PMC3024548 DOI: 10.1007/s13148-010-0011-5] [Citation(s) in RCA: 152] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The emergent interest in cancer epigenetics stems from the fact that epigenetic modifications are implicated in virtually every step of tumorigenesis. More interestingly, epigenetic changes are reversible heritable changes that are not due to the alteration in DNA sequence but have potential to alter gene expression. Dietary agents consist of many bioactive ingredients which actively regulate various molecular targets involved in tumorigenesis. We present evidence that numerous bioactive dietary components can interfere with various epigenetic targets in cancer prevention and therapy. These agents include curcumin (turmeric), genistein (soybean), tea polyphenols (green tea), resveratrol (grapes), and sulforaphane (cruciferous vegetables). These bioactive components alter the DNA methylation and histone modifications required for gene activation or silencing in cancer prevention and therapy. Bioactive components mediate epigenetic modifications associated with the induction of tumor suppressor genes such as p21WAF1/CIP1 and inhibition of tumor promoting genes such as the human telomerase reverse transcriptase during tumorigenesis processes. Here, we present considerable evidence that bioactive components and their epigenetic targets are associated with cancer prevention and therapy which should facilitate novel drug discovery and development. In addition, remarkable advances in our understanding of basic epigenetic mechanisms as well as the rapid progress that is being made in developing powerful new technologies, such as those for sensitive and quantitative detection of epigenetic and epigenomic changes in cancer biology, hold great promise for novel epigenetic approaches to cancer prevention and therapy.
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Affiliation(s)
- Syed M. Meeran
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Campbell Hall 175, Birmingham, AL 35294-1170 USA
| | - Amiya Ahmed
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Campbell Hall 175, Birmingham, AL 35294-1170 USA
| | - Trygve O. Tollefsbol
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Campbell Hall 175, Birmingham, AL 35294-1170 USA
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL USA
- Center for Aging, University of Alabama at Birmingham, Birmingham, AL USA
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL USA
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Link A, Balaguer F, Goel A. Cancer chemoprevention by dietary polyphenols: promising role for epigenetics. Biochem Pharmacol 2010; 80:1771-92. [PMID: 20599773 DOI: 10.1016/j.bcp.2010.06.036] [Citation(s) in RCA: 301] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 06/17/2010] [Accepted: 06/21/2010] [Indexed: 02/07/2023]
Abstract
Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. In mammals, epigenetic mechanisms include changes in DNA methylation, histone modifications and non-coding RNAs. Although epigenetic changes are heritable in somatic cells, these modifications are also potentially reversible, which makes them attractive and promising avenues for tailoring cancer preventive and therapeutic strategies. Burgeoning evidence in the last decade has provided unprecedented clues that diet and environmental factors directly influence epigenetic mechanisms in humans. Dietary polyphenols from green tea, turmeric, soybeans, broccoli and others have shown to possess multiple cell-regulatory activities within cancer cells. More recently, we have begun to understand that some of the dietary polyphenols may exert their chemopreventive effects in part by modulating various components of the epigenetic machinery in humans. In this article, we first discuss the contribution of diet and environmental factors on epigenetic alterations; subsequently, we provide a comprehensive review of literature on the role of various dietary polyphenols. In particular, we summarize the current knowledge on a large number of dietary agents and their effects on DNA methylation, histone modifications and regulation of expression of the non-coding miRNAs in various in vitro and in vivo models. We emphasize how increased understanding of the chemopreventive effects of dietary polyphenols on specific epigenetic alterations may provide unique and yet unexplored novel and highly effective chemopreventive strategies for reducing the health burden of cancer and other diseases in humans.
