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1
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Uçar K, Göktaş Z. Biological activities of naringenin: A narrative review based on in vitro and in vivo studies. Nutr Res 2023; 119:43-55. [PMID: 37738874 DOI: 10.1016/j.nutres.2023.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/21/2023] [Accepted: 08/21/2023] [Indexed: 09/24/2023]
Abstract
Naringenin (4',5,7-trihydroxyflavonone) is a phytochemical mainly found in citrus fruits. It is a promising phytochemical for human health because of its beneficial effects. This review aims to present comprehensive information on naringenin biological activities along with its action mechanisms and explain the pharmacokinetic properties of naringenin. This study involves a comprehensive literature review of in vitro and in vivo studies examining the effects of naringenin. Naringenin has antidiabetic, anticancer, antimicrobial, antiobesity, gastroprotective, immunomodulator, cardioprotective, nephroprotective, and neuroprotective properties. These properties are primarily attributed to its antioxidant and anti-inflammatory activities. The most important antioxidant activities of naringenin including free radical scavenging and preventing lipid peroxidation. Naringenin can increase the concentration of antioxidant enzymes and inhibit metal chelation and various pro-oxidant enzymes. Anti-inflammatory activities of naringenin are associated with decreased mitogen-activated protein kinase activities and nuclear factor kappa B by modulating the expression and release of proinflammatory cytokine and enzymes. In vitro and in vivo studies show that naringenin has promising biological activities for a variety of diseases. More research must be conducted on the bioactivities of naringenin, and to determine its optimum dose. In addition, the efficiency of naringenin must be examined with enhanced bioavailability methods to be able to increase its therapeutic effect.
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Affiliation(s)
- Kübra Uçar
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye
| | - Zeynep Göktaş
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye.
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2
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Elnawasany S, Haggag YA, Shalaby SM, Soliman NA, EL Saadany AA, Ibrahim MAA, Badria F. Anti-cancer effect of nano-encapsulated boswellic acids, curcumin and naringenin against HepG-2 cell line. BMC Complement Med Ther 2023; 23:270. [PMID: 37516826 PMCID: PMC10386659 DOI: 10.1186/s12906-023-04096-4] [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: 06/25/2022] [Accepted: 07/18/2023] [Indexed: 07/31/2023] Open
Abstract
BACKGROUND liver cancer is one of the most common cancers in the world. So far, there is no gold standard treatment for hepatocellular carcinoma. We conducted this in vitro study to assess the effect of three natural products: Boswellic acids, curcumin and naringin versus corresponding nanoparticles (NPs) on Hep G2 cells proliferation. METHODS Boswellic acid, curcumin, naringin-loaded NPs were prepared using nanoprecipitation method. Human liver (HepG2) cell line was cultured in Dulbecco's modified Eagle's medium (DMEM). The cell growth inhibition and cytotoxicity were evaluated by MTT assay. RESULTS Boswellic acid, curcumin, naringin were able to inhibit HepG2 cells proliferation. IC50 at 24 h, 48 h showed significant lower values in NPs versus Free herbs. IC50 values of free Boswellic acids and NPs at 24 h were (24.60 ± 1.89 and 7.78 ± 0.54, P < 0.001), at 48 h were (22.45 ± 1.13 and 5.58 ± 0.27, P < 0.001) respectively. IC50 values of free curcumin and NPs at 24 h were (5.89 ± 0.8 and 3.46 ± 0.23, P < 0.05), at 48 h were (5.57 ± 0.94 and 2.51 ± 0.11, P < 0.05), respectively. For free and naringenin NPs, IC50 values at 24 h were (14.57 ± 1.78 and 7.25 ± 0.17, P < 0.01), at 48 h were (11.37 ± 1.45 and 5.21 ± 0.18, P < 0.01) respectively. CONCLUSION Boswellic acid, curcumin, naringin and their nanoprecipitation prepared nanoparticles suppressed Hep G2 cells proliferation.
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Affiliation(s)
- Sally Elnawasany
- Tropical Medicine Department, Faculty of Medicine, Tanta University, Tanta, Gharbia, 31111 Egypt
| | - Yusuf A. Haggag
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, Gharbia, Egypt
| | - Shahinaz M. Shalaby
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt
| | - Nema A. Soliman
- Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt
| | - Amira A. EL Saadany
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt
| | - Marwa A. A. Ibrahim
- Histology Department, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt
| | - Farid Badria
- Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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3
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Rauf A, Shariati MA, Imran M, Bashir K, Khan SA, Mitra S, Emran TB, Badalova K, Uddin MS, Mubarak MS, Aljohani ASM, Alhumaydhi FA, Derkho M, Korpayev S, Zengin G. Comprehensive review on naringenin and naringin polyphenols as a potent anticancer agent. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:31025-31041. [PMID: 35119637 DOI: 10.1007/s11356-022-18754-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/14/2022] [Indexed: 06/14/2023]
Abstract
Though the incidence of several cancers in Western societies is regulated wisely, some cancers such as breast, lung, and colorectal cancer are currently rising in many low- and middle-income countries due to increased risk factors triggered by societal and development problems. Surgery, chemotherapy, hormone, radiation, and targeted therapies are examples of traditional cancer treatment approaches. However, multiple short- and long-term adverse effects may also significantly affect patient prognosis depending on treatment-associated clinical factors. More and more research has been carried out to find new therapeutic agents in natural products, among which the bioactive compounds derived from plants have been increasingly studied. Naringin and naringenin are abundantly found in citrus fruits, such as oranges and grapefruits. A variety of cell signaling pathways mediates their anti-carcinogenic properties. Naringin and naringenin were also documented to overcome multidrug resistance, one of the major challenges to clinical practice due to multiple defense mechanisms in cancer. The effective parameters underlying the anticancer effects of naringenin and naringin include GSK3β inactivation, suppression of the gene and protein activation of NF-kB and COX-2, JAK2/STAT3 downregulation, downregulation of intracellular adhesion molecules-1, upregulation of Notch1 and tyrocite-specific genes, and activation of p38/MAPK and caspase-3. Thus, this review outlines the potential of naringin and naringenin in managing different types of cancers.
