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Bustani G, Alghetaa H, Mohammed A, Nagarkatti M, Nagarkatti P. The aryl hydrocarbon receptor: a new frontier in male reproductive system. Reprod Biol Endocrinol 2025; 23:70. [PMID: 40369574 PMCID: PMC12076877 DOI: 10.1186/s12958-025-01401-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 04/25/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically recognized for its role in the regulation of toxicity mediated by environmental chemicals. Recent research points to AhR's critical participation in male reproductive physiology, particularly in spermatogenesis, hormone signaling, and the maintenance of sperm quality. Both endogenous ligands (e.g., dietary and gut microbiota-derived metabolites) and exogenous pollutants (e.g., dioxins and benzo-α-pyrene) influence AhR-mediated pathways, making it a key link between environmental exposures and male fertility. RESULTS This review highlights AhR's influence on the male reproductive system, emphasizing the role of endogenous AhR ligands and AhR expression in the maturation and function of male reproductive organs. Environmental AhR agonists have been shown to induce oxidative stress, hormonal imbalance, and sperm DNA damage, which impact harmfully on the spermatogenesis process, which leads to reproductive abnormalities. Conversely, certain natural compounds such as resveratrol, curcumin, and lycopene appear to antagonize AhR activation and reduce its negative effects, thus offering potential protective benefits against male reproductive toxicity. Nevertheless, discrepancies persist regarding the exact interplay between AhR signaling and critical reproductive hormones such as testosterone and LH, and it remains unclear how transgenerational epigenetic changes triggered by AhR activation might affect long-term male fertility. CONCLUSION AhR is pivotal in male reproductive physiology, influencing spermatogenesis, sperm quality, and hormone regulation through its interactions with both endogenous and environmental ligands. Persistent pollutants such as dioxins and polycyclic aromatic hydrocarbons cause oxidative damage and hormonal disturbances via AhR, contributing to reduced sperm quality and fertility.
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Affiliation(s)
- Ghadeer Bustani
- Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Baghdad, Abu Gharib Road, Al-Ameria Ave., Baghdad, Iraq
- The Islamic University, Najaf, Iraq
| | - Hasan Alghetaa
- Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Baghdad, Abu Gharib Road, Al-Ameria Ave., Baghdad, Iraq.
| | - Amira Mohammed
- Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Baghdad, Abu Gharib Road, Al-Ameria Ave., Baghdad, Iraq
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
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2
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Wan X, Wang D. Curcumin: Epigenetic Modulation and Tumor Immunity in Antitumor Therapy. PLANTA MEDICA 2025; 91:320-337. [PMID: 39689889 DOI: 10.1055/a-2499-1140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
Curcumin (turmeric) is the main ingredient of the Chinese herbal turmeric rhizome, used to treat tumors, diabetes, inflammation, neurodegenerative diseases, cardiovascular diseases, metabolic syndrome, and liver diseases. The antitumor effects of curcumin have received even more attention. One of the main mechanisms of the antitumor effects includes inhibition of tumor invasion and migration, induction of tumor cell apoptosis, and inhibition of various cell signaling pathways. It has been found that the antitumor biological activity of curcumin in the body is associated with epigenetic mechanisms. That also implies that curcumin may act as a potential epigenetic modulator to influence the development of tumor diseases. The immune system plays an essential role in the development of tumorigenesis. Tumor immunotherapy is currently one of the most promising research directions in the field of tumor therapy. Curcumin has been found to have significant regulatory effects on tumor immunity and is expected to be a novel adjuvant for tumor immunity. This paper summarizes the antitumor effects of curcumin from four aspects: molecular and epigenetic mechanisms of curcumin against a tumor, mechanisms of curcumin modulation of tumor immunotherapy, reversal of chemotherapy resistance, and a novel drug delivery system of curcumin, which provide new directions for the development of new antitumor drugs.
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Affiliation(s)
- Xin Wan
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dong Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
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3
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Huchzermeier R, van der Vorst EPC. Aryl hydrocarbon receptor (AHR) and nuclear factor erythroid-derived 2-like 2 (NRF2): An important crosstalk in the gut-liver axis. Biochem Pharmacol 2025; 233:116785. [PMID: 39890034 DOI: 10.1016/j.bcp.2025.116785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/18/2024] [Accepted: 01/27/2025] [Indexed: 02/03/2025]
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, mainly involved in detoxification. However, in the intestine, metabolites derived from the diet, which are converted by a wide range of bacteria can also activate the AHR. This intestinal AHR activation plays a key role in maintaining the gut barrier by, for example, upregulating antimicrobial peptides and anti-inflammatory cytokines. Since the gut barrier influences the gut-liver axis by regulating the leaking of metabolites, bacteria, and endotoxins into circulation and particularly into the liver, the AHR is a key factor in the gut-liver axis. Vice versa, certain liver pathologies also influence the gut microbiome, thereby altering bacteria-derived activation of the AHR. Additionally, bile acids can impact the gut via the liver and thereby also affect the AHR. The aryl hydrocarbon receptor (AHR) interacts with several molecular factors, one of which is the nuclear factor erythroid-derived 2-like 2 (NRF2), a transcription factor primarily associated with regulating antioxidant stress responses. The interplay between AHR and NRF2 has been investigated in the context of various diseases; this review highlights the significance of this interaction within the framework of the gut-liver axis.
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Affiliation(s)
- Rosanna Huchzermeier
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany; Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Emiel P C van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany; Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
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4
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Cecerska-Heryć E, Wiśniewska Z, Serwin N, Polikowska A, Goszka M, Engwert W, Michałów J, Pękała M, Budkowska M, Michalczyk A, Dołęgowska B. Can Compounds of Natural Origin Be Important in Chemoprevention? Anticancer Properties of Quercetin, Resveratrol, and Curcumin-A Comprehensive Review. Int J Mol Sci 2024; 25:4505. [PMID: 38674092 PMCID: PMC11050349 DOI: 10.3390/ijms25084505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
Malignant tumors are the second most common cause of death worldwide. More attention is being paid to the link between the body's impaired oxidoreductive balance and cancer incidence. Much attention is being paid to polyphenols derived from plants, as one of their properties is an antioxidant character: the ability to eliminate reactive oxygen and nitrogen species, chelate specific metal ions, modulate signaling pathways affecting inflammation, and raise the level and activity of antioxidant enzymes while lowering those with oxidative effects. The following three compounds, resveratrol, quercetin, and curcumin, are polyphenols modulating multiple molecular targets, or increasing pro-apoptotic protein expression levels and decreasing anti-apoptotic protein expression levels. Experiments conducted in vitro and in vivo on animals and humans suggest using them as chemopreventive agents based on antioxidant properties. The advantage of these natural polyphenols is low toxicity and weak adverse effects at higher doses. However, the compounds discussed are characterized by low bioavailability and solubility, which may make achieving the blood concentrations needed for the desired effect challenging. The solution may lie in derivatives of naturally occurring polyphenols subjected to structural modifications that enhance their beneficial effects or work on implementing new ways of delivering antioxidants that improve their solubility and bioavailability.
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Affiliation(s)
- Elżbieta Cecerska-Heryć
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Zofia Wiśniewska
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Natalia Serwin
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Aleksandra Polikowska
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Małgorzata Goszka
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Weronika Engwert
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Jaśmina Michałów
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Maja Pękała
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
| | - Marta Budkowska
- Department of Medical Analytics, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Anna Michalczyk
- Department of Psychiatry, Pomeranian Medical University of Szczecin, Broniewskiego 26, 71-460 Szczecin, Poland;
| | - Barbara Dołęgowska
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland; (Z.W.); (N.S.); (A.P.); (M.G.); (W.E.); (J.M.); (M.P.); (B.D.)
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Kim M, Jee SC, Sung JS. Hepatoprotective Effects of Flavonoids against Benzo[a]Pyrene-Induced Oxidative Liver Damage along Its Metabolic Pathways. Antioxidants (Basel) 2024; 13:180. [PMID: 38397778 PMCID: PMC10886006 DOI: 10.3390/antiox13020180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Benzo[a]pyrene (B[a]P), a highly carcinogenic polycyclic aromatic hydrocarbon primarily formed during incomplete organic matter combustion, undergoes a series of hepatic metabolic reactions once absorbed into the body. B[a]P contributes to liver damage, ranging from molecular DNA damage to the onset and progression of various diseases, including cancer. Specifically, B[a]P induces oxidative stress via reactive oxygen species generation within cells. Consequently, more research has focused on exploring the underlying mechanisms of B[a]P-induced oxidative stress and potential strategies to counter its hepatic toxicity. Flavonoids, natural compounds abundant in plants and renowned for their antioxidant properties, possess the ability to neutralize the adverse effects of free radicals effectively. Although extensive research has investigated the antioxidant effects of flavonoids, limited research has delved into their potential in regulating B[a]P metabolism to alleviate oxidative stress. This review aims to consolidate current knowledge on B[a]P-induced liver oxidative stress and examines the role of flavonoids in mitigating its toxicity.
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Affiliation(s)
| | | | - Jung-Suk Sung
- Department of Life Science, Dongguk University-Seoul, Goyang 10326, Republic of Korea; (M.K.); (S.-C.J.)
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6
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Peter RM, Chou PJ, Shannar A, Patel K, Pan Y, Dave PD, Xu J, Sarwar MS, Kong ANT. An Update on Potential Molecular Biomarkers of Dietary Phytochemicals Targeting Lung Cancer Interception and Prevention. Pharm Res 2023; 40:2699-2714. [PMID: 37726406 DOI: 10.1007/s11095-023-03595-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/23/2023] [Indexed: 09/21/2023]
Abstract
Since ancient times, dietary phytochemicals are known for their medicinal properties. They are broadly classified into polyphenols, terpenoids, alkaloids, phytosterols, and organosulfur compounds. Currently, there is considerable interest in their potential health effects against various diseases, including lung cancer. Lung cancer is the leading cause of cancer deaths with an average of five-year survival rate of lung cancer patients limited to just 14%. Identifying potential early molecular biomarkers of pre-malignant lung cancer cells may provide a strong basis to develop early cancer detection and interception methods. In this review, we will discuss molecular changes, including genetic alterations, inflammation, signal transduction pathways, redox imbalance, epigenetic and proteomic signatures associated with initiation and progression of lung carcinoma. We will also highlight molecular targets of phytochemicals during lung cancer development. These targets mainly consist of cellular signaling pathways, epigenetic regulators and metabolic reprogramming. With growing interest in natural products research, translation of these compounds into new cancer prevention approaches to medical care will be urgently needed. In this context, we will also discuss the overall pharmacokinetic challenges of phytochemicals in translating to humans. Lastly, we will discuss clinical trials of phytochemicals in lung cancer patients.
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Affiliation(s)
- Rebecca Mary Peter
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Pochung Jordan Chou
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Ahmad Shannar
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Komal Patel
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Yuxin Pan
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Parv Dushyant Dave
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Jiawei Xu
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Md Shahid Sarwar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Ah-Ng Tony Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
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7
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Pharmacological Modulations of Nrf2 and Therapeutic Implications in Aneurysmal Subarachnoid Hemorrhage. Molecules 2023; 28:molecules28041747. [PMID: 36838735 PMCID: PMC9963186 DOI: 10.3390/molecules28041747] [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: 12/31/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
An aneurysmal subarachnoid hemorrhage (aSAH) is a subtype of stroke with high morbidity and mortality. The main causes of a poor prognosis include early brain injury (EBI) and delayed vasospasm, both of which play a significant role in the pathophysiological process. As an important mechanism of EBI and delayed vasospasm, oxidative stress plays an important role in the pathogenesis of aSAH by producing reactive oxygen species (ROS) through the mitochondria, hemoglobin, or enzymatic pathways in the early stages of aSAH. As a result, antioxidant therapy, which primarily targets the Nrf2-related pathway, can be employed as a potential strategy for treating aSAH. In the early stages of aSAH development, increasing the expression of antioxidant enzymes and detoxifying enzymes can relieve oxidative stress, reduce brain damage, and improve prognosis. Herein, the regulatory mechanisms of Nrf2 and related pharmacological compounds are reviewed, and Nrf2-targeted drugs are proposed as potential treatments for aSAH.
