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Zhuang H, Zhang X, Wu S, Yong P, Yan H. Opportunities and challenges of foodborne polyphenols applied to anti-aging health foods. Food Sci Biotechnol 2024; 33:3445-3461. [PMID: 39493397 PMCID: PMC11525373 DOI: 10.1007/s10068-024-01686-x] [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: 04/12/2024] [Revised: 07/27/2024] [Accepted: 08/12/2024] [Indexed: 11/05/2024] Open
Abstract
Abstract With the increasing proportion of the global aging population, aging mechanisms and anti-aging strategies become hot topics. Nonetheless, the safety of non-natural anti-aging active molecule and the changes in physiological function that occur during aging have not been clarified. There is therefore a need to develop safer pharmaceutical interventions for anti-aging. Numerous types of research have shown that food-derived biomolecules are of great interest due to their unique contribution to anti-aging safety issues and the prevention of degenerative diseases. Among these, polyphenolic organic compounds are widely used in anti-aging research for their ability to mitigate the physiological functional changes that occur during aging. The mechanisms include the free radical theory, immune aging theory, cellular autophagy theory, epigenetic modification theory, gut microbial effects on aging theory, telomere shortening theory, etc. This review elucidates the mechanisms underlying the anti-aging effects of polyphenols found in food-derived bioactive molecules, while also addressing the challenges associated with anti-aging pharmaceuticals. The review concludes by offering insights into the current landscape of anti-aging active molecule research, aiming to serve as a valuable resource for further scholarly inquiry. Graphical abstract
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Affiliation(s)
- Hong Zhuang
- College of Food Science and Engineering, Jilin University, Changchun, 130062 Jilin China
| | - Xiaoliang Zhang
- College of Food Science and Engineering, Jilin University, Changchun, 130062 Jilin China
| | - Sijia Wu
- College of Food Science and Engineering, Jilin University, Changchun, 130062 Jilin China
| | - Pang Yong
- College of Food Science and Engineering, Jilin University, Changchun, 130062 Jilin China
| | - Haiyang Yan
- College of Food Science and Engineering, Jilin University, Changchun, 130062 Jilin China
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2
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Sumaira S, Vijayarathna S, Hemagirri M, Adnan M, Hassan MI, Patel M, Gupta R, Shanmugapriya, Chen Y, Gopinath SC, Kanwar JR, Sasidharan S. Plant bioactive compounds driven microRNAs (miRNAs): A potential source and novel strategy targeting gene and cancer therapeutics. Noncoding RNA Res 2024; 9:1140-1158. [PMID: 39022680 PMCID: PMC11250886 DOI: 10.1016/j.ncrna.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/21/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
Irrespective of medical technology improvements, cancer ranks among the leading causes of mortality worldwide. Although numerous cures and treatments exist, creating alternative cancer therapies with fewer adverse side effects is vital. Since ancient times, plant bioactive compounds have already been used as a remedy to heal cancer. These plant bioactive compounds and their anticancer activity can also deregulate the microRNAs (miRNAs) in the cancerous cells. Therefore, the deregulation of miRNAs in cancer cells by plant bioactive compounds and the usage of the related miRNA could be a promising approach for cancer cure, mainly to prevent cancer and overcome chemotherapeutic side effect problems. Hence, this review highlights the function of plant bioactive compounds as an anticancer agent through the underlying mechanism that alters the miRNA expression in cancer cells, ultimately leading to apoptosis. Moreover, this review provides insight into using plant bioactive compounds -driven miRNAs as an anticancer agent to develop miRNA-based cancer gene therapy. They can be the potential resource for gene therapy and novel strategies targeting cancer therapeutics.
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Affiliation(s)
- Sahreen Sumaira
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Soundararajan Vijayarathna
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Manisekaran Hemagirri
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, P.O. Box 2440, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Mitesh Patel
- Research and Development Cell and Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Vadodara, 391760, Gujarat, India
| | - Reena Gupta
- Institute of Pharmaceutical Research, Department. Pharmaceutical Research, GLA University, Mathura, India
| | - Shanmugapriya
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Yeng Chen
- Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Subash C.B. Gopinath
- Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis, Perlis, Malaysia
| | - Jagat R. Kanwar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), 174001, Bilaspur, Himachal Pradesh, India
| | - Sreenivasan Sasidharan
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
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Moar K, Yadav S, Pant A, Deepika, Maurya PK. Anti-tumor Effects of Polyphenols via Targeting Cancer Driving Signaling Pathways: A Review. Indian J Clin Biochem 2024; 39:470-488. [PMID: 39346722 PMCID: PMC11436542 DOI: 10.1007/s12291-024-01222-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/02/2024] [Indexed: 10/01/2024]
Abstract
The use of drugs in chemotherapy poses numerous side effects. Hence the use of natural substances that can help in the prevention and cure of the disease is a dire necessity. Cancer is a deadly illness and combination of diseases, the menace of which is rising with every passing year. The research community and scientists from all over the world are working towards finding a cure of the disease. The use of polyphenols which are naturally derived from plants have a great potential to be used as anti-cancer drugs and also the use of fruits and vegetables which are rich in these polyphenols can also help in the prevention of diseases. The study aims to compile the available literature and research studies on the anti-cancer effects of polyphenols and the signaling pathways that are affected by them. To review the anti-cancer effects of polyphenols, Google Scholar, PubMed and ScienceDirect were used to study the literature available. The article that have been used for literature review were filtered using keywords including cancer, polyphenols and signaling pathways. Majorly articles from the last 10 years have been considered for the review but relevant articles from earlier than 10 years have also been considered. Almost 400 articles were studied for the review and 200 articles have been cited. The current review shows the potential of polyphenols as anti-cancer compounds and how the consumption of a diet rich in polyphenols can help in the prevention of cancer. Because of their capacity to affect a variety of oncogenic and oncosuppressive signaling pathways, phytochemicals derived from plants have been effectively introduced as an alternative anticarcinogenic medicines. Graphical Abstract
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Affiliation(s)
- Kareena Moar
- Department of Biochemistry, Central University of Haryana, Mahendergarh, 123031 India
| | - Somu Yadav
- Department of Biochemistry, Central University of Haryana, Mahendergarh, 123031 India
| | - Anuja Pant
- Department of Biochemistry, Central University of Haryana, Mahendergarh, 123031 India
| | - Deepika
- Department of Biochemistry, Central University of Haryana, Mahendergarh, 123031 India
| | - Pawan Kumar Maurya
- Department of Biochemistry, Central University of Haryana, Mahendergarh, 123031 India
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Poyraz F, Akbaş G, Duranoğlu D, Acar S, Mansuroğlu B, Ersöz M. Sinapic-Acid-Loaded Nanoparticles Optimized via Experimental Design Methods: Cytotoxic, Antiapoptotoic, Antiproliferative, and Antioxidant Activity. ACS OMEGA 2024; 9:40329-40345. [PMID: 39371991 PMCID: PMC11447863 DOI: 10.1021/acsomega.4c00216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 10/08/2024]
Abstract
Nanoparticles are frequently investigated as carrier systems that increase the biological activities of hydrophobic molecules, especially by providing them with water solubility. Sinapic acid (Sa), commonly found in plants, is a phenolic compound with a wide spectrum of biological activities and extensive pharmacological properties. The aim of this study was the synthesis/characterization of optimized sinapic-acid-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SaNPs) to improve the solubility of sinapic acid (Sa) that limit its use in the biological system and investigate the biological activities of these nanoparticles in the breast cancer cell line. For this purpose, sinapic-acid-loaded PLGA nanoparticles were obtained and optimized by experimental design methods. Then, cytotoxic (MTT method), antiapoptotic (terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay), antiproliferative (immunocytochemically by PCNA assay), and antioxidant activities (superoxide dismutase (SOD) and catalase activities, glutathione, malondialdehyde (MDA), and caspase-3 levels) of optimized nanoparticles were examined comperatively with free drug on MCF-7 cells. The IC50 values of the SaNPs (170.6 ± 3.6 nm size) in MCF-7 cells were determined at 180, 168, and 145 μg/mL for 24, 48, and 72 h, respectively, and at these doses, the nanoparticles did not show any toxic effect on the MCF10A cell line. Treatment of Sa and SaNPs at doses of 24 and 48 h showed a statistically significant reduction in the PCNA level in MCF-7 cells, with an increase in the number of cells leading to apoptosis. In MCF-7 cells treated with SaNP at concentrations of 150 and 200 μg/mL for 24 h, MDA levels were significantly increased, SOD activities were significantly decreased, and reduced glutathione (GSH) and catalase levels were increased compared with control groups. The findings of this study indicate that polyphenolic compounds can contribute to the design of drugs for treatment by forming nanoparticle formulations. The developed nanoparticle formulation is thought to be a useful model for other hydrophobic biological active substances.