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Affiliation(s)
- Alexander Link
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
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Sunagawa Y, Morimoto T, Takaya T, Kaichi S, Wada H, Kawamura T, Fujita M, Shimatsu A, Kita T, Hasegawa K. Cyclin-dependent kinase-9 is a component of the p300/GATA4 complex required for phenylephrine-induced hypertrophy in cardiomyocytes. J Biol Chem 2010; 285:9556-9568. [PMID: 20081228 DOI: 10.1074/jbc.m109.070458] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
A zinc finger protein GATA4 is one of the hypertrophy-responsive transcription factors and forms a complex with an intrinsic histone acetyltransferase, p300. Disruption of this complex results in the inhibition of cardiomyocyte hypertrophy and heart failure in vivo. By tandem affinity purification and mass spectrometric analyses, we identified cyclin-dependent kinase-9 (Cdk9) as a novel GATA4-binding partner. Cdk9 also formed a complex with p300 as well as GATA4 and cyclin T1. We showed that p300 was required for the interaction of GATA4 with Cdk9 and for the kinase activity of Cdk9. Conversely, Cdk9 kinase activity was required for the p300-induced transcriptional activities, DNA binding, and acetylation of GATA4. Furthermore, the kinase activity of Cdk9 was required for the phosphorylation of p300 as well as for cardiomyocyte hypertrophy. These findings demonstrate that Cdk9 forms a functional complex with the p300/GATA4 and is required for p300/GATA4- transcriptional pathway during cardiomyocyte hypertrophy.
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Affiliation(s)
- Yoichi Sunagawa
- Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555
| | - Tatsuya Morimoto
- Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555.
| | - Tomohide Takaya
- Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555; Department of Cardiovascular Medicine, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shinji Kaichi
- Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555; Department of Pediatrics, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiromichi Wada
- Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555
| | - Teruhisa Kawamura
- Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555
| | - Masatoshi Fujita
- Human Health Sciences, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akira Shimatsu
- Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555
| | - Toru Kita
- Department of Cardiovascular Medicine, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Koji Hasegawa
- Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555
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Curcuminoids: Spicing up sympathovagal tone. Nutrition 2009; 25:879-80. [PMID: 19539177 DOI: 10.1016/j.nut.2009.03.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2009] [Accepted: 03/18/2009] [Indexed: 11/21/2022]
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Enyeart JA, Liu H, Enyeart JJ. Curcumin inhibits ACTH- and angiotensin II-stimulated cortisol secretion and Ca(v)3.2 current. JOURNAL OF NATURAL PRODUCTS 2009; 72:1533-7. [PMID: 19653644 PMCID: PMC2853174 DOI: 10.1021/np900227x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Adrenocorticotropic hormone and angiotensin II stimulate cortisol secretion from bovine adrenal zona fasciculata cells by the activation of adenylate cyclase and phospholipase C-coupled receptors. Curcumin (1- 20 muM), a compound found in the spice turmeric, inhibited cortisol secretion stimulated by ACTH, AngII, and 8CPT-cAMP. Curcumin also suppressed ACTH-stimulated increases in mRNAs coding for steroid acute regulatory protein and CYP11a1 steroid hydroxylase. In whole cell patch clamp recordings from AZF cells, curcumin at slightly higher concentrations also inhibited Ca(v)3.2 current. These results identify curcumin as an effective inhibitor of ACTH- and AngII-stimulated cortisol secretion. The inhibition of Ca(v)3.2 current by curcumin may contribute to its suppression of secretion.
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Affiliation(s)
- Judith A. Enyeart
- Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210-1239
| | - Haiyan Liu
- Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210-1239
| | - John J. Enyeart
- Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210-1239
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Ghosh SS, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, Fakhry I, Gehr TWB. Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation. Am J Physiol Renal Physiol 2009; 296:F1146-57. [DOI: 10.1152/ajprenal.90732.2008] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
TNF-α and NF-κB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-α-elicited NF-κB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-α, which was associated with NF-κB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor γ (PPARγ) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-α. Curcumin dose dependently antagonized the TNF-α-mediated decrease in PPARγ and blocked transactivation of NF-κB and repression of PPARγ, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.
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Cai J, Yi FF, Bian ZY, Shen DF, Yang L, Yan L, Tang QZ, Yang XC, Li H. Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway. J Cell Mol Med 2008; 13:909-25. [PMID: 19413885 PMCID: PMC3823407 DOI: 10.1111/j.1582-4934.2008.00620.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Oxidative stress plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. Because crocetin represses oxidative stress in vitro and in vivo, we have suggested that crocetin would repress cardiac hypertrophy by targeting oxidative stress-dependent signalling. We tested this hypothesis using primary cultured cardiac myocytes and fibroblasts and one well-established animal model of cardiac hypertrophy. The results showed that crocetin (1–10 μM) dose-dependently blocked cardiac hypertrophy induced by angiogensin II (Ang II; 1 μM) in vitro. Our data further revealed that crocetin (50 mg/kg/day) both prevented and reversed cardiac hypertrophy induced by aortic banding (AB), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardio-graphic parameters and gene expression of hypertrophic markers. The inhibitory effect of crocetin on cardiac hypertrophy is mediated by blocking the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-1/2 (MEK/ERK1/2) pathway and GATA binding protein 4 (GATA-4) activation. Further investigation demonstrated that crocetin inhibited inflammation by blocking nuclear factor kappa B (NF-κB) signalling and attenuated fibrosis and collagen synthesis by abrogating MEK-ERK1/2 signalling. Overall, our results indicate that crocetin, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis by suppression of ROS-dependent signalling pathways.