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8
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Sondermann NC, Faßbender S, Hartung F, Hätälä AM, Rolfes KM, Vogel CFA, Haarmann-Stemmann T. Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway. Biochem Pharmacol 2023; 208:115371. [PMID: 36528068 PMCID: PMC9884176 DOI: 10.1016/j.bcp.2022.115371] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022]
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor regulating adaptive and maladaptive responses toward exogenous and endogenous signals. Research from various biomedical disciplines has provided compelling evidence that the AHR is critically involved in the pathogenesis of a variety of diseases and disorders, including autoimmunity, inflammatory diseases, endocrine disruption, premature aging and cancer. Accordingly, AHR is considered an attractive target for the development of novel preventive and therapeutic measures. However, the ligand-based targeting of AHR is considerably complicated by the fact that the receptor does not always follow the beaten track, i.e. the canonical AHR/ARNT signaling pathway. Instead, AHR might team up with other transcription factors and signaling molecules to shape gene expression patterns and associated physiological or pathophysiological functions in a ligand-, cell- and micromilieu-dependent manner. Herein, we provide an overview about some of the most important non-canonical functions of AHR, including crosstalk with major signaling pathways involved in controlling cell fate and function, immune responses, adaptation to low oxygen levels and oxidative stress, ubiquitination and proteasomal degradation. Further research on these diverse and exciting yet often ambivalent facets of AHR biology is urgently needed in order to exploit the full potential of AHR modulation for disease prevention and treatment.
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Affiliation(s)
- Natalie C Sondermann
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Sonja Faßbender
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Frederick Hartung
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Anna M Hätälä
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Katharina M Rolfes
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Christoph F A Vogel
- Department of Environmental Toxicology and Center for Health and the Environment, University of California, Davis, CA 95616, USA
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9
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Ding Y, Hou R, Yu J, Xing C, Zhuang C, Qu Z. Dietary Phytochemicals as Potential Chemopreventive Agents against Tobacco-Induced Lung Carcinogenesis. Nutrients 2023; 15:491. [PMID: 36771198 PMCID: PMC9920588 DOI: 10.3390/nu15030491] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/23/2022] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Lung cancer is the second most common cancer in the world. Cigarette smoking is strongly connected with lung cancer. Benzo[a]pyrene (BaP) and 4-(N-methyl-N-nitrosamine)-1-(3-pyridyl)-butanone (NNK) are the main carcinogens in cigarette smoking. Evidence has supported the correlation between these two carcinogens and lung cancer. Epidemiology analysis suggests that lung cancer can be effectively prevented through daily diet adjustments. This review aims to summarize the studies published in the past 20 years exploring dietary phytochemicals using Google Scholar, PubMed, and Web of Science databases. Dietary phytochemicals mainly include medicinal plants, beverages, fruits, vegetables, spices, etc. Moreover, the perspectives on the challenges and future directions of dietary phytochemicals for lung cancer chemoprevention will be provided. Taken together, treatment based on the consumption of dietary phytochemicals for lung cancer chemoprevention will produce more positive outcomes in the future and offer the possibility of reducing cancer risk in society.
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Affiliation(s)
- Yan Ding
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
| | - Ruilin Hou
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
| | - Jianqiang Yu
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
| | - Chengguo Xing
- Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA
| | - Chunlin Zhuang
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Zhuo Qu
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
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10
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Şener Akçora D, Erdoğan D, Take Kaplanoğlu G, Göktaş GE, Şeker U, Elmas Ç. Electron microscopic investigation of benzo(a)pyrene-induced alterations in the rat kidney tissue and the protective effects of curcumin. Ultrastruct Pathol 2022; 46:519-530. [DOI: 10.1080/01913123.2022.2152144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Dila Şener Akçora
- Department of Histology and Embryology, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey
| | - Deniz Erdoğan
- Department of Histology and Embryology, Faculty of Medicine, Gazi University, Turkey
| | | | - Gül Eser Göktaş
- Department of Histology and Embryology, Faculty of Medicine, Lokman Hekim University, Turkey
| | - Uğur Şeker
- Department of Histology and Embryology, Faculty of Medicine, Harran University, Sanlıurfa, Turkey
| | - Çiğdem Elmas
- Department of Histology and Embryology, Faculty of Medicine, Gazi University, Turkey
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11
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Nimbalkar VK, Gangar J, Shai S, Rane P, Mohanta SK, Kannan S, Ingle A, Mittal N, Rane S, Mahimkar MB. Prevention of carcinogen-induced oral cancers by polymeric black tea polyphenols via modulation of EGFR-Akt-mTOR pathway. Sci Rep 2022; 12:14516. [PMID: 36008552 PMCID: PMC9411124 DOI: 10.1038/s41598-022-18680-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/17/2022] [Indexed: 11/09/2022] Open
Abstract
The overexpression of Epidermal Growth Factor Receptor (EGFR) and dysregulation of its downstream effector pathways are important molecular hallmarks of oral cancers. Present study investigates the chemopreventive potential of polymeric black tea polyphenols (PBPs)/thearubigins (TRs) in the hamster model of oral carcinogenesis as well as determine the effect of PBPs on EGFR and the molecular players in the EGFR pathway. In dose-dependent manner, pre and concurrent treatment with PBPs (1.5%, 5%, 10%) decreased the number and volume of macroscopic tumors as well as the number and area of microscopic lesions. Interestingly, at 10% dose of PBPs, no macroscopic or microscopic tumors were observed. We observed PBPs mediated dose-dependent decrease in oxidative DNA damage (8OHdG); inflammation (COX-2); proliferation (PCNA, Cyclin D1); expression of EGFR, and its downstream signaling kinases (pAkt, Akt, and mTOR); hypoxia (HIF1α) and angiogenesis (VEGF). There was also a PBPs mediated dose-dependent increase in apoptosis (Bax). Thus, our data clearly indicate that the observed chemopreventive potential of PBPs was due to modulation in the EGFR pathway associated with cell proliferation, hypoxia, and angiogenesis. Taken together, our results demonstrate preclinical chemopreventive efficacy of PBPs and give an insight into its mechanistic role in the chemoprevention of experimental oral cancer.
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Affiliation(s)
- Vaishnavi K Nimbalkar
- Mahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, 410 210, India.,Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India
| | - Jeet Gangar
- Mahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, 410 210, India
| | - Saptarsi Shai
- Mahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, 410 210, India
| | - Pallavi Rane
- Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India.,Clinical Research Secretariat, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India
| | - Subham Kumar Mohanta
- Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India.,Clinical Research Secretariat, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India
| | - Sadhana Kannan
- Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India.,Clinical Research Secretariat, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India
| | - Arvind Ingle
- Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India.,Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India
| | - Neha Mittal
- Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India.,Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre (TMC), Parel, Mumbai, India
| | - Swapnil Rane
- Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India.,Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India
| | - Manoj B Mahimkar
- Mahimkar Lab, Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, 410 210, India. .,Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, 400085, India.
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12
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Sivani BM, Azzeh M, Patnaik R, Pantea Stoian A, Rizzo M, Banerjee Y. Reconnoitering the Therapeutic Role of Curcumin in Disease Prevention and Treatment: Lessons Learnt and Future Directions. Metabolites 2022; 12:metabo12070639. [PMID: 35888763 PMCID: PMC9320502 DOI: 10.3390/metabo12070639] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/30/2022] [Accepted: 07/08/2022] [Indexed: 02/04/2023] Open
Abstract
Turmeric is a plant with a very long history of medicinal use across different cultures. Curcumin is the active part of turmeric, which has exhibited various beneficial physiological and pharmacological effects. This review aims to critically appraise the corpus of literature associated with the above pharmacological properties of curcumin, with a specific focus on antioxidant, anti-inflammatory, anticancer and antimicrobial properties. We have also reviewed the different extraction strategies currently in practice, highlighting the strengths and drawbacks of each technique. Further, our review also summarizes the clinical trials that have been conducted with curcumin, which will allow the reader to get a quick insight into the disease/patient population of interest with the outcome that was investigated. Lastly, we have also highlighted the research areas that need to be further scrutinized to better grasp curcumin’s beneficial physiological and medicinal properties, which can then be translated to facilitate the design of better bioactive therapeutic leads.
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Affiliation(s)
- Bala Mohan Sivani
- Banerjee Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai 505055, United Arab Emirates; (B.M.S.); (M.A.); (R.P.)
| | - Mahmoud Azzeh
- Banerjee Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai 505055, United Arab Emirates; (B.M.S.); (M.A.); (R.P.)
| | - Rajashree Patnaik
- Banerjee Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai 505055, United Arab Emirates; (B.M.S.); (M.A.); (R.P.)
| | - Anca Pantea Stoian
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, 020022 Bucharest, Romania;
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, 90128 Palermo, Italy;
| | - Yajnavalka Banerjee
- Banerjee Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai 505055, United Arab Emirates; (B.M.S.); (M.A.); (R.P.)
- Centre for Medical Education, University of Dundee, Dundee DD1 4HN, UK
- Correspondence: or ; Tel.: +971-527-873-636
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13
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Bayo Jimenez MT, Frenis K, Hahad O, Steven S, Cohen G, Cuadrado A, Münzel T, Daiber A. Protective actions of nuclear factor erythroid 2-related factor 2 (NRF2) and downstream pathways against environmental stressors. Free Radic Biol Med 2022; 187:72-91. [PMID: 35613665 DOI: 10.1016/j.freeradbiomed.2022.05.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/23/2022] [Accepted: 05/19/2022] [Indexed: 12/14/2022]
Abstract
Environmental risk factors, including noise, air pollution, chemical agents, ultraviolet radiation (UVR) and mental stress have a considerable impact on human health. Oxidative stress and inflammation are key players in molecular pathomechanisms of environmental pollution and risk factors. In this review, we delineate the impact of environmental risk factors and the protective actions of the nuclear factor erythroid 2-related factor 2 (NRF2) in connection to oxidative stress and inflammation. We focus on well-established studies that demonstrate the protective actions of NRF2 and its downstream pathways against different environmental stressors. State-of-the-art mechanistic considerations on NRF2 signaling are discussed in detail, e.g. classical concepts like KEAP1 oxidation/electrophilic modification, NRF2 ubiquitination and degradation. Specific focus is also laid on NRF2-dependent heme oxygenase-1 induction with detailed presentation of the protective down-stream pathways of heme oxygenase-1, including interaction with BACH1 system. The significant impact of all environmental stressors on the circadian rhythm and the interactions of NRF2 with the circadian clock will also be considered here. A broad range of NRF2 activators is discussed in relation to environmental stressor-induced health side effects, thereby suggesting promising new mitigation strategies (e.g. by nutraceuticals) to fight the negative effects of the environment on our health.
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Affiliation(s)
- Maria Teresa Bayo Jimenez
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Katie Frenis
- Department of Hematology and Oncology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Omar Hahad
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Langenbeckstraße 1, 55131, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany; Leibniz Insitute for Resilience Research (LIR), Mainz, Germany
| | - Sebastian Steven
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Guy Cohen
- The Skin Research Institute, The Dead Sea and Arava Science Center, Masada, 86910, Israel; Ben Gurion University of the Negev, Eilat Campus, Eilat, 8855630, Israel
| | - Antonio Cuadrado
- Departamento de Bioquímica, Facultad de Medicina, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas 'Alberto Sols' UAM-CSIC, Universidad Autónoma de Madrid, Madrid, Spain
| | - Thomas Münzel
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Langenbeckstraße 1, 55131, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.
| | - Andreas Daiber
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Langenbeckstraße 1, 55131, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.