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Affiliation(s)
- Fatma
Şayan Poyraz
- Department
of Molecular Biology and Genetics, Faculty of Art and Sciences, Yildiz Technical University, Istanbul 34349, Turkey
| | - Gülşah Akbaş
- Department
of Molecular Biology and Genetics, Faculty of Art and Sciences, Yildiz Technical University, Istanbul 34349, Turkey
| | - Dilek Duranoğlu
- Department
of Chemical Engineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul 34210, Turkey
| | - Serap Acar
- Department
of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul 34220, Turkey
| | - Banu Mansuroğlu
- Department
of Molecular Biology and Genetics, Faculty of Art and Sciences, Yildiz Technical University, Istanbul 34349, Turkey
| | - Melike Ersöz
- Department
of Molecular Biology and Genetics, Faculty of Arts and Sciences, Demiroglu Bilim University, Istanbul 34394, Turkey
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Yasmin-Karim S, Richards G, Fam A, Ogurek AM, Sridhar S, Makrigiorgos GM. Aerosol delivery of immunotherapy and Hesperetin-loaded nanoparticles increases survival in a murine lung cancer model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.30.609714. [PMID: 39253436 PMCID: PMC11383516 DOI: 10.1101/2024.08.30.609714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
Purpose Studies have shown that flavonoids like Hesperetin, an ACE2 receptor agonist with antioxidant and pro-apoptotic activity, can induce apoptosis in cancer cells. ACE2 receptors are abundant in lung cancer cells. Here, we explored the application of Hesperetin bound to PLGA-coated nanoparticles (Hesperetin-nanoparticles, HNPs), and anti-CD40 antibody as an aerosol treatment for lung tumor-bearing mice. Methods In-vitro and in-vivo studies were performed in human A549 (ATCC) and murine LLC1 (ATCC) lung cancer cell lines. Hesperetin Nanoparticles (HNP) of about 60nm diameter were engineered using a nano-formulation microfluidic technique. A syngeneic orthotopic murine model of lung adenoma was generated in wild (+/+) C57/BL6 background mice with luciferase-positive cell line LLC1 cells. Lung tumor-bearing mice were treated via aerosol inhalation with HNP, anti-CD40 antibody, or both. Survival was used to analyze the efficacy of aerosol treatment. Cohorts were also analyzed for body condition score, weight, and liver and kidney function. Results Analysis of an orthotopic murine lung cancer model demonstrates a differential uptake of the HNP and anti-CD40 by cancer cells relative to normal cells. A higher survival rate, relative to untreated controls, was observed when aerosol treatment with HNP was added to treatment via anti-CD40 (p<0.001), as compared to CD40 alone (p<0.01). Moreover, 2 out of 9 tumor-bearing mice survived long term, and their tumors diminished. These 2 mice were shown to be refractory to subsequent development of subcutaneous tumors, indicating systemic resilience to tumor formation. Conclusion We successfully established increased therapeutic efficacy of anti-CD40 and HNP in an orthotopic murine lung cancer model using inhalation-based administration. Our findings open the possibility of improved lung cancer treatment using flavonoids and immuno-adjuvants.
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Ficus dubia latex extract prevent DMH-induced rat early colorectal carcinogenesis through the regulation of xenobiotic metabolism, inflammation, cell proliferation and apoptosis. Sci Rep 2022; 12:15472. [PMID: 36104433 PMCID: PMC9474822 DOI: 10.1038/s41598-022-19843-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 09/05/2022] [Indexed: 12/30/2022] Open
Abstract
Ficus dubia latex is recognized as a remedy in Asian traditional medicine with various therapeutic effects. The present study aimed to determine the preventive action of Ficus dubia latex extract (FDLE) on 1,2-dimethylhydrazine (DMH)-induced rat colorectal carcinogenesis and its mechanisms. The experiment included an initiation model in which rats were orally administered with FDLE daily for 1 week before DMH injection until the end of the experiment, while only after DMH injection until the end in the post-initiation model. The results firstly indicated that FDLE treatment could reduce the level of methylazoxymethanol (MAM) in rat colonic lumen by inhibition of the activities of both phase I xenobiotic metabolizing enzymes in the liver and β-glucuronidase in the colon, leading to reduced DNA methylation in colonic mucosal cells, related to the number of ACF in the initiation stage. Besides, FDLE modulated the inflammation which could suppress the growth and induce apoptosis of aberrant colonic mucosal cells, leading to retardation of ACF multiplicity. Therefore, FDLE showed the ability to suppress the DMH-induced rat ACF formation and inflammation promoted growth of ACF. In conclusion, FDLE had the potential to prevent carcinogens-induced rat colorectal carcinogenesis in the initiation stage.
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Cytotoxic Effect of Puya chilensis Collected in Central Chile. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221091671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
This study sought to evaluate the pharmacological activity of metabolites isolated from the dried and lyophilized ethanol extracts as well as other solvent fractions of the currently endangered Puya chilensis Molina (Chagual) by analyzing their effects on a human hepatocellular carcinoma (HCC) cell line. We identified several active metabolites from Chagual extracts and two, in particular, carnosol, were found in all the prepared fractions. In addition, Chagual exhibited considerable cytotoxicity against the cancer cell line used in this study, with a half-maximal inhibitory concentration (IC50) of 0.44 ± 0.11 and 0.27 ± 0.04 after a 72-hour treatment and, therefore, has the potential for further investigation as a source of candidate therapeutic agents.