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Affiliation(s)
- Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar, Swabi, 23561, Khyber Pakhtunkhwa, Pakistan
| | - Mohammad Ali Shariati
- K.G. Razumovsky Moscow State University of Technologies and Management, The First Cossack University), 73 Zemlyanoy Val, Moscow, 109004, Russia
| | - Muhammad Imran
- Department of food science and technology, University of Narowal-Pakistan, Pakistan
- Food, nutrition and lifestyle Unit, King Fahed Medical Research Center, Clinical Biochemistry Department, Faculty of Medicine, King Abdulaziz University, Saudi Arabia
| | - Kashif Bashir
- Department of Microbiology and Biotechnology, Abasyan University Peshawar, Peshawar, Pakistan
| | - Shahid Ali Khan
- Department of Chemistry, University of Swabi, Anbar, Swabi, 23561, Khyber Pakhtunkhwa, Pakistan
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh
| | - Kamala Badalova
- General Toxicological Chemistry Department, Azerbaijan Medical University Azerbaijan, Baku, Azerbaijan
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
| | | | - Abdullah S M Aljohani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Fahad A Alhumaydhi
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Marina Derkho
- Institute of Veterinary Medicine, South-Ural State Agrarian University, Chelyabinsk Region, 13 Gagarin St, Troitsk, 454700, Russian Federation
| | - Serdar Korpayev
- Biotechnology Institute, Ankara University, 06135, Ankara, Turkey
| | - Gokhan Zengin
- Department of Biology, Science Faculty, Selcuk University, Konya, Turkey.
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4
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Skelding KA, Barry DL, Theron DZ, Lincz LF. Targeting the two-pore channel 2 in cancer progression and metastasis. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:62-89. [PMID: 36046356 PMCID: PMC9400767 DOI: 10.37349/etat.2022.00072] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/02/2022] [Indexed: 11/19/2022] Open
Abstract
The importance of Ca2+ signaling, and particularly Ca2+ channels, in key events of cancer cell function such as proliferation, metastasis, autophagy and angiogenesis, has recently begun to be appreciated. Of particular note are two-pore channels (TPCs), a group of recently identified Ca2+-channels, located within the endolysosomal system. TPC2 has recently emerged as an intracellular ion channel of significant pathophysiological relevance, specifically in cancer, and interest in its role as an anti-cancer drug target has begun to be explored. Herein, an overview of the cancer-related functions of TPC2 and a discussion of its potential as a target for therapeutic intervention, including a summary of clinical trials examining the TPC2 inhibitors, naringenin, tetrandrine, and verapamil for the treatment of various cancers is provided.
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Affiliation(s)
- Kathryn A. Skelding
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia
| | - Daniel L. Barry
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia
| | - Danielle Z. Theron
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia
| | - Lisa F. Lincz
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia;Hunter Hematology Research Group, Calvary Mater Newcastle Hospital, Waratah, New South Wales 2298, Australia
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5
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Naraki K, Rezaee R, Karimi G. A review on the protective effects of naringenin against natural and chemical toxic agents. Phytother Res 2021; 35:4075-4091. [PMID: 33724584 DOI: 10.1002/ptr.7071] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/13/2021] [Accepted: 02/23/2021] [Indexed: 12/14/2022]
Abstract
Naringenin (NRG), as a flavanone from flavonoids family, is widely found in grapefruit, lemon tomato, and Citrus fruits. NRG has shown strong anti-inflammatory and antioxidant activities in body organs via mechanisms such as enhancement of glutathione S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity, but reduction of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and malondialdehyde (MDA). Furthermore, NRG anti-apoptotic potential was indicated to be mediated by regulating B-cell lymphoma (Bcl-2), Bcl-2-associated X protein (Bax) and caspase3/9. Overall, these properties make NRG a highly fascinating compound with beneficial pharmacological effects. Based on the literature, NRG-induced protective effects against toxicities produced by natural toxins, pharmaceuticals, heavy metals, and environmental chemicals, were mainly mediated via suppression of lipid peroxidation, oxidative stress (through boosting the antioxidant arsenal), and inflammatory factors (e.g., TNF-α, interleukin [IL]-6, IL-10, and IL-12), and activation of PI3K/Akt and MAPK survival signaling pathways. Despite considerable body of evidence on protective properties of NRG against a variety of toxic compounds, more well-designed experimental studies and particularly, clinical trials are required before reaching a concrete conclusion. The present review discusses how NRG protects against the above-noted toxic compounds.