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14
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Kumar H, Kumar RM, Bhattacharjee D, Somanna P, Jain V. Role of Nrf2 Signaling Cascade in Breast Cancer: Strategies and Treatment. Front Pharmacol 2022; 13:720076. [PMID: 35571115 PMCID: PMC9098811 DOI: 10.3389/fphar.2022.720076] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 03/31/2022] [Indexed: 12/30/2022] Open
Abstract
Breast cancer is the second leading cancer among all types of cancers. It accounts for 12% of the total cases of cancers. The complex and heterogeneous nature of breast cancer makes it difficult to treat in advanced stages. The expression of various enzymes and proteins is regulated by several molecular pathways. Oxidative stress plays a vital role in cellular events that are generally regulated by nuclear factor erythroid 2-related factor 2 (Nrf2). The exact mechanism of Nrf2 behind cytoprotective and antioxidative properties is still under investigation. In healthy cells, Nrf2 expression is lower, which maintains antioxidative stress; however, cancerous cells overexpress Nrf2, which is associated with various phenomena, such as the development of drug resistance, angiogenesis, development of cancer stem cells, and metastasis. Aberrant Nrf2 expression diminishes the toxicity and potency of therapeutic anticancer drugs and provides cytoprotection to cancerous cells. In this article, we have discussed the attributes associated with Nrf2 in the development of drug resistance, angiogenesis, cancer stem cell generation, and metastasis in the specific context of breast cancer. We also discussed the therapeutic strategies employed against breast cancer exploiting Nrf2 signaling cascades.
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Affiliation(s)
| | | | | | | | - Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
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15
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Wang Y, Liu F, Liu M, Zhou X, Wang M, Cao K, Jin S, Shan A, Feng X. Curcumin mitigates aflatoxin B1-induced liver injury via regulating the NLRP3 inflammasome and Nrf2 signaling pathway. Food Chem Toxicol 2022; 161:112823. [DOI: 10.1016/j.fct.2022.112823] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/18/2021] [Accepted: 01/11/2022] [Indexed: 12/21/2022]
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16
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Curcumin Suppresses the Lipid Accumulation and Oxidative Stress Induced by Benzo[a]pyrene Toxicity in HepG2 Cells. Antioxidants (Basel) 2021; 10:antiox10081314. [PMID: 34439562 PMCID: PMC8389208 DOI: 10.3390/antiox10081314] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 01/14/2023] Open
Abstract
Benzo[a]pyrene (B[a]P) is a potentially hepatotoxic group-1 carcinogen taken up by the body through ingestion of daily foods. B[a]P is widely known to cause DNA and protein damages, which are closely related to cell transformation. Accordingly, studies on natural bioactive compounds that attenuate such chemical-induced toxicities have significant impacts on public health. This study aimed to uncover the mechanism of curcumin, the major curcuminoid in turmeric (Curcuma longa), in modulating the lipid accumulation and oxidative stress mediated by B[a]P cytotoxicity in HepG2 cells. Curcumin treatment reduced the B[a]P-induced lipid accumulation and reactive oxygen spicies (ROS) upregulation and recovered the cell viability. Cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) and Cytochrome P450 subfamily B polypeptide 1 (CYP1B1) downregulation resulting from decreased aryl hydrocarbon receptor (AhR) translocation into nuclei attenuated the effects of B[a]P-induced lipid accumulation and repressed cell viability, respectively. Moreover, the curcumin-induced reduction in ROS generation decreased the nuclear translocation of Nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of phase-II detoxifying enzymes. These results indicate that curcumin suppresses B[a]P-induced lipid accumulation and ROS generation which can potentially induce nonalcoholic fatty liver disease (NAFLD) and can shed a light on the detoxifying effect of curcumin.
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17
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Lymphoid Organ Proteomes Identify Therapeutic Efficacy Biomarkers Following the Intracavitary Administration of Curcumin in a Highly Invasive Rat Model of Peritoneal Mesothelioma. Int J Mol Sci 2021; 22:ijms22168566. [PMID: 34445271 PMCID: PMC8395293 DOI: 10.3390/ijms22168566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/30/2021] [Accepted: 08/05/2021] [Indexed: 12/16/2022] Open
Abstract
This study aimed to identify the proteomic changes produced by curcumin treatment following stimulation of the host immune system in a rat model of malignant mesothelioma. We analyzed the proteomes of secondary lymphoid organs from four normal rats, four untreated tumor-bearing rats, and four tumor-bearing rats receiving repeated intraperitoneal administrations of curcumin. Cross-comparing proteome analyses of histological sections of the spleen from the three groups first identified a list of eighty-three biomarkers of interest, thirteen of which corresponded to proteins already reported in the literature and involved in the anticancer therapeutic effects of curcumin. In a second step, comparing these data with proteomic analyses of histological sections of mesenteric lymph nodes revealed eight common biomarkers showing a similar pattern of changes in both lymphoid organs. Additional findings included a partial reduction of the increase in spleen-circulating biomarkers, a decrease in C-reactive protein and complement C3 in the spleen and lymph nodes, and an increase in lymph node purine nucleoside phosphorylase previously associated with liver immunodeficiency. Our results suggest some protein abundance changes could be related to the systemic, distant non-target antitumor effects produced by this phytochemical.
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18
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Memarzia A, Khazdair MR, Behrouz S, Gholamnezhad Z, Jafarnezhad M, Saadat S, Boskabady MH. Experimental and clinical reports on anti-inflammatory, antioxidant, and immunomodulatory effects of Curcuma longa and curcumin, an updated and comprehensive review. Biofactors 2021; 47:311-350. [PMID: 33606322 DOI: 10.1002/biof.1716] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 01/26/2021] [Indexed: 12/17/2022]
Abstract
Curcuma longa (C. longa) or turmeric is a plant with a long history of use in traditional medicine, especially for treating inflammatory conditions C. longa and its main constituent, curcumin (CUR), showed various pharmacological effects such as antioxidant and anti-microbial properties. The updated knowledge of anti-inflammatory, antioxidant, and immunomodulatory effects of C. longa and CUR is provided in this review article. Pharmacological effects of C. longa, and CUR, including anti-inflammatory, antioxidant, and immunomodulatory properties, were searched using various databases and appropriate keywords until September 2020. Various studies showed anti-inflammatory effects of C. longa and CUR, including decreased white blood cell, neutrophil, and eosinophil numbers, and its protective effects on serum levels of inflammatory mediators such as phospholipase A2 and total protein in different inflammatory disorders. The antioxidant effects of C. longa and CUR were also reported in several studies. The plant extracts and CUR decreased malondialdehyde and nitric oxide levels but increased thiol, superoxide dismutase, and catalase levels in oxidative stress conditions. Treatment with C. longa and CUR also improved immunoglobulin E (Ig)E, pro-inflammatory cytokine interleukin 4 (IL)-4, transforming growth factor-beta, IL-17, interferon-gamma levels, and type 1/type 2 helper cells (Th1)/(Th2) ratio in conditions with disturbance in the immune system. Therefore C. longa and CUR showed anti-inflammatory, antioxidant, and immunomodulatory effects, indicating a potential therapeutic effect of the plant and its constituent, CUR, for treating of inflammatory, oxidative, and immune dysregulation disorders.
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Affiliation(s)
- Arghavan Memarzia
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad R Khazdair
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Sepideh Behrouz
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Gholamnezhad
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Jafarnezhad
- Department of Anesthesia, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Saeideh Saadat
- Department of Physiology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohammad H Boskabady
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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19
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Involvement of NRF2 in Breast Cancer and Possible Therapeutical Role of Polyphenols and Melatonin. Molecules 2021; 26:molecules26071853. [PMID: 33805996 PMCID: PMC8038098 DOI: 10.3390/molecules26071853] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress is defined as a disturbance in the prooxidant/antioxidant balance in favor of the former and a loss of control over redox signaling processes, leading to potential biomolecular damage. It is involved in the etiology of many diseases, varying from diabetes to neurodegenerative diseases and cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor and reported as one of the most important oxidative stress regulators. Due to its regulatory role in the expression of numerous cytoprotective genes involved in the antioxidant and anti-inflammatory responses, the modulation of NRF2 seems to be a promising approach in the prevention and treatment of cancer. Breast cancer is the prevalent type of tumor in women and is the leading cause of death among female cancers. Oxidative stress-related mechanisms are known to be involved in breast cancer, and therefore, NRF2 is considered to be beneficial in its prevention. However, its overactivation may lead to a negative clinical impact on breast cancer therapy by causing chemoresistance. Some known “oxidative stress modulators”, such as melatonin and polyphenols, are suggested to play an important role in the prevention and treatment of cancer, where the activation of NRF2 is reported as a possible underlying mechanism. In the present review, the potential involvement of oxidative stress and NRF2 in breast cancer will be reviewed, and the role of the NRF2 modulators—namely, polyphenols and melatonin—in the treatment of breast cancer will be discussed.
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20
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Thimmulappa RK, Mudnakudu-Nagaraju KK, Shivamallu C, Subramaniam K, Radhakrishnan A, Bhojraj S, Kuppusamy G. Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19. Heliyon 2021; 7:e06350. [PMID: 33655086 PMCID: PMC7899028 DOI: 10.1016/j.heliyon.2021.e06350] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/02/2020] [Accepted: 02/19/2021] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease-19 (COVID-19), a devastating respiratory illness caused by SARS-associated coronavirus-2 (SARS-CoV-2), has already affected over 64 million people and caused 1.48 million deaths, just 12 months from the first diagnosis. COVID-19 patients develop serious complications, including severe pneumonia, acute respiratory distress syndrome (ARDS), and or multiorgan failure due to exaggerated host immune response following infection. Currently, drugs that were effective against SARS-CoV are being repurposed for SARS-CoV-2. During this public health emergency, food nutraceuticals could be promising prophylactic therapeutics for COVID-19. Curcumin, a bioactive compound in turmeric, exerts diverse pharmacological activities and is widely used in foods and traditional medicines. This review presents several lines of evidence, which suggest curcumin as a promising prophylactic, therapeutic candidate for COVID-19. First, curcumin exerts antiviral activity against many types of enveloped viruses, including SARS-CoV-2, by multiple mechanisms: direct interaction with viral membrane proteins; disruption of the viral envelope; inhibition of viral proteases; induce host antiviral responses. Second, curcumin protects from lethal pneumonia and ARDS via targeting NF-κB, inflammasome, IL-6 trans signal, and HMGB1 pathways. Third, curcumin is safe and well-tolerated in both healthy and diseased human subjects. In conclusion, accumulated evidence indicates that curcumin may be a potential prophylactic therapeutic for COVID-19 in the clinic and public health settings.
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Affiliation(s)
- Rajesh K. Thimmulappa
- Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysore, India
| | - Kiran Kumar Mudnakudu-Nagaraju
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, JSS Academy of Higher Education & Research, Mysore, India
| | - Chandan Shivamallu
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, JSS Academy of Higher Education & Research, Mysore, India
| | - K.J.Thirumalai Subramaniam
- Centre of Excellence in Nanoscience & Technology, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
| | - Arun Radhakrishnan
- Centre of Excellence in Nanoscience & Technology, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
| | | | - Gowthamarajan Kuppusamy
- Centre of Excellence in Nanoscience & Technology, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
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21
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Siddika A, Arifuzzaman M, Hossain L, Adnan MH, Diba F, Hasan MZ, Asaduzzaman S, Uddin MJ. Assortment of Human Amniotic Membrane and Curcumin: a Potential Therapeutic Strategy for Burn Wound Healing. CURRENT DRUG THERAPY 2021. [DOI: 10.2174/1574885515999200706013824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Burn wound associated injury management is one of the major unresolved clinical concerns.
Most of the drugs and dressing materials available in the market cause dose escalation and
even exert side effects. Besides, a severe burn injury is susceptible to microbial infection that leads
to the prolonged hospital stay, which ultimately causes a financial crisis to the victims. To get rid of
this problem, researchers are being interested in developing such materials that are cost-effective,
easily available and accelerate faster healing. Human amniotic membrane (AM) and various herbal
extracts like curcumin are a potential source of burn wound healing. AM has various healing properties
and is being used as the best burn wound dressing material for centuries. Similarly, curcumin
has been proven as a faster dressing material for the treatment of burn injury. Since both AM and
curcumin are a potential source of burn and wound healing, if a gel/agent could be formulated by
mixing these two things, this combination may be a potential therapeutic strategy to treat burn
wound healing.