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Sohel M, Sultana H, Sultana T, Al Amin M, Aktar S, Ali MC, Rahim ZB, Hossain MA, Al Mamun A, Amin MN, Dash R. Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review. Heliyon 2022; 8:e08815. [PMID: 35128104 PMCID: PMC8810372 DOI: 10.1016/j.heliyon.2022.e08815] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/23/2021] [Accepted: 01/19/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Cancer has become a significant concern in the medical sector with increasing disease complexity. Although some available conventional treatments are still a blessing for cancer patients, short-and long-term adverse effects and poor efficiency make it more difficult to treat cancer patients, demonstrating the need for new potent and selective anticancer drugs. In search of potent anticancer agents, naturally occurring compounds have always been admired due to their structural diversity, where Hesperetin (HSP) may be one of the potent candidates. PURPOSE We aimed to summarize all sources, pharmacological properties, anticancer activities of HSP against numerous cancers types through targeting multiple pathological processes, mechanism of HSP on sensitizing the current anti-cancer agents and other phytochemicals, overcoming resistance pattern and determining absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox). METHODS Information was retrieved from PubMed, Science Direct, and Google Scholar based on some key points like Hesperetin, cancer name, anticancer resistance, nanoformulation, and ADME/Tox was determined by in silico approaches. RESULT HSP is a phytoestrogen present in citrus fruits in a high concentration (several hundred mg/kg) and exhibited anti-cancer activities through interfering at several pathways. HSP can suppress tumor formation by targeting several cellular proteins such as cell cycle regulatory, apoptosis, metastatic, tyrosine kinase, growth factor receptor, estrogen metabolism, and antioxidant-related protein.HSP has shown remarkable synergistic properties in combination therapy and has been reported to overcome multidrug cancer resistance drugs, leading to an improved defensive mechanism. These anticancer activities of HSP may be due to proper structural chemistry. CONCLUSION Overall, HSP showed potential anticancer activities against all cancer and possess better pharmacokinetic properties. So this phytochemical alone or combination with other agents can be an effective alternative drug for cancer treatment.
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Affiliation(s)
- Md Sohel
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Habiba Sultana
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Tayeba Sultana
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Md. Al Amin
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Suraiya Aktar
- Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi, Bangladesh
| | - Md. Chayan Ali
- Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia 7003, Bangladesh
| | - Zahed Bin Rahim
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Md. Arju Hossain
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Abdullah Al Mamun
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Mohammad Nurul Amin
- Department of Pharmacy, Atish Dipankar University of Science and Technology, Dhaka 1230, Bangladesh
- Pratyasha Health Biomedical Research Center, Dhaka 1230 Bangladesh
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
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Sousa C, Duarte D, Silva-Lima B, Videira M. Repurposing Natural Dietary Flavonoids in the Modulation of Cancer Tumorigenesis: Decrypting the Molecular Targets of Naringenin, Hesperetin and Myricetin. Nutr Cancer 2021; 74:1188-1202. [PMID: 34739306 DOI: 10.1080/01635581.2021.1955285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
In the past few years flavonoids have been gaining more attention regarding their (still un) exploited anticancer properties. Flavonoids are natural compounds present in fruits, vegetables, and seeds, meaning that they are already present in the daily life of every person, with a described broad-spectrum of pharmacological activities, including anticancer, anti-inflammatory and antioxidant. In the present review we discuss the anticancer activity of three important flavonoids - myricetin (MYR) (flavanol group), hesperetin (HESP) and naringenin (NAR) (flavanone group). Although some mechanisms underlying their activities remain still unclear, they can act as potential inhibitors of key tumorigenic signaling pathways, such as PI3K/Akt/mTOR, p38 MAPK and NF-κB. Simultaneously, they can reset the levels of pro-apoptotic proteins that belong to the Bcl-2 and caspase family and decrease the intracellular levels of ROS and pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6. Together with their synergetic effect they have the potential to become key elements in the prevention and/or treatment of several types of cancer, with the major improvement to the patient life quality, due to their non-existent toxicity.
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Affiliation(s)
- Carolina Sousa
- Pharmacological and Regulatory Sciences Group (PharmRegSci), Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia da Universidade de Lisboa, Lisboa, Portugal
| | - Denise Duarte
- Pharmacological and Regulatory Sciences Group (PharmRegSci), Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia da Universidade de Lisboa, Lisboa, Portugal
| | - Beatriz Silva-Lima
- Pharmacological and Regulatory Sciences Group (PharmRegSci), Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia da Universidade de Lisboa, Lisboa, Portugal
| | - Mafalda Videira
- Pharmacological and Regulatory Sciences Group (PharmRegSci), Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia da Universidade de Lisboa, Lisboa, Portugal
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Raghavan S, Gurunathan J. Citrus species – a golden treasure box of metabolites that is beneficial against disorders. J Herb Med 2021. [DOI: 10.1016/j.hermed.2021.100438] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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El-Deek SEM, Abd-Elghaffar SKH, Hna RS, Mohamed HG, El-Deek HEM. Effect of Hesperidin against Induced Colon Cancer in Rats: Impact of Smad4 and Activin A Signaling Pathway. Nutr Cancer 2021; 74:697-714. [PMID: 33818196 DOI: 10.1080/01635581.2021.1907424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 08/01/2020] [Accepted: 03/04/2021] [Indexed: 01/10/2023]
Abstract
SCOPE To evaluate the chemopreventive efficacy of hesperidin (Hsd) in 1,2-dimethylhydrazine (DMH)-induced colorectal cancer (CRC) and demonstrate its role in mothers against decapentaplegic homolog 4(Smad4) and activin A signaling pathways. METHODS AND RESULTS A CRC rat model was established by DMH exposure, and the animals were randomly divided into five groups: Control group, Hsd, DMH, DMH + Hsd, and DMH followed by Hsd. The resected colon was subjected to macroscopic, microscopic, molecular, histopathological, and immunohistochemical examination. Activin A, Smad4, malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) levels in tissues were also measured. The DMH group exhibited a significant increase in the gene and protein expression of activin A as well as MDA and NO levels in tissues. There was a significant reduction in the gene and protein expression of Smad4 as well as GSH and SOD levels in tissues. Administration of Hsd significantly upregulated Smad4 and activin A gene expressions in both the DMH + Hsd and DMH followed by Hsd groups. Moreover, Hsd improved the antioxidant status of the former two groups. CONCLUSION This study demonstrated the chemopreventive effect of Hsd against CRC by modulating Smad4 and activin A signaling in vivo. Further studies are needed to demonstrate its clinical value and explore its possible role in advanced malignancy.