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Affiliation(s)
- Karim Naraki
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramin Rezaee
- Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Pharmaceutical Research Center Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
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6
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Murti Y, Semwal BC, Goyal A, Mishra P. Naringenin Scaffold as a Template for Drug Designing. CURRENT TRADITIONAL MEDICINE 2021. [DOI: 10.2174/2215083805666190617144652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Natural products provide cornucopia of heterocyclic systems. The nucleus of 2-
phenyl chromane is one of the important and well-known heterocycles found in the natural
products. Naringenin, a plant-derived flavanone (2-phenyl chroman-4-one) belongs to the family
of flavanoids. It possesses diverse biologic activities such as antidiabetic, antiatherogenic,
antidepressant, antiandrogenic, antiestrogenic, immunomodulatory, antitumor, antimicrobial,
anti-inflammatory, antiviral, hypolipidemic, antihypertensive, antioxidant, neuroprotective,
anti-obesity, anti-Alzheimer, and memory enhancer activity. It has the potential to be used as
an active pharmacophore. There have been reports of a number of molecular mechanisms
underlying their beneficial activities. With emerging interest in traditional medicine and
exploiting their potential based on a variety of health care systems, naringenin literature was
thought to be explored. Further, this review aims to provide a new era of flavonoid-based
therapeutic agents with new insights into naringenin and its derivatives as a lead compound
in drug design.
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Affiliation(s)
- Yogesh Murti
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
| | - Bhupesh Chander Semwal
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
| | - Pradeep Mishra
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
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7
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Fishbein A, Hammock BD, Serhan CN, Panigrahy D. Carcinogenesis: Failure of resolution of inflammation? Pharmacol Ther 2021; 218:107670. [PMID: 32891711 PMCID: PMC7470770 DOI: 10.1016/j.pharmthera.2020.107670] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
Abstract
Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.
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Affiliation(s)
- Anna Fishbein
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Bruce D. Hammock
- Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
| | - Charles N. Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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8
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Badr El-Din NK, Ali DA, Othman R, French SW, Ghoneum M. Chemopreventive role of arabinoxylan rice bran, MGN-3/Biobran, on liver carcinogenesis in rats. Biomed Pharmacother 2020; 126:110064. [PMID: 32278271 DOI: 10.1016/j.biopha.2020.110064] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 02/26/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and one of the most lethal. MGN-3/Biobran is a natural product derived from rice bran hemicelluloses and has been reported to possess a potent anticancer effect in a clinical study of patients with HCC. The current study examines the mechanisms by which Biobran protects against chemically induced hepatocarcinogenesis in rats. The chemical carcinogen used in this study is N-nitrosodiethylamine (NDEA) plus carbon tetrachloride (CCl4). Rats were treated with this carcinogen, and the animals were pretreated or posttreated with Biobran via intraperitoneal injections until the end of the experiment. Treatment with Biobran resulted in: 1) significant alleviation of liver preneoplastic lesions towards normal hepatocellular architecture in association with inhibition of collagen fiber deposition; 2) arrest of cancer cells in the sub-G1 phase of the cell cycle; 3) increased DNA fragmentation in cancer cells; 4) down-regulated expression of Bcl-2 and up-regulated expression of p53, Bax, and caspase-3; and 5) protection against carcinogen-induced suppression of IkappaB-alpha (IκB-α) mRNA expression and inhibition of nuclear factor kappa-B (NF-κB/p65) expression. Additionally, the effect of Biobran treatment was found to be more significant when supplemented prior to carcinogen-induced hepatocarcinogenesis as compared to posttreatment. We conclude that Biobran inhibits hepatocarcinogenesis in rats by mechanisms that include induction of apoptosis, inhibition of inflammation, and suppression of cancer cell proliferation. Biobran may be a promising chemopreventive and chemotherapeutic agent for liver carcinogenesis.