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Affiliation(s)
- Ayesha Siddika
- Institute of Tissue Banking and Biomaterial Research, Atomic Energy Research Establishment (AERE), Savar, Dhaka- 1349,Bangladesh
| | - Md. Arifuzzaman
- Institute of Tissue Banking and Biomaterial Research, Atomic Energy Research Establishment (AERE), Savar, Dhaka- 1349,Bangladesh
| | - Liakat Hossain
- Institute of Tissue Banking and Biomaterial Research, Atomic Energy Research Establishment (AERE), Savar, Dhaka- 1349,Bangladesh
| | - Md. Hasib Adnan
- Institute of Tissue Banking and Biomaterial Research, Atomic Energy Research Establishment (AERE), Savar, Dhaka- 1349,Bangladesh
| | - Farzana Diba
- Institute of Tissue Banking and Biomaterial Research, Atomic Energy Research Establishment (AERE), Savar, Dhaka- 1349,Bangladesh
| | - Md. Zahid Hasan
- Institute of Tissue Banking and Biomaterial Research, Atomic Energy Research Establishment (AERE), Savar, Dhaka- 1349,Bangladesh
| | - S.M. Asaduzzaman
- Institute of Tissue Banking and Biomaterial Research, Atomic Energy Research Establishment (AERE), Savar, Dhaka- 1349,Bangladesh
| | - Md. Jamal Uddin
- ABEx Bio-Research Center, East Azampur, Uttara, Dhaka-1230,Bangladesh
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22
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Li S, Wang X, Xiao Y, Wang Y, Wan Y, Li X, Li Q, Tang X, Cai D, Ran B, Wu C. Curcumin ameliorates mercuric chloride-induced liver injury via modulating cytochrome P450 signaling and Nrf2/HO-1 pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 208:111426. [PMID: 33096358 DOI: 10.1016/j.ecoenv.2020.111426] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/21/2020] [Accepted: 09/26/2020] [Indexed: 06/11/2023]
Abstract
Environmental mercury is a concern for coastal ecosystem health, and exerts adverse effects on human health. Despite the growing body of evidence showing the hepatoprotective roles of curcumin on mercury, the knowledge between the macroscopic descriptions and the actual mechanism(s) underlying these processes is getting larger remains elusive. Herein, mice received single injection of mercuric chloride (HgCl2) (5 mg/kg body weight) and/or curcumin (50 mg/kg, body weight, p.o.). Firstly, the results showed curcumin could decline HgCl2-induced up-regulated the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, we also found that curcumin could suppress inflammatory damage, unbalance of trace elements (including sodium, magnesium, kalium, calcium overload), oxidative burst induced by HgCl2, which could be associated with cytochrome P450 (CYP450) signaling. Secondly, we found that curcumin could prevent HgCl2-induced cell death both in vivo and in vitro. Furthermore, curcumin significantly increased the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and consequently upregulated the expression of heme oxygenase 1 (HO-1) under HgCl2 treatment. Meanwhile, inhibition of HO-1 by zinc protoporphyria could abolish the cytoprotective effects of curcumin in HgCl2-treated L02 hepatocytes. In conclusion, our data identify that curcumin could enhance Nrf2-mediated HO-1 to upregulate antioxidant ability, which might be associate with CYP450 signaling to suppress liver damage induced by HgCl2. The present study further enriches and perfects the mechanism theory of HgCl2 toxicity and suggest that the CYP450 signaling and Nrf2/HO-1 pathway is important in shedding light on curcumin's hepatoprotective effects in HgCl2 toxicity.
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Affiliation(s)
- Siwen Li
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Xiali Wang
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Yewei Xiao
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Yanling Wang
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Ying Wan
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Xinlian Li
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Qiuyue Li
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Xiaoqing Tang
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Daihong Cai
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China
| | - Bing Ran
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China.
| | - Chunling Wu
- Department of Physiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China.
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23
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Health Benefits of Turmeric and Curcumin Against Food Contaminants. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1328:171-197. [DOI: 10.1007/978-3-030-73234-9_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Yap CK, Wong KW, Al-Shami SA, Nulit R, Cheng WH, Aris AZ, Sharifinia M, Bakhtiari AR, Okamura H, Saleem M, Chew W, Ismail MS, Al-Mutairi KA. Human Health Risk Assessments of Trace Metals on the Clam Corbicula javanica in a Tropical River in Peninsular Malaysia. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 18:ijerph18010195. [PMID: 33383875 PMCID: PMC7794960 DOI: 10.3390/ijerph18010195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 12/21/2022]
Abstract
This study aimed to analyse ten trace metal concentrations in the edible part of the freshwater clam Corbicula javanica and to provide a critical assessment of the potential risks to human health through consumption of this clam as food based on well-established indices and food safety guidelines. The clams were captured from a pristine original site and transplanted to other sites with different environmental qualities. The trace metal levels in the edible total soft tissue (TST) of the clam were below those of the food safety guidelines referred to except for Pb, which exceeded the permissible limit set by the European Commission (2006) and the US Food and Drug Administration/ Center for Food Safety and Applied Nutrition); Interstate Shellfish Sanitation Conference. (USFDA/CFSAN; ISSC) (2007). The estimated daily intake (EDI) values of the clam were found to be lower than the oral reference dose and the calculated target hazard quotient (THQ) and total THQ were found to be less than 1. Therefore, in conclusion, the human health risk for consumption of TST of C. javanica at both average and high-level were insignificant regardless of the environment it was exposed to.
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Affiliation(s)
- Chee Kong Yap
- Department of Biology, Faculty of Science, Universiti Putra Malaysia, Selangor 43400, Malaysia; (K.W.W.); (R.N.)
- Correspondence: or
| | - Koe Wei Wong
- Department of Biology, Faculty of Science, Universiti Putra Malaysia, Selangor 43400, Malaysia; (K.W.W.); (R.N.)
| | - Salman Abdo Al-Shami
- Indian River Research and Education Center, IFAS, University of Florida, Fort Pierce, FL 34945, USA;
| | - Rosimah Nulit
- Department of Biology, Faculty of Science, Universiti Putra Malaysia, Selangor 43400, Malaysia; (K.W.W.); (R.N.)
| | - Wan Hee Cheng
- Faculty of Health and Life Sciences, Inti International University, Sembilan 71800, Malaysia;
| | - Ahmad Zaharin Aris
- Department of Environmental Sciences, Faculty of Environmental Studies, Universiti Putra Malaysia, Selangor 43400, Malaysia;
| | - Moslem Sharifinia
- Shrimp Research Center, Iranian Fisheries Science Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Bushehr 7516989177, Iran;
| | - Alireza Riyahi Bakhtiari
- Department of Environmental Sciences, Faculty of Natural Resources and Marine Sciences, Tarbiat Modares University, Mazandaran 46417-76489, Iran;
| | - Hideo Okamura
- Faculty of Maritime Sciences, Graduate School of Maritime Sciences, Kobe University, Kobe 658-0022, Japan;
| | - Muhammad Saleem
- Department of Chemistry, Government Post Graduate College, Mirpur University of Science and Technology, Mirpur 10250, Pakistan;
| | - Weiyun Chew
- Centre for Pre-University Study, MAHSA University, Selangor 42610, Malaysia;
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Inhibitory Effect of Delphinidin on Oxidative Stress Induced by H 2O 2 in HepG2 Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4694760. [PMID: 33274001 PMCID: PMC7700032 DOI: 10.1155/2020/4694760] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/14/2020] [Accepted: 10/26/2020] [Indexed: 12/13/2022]
Abstract
Chronic liver diseases (CLDs) are correlated with oxidative stress induced by the accumulation of intracellular reactive oxygen species (ROS). In this study, we employed HepG2, a human liver carcinoma cell line containing many antioxidant enzymes, to explore the function of delphinidin against oxidative stress induced by H2O2 and to provide scientific data of the molecular mechanism. Cells were pretreated with different concentrations of delphinidin (10 μmol/L, 20 μmol/L, and 40 μmol/L) for 2 h before treatment with 750 μM H2O2 for 1 h. The results showed that H2O2 decreased the survival rate of HepG2 cells and increased the level of ROS, but delphinidin pretreatment could possess the opposite result. At the same time, the expression of Nrf2 was enhanced by the delphinidin pretreatment. This was because delphinidin promoted Nrf2 nuclear translocation and inhibited its degradation, which led to the increase expression of antioxidant protein HO-1 (Nrf2-related phase II enzyme heme oxygenase-1). Besides, we found that delphinidin could significantly alleviate the reduction of Nrf2 protein levels and the accumulation of intracellular ROS levels in Nrf2 knockdown HepG2 cells. In conclusion, our study suggested that delphinidin, as an effective antioxidant, protected HepG2 cells from oxidative stress by regulating the expression of Nrf2/HO-1.
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Mansouri K, Rasoulpoor S, Daneshkhah A, Abolfathi S, Salari N, Mohammadi M, Rasoulpoor S, Shabani S. Clinical effects of curcumin in enhancing cancer therapy: A systematic review. BMC Cancer 2020; 20:791. [PMID: 32838749 PMCID: PMC7446227 DOI: 10.1186/s12885-020-07256-8] [Citation(s) in RCA: 214] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 08/04/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Curcumin is herbal compound that has been shown to have anti-cancer effects in pre-clinical and clinical studies. The anti-cancer effects of curcumin include inhibiting the carcinogenesis, inhibiting angiogenesis, and inhibiting tumour growth. This study aims to determine the Clinical effects of curcumin in different types of cancers using systematic review approach. METHODS A systematic review methodology is adopted for undertaking detailed analysis of the effects of curcumin in cancer therapy. The results presented in this paper is an outcome of extracting the findings of the studies selected from the articles published in international databases including SID, MagIran, IranMedex, IranDoc, Google Scholar, ScienceDirect, Scopus, PubMed and Web of Science (ISI). These databases were thoroughly searched, and the relevant publications were selected based on the plausible keywords, in accordance with the study aims, as follows: prevalence, curcumin, clinical features, cancer. RESULTS The results are derived based on several clinical studies on curcumin consumption with chemotherapy drugs, highlighting that curcumin increases the effectiveness of chemotherapy and radiotherapy which results in improving patient's survival time, and increasing the expression of anti-metastatic proteins along with reducing their side effects. CONCLUSION The comprehensive systematic review presented in this paper confirms that curcumin reduces the side effects of chemotherapy or radiotherapy, resulting in improving patients' quality of life. A number of studies reported that, curcumin has increased patient survival time and decreased tumor markers' level.