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Affiliation(s)
- Sahar E M El-Deek
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Sary K H Abd-Elghaffar
- Pathology and Clinical Pathology Department, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - Randa S Hna
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Heba G Mohamed
- Biochemistry Department, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - Heba E M El-Deek
- Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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12
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Wang SW, Sheng H, Zheng F, Zhang F. Hesperetin promotes DOT1L degradation and reduces histone H3K79 methylation to inhibit gastric cancer metastasis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 84:153499. [PMID: 33667841 DOI: 10.1016/j.phymed.2021.153499] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/07/2021] [Accepted: 02/04/2021] [Indexed: 05/27/2023]
Abstract
BACKGROUND There have been many researches on the effects of flavonoids on tumor treatment or adjuvant therapy, but there are few studies revealing their epigenetic effect on tumors. Hesperetin is a common citrus flavanone widely distributed among citrus fruits. The role of hesperetin in gastric cancer metastasis is unclear. PURPOSE To investigate the effect of hesperetin on gastric cancer metastasis and its underlying mechanism. METHODS We used cancer cell lines cultured in medium and nude mice implantation as in vitro and in vivo models to investigate the impact of hesperetin treatment on the migration and invasion of gastric cancer cells. The molecular biological experiments such as transwell assay, western blotting, qPCR, ChIP-qPCR, immunostaining and transfection were conducted to explore the molecular mechanisms. RESULTS We found that hesperetin obviously reduced the protein abundance of DOT1L and the methylation of histone H3K79 in a variety of cells. In gastric cancer cells, the treatment of hesperetin decreased cell migration and invasion and the expression of genes closely related to the metastatic capability. Mechanistically, hesperetin affected the stability of DOT1L protein by regulating the activity of CBP. CONCLUSION These findings highlight the epigenetic effect of hesperetin and provide a new perspective to understand the tumor suppressive effect of flavonoids.
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Affiliation(s)
- Si-Wei Wang
- Quzhou Hospital, Zhejiang University School of Medicine, Quzhou 324000, China; Department of Core Facility, Quzhou People's Hospital, Quzhou 324000, China
| | - Hao Sheng
- Quzhou Hospital, Zhejiang University School of Medicine, Quzhou 324000, China; Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Fang Zheng
- Department of Core Facility, Quzhou People's Hospital, Quzhou 324000, China
| | - Feng Zhang
- Quzhou Hospital, Zhejiang University School of Medicine, Quzhou 324000, China; Department of Core Facility, Quzhou People's Hospital, Quzhou 324000, China; Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Clinical Laboratory, Quzhou People's Hospital, Quzhou 324000, China.
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A. Attia M, Enan ET, Hashish AA, M. H. El-kannishy S, Gardouh AR, K. Tawfik M, Faisal S, El-Mistekawy A, Salama A, Alomar SY, H. Eltrawy A, Yagub Aloyouni S, Zaitone SA. Chemopreventive Effect of 5-Flurouracil Polymeric Hybrid PLGA-Lecithin Nanoparticles against Colon Dysplasia Model in Mice and Impact on p53 Apoptosis. Biomolecules 2021; 11:biom11010109. [PMID: 33467560 PMCID: PMC7830948 DOI: 10.3390/biom11010109] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023] Open
Abstract
The use of 5-fluorouracil (5FU) is associated with multifaceted challenges and poor pharmacokinetics. Poly(lactic-co-glycolic acid)-lipid hybrid nanoparticles (PLNs)-based therapy has received attention as efficient carriers for a diversity of drugs. This study evaluated the in vivo chemotherapeutic and anti-proliferative efficacy of 5FU-loaded PLNs against 1,2-dimethylhydrazine (Di-MH) prompted colon dysplasia in mice compared to free 5FU. 5FU PLNs were prepared. Male Swiss albino mice were distributed to six experimental groups. Group 1: Saline group. All the other groups were injected weekly with Di-MH [20 mg/kg, s.c.]. Group 2: Di-MH induced colon dysplasia control group. Groups 3 and 4: Di-MH + free 5FU treated group [2.5 and 5 mg/kg]. Groups 5 and 6: Di-MH + 5FU-PLNs treated group [2.5 and 5 mg/kg]. Free 5FU and 5FU-PLNs doses were administered orally, twice weekly. Treatment with 5FU-PLNs induced a higher cytoprotective effect compared to free 5FU as indicated by lower mucosal histopathologic score and reduction in number of Ki-67 immunpositive proliferating nuclei. Additionally, there was significant upregulation of p53 and caspase 3 genes in colon specimens. Our results support the validity of utilizing the PLNs technique to improve the chemopreventive action of 5FU in treating colon cancer.
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Affiliation(s)
- Mohammed A. Attia
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
- Department of Pharmacology, College of Medicine, AlMaarefa University, Riyadh 11597, Saudi Arabia
| | - Eman T. Enan
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
| | - Abdullah A. Hashish
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
- Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Sherif M. H. El-kannishy
- Department of Toxicology, Mansoura Hospital, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Ahmed R. Gardouh
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt;
- Department of Pharmacy, Faculty of Pharmacy, Jadara University, Irbid 21110, Jordan
| | - Mona K. Tawfik
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Correspondence: or (M.K.T.); (S.Y.A.); or (S.A.Z.); Tel.: +20-12-2271-9473 (M.K.T.); +966-05-0076-7717 (S.Y.A.); +20-10-6891-6396 (S.A.Z.)
| | - Salwa Faisal
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Amr El-Mistekawy
- Department of Internal Medicine, Gastroenterology Division, Faculty of Medicine, Al-Azhar University, Cairo 11651, Egypt;
| | - Ayman Salama
- Department of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11751, Egypt
| | - Suliman Y. Alomar
- Doping Research Chair, Department of Zoology, College of Science, King Saud University, Riyadh 11495, Saudi Arabia
- Correspondence: or (M.K.T.); (S.Y.A.); or (S.A.Z.); Tel.: +20-12-2271-9473 (M.K.T.); +966-05-0076-7717 (S.Y.A.); +20-10-6891-6396 (S.A.Z.)
| | - Amira H. Eltrawy
- Department of Anatomy and Embryology, Faculty of Medicine, Alexandria University, Alexandria 22785, Egypt;
| | - Sheka Yagub Aloyouni
- Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, Riyadh 84428, Saudi Arabia;
| | - Sawsan A. Zaitone
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
- Correspondence: or (M.K.T.); (S.Y.A.); or (S.A.Z.); Tel.: +20-12-2271-9473 (M.K.T.); +966-05-0076-7717 (S.Y.A.); +20-10-6891-6396 (S.A.Z.)
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Amin H, Khan A, Makeen HA, Rashid H, Amin I, Masoodi MH, Khan R, Arafah A, Rehman MU. Nanosized delivery systems for plant-derived therapeutic compounds and their synthetic derivative for cancer therapy. PHYTOMEDICINE 2021:655-675. [DOI: 10.1016/b978-0-12-824109-7.00020-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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15
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Ferreira de Oliveira JMP, Santos C, Fernandes E. Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 73:152887. [PMID: 30975541 DOI: 10.1016/j.phymed.2019.152887] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/20/2019] [Accepted: 03/09/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND The ability of cancer cells to divide without restriction and to escape programmed cell death is a feature of the proliferative state. Citrus flavanones are flavonoids with potential multiple anticancer actions, from antioxidant and chemopreventive, to anti-inflammatory, anti-angiogenic, cytostatic and cytotoxic in different cancer models. PURPOSE This review aims to summarize the current knowledge on the antiproliferative actions of the citrus flavanones hesperidin (HSD) and hesperetin (HST), with emphasis on cell cycle arrest and apoptosis. METHODS Cochrane Library, Scopus, Pubmed and Web of Science collection databases were queried for publications reporting antiproliferative effects of HSD and HST in cancer models. RESULTS HSD and HST have been proven to delay cell proliferation in several cancer models. Depending on the compound, dose and cell line studied, different effects have been reported. Cell cycle arrest associated with cytostatic effects has been reported in cells with increased levels of p53 and also cyclin-dependent kinase inhibitors, as well as decreased levels of specific cyclins and cyclin-dependent kinases. Moreover, apoptotic effects have been found to be associated with altered ratios of pro-/antiapoptotic proteins, caspase activation, c-Jun N-terminal kinase (JNK) pathway activation and caspase-independent pathways. CONCLUSION Available scientific literature data indicate complex effects, dependent on cell lines and exposure conditions, suggesting that HSD and HST doses need to be optimized according to the cellular and organismal context. The establishment of the main antiproliferative mechanisms is of utmost importance for a possible therapeutic benefit of citrus flavanones in the context of cancer.