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Affiliation(s)
| | - Doaa A Ali
- Department of Zoology, Faculty of Science, University of Mansoura, Mansoura, Egypt
| | - Reem Othman
- Department of Zoology, Faculty of Science, University of Mansoura, Mansoura, Egypt
| | - Samuel W French
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA
| | - Mamdooh Ghoneum
- Department of Surgery, Charles Drew University of Medicine and Science, Los Angeles, CA, 90059, USA
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9
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Sadeeshkumar V, Duraikannu A, Aishwarya T, Jayaram P, Ravichandran S, Ganeshamurthy R. Radioprotective efficacy of dieckol against gamma radiation-induced cellular damage in hepatocyte cells. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:1031-1041. [PMID: 31028451 DOI: 10.1007/s00210-019-01652-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 04/09/2019] [Indexed: 12/29/2022]
Abstract
Naturally occurring antioxidants prevent or delay the harmful effect of free radical formation and radioprotection. The present study aimed to investigate the radioprotective effect of dieckol, a naturally occurring marine bioactive phenolic compound on lipid peroxidation and antioxidant status, DNA damage, and inflammation in gamma-radiation-induced rat primary hepatocytes. Isolated hepatocyte cells exposed to gamma-radiation showed an increased level of lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) accompanied with the decrease in the activities of enzymatic (SOD, CAT, and GPx) and non-enzymatic (vitamin C, vitamin E, and GSH) antioxidants associated with increased DNA damage coupled with upregulation of inflammatory proteins (NF-κB and COX-2) compared to control. Treatment of dieckol (5, 10, 20 μM) reduces the γ-radiation-induced toxicity and the associated pro-oxidant and antioxidant imbalance as well as decreasing the DNA damage (tail length, tail moment, %DNA in a tail and olive tail moment) and inflammation in hepatocyte cells. These findings indicate that treatment of dieckol offers protection against γ-radiation-induced cellular damage in the liver cells.
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Affiliation(s)
- Velayutham Sadeeshkumar
- Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Tamil Nadu, 608 502, India. .,Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, 608 002, India.
| | - Arul Duraikannu
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, 608 002, India.,Division of Neurology, Department of Medicine & Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada
| | - Thiyagarajan Aishwarya
- Department of Plant Breeding and Genetics, Agricultural College and Research Institute, Killikulam, Vallanadu, Tamil Nadu, 628 252, India
| | - Prithi Jayaram
- Pondicherry Institute of Medical Sciences, Ganapathichettikulam, Kalapet, Puducherry, 605 014, India
| | - Samuthrapandian Ravichandran
- Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Tamil Nadu, 608 502, India
| | - Raghunathan Ganeshamurthy
- Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Tamil Nadu, 608 502, India
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10
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Cui W, He Z, Zhang Y, Fan Q, Feng N. Naringenin Cocrystals Prepared by Solution Crystallization Method for Improving Bioavailability and Anti-hyperlipidemia Effects. AAPS PharmSciTech 2019; 20:115. [PMID: 30771018 DOI: 10.1208/s12249-019-1324-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 01/30/2019] [Indexed: 02/07/2023] Open
Abstract
Naringenin exerts anti-inflammatory, hypolipidemic, and hepatoprotective effects; however, it shows low oral bioavailability because of poor water solubility. In this work, cocrystals of naringenin were formed to address these issues. Using the solution crystallization method, various naringenin cocrystals were prepared with different cocrystal coformers, including naringenin-nicotinamide, naringenin-isonicotinamide, naringenin-caffeine, naringenin-betaine, and naringenin-L-proline. The formation of these cocrystals was assayed by using DSC, XRD, and FT-IR spectroscopy. The stoichiometric ratio of naringenin and the CCFs in the corresponding cocrystals was investigated by NMR. The solubility of naringenin, as well as its dissolution rate, was markedly improved by forming cocrystals. The oral bioavailability of naringenin administered as naringenin-L-proline and naringenin-betaine cocrystals was achieved significantly greater than that of pure naringenin (p < 0.05). In particular, the Cmax of naringenin-L-proline and naringenin-betaine cocrystals were 2.00-fold and 3.35-fold higher, and the AUC of naringenin-L-proline and naringenin-betaine cocrystals were 2.39-fold and 4.91-fold, respectively, higher than pure naringenin in rats. With the naringenin-betaine cocrystals for oral delivery, the drug distribution in the liver was significantly increased compared to pure naringenin. Accordingly, the naringenin-betaine cocrystals showed improved anti-hyperlipidemia effects on the C57 BL/6J PNPLA3 I148M transgenic mouse hyperlipidemia model. Collectively, cocrystal formation is a promising way to increase the bioavailability of naringenin for treating hyperlipidemia.
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11
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Kirsanov KI, Vlasova OA, Fetisov TI, Zenkov RG, Lesovaya EA, Belitsky GA, Gurova K, Yakubovskaya MG. Influence of DNA-binding compounds with cancer preventive activity on the mechanisms of gene expression regulation. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2018-5-4-41-63] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- K. I. Kirsanov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Peoples’ Friendship University of Russia
| | - O. A. Vlasova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - T. I. Fetisov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - R. G. Zenkov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - E. A. Lesovaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; I.P. Pavlov Ryazan State Medical University
| | - G. A. Belitsky
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | | | - M. G. Yakubovskaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
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12
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Zheng J, He J, Liao S, Cheng Z, Lin J, Huang K, Li X, Zheng K, Chen X, Lin L, Xia F, Liu J, Xu M, Chen T, Huang X, Cao X, Yang Z. Preventive effects of combinative natural foods produced by elite crop varieties rich in anticancer effects on N-nitrosodiethylamine-induced hepatocellular carcinoma in rats. Food Sci Nutr 2019; 7:339-355. [PMID: 30680188 PMCID: PMC6341211 DOI: 10.1002/fsn3.896] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 11/05/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
The World Cancer Research Fund International has released 32 anticancer effects (ACEs) that targeted every stage of cancer processes. Thus, we designed two formulas of natural food combination Diet I and Diet II, mainly produced by elite crop varieties rich in ACEs with different mixture ratios, and evaluated their cancer preventive effects on N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis. After 20 weeks of dietary intervention, Diet I and Diet II reduced incidence, size, and number of hepatic nodules (p < 0.01) and prevented hepatic tumor formation in NDEA-induced hepatocarcinogenesis rats. Low-grade hepatic dysplasia incidence was 20% for Diet II and 40% for Diet I, and apparent hepatocellular carcinomas (HCC) rates were both 0, while 90% HCC in control diet treatment group (p < 0.01). Diet I and Diet II ameliorated abnormal liver function enzymes, reduced serum alpha fetal protein, tumor-specific growth factor, dickkopf-related protein 1, tumor necrosis factor-alpha and interleukin-6 levels, regulated hepatic phase I and II xenobiotic-metabolizing enzymes, enhanced antioxidant capacity, suppressed NDEA-initiated oxidative DNA damage, and induced apoptosis coupled to down-regulation of proinflammatory, invasion, and angiogenesis markers. Daily intake of combination diet produced from ACEs-rich elite crop varieties can effectively prevent or delay occurrence and development of NDEA-induced hepatocarcinogenesis in rats.