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Affiliation(s)
- Jun Cai
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Bian Z, Cai J, Shen DF, Chen L, Yan L, Tang Q, Li H. Cellular repressor of E1A-stimulated genes attenuates cardiac hypertrophy and fibrosis. J Cell Mol Med 2008; 13:1302-13. [PMID: 19413895 PMCID: PMC4496144 DOI: 10.1111/j.1582-4934.2008.00633.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein of 220 amino acids. It has been proposed that CREG acts as a ligand that enhances differentiation and/or reduces cell proliferation. CREG has been shown previously to attenuate cardiac hypertrophy in vitro. However, such a role has not been determined in vivo. In the present study, we tested the hypothesis that overexpression of CREG in the murine heart would protect against cardiac hypertrophy and fibrosis in vivo. The effects of constitutive human CREG expression on cardiac hypertrophy were investigated using both in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding and infusion of angiotensin II in CREG transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive over-expression of human CREG in the murine heart attenuated the hypertrophic response, markedly reduced inflammation. Cardiac function was also preserved in hearts with increased CREG levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase 1 (MEK-ERK1)/2-dependent signalling cascade. In addition, CREG expression blocked fibrosis and collagen synthesis through blocking MEK-ERK1/2-dependent Smad 2/3 activation in vitro and in vivo. Therefore, the expression of CREG improves cardiac functions and inhibits cardiac hypertrophy, inflammation and fibrosis through blocking MEK-ERK1/2-dependent signalling.
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Affiliation(s)
- Zhouyan Bian
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China
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Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3beta signaling. J Mol Med (Berl) 2008; 87:249-60. [PMID: 19096818 DOI: 10.1007/s00109-008-0423-2] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Revised: 11/02/2008] [Accepted: 11/24/2008] [Indexed: 02/01/2023]
Abstract
The lysosomal cysteine peptidase cathepsin L (CTSL) is an important lysosomal proteinase involved in a variety of cellular functions including intracellular protein turnover, epidermal homeostasis, and hair development. Deficiency of CTSL in mice results in a progressive dilated cardiomyopathy. In the present study, we tested the hypothesis that cardiac overexpression of human CTSL in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human CTSL expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding (AB) in CTSL transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive overexpression of human CTSL in the murine heart attenuated the hypertrophic response, markedly reduced apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased CTSL levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the Akt/GSK3beta signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3beta signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3beta signaling.
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Wei JQ, Shehadeh LA, Mitrani JM, Pessanha M, Slepak TI, Webster KA, Bishopric NH. Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300. Circulation 2008; 118:934-46. [PMID: 18697823 DOI: 10.1161/circulationaha.107.760488] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Acetyltransferase p300 is essential for cardiac development and is thought to be involved in cardiac myocyte growth through MEF2- and GATA4-dependent transcription. However, the importance of p300 in the modulation of cardiac growth in vivo is unknown. METHODS AND RESULTS Pressure overload induced by transverse aortic coarctation, postnatal physiological growth, and human heart failure were associated with large increases in p300. Minimal transgenic overexpression of p300 (1.5- to 3.5-fold) induced striking myocyte and cardiac hypertrophy. Both mortality and cardiac mass were directly related to p300 protein dosage. Heterozygous loss of a single p300 allele reduced pressure overload-induced hypertrophy by approximately 50% and rescued the hypertrophic phenotype of p300 overexpressers. Increased p300 expression had no effect on total histone deacetylase activity but was associated with proportional increases in p300 acetyltransferase activity and acetylation of the p300 substrates histone 3 and GATA-4. Remarkably, a doubling of p300 levels was associated with the de novo acetylation of MEF2. Consistent with this, genes specifically upregulated in p300 transgenic hearts were highly enriched for MEF2 binding sites. CONCLUSIONS Small increments in p300 are necessary and sufficient to drive myocardial hypertrophy, possibly through acetylation of MEF2 and upstream of signals promoting phosphorylation or nuclear export of histone deacetylases. We propose that induction of myocardial p300 content is a primary rate-limiting event in the response to hemodynamic loading in vivo and that p300 availability drives and constrains adaptive myocardial growth. Specific reduction of p300 content or activity may diminish stress-induced hypertrophy and forestall the development of heart failure.