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Affiliation(s)
- Kamran Mansouri
- Medical Biology Research Centre, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shna Rasoulpoor
- Department of Biology, Islamic Azad University Urmia, Urmia, Iran
| | - Alireza Daneshkhah
- School of Computing, Electronics and Maths, Coventry University, Coventry, UK
| | - Soroush Abolfathi
- Centre for Predictive Modelling, University of Warwick, Coventry, CV4 7AL UK
| | - Nader Salari
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Mohammadi
- Department of Nursing, School of Nursing and Midwifery, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shabnam Rasoulpoor
- Department of Nursing, School of Nursing and Midwifery, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shervin Shabani
- Department of Biology, Islamic Azad University Urmia, Urmia, Iran
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Kulkarni B, Gondaliya P, Kirave P, Rawal R, Jain A, Garg R, Kalia K. Exosome-mediated delivery of miR-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2. Oncotarget 2020; 11:1832-1845. [PMID: 32499869 PMCID: PMC7244014 DOI: 10.18632/oncotarget.27557] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/19/2020] [Indexed: 12/12/2022] Open
Abstract
Exosomes facilitate cross-talk amongst tumor cells, and thus also possess the potential to influence tumor-microenvironment and chemo-resistance. miRNAs, the important constituent of exosomes, are often dysregulated in cancer. They have been shown to play an essential role in tumor progression, metastasis, invasion, and resistance developed against different therapies. Acquisition of cisplatin-chemoresistance remains a major hurdle in the effective treatment of oral squamous cell carcinoma (OSCC). In this study, we demonstrate the importance of exosome-mediated miR-30a transfer in conferring cisplatin sensitivity in the otherwise resistant OSCC cells. Notably, miR-30a was found to be significantly reduced in exosomes isolated from the serum of OSCC patients, especially those having disease-recurrence, post cisplatin treatment. In conjunction with the findings in clinical samples, decreased miR-30a expression was observed in vitro in the cisplatin-resistant cultured OSCC cells compared to the cisplatin-sensitive cells. Besides, we identified Beclin1, an autophagy-related marker, as a target of miR-30a and found it to be overexpressed in cisplatin-resistant OSCC cells, thus indicating at its possible negative-regulation by miR30a. Exosomes from the cisplatin-resistant cells that have been transfected with miR-30a mimics, when delivered to the naïve cisplatin-resistant cells, caused not only the significant enhancements in miR-30a expression but also a concomitant decrease in Beclin1 and Bcl2 expression (autophagic and anti-apoptotic marker). More importantly, this together resulted in the sensitization of cisplatin-resistant cells. Thus, our study highlighted the role of exosomal-mediated miR-30a transfer in regaining sensitivity of the cisplatin-resistant OSCC cells via Beclin1 and Bcl2 regulation and hence suggests at its potential therapeutic role.
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Affiliation(s)
- Bhagyashri Kulkarni
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India.,These authors contributed equally to this work
| | - Piyush Gondaliya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India.,These authors contributed equally to this work
| | - Prathibha Kirave
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India.,These authors contributed equally to this work
| | - Rakesh Rawal
- Department of Life Science, Gujarat University, Ahmedabad, Gujarat, India
| | - Alok Jain
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
| | - Rachana Garg
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
| | - Kiran Kalia
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
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Vargas-Mendoza N, Morales-González Á, Morales-Martínez M, Soriano-Ursúa MA, Delgado-Olivares L, Sandoval-Gallegos EM, Madrigal-Bujaidar E, Álvarez-González I, Madrigal-Santillán E, Morales-Gonzalez JA. Flavolignans from Silymarin as Nrf2 Bioactivators and Their Therapeutic Applications. Biomedicines 2020; 8:122. [PMID: 32423098 PMCID: PMC7277158 DOI: 10.3390/biomedicines8050122] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/06/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023] Open
Abstract
Silymarin (SM) is a mixture of flavolignans extracted from the seeds of species derived from Silybum marianum, commonly known as milk thistle or St. Mary'sthistle. These species have been widely used in the treatment of liver disorders in traditional medicine since ancient times. Several properties had been attributed to the major SM flavolignans components, identified as silybin, isosilybin, silychristin, isosilychristin, and silydianin. Previous research reported antioxidant and protective activities, which are probably related to the activation of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), known as a master regulator of the cytoprotector response. Nrf2 is a redox-sensitive nuclear transcription factor able to induce the downstream-associated genes. The disruption of Nrf2 signaling has been associated with different pathological conditions. Some identified phytochemicals from SM had shown to participate in the Nrf2 signaling pathway; in particular, they have been suggested as activators that disrupt interactions in the Keap1-Nrf2 system, but also as antioxidants or with additional actions regarding Nrf2 regulation. Thus, the study of these molecules makes them appear attractive as novel targets for the treatment or prevention of several diseases.
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Affiliation(s)
- Nancy Vargas-Mendoza
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México Escuela Superior de Medicina, Plan de San Luis y Díaz Mirón, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico;
| | - Ángel Morales-González
- Escuela Superior de Cómputo, Instituto Politécnico Nacional, Av. Juan de Dios Bátiz s/n esquina Miguel Othón de Mendizabal, Unidad Profesional Adolfo López Mateos, Mexico City CP 07738, Mexico;
| | - Mauricio Morales-Martínez
- Licenciatura en Nutrición, Universidad Intercontinental, Insurgentes Sur 4303, Santa Úrsula Xitla, Alcaldía Tlalpan, Mexico City CP 14420, Mexico;
| | - Marvin A. Soriano-Ursúa
- Academia de Fisiología Humana, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Col. Casco de Santo Tomás, Del. Miguel Hidalgo, Mexico City 11340, Mexico;
| | - Luis Delgado-Olivares
- Centro de Investigación Interdisciplinario, Área Académica de Nutrición, Instituto de Ciencias de la Salud. Universidad Autónoma del Estado de Hidalgo. Circuito Actopan-Tilcuauttla, s/n, Ex hacienda La Concepción, San Agustín Tlaxiaca, Hidalgo CP 42160, Mexico; (L.D.-O.); (E.M.S.-G.)
| | - Eli Mireya Sandoval-Gallegos
- Centro de Investigación Interdisciplinario, Área Académica de Nutrición, Instituto de Ciencias de la Salud. Universidad Autónoma del Estado de Hidalgo. Circuito Actopan-Tilcuauttla, s/n, Ex hacienda La Concepción, San Agustín Tlaxiaca, Hidalgo CP 42160, Mexico; (L.D.-O.); (E.M.S.-G.)
| | - Eduardo Madrigal-Bujaidar
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, “Unidad Profesional A. López Mateos”. Av. Wilfrido Massieu. Col., Zacatenco, Mexico City 07738, Mexico; (E.M.-B.); (I.Á.-G.)
| | - Isela Álvarez-González
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, “Unidad Profesional A. López Mateos”. Av. Wilfrido Massieu. Col., Zacatenco, Mexico City 07738, Mexico; (E.M.-B.); (I.Á.-G.)
| | - Eduardo Madrigal-Santillán
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México Escuela Superior de Medicina, Plan de San Luis y Díaz Mirón, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico;
| | - José A. Morales-Gonzalez
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México Escuela Superior de Medicina, Plan de San Luis y Díaz Mirón, Col. Casco de Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico;
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Kirave P, Gondaliya P, Kulkarni B, Rawal R, Garg R, Jain A, Kalia K. Exosome mediated miR-155 delivery confers cisplatin chemoresistance in oral cancer cells via epithelial-mesenchymal transition. Oncotarget 2020; 11:1157-1171. [PMID: 32284792 PMCID: PMC7138164 DOI: 10.18632/oncotarget.27531] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/03/2020] [Indexed: 01/07/2023] Open
Abstract
Cisplatin is used as chemotherapeutic drug for oral squamous cell carcinoma (OSCC). However, OSCC cells develop resistance following long-term cisplatin exposure. Resistance against cisplatin chemo-therapy is accredited to the process of epithelial-to-mesenchymal transition, which in-turn has been linked to tumor-recurrence. miRNA deregulation, a common event in cancer, plays contributory role in chemo-resistance. Exosomes acts as the natural cargo for miRNA and facilitates inter-cell communication in the tumor micro-environment. Hence, exosomal-mediated miRNA transference may play essential role in drug resistance and serve as a target for cancer-therapy. miR-155 upregulation in OSCC has been described, however, its relevance in the observed chemo-resistance is unclear and also, if exosomes have any role in miR-155 regulation remain elusive. In the present study, we document for the first time the critical role of exosomes in mediating increments in miR-155 expression in OSCC cells that have acquired cisplatin resistance (cisRes cells). Importantly, exosomal transfer from cisRes to the cisplatin sensitive (cisSens) cells was found to confer significant miR-155 induction in the recipient cisSens cells. Restoration of miR-155 expression in cisSens cells following miR-155 mimics treatment led to epithelial to mesenchymal transition, enhancements in their migratory potential as well as acquisition of resistant phenotype. Notably, similar augmentations in the migratory and chemo-resistant traits were seen upon delivery of exosomes from cisRes to the recipient cisSens cells. Overall, our findings establish the significance of exosomal-mediated miR-155 shuttling in the cisplatin-chemoresistance, commonly observed in OSCC cells, thereby providing rationale for targeting miR-155 signalling for oral cancer therapy.
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Affiliation(s)
- Prathibha Kirave
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
- These authors contributed equally to this work and are first authors
| | - Piyush Gondaliya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
- These authors contributed equally to this work and are first authors
| | - Bhagyashri Kulkarni
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
- These authors contributed equally to this work and are first authors
| | - Rakesh Rawal
- Department of Life Science, Gujarat University, Ahmedabad, Gujarat, India
| | - Rachana Garg
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
| | - Alok Jain
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
| | - Kiran Kalia
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India
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Zeng Z, Wang ZY, Li YK, Ye DM, Zeng J, Hu JL, Chen PF, Xiao J, Zou J, Li ZH. Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in non-small cell lung cancer. Life Sci 2020; 254:117325. [PMID: 31954159 DOI: 10.1016/j.lfs.2020.117325] [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: 12/09/2019] [Revised: 01/10/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022]
Abstract
Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor that can regulate downstream target gene expression. Kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2 activation and translocation to target its 26S proteasomal degradation. It has been widely reported that the Keap1/Nrf2 pathway is associated with tumorigenesis, chemotherapy resistance and progression and development of non-small cell lung cancer (NSCLC). High expression of Nrf2 and low abundance of Keap1 contribute to the abnormalities and unrealistic treatment prognosis of NSCLC. Therefore, elucidating the role and potential mechanism of Nrf2 in NSCLC is essential for understanding tumorigenesis and for the development of strategies for effective clinical management. Here, we summarize current knowledge about the molecular structure and biological function of Nrf2, and we discuss the roles of Nrf2 in tumorigenesis, which will further provide a possible therapeutic strategy for NSCLC.
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Affiliation(s)
- Zhi Zeng
- Department of Pathology, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning 437000, PR China
| | - Zi-Yao Wang
- Ultrasound B Imaging Division, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, PR China
| | - Yu-Kun Li
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China
| | - Dong-Mei Ye
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China
| | - Juan Zeng
- Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, PR China
| | - Jia-Li Hu
- Department of Pathology, Jiujiang University Clinic College Hospital, Jiujiang, Jiangxi 332000, PR China
| | - Pi-Feng Chen
- Department of Pediatric Surgery, Jiujiang Maternal and Child Health Hospital, Jiujiang, Jiangxi 332000, PR China
| | - Jiao Xiao
- Department of Endocrinology, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, PR China
| | - Juan Zou
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China.
| | - Zhen-Hua Li
- Department of Cardiothoracic Surgery, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning 437000, PR China.
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Supplementation of p-coumaric acid exhibits chemopreventive effect via induction of Nrf2 in a short-term preclinical model of colon cancer. Eur J Cancer Prev 2019; 28:472-482. [DOI: 10.1097/cej.0000000000000496] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Yen CC, Liu YT, Lin YJ, Yang YC, Chen CC, Yao HT, Chen HW, Lii CK. Bioavailability of the diterpenoid 14-deoxy-11,12-didehydroandrographolide in rats and up-regulation of hepatic drug-metabolizing enzyme and drug transporter expression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 61:152841. [PMID: 31035043 DOI: 10.1016/j.phymed.2019.152841] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 01/09/2019] [Accepted: 01/12/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND 14-Deoxy-11,12-didehydroandrographolide (deAND) is the second most abundant diterpenoid in Andrographis paniculata (Burm. f.) Nees, a traditional medicine used in Asia. To date, the biological activity of deAND has not been clearly investigated. PURPOSE In this study, we intended to examine the modulatory effect of deAND on hepatic drug metabolism as well as its bioavailability. STUDY DESIGN deAND prepared from A. paniculata was orally given to Sprague-Dawley rats and changes in plasma deNAD were determined by HPLC-MS. Modulation of deAND on drug-metabolizing enzyme and drug transporter expression as well as the possible mechanism involved was examined in primary rat hepatocytes. RESULTS After a single oral administration of 50 mg/kg deAND to rats, the maximum plasma concentration (Cmax), time to reach the Cmax, area under the curve (AUC0-24h), mean retention time, and half-life (t1/2) of deAND were 2.65 ± 0.68 μg/ml, 0.29 ± 0.15 h, 6.30 ± 1.66 μg/ml•h, 5.55 ± 2.52 h, and 3.56 ± 1.05 h, respectively. The oral bioavailability was 3.42%. In primary rat hepatocytes treated with up to 10 μM deAND, a dose-dependent increase was noted in the expression of cytochrome P450 (CYP) 1A1/2, CYP2C6, and CYP3A1/2; UDP-glucuronosyltransferase (UGT) 1A1, NAD(P)H:quinone oxidoreductase (NQO1), π form of GSH S-transferase (GSTP), multidrug resistance-associated protein 2, p-glycoprotein, and organic anion transporter protein 2B1. Immunoblotting assay and EMSA revealed that deAND increases the nuclear translocation and DNA binding activity of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). Knockdown of AhR and Nrf2 expression abolished deAND induction of CYP isozymes and UGT1A1, NQO1, and GSTP expression, respectively. CONCLUSION These results indicate that deAND quickly passes through enterocytes in rats and effectively up-regulates hepatic drug-metabolizing enzyme and drug transporter expression in an AhR-, PXR-, and Nrf2-dependent manner.