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Affiliation(s)
- Jingui Zheng
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Jun He
- Institute of Laboratory Animal ScienceChinese Academy of Medical SciencesBeijingChina
| | - Sufeng Liao
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Zuxin Cheng
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Jinke Lin
- Anxi College of Tea ScienceFujian Agriculture and Forestry UniversityFuzhouChina
| | - Ke Huang
- College of Horticulture and LandscapeHunan Agricultural UniversityChangshaChina
| | - Xiaocen Li
- Institute of Laboratory Animal ScienceChinese Academy of Medical SciencesBeijingChina
| | - Kaibin Zheng
- Institute of Sub‐tropical AgricultureFujian Academy of Agricultural SciencesFuzhouChina
| | - Xuanyang Chen
- Key Laboratory of Ministry for Education for Genetics, Breeding and Multiple Utilization of CropsFujian Agriculture and Forestry UniversityFuzhouChina
| | - Lihui Lin
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Fagang Xia
- Key Laboratory of Ministry for Education for Genetics, Breeding and Multiple Utilization of CropsFujian Agriculture and Forestry UniversityFuzhouChina
| | - Jianghong Liu
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Ming Xu
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Tuansheng Chen
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Xinying Huang
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Xiaohua Cao
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
| | - Zhijian Yang
- Agricultural Product Quality InstituteFujian Agriculture and Forestry UniversityFuzhouChina
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13
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Zhao C, Wang F, Lian Y, Xiao H, Zheng J. Biosynthesis of citrus flavonoids and their health effects. Crit Rev Food Sci Nutr 2018; 60:566-583. [DOI: 10.1080/10408398.2018.1544885] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Chengying Zhao
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Feng Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yunhe Lian
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Jinkai Zheng
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China
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14
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Cypripedin diminishes an epithelial-to-mesenchymal transition in non-small cell lung cancer cells through suppression of Akt/GSK-3β signalling. Sci Rep 2018; 8:8009. [PMID: 29789636 PMCID: PMC5964153 DOI: 10.1038/s41598-018-25657-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 04/26/2018] [Indexed: 12/15/2022] Open
Abstract
Lung cancer appears to have the highest rate of mortality among cancers due to its metastasis capability. To achieve metastasis, cancer cells acquire the ability to undergo a switch from epithelial to mesenchymal behaviour, termed the epithelial-to-mesenchymal transition (EMT), which is associated with poor clinical outcomes. Drug discovery attempts have been made to find potent compounds that will suppress EMT. Cypripedin, a phenanthrenequinone isolated from Thai orchid, Dendrobium densiflorum, exhibits diverse pharmacological activities. In this study, we found that cypripedin attenuated typical mesenchymal phenotypes, including migratory behaviour, of non-small cell lung cancer H460 cells, with a significant reduction of actin stress fibres and focal adhesion and with weakened anchorage-independent growth. Western blot analysis revealed that the negative activity of this compound on EMT was a result of the down-regulation of the EMT markers Slug, N-Cadherin and Vimentin, which was due to ATP-dependent tyrosine kinase (Akt) inactivation. As a consequence, the increase in the Slug degradation rate via a ubiquitin-proteasomal mechanism was encouraged. The observation in another lung cancer H23 cell line also supported this finding, indicating that cypripedin exhibits a promising pharmacological action on lung cancer metastasis that could provide scientific evidence for the further development of this compound.
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15
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Hernández-Aquino E, Muriel P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J Gastroenterol 2018; 24:1679-1707. [PMID: 29713125 PMCID: PMC5922990 DOI: 10.3748/wjg.v24.i16.1679] [Citation(s) in RCA: 224] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/04/2018] [Accepted: 04/15/2018] [Indexed: 02/06/2023] Open
Abstract
Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor (TGF-β) pathway and the prevention of the transdifferentiation of hepatic stellate cells (HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase (MAPK), toll-like receptor (TLR) and TGF-β non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease (NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-β and vascular endothelial growth factor (VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases.