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Affiliation(s)
- José Miguel P Ferreira de Oliveira
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, 4050-313 Porto, Portugal.
| | - Conceição Santos
- Integrated Biology and Biotechnology Laboratory, Department of Biology, Faculty of Sciences, University of Porto, Rua Campo Alegre, 4169-007 Porto, Portugal; LAQV, REQUIMTE, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, 4050-313 Porto, Portugal.
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Venkatachalam K, Vinayagam R, Arokia Vijaya Anand M, Isa NM, Ponnaiyan R. Biochemical and molecular aspects of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis: a review. Toxicol Res (Camb) 2020; 9:2-18. [PMID: 32440334 DOI: 10.1093/toxres/tfaa004] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 01/20/2020] [Accepted: 02/12/2020] [Indexed: 02/07/2023] Open
Abstract
1,2-dimethylhydrazine (DMH) is a member in the class of hydrazines, strong DNA alkylating agent, naturally present in cycads. DMH is widely used as a carcinogen to induce colon cancer in animal models. Exploration of DMH-induced colon carcinogenesis in rodent models provides the knowledge to perceive the biochemical, molecular, and histological mechanisms of different stages of colon carcinogenesis. The procarcinogen DMH, after a series of metabolic reactions, finally reaches the colon, there produces the ultimate carcinogen and reactive oxygen species (ROS), which further alkylate the DNA and initiate the development of colon carcinogenesis. The preneolpastic lesions and histopathological observations of DMH-induced colon tumors may provide typical understanding about the disease in rodents and humans. In addition, this review discusses about the action of biotransformation and antioxidant enzymes involved in DMH intoxication. This understanding is essential to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH-induced animal colon carcinogenesis.
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Affiliation(s)
- Karthikkumar Venkatachalam
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Al Ain-17666, United Arab Emirates
| | - Ramachandran Vinayagam
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore, Tamilnadu 632 115, India
| | | | - Nurulfiza Mat Isa
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, 43400 Seri Kembangan, Selangor, Malaysia
| | - Rajasekar Ponnaiyan
- Department of Zoology, Jamal Mohamed College, Tiruchirappalli, Tamil Nadu 620020, India
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Duran Y, Karaboğa İ. Effect of hesperetin on systemic inflammation and hepatic injury after blunt chest trauma in rats. Biotech Histochem 2019; 95:297-304. [PMID: 31850807 DOI: 10.1080/10520295.2019.1691265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
We investigated the protective effect of hesperetin on hepatic damage after blunt chest trauma in rats using histological and biochemical methods. We used 18 adult male rats in three groups of six: control, chest trauma and chest trauma + hesperetin. Chest trauma was caused by dropping a metal cylinder onto the right hemithorax. Hesperetin, 100 mg/kg, was administered orally for 7 days. At the end of the seventh day, liver tissue samples were obtained. Serum tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), alanine aminotransferase (AST), aspartate transferase (ALT) and lactate dehydrogenase (LDH) enzyme activities were measured in blood samples taken from the heart. The general structure of liver tissue was investigated using hematoxylin and eosin staining. Nuclear factor kappa beta (Nf-κβ) expression in liver tissue was determined by the indirect immunohistochemical method. Apoptosis was determined using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method. Decreased TNF-α, AST and ALT enzyme activity, fewer histopathological changes and lower Nf-kB expression were observed in the hesperetin treated group compared to the chest trauma group. We also found reduced hepatic apoptosis in the chest trauma + hesperetin group compared to the chest trauma group. Hesperetine inhibits liver damage by reducing proinflammatory cytokines and by suppressing Nf-κβ activity in a blunt chest trauma model in rats.
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Affiliation(s)
- Yasin Duran
- Tekirdag Namık Kemal University, Faculty of Medicine, Department of General Surgery, 59030, Tekirdag, Turkey
| | - İhsan Karaboğa
- Tekirdag Namık Kemal University, School of Health, Department of Emergency and Disaster Management, 59030, Tekirdag, Turkey
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Arora I, Sharma M, Tollefsbol TO. Combinatorial Epigenetics Impact of Polyphenols and Phytochemicals in Cancer Prevention and Therapy. Int J Mol Sci 2019; 20:ijms20184567. [PMID: 31540128 PMCID: PMC6769666 DOI: 10.3390/ijms20184567] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/08/2019] [Accepted: 09/11/2019] [Indexed: 12/24/2022] Open
Abstract
Polyphenols are potent micronutrients that can be found in large quantities in various food sources and spices. These compounds, also known as phenolics due to their phenolic structure, play a vital nutrient-based role in the prevention of various diseases such as diabetes, cardiovascular diseases, neurodegenerative diseases, liver disease, and cancers. However, the function of polyphenols in disease prevention and therapy depends on their dietary consumption and biological properties. According to American Cancer Society statistics, there will be an expected rise of 23.6 million new cancer cases by 2030. Due to the severity of the increased risk, it is important to evaluate various preventive measures associated with cancer. Relatively recently, numerous studies have indicated that various dietary polyphenols and phytochemicals possess properties of modifying epigenetic mechanisms that modulate gene expression resulting in regulation of cancer. These polyphenols and phytochemicals, when administrated in a dose-dependent and combinatorial-based manner, can have an enhanced effect on epigenetic changes, which play a crucial role in cancer prevention and therapy. Hence, this review will focus on the mechanisms of combined polyphenols and phytochemicals that can impact various epigenetic modifications such as DNA methylation and histone modifications as well as regulation of non-coding miRNAs expression for treatment and prevention of various types of cancer.
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Affiliation(s)
- Itika Arora
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA.
| | - Manvi Sharma
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA.
| | - Trygve O Tollefsbol
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA.
- Comprehensive Center for Healthy Aging, University of Alabama Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA.
- Comprehensive Cancer Center, University of Alabama Birmingham, 1802 6th Avenue South, Birmingham, AL 35294, USA.
- Nutrition Obesity Research Center, University of Alabama Birmingham, 1675 University Boulevard, Birmingham, AL 35294, USA.