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Affiliation(s)
- Chih-Ching Yen
- Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan; Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Yun-Ta Liu
- Department of Nutrition, China Medical University, Taichung 404, Taiwan
| | - Ying-Jyan Lin
- Department of Nutrition, China Medical University, Taichung 404, Taiwan
| | - Ya-Chen Yang
- Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan
| | - Chien-Chih Chen
- Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan 333, Taiwan
| | - Hsien-Tsung Yao
- Department of Nutrition, China Medical University, Taichung 404, Taiwan
| | - Haw-Wen Chen
- Department of Nutrition, China Medical University, Taichung 404, Taiwan.
| | - Chong-Kuei Lii
- Department of Nutrition, China Medical University, Taichung 404, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan.
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Patri M, Singh A. Protective effects of noradrenaline on benzo[a]pyrene-induced oxidative stress responses in brain tumor cell lines. In Vitro Cell Dev Biol Anim 2019; 55:665-675. [PMID: 31292939 DOI: 10.1007/s11626-019-00378-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 06/04/2019] [Indexed: 12/01/2022]
Abstract
Benzo[a]pyrene (B[a]P) is an ubiquitous environmental pollutant that is generated during combustion of fossil fuels. We examine the effect of noradrenaline (NA) on B[a]P-induced neurotoxicity in brain tumor cell lines like neuroblastoma (Neuro2a) and glioma (C6). We pre-treated tumor cells with NA for 6 h, followed by addition of B[a]P for additional 24 h. Cell viability was measured using trypan blue dye-exclusion assay and comet assay was performed to measure DNA damage. Cell cycle status was analyzed using flow cytometry and oxidative DNA damage (8-oxodG) production was examined by immunostaining. The intracellular Ca2+ concentration was analyzed using Fura-2AM. Our results showed viability of Neuro2a and C6 cells declined (24% and 20%) in B[a]P-treated groups. However, pre-treating with NA increased viability of cells by reducing percentage of cell death in both. Furthermore, B[a]P-induced deregulation of cell cycle (G2/M and S phase cell arrest) was significantly restored by pre-treatment with NA in Neuro2a cells as compared to C6 cells. We further observed increased 8-oxodG production in B[a]P-treated cells; however, NA pre-treatment significantly (p < 0.05) reduced the 8-oxodG production in Neuro2a, while C6 cells were less affected possibly due to better protective machinery. B[a]P-induced intracellular Ca2+ influx was significantly reduced in both the cell lines due to co-treatment of NA possibly by reducing Ca2+ influx. NA protects brain tumor cells against B[a]P-induced neurotoxicity may be by decreasing percentage of G2 cell arrest, oxidative DNA damage, and reducing intracellular Ca2+ influx. These findings suggested that NA may be considered as a natural potential protective agent against B[a]P-induced neurotoxicity. Graphical abstract Graphical abstract showing differential protective mechanism of NA against B[a]P-induced toxicity through antioxidant mechanism maintaining homeostasis for oxidative stress in Neuro2a and C6 cell lines. The schematic graph showed the biological significance of the NA that regulates the induction of metabolic processes of cell cycle after exposure to the environmental pollutants. B[a]P increases the intracellular levels of Ca2+, but also induces damage to cellular molecules including DNA causing cell cycle arrest. The B[a]P-induced DNA damage due to base lesions generated in the genome, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is one of the most abundant because of guanine's lowest redox potential among DNA bases through intracellular calcium homoeostasis.
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Affiliation(s)
- Manorama Patri
- Neurobiology Laboratory, Department of Zoology, School of Life Sciences, Ravenshaw University, Cuttack, 753003, India.
| | - Abhisek Singh
- Neurobiology Laboratory, Department of Zoology, School of Life Sciences, Ravenshaw University, Cuttack, 753003, India
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El-Naggar ME, Al-Joufi F, Anwar M, Attia MF, El-Bana MA. Curcumin-loaded PLA-PEG copolymer nanoparticles for treatment of liver inflammation in streptozotocin-induced diabetic rats. Colloids Surf B Biointerfaces 2019; 177:389-398. [PMID: 30785036 DOI: 10.1016/j.colsurfb.2019.02.024] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/06/2019] [Accepted: 02/11/2019] [Indexed: 12/11/2022]
Abstract
This report focused on loading curcumin (CUR) drug into biodegradable Polylactide-poly(ethylene glycol) (PLA-PEG) copolymer nanoparticles as an effective anti-inflammatory agent in vivo to overcome the limitations resulted from the free CUR. By a simple nano-emulsification technique, hydrophobic CUR was loaded into hydrophobic polymer's segments and stabilized by cationic surfactant. They were then characterized by DLS, TEM, and SEM techniques providing monodispersed and spherical nanoparticles with an average diameter of 117 nm and high surface charge of +35 mV. Thereafter, they were orally administrated into five groups of rats, typically, control (healthy rats), streptozotocin (STZ)-induced diabetic rats, diabetics treated with free CUR, diabetics treated with PLA-PEG NPs, and diabetics treated with CUR-encapsulated PLA-PEG NPs. Next, complete blood analyses were assessed including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and nuclear factor kappa B (NF-ҡB), reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), cyclooxygenase (COX-2), Peroxisome proliferator-activated receptors (PPAR-γ) and transforming growth factor-β1 (TGF-β1). The obtained results demonstrated that diabetes initially produced liver inflammation in rats manifested by leveraging the mean levels of serum AST, ALT inducing oxidative stress resulting in a clear increase in the levels of hepatic MDA and NO concomitant with a remarkable decrease in GSH. Moreover, diabetes significantly increased serum NF-ҡB, hepatic COX-2 and TGF-β1, while highly reduced hepatic PPAR-γ. In contrast, both CUR free and CUR-encapsulated NPs ameliorated the negative changes in diabetes but CUR-encapsulated NPs showed more pronounced treated effect than free CUR. In addition, histopathological investigations were performed on the liver tissues of all groups, showing a mitigation in inflammation while treating with CUR-NPs.
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Affiliation(s)
- Mehrez E El-Naggar
- Department of Pre-Treatment and Finishing of Cellulosic Fabric, Textile Research Division, National Research Centre, Giza, Egypt.
| | - Fakhria Al-Joufi
- Department of Pharmacology, Aljouf University, Sakaka, Saudi Arabia
| | - Mona Anwar
- Research on Children with Special Needs Department, National Research Centre, Giza, Egypt; Department of Basic Sciences and Biomechanics, College of Physical Therapy, Heliopolis University, Cairo, Egypt
| | - Mohamed F Attia
- Department of Pre-Treatment and Finishing of Cellulosic Fabric, Textile Research Division, National Research Centre, Giza, Egypt; Department of Bioengineering, Clemson University, Clemson, SC, 29634, USA.
| | - Mona A El-Bana
- Department of Medical Biochemistry, National Research Centre, Giza, Egypt
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Role of Nrf2 and Its Activators in Respiratory Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7090534. [PMID: 30728889 PMCID: PMC6341270 DOI: 10.1155/2019/7090534] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/22/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023]
Abstract
Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidant response element- (ARE-) driven cytoprotective protein expression. The activation of Nrf2 signaling plays an essential role in preventing cells and tissues from injury induced by oxidative stress. Under the unstressed conditions, natural inhibitor of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), traps Nrf2 in the cytoplasm and promotes the degradation of Nrf2 by the 26S proteasome. Nevertheless, stresses including highly oxidative microenvironments, impair the ability of Keap1 to target Nrf2 for ubiquitination and degradation, and induce newly synthesized Nrf2 to translocate to the nucleus to bind with ARE. Due to constant exposure to external environments, including diverse pollutants and other oxidants, the redox balance maintained by Nrf2 is fairly important to the airways. To date, researchers have discovered that Nrf2 deletion results in high susceptibility and severity of insults in various models of respiratory diseases, including bronchopulmonary dysplasia (BPD), respiratory infections, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and lung cancer. Conversely, Nrf2 activation confers protective effects on these lung disorders. In the present review, we summarize Nrf2 involvement in the pathogenesis of the above respiratory diseases that have been identified by experimental models and human studies and describe the protective effects of Nrf2 inducers on these diseases.
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Sheweita SA, Almasmari AA, El-Banna SG. Tramadol-induced hepato- and nephrotoxicity in rats: Role of Curcumin and Gallic acid as antioxidants. PLoS One 2018; 13:e0202110. [PMID: 30110401 PMCID: PMC6093657 DOI: 10.1371/journal.pone.0202110] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 07/27/2018] [Indexed: 11/18/2022] Open
Abstract
Tramadol is an analgesic used to treat moderate to severe pain caused by cancer, osteoarthritis, and other musculoskeletal diseases. Cytochrome P450 system metabolizes tramadol and induces oxidative stress in different organs. Therefore, the present study aims at investigating the changes in the activities and the protein expressions of CYPs isozymes (2E1, 3A4, 2B1/2), antioxidants status, free radicals levels after pretreatment of rats with Curcumin and/or Gallic as single- and/or repeated-doses before administration of tramadol. In repeated-dose treatments of rats with tramadol, the activities of cytochrome P450, cytochrome b5, and NADPH-cytochrome-c-reductase, and the antioxidant enzymes including glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, superoxide dismutase, and levels of glutathione were inhibited in the liver and the kidney of rats. Interestingly, such changes caused by tramadol restored to their normal levels after pretreatment of rats with either Curcumin and/or Gallic acid. On the other hand, repeated-dose treatment of rats with tramadol increased the activities of both dimethylnitrosamine N-demethylase I (DMN-dI), and aryl hydrocarbon hydroxylase (AHH) compared to the control group. However, pretreatment of rats with Curcumin and/or Gallic acid prior to administration of tramadol restored the inhibited DMN-dI activity and its protein expression (CYP 2E1) to their normal levels. On the other hand, tramadol inhibited the activity of ethoxycoumarin O-deethylase (ECOD) and suppressed its protein marker expression (CYP2B1/2), whereas Curcumin, Gallic acid and/or their mixture restored such changes to their normal levels. In conclusion, Curcumin and/or Gallic acid alleviated the adverse effects caused by tramadol. In addition, patients should be advice to take Curcumin and/or Gallic acid prior to tramadol treatment to alleviate the hepatic and renal toxicities caused by tramadol.