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Affiliation(s)
- Erika Hernández-Aquino
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07000, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07000, Mexico
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16
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Rehman MU, Rahman Mir MU, Farooq A, Rashid SM, Ahmad B, Bilal Ahmad S, Ali R, Hussain I, Masoodi M, Muzamil S, Madkhali H, Ahmad Ganaie M. Naringenin (4,5,7-trihydroxyflavanone) suppresses the development of precancerous lesions via controlling hyperproliferation and inflammation in the colon of Wistar rats. ENVIRONMENTAL TOXICOLOGY 2018; 33:422-435. [PMID: 29345053 DOI: 10.1002/tox.22528] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 12/22/2017] [Accepted: 12/26/2017] [Indexed: 06/07/2023]
Abstract
Colon cancer is a world-wide health problem and one of the most dangerous type of cancer, affecting both men and women. Naringenin (4, 5, 7-trihydroxyflavanone) is one of the major flavone glycoside present in citrus fruits. Naringenin has long been used in Chinese's traditional medicine because of its exceptional pharmacological properties and non-toxic nature. In the present study, we investigated the chemopreventive potential of Naringenin against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions, that is, aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the oxidative stress, inflammation and hyperproliferation, in the colon of Wistar rats. Animals were divided into five groups. In groups 3-5, Naringenin was administered at the dose of 50 mg/kg b. wt. orally while in groups 2-4, DMH was administered subcutaneously in the groin at the dose of 20 mg/kg b. wt. once a week for first 5 weeks and animals were euthanized after 10 weeks. Administration of Naringenin ameliorated the development of DMH-induced lipid peroxidation, ROS formation, precancerous lesions (ACF and MDF) and it also reduced the infiltration of mast cells, suppressed the immunostaining of NF-κB-p65, COX-2, i-NOS PCNA and Ki 67 Naringenin treatment significantly attenuated the level of TNF-α and it also prevented the depletion of the mucous layer. Our findings suggest that Naringenin has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of Naringenin.
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Affiliation(s)
- Muneeb U Rehman
- Molecular Biology Laboratory, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Manzoor Ur Rahman Mir
- Molecular Biology Laboratory, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Adil Farooq
- RAKCOPS, RAK Medical and Health Sciences University, Ras AL, Khaimah, 11172, United Arab Emirates
| | - Shahzada Mudasir Rashid
- Molecular Biology Laboratory, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Bilal Ahmad
- Molecular Biology Laboratory, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Sheikh Bilal Ahmad
- Molecular Biology Laboratory, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Rayeesa Ali
- Division of Veterinary Pathology, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Ishraq Hussain
- Molecular Biology Laboratory, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Mubashir Masoodi
- Department of Pharmaceutical sciences, Faculty of Applied Sciences, University of Kashmir, Hazratbal, Srinagar, J&K, 190006, India
| | - Showkeen Muzamil
- Molecular Biology Laboratory, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sheri Kashmir University of Agricultural Science and Technology (SKUAST-K), Alustang, Shuhama, Srinagar, J&K, 190006, India
| | - Hassan Madkhali
- Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Kingdom of Saudi Arabia
| | - Majid Ahmad Ganaie
- Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Kingdom of Saudi Arabia
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17
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Naringenin Impairs Two-Pore Channel 2 Activity And Inhibits VEGF-Induced Angiogenesis. Sci Rep 2017; 7:5121. [PMID: 28698624 PMCID: PMC5505983 DOI: 10.1038/s41598-017-04974-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 05/23/2017] [Indexed: 12/11/2022] Open
Abstract
Our research introduces the natural flavonoid naringenin as a novel inhibitor of an emerging class of intracellular channels, Two-Pore Channel 2 (TPC2), as shown by electrophysiological evidence in a heterologous system, i.e. Arabidopsis vacuoles lacking endogenous TPCs. In view of the control exerted by TPC2 on intracellular calcium signaling, we demonstrated that naringenin dampens intracellular calcium responses of human endothelial cells stimulated with VEGF, histamine or NAADP-AM, but not with ATP or Angiopoietin-1 (negative controls). The ability of naringenin to impair TPC2-dependent biological activities was further explored in an established in vivo model, in which VEGF-containing matrigel plugs implanted in mice failed to be vascularized in the presence of naringenin. Overall, the present data suggest that naringenin inhibition of TPC2 activity and the observed inhibition of angiogenic response to VEGF are linked by impaired intracellular calcium signaling. TPC2 inhibition is emerging as a key therapeutic step in a range of important pathological conditions including the progression and metastatic potential of melanoma, Parkinson’s disease, and Ebola virus infection. The identification of naringenin as an inhibitor of TPC2-mediated signaling provides a novel and potentially relevant tool for the advancement of this field of research.