- Comprehensive Diabetes Center, University of Alabama Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
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Kaya S, Albayrak Kaya S, Polat E, Fidanol Erboğa Z, Duran Y, Polat FR, Okuyan HM, Karaboğa İ. Protective effects of hesperetin on lipopolysaccharide-induced acute lung injury in a rat model. TURK GOGUS KALP DAMAR CERRAHISI DERGISI 2019; 28:359-368. [PMID: 32551168 PMCID: PMC7298383 DOI: 10.5606/tgkdc.dergisi.2020.18816] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/22/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND In this experimental study, we aimed to investigate the effects of hesperetin, a natural flavonoid, on a lipopolysaccharideinduced acute lung injury model in rats. METHODS Between March 2019 and May 2019, a total of 18 adult male Wistar albino rats, weighing approximately 250 to 300 g, were randomly divided into three groups as control, lipopolysaccharide, and lipopolysaccharide + hesperetin groups (n=6 in each group). The wet/dry weight ratio of lung tissue was determined. Histopathological changes were examined using light and scanning electron microscopy. Pulmonary nuclear factor-kappa beta, inducible nitric oxide synthase, and alpha-smooth muscle antigen activity were determined with indirect immunohistochemical methods. Pulmonary apoptosis was detected with the terminal deoxynucleotidyl transferase dUTP nick-end labeling method. Tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and interleukin-10 concentrations were measured with enzyme-linked immunosorbent assay. RESULTS Treatment with hesperetin significantly improved the architecture of lung tissue and reduced the wet/dry weight ratio, nuclear factor-kappa beta, inducible nitric oxide synthase, and alphasmooth muscle antigen expression, pulmonary apoptosis, and levels of proinflammatory cytokines. CONCLUSION Our study results suggest that hesperetin has a potent protective effect against lipopolysaccharide-induced acute lung injury in rats via suppression of the proinflammatory cytokine cascade, nuclear factor-kappa beta, signaling pathway activation, and apoptosis.
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Affiliation(s)
- Serkan Kaya
- Department of Thoracic Surgery, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, Turkey
| | - Sinem Albayrak Kaya
- Department of Midwifery, Biruni University, Faculty of Health Sciences, Istanbul, Turkey
| | - Elif Polat
- Department of Histology and Embriology, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, Turkey
| | - Zeynep Fidanol Erboğa
- Department of Histology and Embriology, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, Turkey
| | - Yasin Duran
- Department of General Surgery, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, Turkey
| | - Fatin Rüştü Polat
- Department of General Surgery, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, Turkey
| | - Hamza Malik Okuyan
- Department of Medical Services and Techniquies, Mustafa Kemal University, Hatay Vocational School of Health Sciences, Hatay, Turkey
| | - İhsan Karaboğa
- Department of Emergency and Disaster Medicine, Tekirdağ Namık Kemal University, School of Health, Tekirdağ, Turkey
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Afshari K, Haddadi NS, Haj-Mirzaian A, Farzaei MH, Rohani MM, Akramian F, Naseri R, Sureda A, Ghanaatian N, Abdolghaffari AH. Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies. J Cell Physiol 2019; 234:21519-21546. [PMID: 31087338 DOI: 10.1002/jcp.28777] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/07/2019] [Accepted: 04/11/2019] [Indexed: 12/18/2022]
Abstract
Flavonoids comprise a group of natural polyphenols consisting of more than 5,000 subtypes mostly existing in fruits and vegetables. Flavonoids consumption could potentially attenuate the incidence and recurrence risk of colorectal cancers through their antiperoxidative, antioxidant, and anti-inflammatory effects. In addition, these compounds regulate the mitochondrial function, balance the bacterial flora and promote the apoptosis process in cancerous cells. However, some previous data failed to show the effectiveness of flavonoids in reducing the risk of colorectal cancer. In this study, we have reviewed the efficacy of different flavonoids subtypes on the risk of colon cancer and molecular mechanisms involved in this process in both clinical and animal studies. In addition, we tried to elucidate the potential synergy between these compounds and current colorectal cancer treatments.
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Affiliation(s)
- Khashayar Afshari
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nazgol-Sadat Haddadi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arvin Haj-Mirzaian
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Mojtaba Rohani
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Freshteh Akramian
- Department of Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Rozita Naseri
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands, Palma de Mallorca, Spain.,CIBEROBN (Physiopathology of Obesity and Nutrition, CB12/03/30038), Instituto de Salud Carlos III, Madrid, Spain
| | - Negar Ghanaatian
- Department of Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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21
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Ganaie MA, Al Saeedan A, Madhkali H, Jan BL, Khatlani T, Sheikh IA, Rehman MU, Wani K. Chemopreventive efficacy zingerone (4-[4-hydroxy-3-methylphenyl] butan-2-one) in experimental colon carcinogenesis in Wistar rats. ENVIRONMENTAL TOXICOLOGY 2019; 34:610-625. [PMID: 30720227 DOI: 10.1002/tox.22727] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 01/09/2019] [Accepted: 01/13/2019] [Indexed: 06/09/2023]
Abstract
Colorectal cancer is one of the most common cancers worldwide. Development of naturally occurring inexpensive and safe alternatives can be effective in suppressing colon related proliferations. Zingerone (4-[4-hydroxy-3-methylphenyl] butan-2-one), a polyphenolic alkanone of ginger, has massive pharmacological properties and thus can be used as promising candidate against various ailments. In the current study, we aimed at demonstrating the protective effect of zingerone against experimental colon carcinogenesis and elucidating its possible mechanism by studying inflammatory and Nrf-2 signaling cascade. Four groups of animals (I-IV) were made with six animals each. Group I (control) was given normal saline orally. Group II was given 1,2-dimethylhydrazine (DMH) at the dose rate of 20 mg/kg body weight. Group III and IV were treated with DMH at the dose rate of 20 mg/kg body weight and also received oral treatment of zingerone at a dose rate of 50 and 100 mg/kg body weight, respectively, for first 5 weeks and animals were euthanized after 16 weeks. Our results reveal that DMH treated rats exhibited elevated ROS and MDA levels, increased activity of cytochrome P450 2E1 and serum marker enzyme carcinoembreyonic antigen (CEA), increased no of aberrant crypts of foci (ACF), and elevated expression of inflammatory and proliferative proteins. Nrf-2 was downregulated by DMH treatment. Treatment with zingerone to DMH treated rats, resulted in alterations in the activity of the cytochrome P450 2E1 and CEA. In addition, immunostaining of NF-kB-p65, COX-2, iNOS, and PCNA, Ki-67 was suppressed by zingerone. Furthermore, zingerone administration also attenuated the level of IL-6 and TNF-α and it also helps in preserving mucous layer. Thus, zingerone could be considered as a good chemopreventive agent in experimental model of colon carcinogenesis. Further studies are required to study other pathways involved in colon carcinogenesis and their modulation buy zingerone.