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Affiliation(s)
- Jian Qin Wei
- University of Miami School of Medicine, Department of Molecular and Cellular Pharmacology, Miami, FL, USA
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Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 2008; 41:40-59. [PMID: 18662800 DOI: 10.1016/j.biocel.2008.06.010] [Citation(s) in RCA: 1192] [Impact Index Per Article: 70.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Revised: 06/16/2008] [Accepted: 06/23/2008] [Indexed: 12/12/2022]
Abstract
Although safe in most cases, ancient treatments are ignored because neither their active component nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. For centuries it has been known that turmeric exhibits anti-inflammatory activity, but extensive research performed within the past two decades has shown that this activity of turmeric is due to curcumin (diferuloylmethane). This agent has been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. The process of inflammation has been shown to play a major role in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the current review, we provide evidence for the potential role of curcumin in the prevention and treatment of various proinflammatory chronic diseases. These features, combined with the pharmacological safety and negligible cost, render curcumin an attractive agent to explore further.
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Abstract
Curcumin, a commonly available spice and alternative medicine, has been tested in the laboratory and the clinic for activity against a wide range of diseases. It is thought to possess antiinflammatory and antioxidant activities and may also function to inhibit histone acetyl transferases, which activate gene expression via chromatin remodeling. Two reports in this issue of the JCI, by Morimoto et al. and Li et al., suggest that curcumin may inhibit cardiac hypertrophy in rodent models and provide beneficial effects after myocardial infarction or in the setting of hypertension (see the related articles beginning on pages 868 and 879, respectively). These results will spur further mechanistic inquiry into the role of chromatin remodeling in the regulation of cardiac homeostasis.
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Affiliation(s)
- Jonathan A Epstein
- Department of Cell and Developmental Biology, Cardiovascular Institute, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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Enyeart JA, Liu H, Enyeart JJ. Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells. Biochem Biophys Res Commun 2008; 370:623-8. [PMID: 18406348 DOI: 10.1016/j.bbrc.2008.04.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2008] [Accepted: 04/02/2008] [Indexed: 11/18/2022]
Abstract
Bovine adrenal zona fasciculata (AZF) cells express bTREK-1 K(+) channels that set the resting membrane potential. Inhibition of these channels by adrenocorticotropic hormone (ACTH) is coupled to membrane depolarization and cortisol secretion. Curcumin, a phytochemical with medicinal properties extracted from the spice turmeric, was found to modulate both bTREK-1 K(+) currents and cortisol secretion from AZF cells. In whole-cell patch clamp experiments, curcumin inhibited bTREK-1 with an IC(50) of 0.93muM by a mechanism that was voltage-independent. bTREK-1 inhibition by curcumin occurred through interaction with an external binding site and was independent of ATP hydrolysis. Curcumin produced a concentration-dependent increase in cortisol secretion that persisted for up to 24h. At a maximally effective concentration of 50muM, curcumin increased secretion as much as 10-fold. These results demonstrate that curcumin potently inhibits bTREK-1 K(+) channels and stimulates cortisol secretion from bovine AZF cells. The inhibition of bTREK-1 by curcumin may be linked to cortisol secretion through membrane depolarization. Since TREK-1 is widely expressed in a variety of cells, it is likely that some of the biological actions of curcumin, including its therapeutic effects, may be mediated through inhibition of these K(+) channels.
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Affiliation(s)
- Judith A Enyeart
- Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, 5196 Graves Hall, 333 W.10th Avenue, Columbus, OH 43210-1239, USA.
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