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Affiliation(s)
- Salah A. Sheweita
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandra, Egypt
| | - Ainour A. Almasmari
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandra, Egypt
| | - Sabah G. El-Banna
- Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Alexandra, Egypt
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Shen T, Li HZ, Li AL, Li YR, Wang XN, Ren DM. Homoeriodictyol protects human endothelial cells against oxidative insults through activation of Nrf2 and inhibition of mitochondrial dysfunction. Vascul Pharmacol 2018; 109:72-82. [PMID: 29902531 DOI: 10.1016/j.vph.2018.06.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 06/02/2018] [Accepted: 06/09/2018] [Indexed: 12/19/2022]
Abstract
Excess intracellular reactive oxygen species (ROS) production is a significant causative factor of many diseases, exemplified by vascular diseases. Mitochondria are a major source of endogenous ROS, which simultaneously induce mitochondrial dysfunction. Nuclear factor-erythroid 2-related factor 2 (Nrf2) represents an important intracellular defense system that protects cells against oxidative insults caused by ROS. Therefore, molecules with the capacities of inducing Nrf2, and preventing mitochondrial dysfunction can inhibit cell apoptosis, and thus are potential drug candidates for the therapy of ROS-mediated vascular diseases. Homoeriodictyol (HE), previously isolated from Viscum articulatum Burm, has been found to be an Nrf2 inducer. In the present study, we investigated its protection on ROS-induced endothelial cell injury using a H2O2-induced human umbilical vein EA.hy926 cell oxidative insult model. Our results indicated that HE activated Nrf2 signaling pathway and protected cells against H2O2-induced cell damage. HE alleviated H2O2-induced loss of mitochondrial membrane potential (MMP), blocked the releases of cytochrome C and apoptosis inducing factor (AIF) from mitochondria, and thus inhibited mitochondria-mediated cell apoptosis. Furthermore, HE inhibited H2O2-induced changes of apoptosis-related proteins, such as Bcl-2, Bcl-xL, caspases -3, -9 and PARP. Further study demonstrated that the protection of HE against H2O2-induced endothelial cell damage was Nrf2-dependent. Collectively, our observations suggest that HE is capable of counteracting oxidative insults in endothelial cells, and has a potential to be a therapeutic agent against ROS-mediated vascular diseases.
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Affiliation(s)
- Tao Shen
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Hai-Zhen Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Ai-Ling Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Yan-Ru Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Xiao-Ning Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Dong-Mei Ren
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.
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Muhammad I, Wang H, Sun X, Wang X, Han M, Lu Z, Cheng P, Hussain MA, Zhang X. Dual Role of Dietary Curcumin Through Attenuating AFB 1-Induced Oxidative Stress and Liver Injury via Modulating Liver Phase-I and Phase-II Enzymes Involved in AFB 1 Bioactivation and Detoxification. Front Pharmacol 2018; 9:554. [PMID: 29887802 PMCID: PMC5981209 DOI: 10.3389/fphar.2018.00554] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 05/08/2018] [Indexed: 12/16/2022] Open
Abstract
It is well understood that liver cytochrome p450 enzymes are responsible for AFB1 bioactivation, while phase-II enzymes regulated by the transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) are involved in detoxification of AFB1. In this study, we explored the potential of curcumin to prevent AFB1-induced liver injury by modulating liver phase-I and phase-II enzymes along with Nrf2 involved in AFB1 bioactivation and detoxification. Arbor Acres broiler were divided into four groups including control group (G1; fed only basal feed), curcumin alone-treated group (G2; 450 mg/kg feed), AFB1-fed group (G3; 5 mg/kg feed), and curcumin plus AFB1 group (G4; 5 mg AFB1+450 mg curcumin/kg feed). After 28 days, liver and blood samples were collected for different analyses. Histological and phenotypic results revealed that AFB1-induced liver injury was partially ameliorated by curcumin supplementation. Compared to AFB1 alone-treated group, serum biochemical parameters and liver antioxidant status showed that curcumin supplementation significantly prevented AFB1-induced liver injury. RT-PCR and western blot results revealed that curcumin inhibited CYP enzymes-mediated bioactivation of AFB1 at mRNA and protein level. Transcription factor Nrf2, its downstream genes such as GSTA3, and GSTM2 mRNA, and protein expression level significantly upregulated via dietary curcumin. In addition, GSTs enzyme activity was enhanced with dietary curcumin which plays a crucial role in AFB1-detoxification. Conclusively, the study provided a scientific basis for the use of curcumin in broiler's diet and contributed to explore the multi-target preventive actions of curcumin against AFB1-induced liver injury through the modulation of phase-I and phase-II enzymes, and its potent anti-oxidative effects.
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Affiliation(s)
- Ishfaq Muhammad
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - He Wang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xiaoqi Sun
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xinghe Wang
- Laboratory of Veterinary Pathology, Faculty of Basic Veterinary Science, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Meiyu Han
- Changchun Dirui Medical Company Ltd., Changchun, China
| | - Ziyin Lu
- College of Life Science Engineering, Shenyang Institute of Technology, Fushun, China
| | - Ping Cheng
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | | | - Xiuying Zhang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
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Sklirou A, Papanagnou ED, Fokialakis N, Trougakos IP. Cancer chemoprevention via activation of proteostatic modules. Cancer Lett 2018; 413:110-121. [DOI: 10.1016/j.canlet.2017.10.034] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/16/2017] [Accepted: 10/20/2017] [Indexed: 12/11/2022]
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Mohajeri M, Behnam B, Cicero AFG, Sahebkar A. Protective effects of curcumin against aflatoxicosis: A comprehensive review. J Cell Physiol 2017; 233:3552-3577. [PMID: 29034472 DOI: 10.1002/jcp.26212] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 09/29/2017] [Indexed: 12/22/2022]
Abstract
Aflatoxicosis is a deleterious medical condition that results from aflatoxins (AFs) or ochratoxins (OTs). Contamination with these toxins exerts detrimental effects on the liver, kidneys, reproductive organs, and also on immunological and cardiovascular systems. Aflatoxicosis is closely associated with overproduction of reactive oxygen species (ROS) as key contributors to oxidative and nitrosative stress responses, and subsequent damages to lipids, proteins, RNA, and DNA. The main target organ for AF toxicity is the liver, where DNA adducts, degranulation of endoplasmic reticulum, increased hepatic lipid peroxide, GSH depletion, mitochondrial dysfunction, and reduction of enzymatic and non-enzymatic antioxidants are manifestations of aflatoxicosis. Curcuma longa L. (turmeric) is a medicinal plant widely utilized all over the world for culinary and phytomedical purposes. Considering the antioxidant characteristic of curcumin, the main active component of turmeric, this review is intended to critically summarize the available evidence supporting possible effectiveness of curcumin against aflatoxicosis. Curcumin can serve as a promising candidate for attenuation of the adverse consequences of aflatoxicosis, acting mainly through intrinsic antioxidant effects aroused from its structure, modulation of the immune system as reflected by interleukin-1β and transforming growth factor-β, and interfering with AF's biotransformation by cytochrome P450 isoenzymes CYP1A, CYP3A, CYP2A, CYP2B, and CYP2C.
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Affiliation(s)
- Mohammad Mohajeri
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Behzad Behnam
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.,Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Arrigo F G Cicero
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Mohajeri M, Rezaee M, Sahebkar A. Cadmium-induced toxicity is rescued by curcumin: A review. Biofactors 2017; 43:645-661. [PMID: 28719149 DOI: 10.1002/biof.1376] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 06/16/2017] [Accepted: 06/22/2017] [Indexed: 12/16/2022]
Abstract
Cadmium (Cd) is one of the most common environmental and occupational heavy metals with extended distribution. Exposure to Cd may be associated with several deleterious consequences on the liver, bones, kidneys, lungs, testes, brain, immunological, and cardiovascular systems. Overproduction of reactive oxygen species (ROS) as the main mechanism behind its toxicity causes oxidative stress and subsequent damages to lipids, proteins, and DNA. Therefore, antioxidants along with chelating agents have shown promising outcomes against Cd-induced toxicity. Curcumin with various beneficial effects and medical efficacy has been evaluated for its inhibitory activities against biological impairments caused by Cd. Thus, this article is intended to address the effectiveness of curcumin against toxicity following Cd entry. Curcumin can afford to attenuate lipid peroxidation, glutathione depletion, alterations in antioxidant enzyme, and so forth through scavenging and chelating activities or Nrf2/Keap1/ARE pathway induction. © 2017 BioFactors, 43(5):645-661, 2017.
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Affiliation(s)
- Mohammad Mohajeri
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Rezaee
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Pandey MK, Gupta SC, Nabavizadeh A, Aggarwal BB. Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment. Semin Cancer Biol 2017; 46:158-181. [PMID: 28823533 DOI: 10.1016/j.semcancer.2017.07.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 07/05/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022]
Abstract
Although it is widely accepted that better food habits do play important role in cancer prevention and treatment, how dietary agents mediate their effects remains poorly understood. More than thousand different polyphenols have been identified from dietary plants. In this review, we discuss the underlying mechanism by which dietary agents can modulate a variety of cell-signaling pathways linked to cancer, including transcription factors, nuclear factor κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), activator protein-1 (AP-1), β-catenin/Wnt, peroxisome proliferator activator receptor- gamma (PPAR-γ), Sonic Hedgehog, and nuclear factor erythroid 2 (Nrf2); growth factors receptors (EGFR, VEGFR, IGF1-R); protein Kinases (Ras/Raf, mTOR, PI3K, Bcr-abl and AMPK); and pro-inflammatory mediators (TNF-α, interleukins, COX-2, 5-LOX). In addition, modulation of proteasome and epigenetic changes by the dietary agents also play a major role in their ability to control cancer. Both in vitro and animal based studies support the role of dietary agents in cancer. The efficacy of dietary agents by clinical trials has also been reported. Importantly, natural agents are already in clinical trials against different kinds of cancer. Overall both in vitro and in vivo studies performed with dietary agents strongly support their role in cancer prevention. Thus, the famous quote "Let food be thy medicine and medicine be thy food" made by Hippocrates 25 centuries ago still holds good.
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Affiliation(s)
- Manoj K Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA.
| | - Subash C Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ali Nabavizadeh
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
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Muralidharan P, Connors CT, Mohammed AS, Sarmah S, Marrs K, Marrs JA, Chism GW. Turmeric Extract Rescues Ethanol-Induced Developmental Defect in the Zebrafish Model for Fetal Alcohol Spectrum Disorder (FASD). J Food Sci 2017; 82:2221-2225. [PMID: 28796310 DOI: 10.1111/1750-3841.13830] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 06/03/2017] [Accepted: 07/10/2017] [Indexed: 12/22/2022]
Abstract
Prenatal ethanol exposure causes the most frequent preventable birth disorder, fetal alcohol spectrum disorder (FASD). The effect of turmeric extracts in rescuing an ethanol-induced developmental defect using zebrafish as a model was determined. Ethanol-induced oxidative stress is one of the major mechanisms underlying FASD. We hypothesize that antioxidant inducing properties of turmeric may alleviate ethanol-induced defects. Curcuminoid content of the turmeric powder extract (5 mg/mL turmeric in ethanol) was determined by UPLC and found to contain Curcumin (124.1 ± 0.2 μg/mL), Desmethoxycurcumin (43.4 ± 0.1 μg/mL), and Bisdemethoxycurcumin (36.6 ± 0.1 μg/mL). Zebrafish embryos were treated with 100 mM (0.6% v/v) ethanol during gastrulation through organogenesis (2 to 48 h postfertilization (hpf)) and supplemented with turmeric extract to obtain total curcuminoid concentrations of 0, 1.16, 1.72, or 2.32 μM. Turmeric supplementation showed significant rescue of the body length at 72 hpf compared to ethanol-treated embryos. The mechanism underlying the rescue remains to be determined.