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Affiliation(s)
- Majid Ahmad Ganaie
- Department of Pharmacology, College of Pharmacy, Prince Sattan Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Abdulaziz Al Saeedan
- Department of Pharmacology, College of Pharmacy, Prince Sattan Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Hassan Madhkali
- Department of Pharmacology, College of Pharmacy, Prince Sattan Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Basit Lateef Jan
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Tanvir Khatlani
- Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Ishfaq Ahmad Sheikh
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muneeb U Rehman
- Department of Biochemistry, Govt. Medical College (GMC-Srinagar), Srinagar J&K, India
| | - Khalida Wani
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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22
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Ersoz M, Erdemir A, Duranoglu D, Uzunoglu D, Arasoglu T, Derman S, Mansuroglu B. Comparative evaluation of hesperetin loaded nanoparticles for anticancer activity against C6 glioma cancer cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:319-329. [DOI: 10.1080/21691401.2018.1556213] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Melike Ersoz
- Department of Molecular Biology and Genetics, Faculty of Arts and Science, Istanbul Bilim University, Istanbul, Turkey
| | - Aysegul Erdemir
- Department of Molecular Biology and Genetics, Faculty of Arts and Science, Yildiz Technical University, Istanbul, Turkey
| | - Dilek Duranoglu
- Department of Chemical Engineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Deniz Uzunoglu
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Tulin Arasoglu
- Department of Molecular Biology and Genetics, Faculty of Arts and Science, Yildiz Technical University, Istanbul, Turkey
| | - Serap Derman
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Banu Mansuroglu
- Department of Molecular Biology and Genetics, Faculty of Arts and Science, Yildiz Technical University, Istanbul, Turkey
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Orientin, a flavanoid, mitigates 1, 2 dimethylhydrazine-induced colorectal lesions in Wistar rats fed a high-fat diet. Toxicol Rep 2018; 5:977-987. [PMID: 30319939 PMCID: PMC6180431 DOI: 10.1016/j.toxrep.2018.09.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 09/14/2018] [Accepted: 09/20/2018] [Indexed: 02/01/2023] Open
Abstract
DMH induced preneoplastic lesions in colonic mucosa. Orientin treatment reduced DMH induction of cytochrome P450. Orientin attenuates DMH induced aberrant crypt formation. Orientin suppresses colonic tumor cell proliferation. Orientin, a c- glycosyl flavonoid found copiously in roobios tea and various medicinal plants is well known for its antioxidant, anti-inflammatory, and antitumor effects. The present study aims to investigate the anti-cancer efficacy of orientin on 1,2 dimethyl hydrazine induced colonic aberrant crypt foci (ACF) and cell proliferation in Wistar rats. Rats were randomly divided into six groups and fed with high fat diet. Group 1 left as untreated control. Group 2 administered with DMH (20 mg/kg body weight) for initial 4 weeks and left untreated. Group 3 received orientin (10 mg/kg body weight) alone for the entire period. Group 4 received orientin along with DMH for initial 4 weeks and left untreated; Group 5 administered DMH for initial 4 weeks and treated with orientin for remaining 12 weeks; Group 6 administered DMH and treated with orientin throughout the entire period. Our preclinical findings suggest that the administration of orientin decreases the occurrence of DMH induced colonic polyps and aberrant crypt foci, augments antioxidant defense and altered the activities of drug metabolizing phase I and phase II enzymes in colonic and hepatic tissues and thereby ensuring the detoxification of carcinogen. Furthermore, orientin attenuates the aberrant crypt foci formation and reinstates the DMH induced cell proliferation, as evident from the AgNORs staining of colonic tissues of experimental rats. Thus, our study emphasizes that orientin may prevent DMH induced precancerous lesions and proven to be a potent antioxidant and antiproliferative agent.
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Sassi A, Maatouk M, El gueder D, Bzéouich IM, Abdelkefi-Ben Hatira S, Jemni-Yacoub S, Ghedira K, Chekir-Ghedira L. Chrysin, a natural and biologically active flavonoid suppresses tumor growth of mouse B16F10 melanoma cells: In vitro and In vivo study. Chem Biol Interact 2018; 283:10-19. [DOI: 10.1016/j.cbi.2017.11.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 11/15/2017] [Accepted: 11/26/2017] [Indexed: 01/22/2023]
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Tao J, Li Y, Li S, Li HB. Plant foods for the prevention and management of colon cancer. J Funct Foods 2018. [DOI: 10.1016/j.jff.2017.12.064] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Citrus aurantium Naringenin Prevents Osteosarcoma Progression and Recurrence in the Patients Who Underwent Osteosarcoma Surgery by Improving Antioxidant Capability. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:8713263. [PMID: 29576857 PMCID: PMC5821951 DOI: 10.1155/2018/8713263] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 12/04/2017] [Indexed: 12/11/2022]
Abstract
Citrus aurantium is rich in flavonoids, which may prevent osteosarcoma progression, but its related molecular mechanism remains unclear. Flavonoids were extracted from C. aurantium and purified by reparative HPLC. Each fraction was identified by using electrospray ionisation mass spectrometry (ESI-MS). Three main components (naringin, naringenin, and hesperetin) were isolated from C. aurantium. Naringenin inhibited the growth of MG-63 cells, whereas naringin and hesperetin had no inhibitory function on cell growth. ROS production was increased in naringin- and hesperetin-treated groups after one day of culture while the level was always lowest in the naringenin-treated group after three days of culture. 95 osteosarcoma patients who underwent surgery were assigned into two groups: naringenin group (NG, received 20 mg naringenin daily, n = 47) and control group (CG, received 20 mg placebo daily, n = 48). After an average of two-year follow-up, osteosarcoma volumes were smaller in the NG group than in the CG group (P > 0.01). The rate of osteosarcoma recurrence was also lower in the NG group than in CG group. ROS levels were lower in the NG group than in the CG group. Thus, naringenin from Citrus aurantium inhibits osteosarcoma progression and local recurrence in the patients who underwent osteosarcoma surgery by improving antioxidant capability.
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Polyphenols in Colorectal Cancer: Current State of Knowledge including Clinical Trials and Molecular Mechanism of Action. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4154185. [PMID: 29568751 PMCID: PMC5820674 DOI: 10.1155/2018/4154185] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 11/08/2017] [Accepted: 12/17/2017] [Indexed: 02/08/2023]
Abstract
Polyphenols have been reported to have wide spectrum of biological activities including major impact on initiation, promotion, and progression of cancer by modulating different signalling pathways. Colorectal cancer is the second most major cause of mortality and morbidity among females and the third among males. The objective of this review is to describe the activity of a variety of polyphenols in colorectal cancer in clinical trials, preclinical studies, and primary research. The molecular mechanisms of major polyphenols related to their beneficial effects on colorectal cancer are also addressed. Synthetic modifications and other future directions towards exploiting of natural polyphenols against colorectal cancer are discussed in the last section.
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Thangaraj K, Vaiyapuri M. Orientin, a C-glycosyl dietary flavone, suppresses colonic cell proliferation and mitigates NF-κB mediated inflammatory response in 1,2-dimethylhydrazine induced colorectal carcinogenesis. Biomed Pharmacother 2017; 96:1253-1266. [PMID: 29198745 DOI: 10.1016/j.biopha.2017.11.088] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 11/04/2017] [Accepted: 11/17/2017] [Indexed: 02/07/2023] Open
Abstract
Orientin, a C-glycosyl dietary flavone profusely found in rooibos tea and passion fruit have gained much attention owing to their multiple pharmacological potentials. The present study intends to investigate the anti-proliferative and anti-inflammatory efficacy of Orientin in 1,2-dimethyl hydrazine (DMH) induced colorectal cancer (CRC) in rats. Animals were arbitrarily segmented into six groups and fed with high-fat diet. Group 1 served as control. Group 2 received weekly subcutaneous injections of DMH (20 mg/kg b.w.), for first 15 weeks. Group 3 administered with Orientin (10 mg/kg b.w., i.p.) whereas Groups 4-6 treated with Orientin in three phases, namely initiation (along with DMH), post-initiation (post-DMH injection) and entire period. Orientin ameliorates tumor marker levels significantly (p < 0.05) and reinstates the histological changes induced by DMH. The proliferative markers (PCNA and Ki67) were observed to be suppressed significantly (p < 0.05) in Orientin treated rats. Orientin abrogates (p < 0.05) the inflammatory mast cells and diminishes the expression of pro-inflammatory NF-κB and cytokines (TNF-α and IL-6). It also down-regulates over expression of inflammatory inducible enzymes (iNOS and COX-2) significantly (p < 0.05) and further substantiated by GLIDE XP and QPLD studies. Overall results promptly elucidate the anti-proliferative and anti-inflammatory efficacy of Orientin against CRC. Orientin can be developed as a promising chemotherapeutic agent, on further validation of other molecular mechanisms.