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18
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Sadeeshkumar V, Duraikannu A, Ravichandran S, Kodisundaram P, Fredrick WS, Gobalakrishnan R. Modulatory efficacy of dieckol on xenobiotic-metabolizing enzymes, cell proliferation, apoptosis, invasion and angiogenesis during NDEA-induced rat hepatocarcinogenesis. Mol Cell Biochem 2017; 433:195-204. [PMID: 28397013 DOI: 10.1007/s11010-017-3027-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/01/2017] [Indexed: 12/25/2022]
Abstract
Dieckol (DEK) is a major polyphenol of marine brown seaweed Ecklonia cava which is a potential candidate for cancer therapy. However, the underlying mechanism of DEK as an anticancer drug remains to be elucidated. In this study, we evaluated the molecular mechanisms involved in the chemopreventive efficacy of DEK in N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis rats by analyzing markers of xenobiotic-metabolizing enzymes (XMEs), apoptosis, invasion, and angiogenesis. Rats administered NDEA developed hepatocarcinogenesis that displayed apoptosis avoidance coupled to upregulation of pro-inflammatory, invasion, and angiogenesis markers. Treatment of DEK effectively suppressed the NDEA-initiated hepatocarcinogenesis by modulation of XMEs, inducing of apoptosis via the mitochondrial pathway as revealed by modulating the Bcl-2 family proteins, cytochrome C, caspases, and inhibiting invasion, and angiogenesis as evidenced by changes in the activities of MMPs (MMP2/9) and the expression of VEGF. In addition, DEK exerts its anticancer effects via inhibition of pro-inflammatory transcription factor NF-κB (nuclear factor κB) and COX2 in NDEA-induced hepatocarcinogenesis. Taken together, this study demonstrates that DEK modulates the expression of key molecules that regulate apoptosis, inflammation, invasion, and angiogenesis. These results strongly indicate that DEK from E. cava is an attractive candidate for chemoprevention.
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Affiliation(s)
- Velayutham Sadeeshkumar
- Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Chidambaram, Tamil Nadu, 608 502, India.
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, 608 002, India.
| | - Arul Duraikannu
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, 608 002, India
- Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, T6G 2G3, Canada
| | - Samuthrapandian Ravichandran
- Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Chidambaram, Tamil Nadu, 608 502, India
| | - Paulrasu Kodisundaram
- Department of Chemistry, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, 608 002, India
| | - Wilson Sylvester Fredrick
- Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Chidambaram, Tamil Nadu, 608 502, India
| | - Rajagopal Gobalakrishnan
- Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Chidambaram, Tamil Nadu, 608 502, India
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19
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Cirmi S, Ferlazzo N, Lombardo GE, Maugeri A, Calapai G, Gangemi S, Navarra M. Chemopreventive Agents and Inhibitors of Cancer Hallmarks: May Citrus Offer New Perspectives? Nutrients 2016; 8:E698. [PMID: 27827912 PMCID: PMC5133085 DOI: 10.3390/nu8110698] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 10/11/2016] [Accepted: 10/13/2016] [Indexed: 12/12/2022] Open
Abstract
Fruits and vegetables have long been recognized as potentially important in the prevention of cancer risk. Thus, scientific interest in nutrition and cancer has grown over time, as shown by increasing number of experimental studies about the relationship between diet and cancer development. This review attempts to provide an insight into the anti-cancer effects of Citrus fruits, with a focus on their bioactive compounds, elucidating the main cellular and molecular mechanisms through which they may protect against cancer. Scientific literature was selected for this review with the aim of collecting the relevant experimental evidence for the anti-cancer effects of Citrus fruits and their flavonoids. The findings discussed in this review strongly support their potential as anti-cancer agents, and may represent a scientific basis to develop nutraceuticals, food supplements, or complementary and alternative drugs in a context of a multi-target pharmacological strategy in the oncology.
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Affiliation(s)
- Santa Cirmi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
| | - Nadia Ferlazzo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
| | - Giovanni E Lombardo
- Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro I-88100, Italy.
| | - Alessandro Maugeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
| | - Gioacchino Calapai
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina I-98125, Italy.
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, University of Messina, Messina I-98125, Italy.
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council (CNR), Pozzuoli I-80078, Italy.
| | - Michele Navarra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
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20
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Bodduluru LN, Kasala ER, Madhana RM, Barua CC, Hussain MI, Haloi P, Borah P. Naringenin ameliorates inflammation and cell proliferation in benzo(a)pyrene induced pulmonary carcinogenesis by modulating CYP1A1, NFκB and PCNA expression. Int Immunopharmacol 2016; 30:102-110. [DOI: 10.1016/j.intimp.2015.11.036] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 11/22/2015] [Accepted: 11/30/2015] [Indexed: 10/22/2022]
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21
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Martinez RM, Pinho-Ribeiro FA, Steffen VS, Caviglione CV, Vignoli JA, Barbosa DS, Baracat MM, Georgetti SR, Verri WA, Casagrande R. Naringenin Inhibits UVB Irradiation-Induced Inflammation and Oxidative Stress in the Skin of Hairless Mice. JOURNAL OF NATURAL PRODUCTS 2015; 78:1647-55. [PMID: 26154512 DOI: 10.1021/acs.jnatprod.5b00198] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Ultraviolet B (UVB) irradiation may cause inflammation- and oxidative-stress-dependent skin cancer and premature aging. Naringenin (1) has been reported to have anti-inflammatory and antioxidant properties, but its effects and mechanisms on UVB irradiation-induced inflammation and oxidative stress are still not known. Thus, the present study aimed to investigate the potential of naringenin to mitigate UVB irradiation-induced inflammation and oxidative damage in the skin of hairless mice. Skin edema, myeloperoxidase (neutrophil marker) and matrix metalloproteinase-9 (MMP-9) activity, and cytokine production were measured after UVB irradiation. Oxidative stress was evaluated by 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS) scavenging ability, ferric reducing antioxidant power (FRAP), reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, and gp91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR. The intraperitoneal treatment with naringenin reduced skin inflammation by inhibiting skin edema, neutrophil recruitment, MMP-9 activity, and pro-inflammatory (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, IL-22, and IL-23) and anti-inflammatory (TGF-β and IL-10) cytokines. Naringenin also inhibited oxidative stress by reducing superoxide anion production and the mRNA expression of gp91phox. Therefore, naringenin inhibits UVB irradiation-induced skin damage and may be a promising therapeutic approach to control skin disease.