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Affiliation(s)
- Pooja Muralidharan
- Dept. of Biology, Indiana Univ.-Purdue Univ. Indianapolis, Indianapolis, Ind., 46202, U.S.A
| | - Craig T Connors
- Dept. of Biology, Indiana Univ.-Purdue Univ. Indianapolis, Indianapolis, Ind., 46202, U.S.A
| | - Arooj S Mohammed
- Dept. of Biology, Indiana Univ.-Purdue Univ. Indianapolis, Indianapolis, Ind., 46202, U.S.A
| | - Swapnalee Sarmah
- Dept. of Biology, Indiana Univ.-Purdue Univ. Indianapolis, Indianapolis, Ind., 46202, U.S.A
| | - Kathleen Marrs
- Dept. of Biology, Indiana Univ.-Purdue Univ. Indianapolis, Indianapolis, Ind., 46202, U.S.A
| | - James A Marrs
- Dept. of Biology, Indiana Univ.-Purdue Univ. Indianapolis, Indianapolis, Ind., 46202, U.S.A
| | - Grady W Chism
- Dept. of Biology, Indiana Univ.-Purdue Univ. Indianapolis, Indianapolis, Ind., 46202, U.S.A
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Sadeghi MR, Jeddi F, Soozangar N, Somi MH, Samadi N. The role of Nrf2-Keap1 axis in colorectal cancer, progression, and chemoresistance. Tumour Biol 2017. [PMID: 28621229 DOI: 10.1177/1010428317705510] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the third common cancer after lung and genital cancers worldwide with more than 1.2 million new cases diagnosed annually. Although extensive progress has been made in the treatment of colorectal cancer, finding novel targets for early diagnosis and effective treatment of these patients is an urgent need. Nuclear factor-erythroid 2-kelch-like ECH-associated protein 1 signaling pathway plays a key role in protecting cells from the damage of intracellular oxidative stress and extracellular oxidizing agents. Nuclear factor-erythroid 2 is a transcription factor that creates intracellular redox homeostasis via transcriptional activity and interaction with kelch-like ECH-associated protein 1. Furthermore, it contributes to survival and chemoresistance of colorectal cancer cells which is mediated by overexpression of cytoprotective and multidrug resistance genes. In this review, the dual role of nuclear factor-erythroid 2 signaling in induction of colorectal cancer cell survival and death as well as the possibility of targeting nuclear factor-erythroid 2-kelch-like ECH-associated protein 1 axis as an advanced strategy in prevention and effective treatment of colorectal cancer patients have been discussed.
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Affiliation(s)
- Mohammad Reza Sadeghi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- 3 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jeddi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Soozangar
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- 4 Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment. Pharmacol Rep 2017; 69:393-402. [DOI: 10.1016/j.pharep.2016.12.011] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 12/15/2016] [Accepted: 12/21/2016] [Indexed: 12/16/2022]
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Muhammad I, Sun X, Wang H, Li W, Wang X, Cheng P, Li S, Zhang X, Hamid S. Curcumin Successfully Inhibited the Computationally Identified CYP2A6 Enzyme-Mediated Bioactivation of Aflatoxin B1 in Arbor Acres broiler. Front Pharmacol 2017; 8:143. [PMID: 28377720 PMCID: PMC5359250 DOI: 10.3389/fphar.2017.00143] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 03/07/2017] [Indexed: 11/13/2022] Open
Abstract
Cytochrome P450 enzymes are often responsible for the toxic and carcinogenic effects of toxicants, such as aflatoxin B1 (AFB1). The human hepatic CYP2A6 enzyme mediates the oxidative metabolism of several procarcinogens. In this study, we characterized a partial sequence of CYP2A6 gene from Arbor Acres (AA) broiler and studied its role in AFB1 bioactivation. Moreover, the effect of curcumin on CYP2A6 is illustrated. Six groups of AA broiler were treated for 28 days including the control group (fed only basal diet), curcumin alone-treated group (450 mg/kg feed), the group fed AFB1-contaminated feed (5 mg/kg feed) plus the low (150 mg), medium (300 mg) or high (450 mg) of curcumin, and the group fed AFB1-contaminated diet alone (5 mg/kg feed). After the end of treatment period, liver samples were collected for different analyses. The results revealed that the histopathological examination showed clear signs of liver toxicity in AA broliers in AFB1-fed group, but curcumin-supplementation in feed prevented partially AFB1-induced liver toxicity. Liver and body weights were recorded to study the AFB1 harmful effects. We noted an obvious increase in liver weight and decrease in body weight in AFB1-fed group. But, the administration of curcumin partially ameliorated the increase in liver weight and decrease in body weight in a dose-dependent manner. The results (RT-PCR and Elisa) revealed that mRNA and protein expression level enhanced in AFB1-fed group. Consistently, CYP2A6 enzyme activity also increased in AFB1-fed group, suggesting that AA broiler CYP2A6 actively involved in bioactivation of AFB1. However, curcumin treatment inhibited CYP2A6 at mRNA and protein levels in AFB1 treated AA broiler in a dose-dependent manner. Maximum inhibition of liver CYP2A6 enzyme activity in AA broiler has been achieved at a dose of 450 mg/kg curcumin. This is the first study identifying and confirming the role of CYP2A6 enzyme in AFB1 bioactivation in AA broiler liver (in vivo), and the hepatoprotective role of curcumin via inhibiting CYP2A6 expression and enzyme activity. The study contributed to identify an important CYP enzyme involved in AFB1 bioactivation in broilers and thus could pave the way for the prevention of the harmful effects of AFB1 in broilers.
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Affiliation(s)
- Ishfaq Muhammad
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - Xiaoqi Sun
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - He Wang
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - Wei Li
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - Xinghe Wang
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - Ping Cheng
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - Sihong Li
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - Xiuying Zhang
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
| | - Sattar Hamid
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University Harbin, China
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Mirbod M, Mahdavi AH, Samie AH, Mehri M. Effects of Curcuma longa rhizome powder on egg quality, performance and some physiological indices of laying hens fed different levels of metabolizable energy. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2017; 97:1286-1294. [PMID: 27328772 DOI: 10.1002/jsfa.7862] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 06/13/2016] [Accepted: 06/16/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND High-energy diets of laying hens may improve roductive performance, although some negative effects may also appear with respect to egg quality and physiological parameters. Curcuma longa rhizome powder (CRP) has beneficial effects on health indices of the birds through antioxidant and antimicrobial properties, especially when the birds experience nutritional stress. RESULTS Increasing dietary CRP enhanced egg quality by improving eggshell thickness and hardness but decreasing yolk cholesterol content (P < 0.05). The best feed conversion ratio was obtained in birds fed high-apparent metabolizable energy (AME) diets supplemented with 2.0 g kg-1 CRP (P < 0.05). Although increasing dietary AME elevated the serum concentration of triglycerides (P < 0.05) and enzymatic activities of alanine aminotransferase and aspartate aminotransferase (P < 0.05), dietary inclusion of CRP alleviates the blood levels of these enzymes (P < 0.01). Low level of dietary CRP boosted the immune responses to Newcastle virus (P < 0.01) and sheep red blood cells (P < 0.05) antigens but decreased the heterophil to lymphocyte ratio (P < 0.05). Inclusion of at least 2.0 g kg-1 CRP in the diet of laying decreased Escherichia coli enumerations in the ileal content (P < 0.01) and improved villus height, crypt depth and goblet cell numbers (P < 0.05). CONCLUSION An improvement in the productive performance of laying hens fed high-energy diets might be associated with decreasing health indices and product quality, which could potentially be amended by nutritional modifications such as incorporating medicinal herbs in the feed. © 2016 Society of Chemical Industry.
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Affiliation(s)
- Mahsa Mirbod
- Department of Animal Sciences, College of Agriculture, Isfahan University of Technology, Isfahan, 84156-83111, Iran
| | - Amir Hossein Mahdavi
- Department of Animal Sciences, College of Agriculture, Isfahan University of Technology, Isfahan, 84156-83111, Iran
| | - Abdol-Hossein Samie
- Department of Animal Sciences, College of Agriculture, Isfahan University of Technology, Isfahan, 84156-83111, Iran
| | - Mehran Mehri
- Department of Animal Science, College of Agriculture, University of Zabol, Zabol, 98661-5538, Iran
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Xue Z, Li D, Yu W, Zhang Q, Hou X, He Y, Kou X. Mechanisms and therapeutic prospects of polyphenols as modulators of the aryl hydrocarbon receptor. Food Funct 2017; 8:1414-1437. [DOI: 10.1039/c6fo01810f] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Polyphenolic AhR modulators displayed concentration-, XRE-, gene-, species- and cell-specific agonistic/antagonistic activity.
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Affiliation(s)
- Zhaohui Xue
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300072
- China
| | - Dan Li
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300072
- China
| | - Wancong Yu
- Medical Plant Laboratory
- Tianjin Research Center of Agricultural Biotechnology
- Tianjin 3000381
- China
| | - Qian Zhang
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300072
- China
| | - Xiaonan Hou
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300072
- China
| | - Yulong He
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300072
- China
| | - Xiaohong Kou
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300072
- China
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49
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Zhang NY, Qi M, Zhao L, Zhu MK, Guo J, Liu J, Gu CQ, Rajput SA, Krumm CS, Qi DS, Sun LH. Curcumin Prevents Aflatoxin B₁ Hepatoxicity by Inhibition of Cytochrome P450 Isozymes in Chick Liver. Toxins (Basel) 2016; 8:E327. [PMID: 27834912 PMCID: PMC5127124 DOI: 10.3390/toxins8110327] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 11/04/2016] [Accepted: 11/07/2016] [Indexed: 01/20/2023] Open
Abstract
This study was designed to establish if Curcumin (CM) alleviates Aflatoxin B₁ (AFB₁)-induced hepatotoxic effects and to determine whether alteration of the expression of cytochrome P450 (CYP450) isozymes is involved in the regulation of these effects in chick liver. One-day-old male broilers (n = 120) were divided into four groups and used in a two by two factorial trial in which the main factors included supplementing AFB₁ (< 5 vs. 100 μg/kg) and CM (0 vs. 150 mg/kg) in a corn/soybean-based diet. Administration of AFB₁ induced liver injury, significantly decreasing albumin and total protein concentrations and increasing alanine aminotransferase and aspartate aminotransferase activities in serum, and induced hepatic histological lesions at week 2. AFB₁ also significantly decreased hepatic glutathione peroxidase, catalase, and glutathione levels, while increasing malondialdehyde, 8-hydroxydeoxyguanosine, and exo-AFB₁-8,9-epoxide (AFBO)-DNA concentrations. In addition, the mRNA and/or activity of enzymes responsible for the bioactivation of AFB₁ into AFBO-including CYP1A1, CYP1A2, CYP2A6, and CYP3A4-were significantly induced in liver microsomes after 2-week exposure to AFB₁. These alterations induced by AFB₁ were prevented by CM supplementation. Conclusively, dietary CM protected chicks from AFB₁-induced liver injury, potentially through the synergistic actions of increased antioxidant capacities and inhibition of the pivotal CYP450 isozyme-mediated activation of AFB₁ to toxic AFBO.
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Affiliation(s)
- Ni-Ya Zhang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Ming Qi
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Ling Zhao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Ming-Kun Zhu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Jiao Guo
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Jie Liu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Chang-Qin Gu
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| | - Shahid Ali Rajput
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | | | - De-Sheng Qi
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Lv-Hui Sun
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
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Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:7316492. [PMID: 27847554 PMCID: PMC5099458 DOI: 10.1155/2016/7316492] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 07/08/2016] [Accepted: 09/20/2016] [Indexed: 01/01/2023]
Abstract
The transcription factor Nrf2 (NF-E2 related factor 2) is a master regulator of the cell antioxidant response associated with tumor growth and resistance to cytotoxic treatments. In particular, Nrf2 induces upregulation of cytoprotective genes by interacting with the closely situated AREs (Antioxidant Response Elements) in response to endogenous or exogenous stress stimuli and takes part to several oncogenic signaling pathways. Among these, the crosstalk with Notch pathway has been shown to enhance cytoprotection and maintenance of cellular homeostasis, tissue organization by modulating cell proliferation kinetics, and stem cell self-renewal in several organs. The role of Notch and Nrf2 related pathways in tumorigenesis is highly variable and when they are both abnormally activated they can synergistically cause neoplastic proliferation by promoting cell survival, differentiation, invasion, and metastases. NFE2L2, KEAP1, and NOTCH genes family appear in the list of significantly mutated genes in tumors in both combined and individual sets, supporting the crucial role that the aberrant Nrf2-Notch crosstalk might have in cancerogenesis. In this review, we summarize current knowledge about the alterations of Nrf2 and Notch pathways and their reciprocal transcriptional regulation throughout tumorigenesis and progression of lung tumors, supporting the potentiality of putative biomarkers and therapeutic targets.
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