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Affiliation(s)
- Renata M Martinez
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Felipe A Pinho-Ribeiro
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Vinicius S Steffen
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Carla V Caviglione
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Josiane A Vignoli
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Décio S Barbosa
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Marcela M Baracat
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Sandra R Georgetti
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Waldiceu A Verri
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
| | - Rubia Casagrande
- †Departamento de Ciências Farmacêuticas and ⊥Departamento de Patologia, Análises Clínicas e Toxicológicas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86039-440 Londrina, Paraná, Brazil
- ‡Departamento de Ciências Patológicas and §Departamento de Bioquímica e Biotecnologia, Universidade Estadual de Londrina-UEL, Rodovia Celso Garcia Cid, Km 380, PR445, Cx. Postal 10.011, 86057-970 Londrina, Paraná, Brazil
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Mir IA, Tiku AB. Chemopreventive and therapeutic potential of "naringenin," a flavanone present in citrus fruits. Nutr Cancer 2014; 67:27-42. [PMID: 25514618 DOI: 10.1080/01635581.2015.976320] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Cancer is one of the major causes of deaths in developed countries and is emerging as a major public health burden in developing countries too. Changes in cancer prevalence patterns have been noticed due to rapid urbanization and changing lifestyles. One of the major concerns is an influence of dietary habits on cancer rates. Approaches to prevent cancer are many and chemoprevention or dietary cancer prevention is one of them. Therefore, nutritional practices are looked at as effective types of dietary cancer prevention strategies. Attention has been given to identifying plant-derived dietary agents, which could be developed as a promising chemotherapeutic with minimal toxic side effects. Naringenin, a phytochemical mainly present in citrus fruits and tomatoes, is a frequent component of the human diet and has gained increasing interest because of its positive health effects not only in cancer prevention but also in noncancer diseases. In the last few years, significant progress has been made in studying the biological effects of naringenin at cellular and molecular levels. This review examines the cancer chemopreventive/therapeutic effects of naringenin in an organ-specific format, evaluating its limitations, and its considerable potential for development as a cancer chemopreventive/therapeutic agent.
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Affiliation(s)
- Irfan Ahmad Mir
- a Department of Clinical Biochemistry , University of Kashmir , Kashmir , India
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LIAO ALEXCHIENHWA, KUO CHIACHENG, HUANG YEICHUNG, YEH CHIWEI, HSEU YOUCHENG, LIU JERYUH, HSU LISUNG. Naringenin inhibits migration of bladder cancer cells through downregulation of AKT and MMP-2. Mol Med Rep 2014; 10:1531-6. [DOI: 10.3892/mmr.2014.2375] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 05/02/2014] [Indexed: 11/05/2022] Open
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Kapoor S. Tumor Growth Attenuating Effects of Naringenin. Pathol Oncol Res 2013; 20:483. [DOI: 10.1007/s12253-013-9702-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 10/02/2013] [Indexed: 10/25/2022]
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Arul D, Subramanian P. Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats. Biochem Biophys Res Commun 2013; 434:203-9. [PMID: 23523793 DOI: 10.1016/j.bbrc.2013.03.039] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 03/09/2013] [Indexed: 12/20/2022]
Abstract
We evaluated the effects of naringenin on N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. Administration of NDEA induced hepatocellular carcinoma (HCC), as evidenced by changes in histopathological architecture, increased activity of cytochrome P450, decreased activity of glutathione S-transferase (GST) as well as decreased antioxidant status, enhanced lipid peroxidation and increased liver marker enzymes. Pre- and post-treatment with naringenin effectively suppressed NDEA-initiated hepatocarcinoma and the associated preneoplastic lesions by modulating xenobiotic-metabolizing enzymes (XMEs), alleviating lipid peroxidation (through both free radical scavenging and the enhanced antioxidant status), and decreased levels of liver marker enzymes. These results indicate that naringenin prevents lipid peroxidation and hepatic cell damage and also protects the antioxidant system in N-nitrosdithylamine-induced hepatocarcinogenesis.
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Affiliation(s)
- Duraikannu Arul
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Tamil Nadu, India.
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