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Affiliation(s)
- Kalaiyarasu Thangaraj
- Molecular Oncology Lab, Department of Biochemistry, Periyar University, Salem, Tamil Nadu, 636 011, India
| | - Manju Vaiyapuri
- Molecular Oncology Lab, Department of Biochemistry, Periyar University, Salem, Tamil Nadu, 636 011, India.
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Wolfram J, Scott B, Boom K, Shen J, Borsoi C, Suri K, Grande R, Fresta M, Celia C, Zhao Y, Shen H, Ferrari M. Hesperetin Liposomes for Cancer Therapy. Curr Drug Deliv 2017; 13:711-9. [PMID: 26502889 DOI: 10.2174/1567201812666151027142412] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 08/27/2015] [Accepted: 10/26/2015] [Indexed: 12/31/2022]
Abstract
Hesperetin is a compound from citrus fruit that has previously been found to exert anticancer activity through a variety of mechanisms. However, the application of hesperetin to cancer therapy has been hampered by its hydrophobicity, necessitating the use of toxic solubilizing agents. Here, we have developed the first liposome-based delivery system for hesperetin. Liposomes were fabricated using the thin-layer evaporation technique and physical and pharmacological parameters were measured. The liposomes remained stable for prolonged periods of time in serum and under storage conditions, and displayed anticancer efficacy in both H441 lung cancer cells and MDA-MB-231 breast cancer cells. Furthermore, the anticancer activity was not impaired in cells expressing the multidrug resistance protein 1 (MDR-1). In conclusion, the encapsulation of hesperetin in liposomes does not interfere with therapeutic efficacy and provides a biocompatible alternative to toxic solubilizing agents, thereby enabling future clinical use of this compound for cancer therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Mauro Ferrari
- Department of Nanomedicine, Houston Methodist Research Institute, R8460-9, 6670 Bertner Ave, Houston, TX 77030, USA.
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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: 64] [Impact Index Per Article: 7.1] [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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Natural Polyphenols for Prevention and Treatment of Cancer. Nutrients 2016; 8:nu8080515. [PMID: 27556486 PMCID: PMC4997428 DOI: 10.3390/nu8080515] [Citation(s) in RCA: 428] [Impact Index Per Article: 47.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 08/12/2016] [Accepted: 08/12/2016] [Indexed: 02/06/2023] Open
Abstract
There is much epidemiological evidence that a diet rich in fruits and vegetables could lower the risk of certain cancers. The effect has been attributed, in part, to natural polyphenols. Besides, numerous studies have demonstrated that natural polyphenols could be used for the prevention and treatment of cancer. Potential mechanisms included antioxidant, anti-inflammation as well as the modulation of multiple molecular events involved in carcinogenesis. The current review summarized the anticancer efficacy of major polyphenol classes (flavonoids, phenolic acids, lignans and stilbenes) and discussed the potential mechanisms of action, which were based on epidemiological, in vitro, in vivo and clinical studies within the past five years.
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Abstract
Citrus aurantifolia (family: Rutaceae) is mainly used in daily consumption, in many cultural cuisines, and in juice production. It is widely used because of its antibacterial, anticancer, antidiabetic, antifungal, anti-hypertensive, anti-inflammation, anti-lipidemia, and antioxidant properties; moreover, it can protect heart, liver, bone, and prevent urinary diseases. Its secondary metabolites are alkaloids, carotenoids, coumarins, essential oils, flavonoids, phenolic acids, and triterpenoids. The other important constituents are apigenin, hesperetin, kaempferol, limonoids, quercetin, naringenin, nobiletin, and rutin, all of these contribute to its remedial properties. The scientific searching platforms were used for publications from 1990 to present. The abstracts and titles were screened, and the full-text articles were selected. The present review is up-to-date of the phytochemical property of C. aurantifolia to provide a reference for further study.
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Affiliation(s)
- Nithithep Narang
- Mahidol University International College, Mahidol University, Salaya Campus, Nakhon Pathom 73170, Thailand
| | - Wannee Jiraungkoorskul
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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Lv X, Zhao S, Ning Z, Zeng H, Shu Y, Tao O, Xiao C, Lu C, Liu Y. Citrus fruits as a treasure trove of active natural metabolites that potentially provide benefits for human health. Chem Cent J 2015; 9:68. [PMID: 26705419 PMCID: PMC4690266 DOI: 10.1186/s13065-015-0145-9] [Citation(s) in RCA: 150] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/25/2015] [Indexed: 02/08/2023] Open
Abstract
Citrus fruits, which are cultivated worldwide, have been recognized as some of the most high-consumption fruits in terms of energy, nutrients and health supplements. What is more, a number of these
fruits have been used as traditional medicinal herbs to cure diseases in several Asian countries. Numerous studies have focused on Citrus secondary metabolites as well as bioactivities and have been intended to develop new chemotherapeutic or complementary medicine in recent decades. Citrus-derived secondary metabolites, including flavonoids, alkaloids, limonoids, coumarins, carotenoids, phenolic acids and essential oils, are of vital importance to human health due to their active properties. These characteristics include anti-oxidative, anti-inflammatory, anti-cancer, as well as cardiovascular protective effects, neuroprotective effects, etc. This review summarizes the global distribution and taxonomy, numerous secondary metabolites and bioactivities of Citrus fruits to provide a reference for further study. Flavonoids as characteristic bioactive metabolites in Citrus fruits are mainly introduced.
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Affiliation(s)
- Xinmiao Lv
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Siyu Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Zhangchi Ning
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Honglian Zeng
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Yisong Shu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Ou Tao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029 China
| | - Cheng Xiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, 100029 China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700 China ; School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, 999077 China
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029 China
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Antiproliferative and antioxidant potential of hesperetin against benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Chem Biol Interact 2015; 242:345-52. [DOI: 10.1016/j.cbi.2015.10.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 10/16/2015] [Accepted: 10/23/2015] [Indexed: 11/22/2022]
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Hesperetin Induces the Apoptosis of Gastric Cancer Cells via Activating Mitochondrial Pathway by Increasing Reactive Oxygen Species. Dig Dis Sci 2015; 60:2985-95. [PMID: 25972151 DOI: 10.1007/s10620-015-3696-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 04/29/2015] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hesperetin, has been shown to exert biological activities on various types of human cancers. However, few related studies on gastric cancer are available. AIM In this study, we sought to investigate the effect of hesperetin on gastric cancer and clarify its specific mechanism. MATERIALS AND METHODS Cell Counting Kit-8, 2',7'-dichlorofluorescin diacetate, JC-1, Hoechst 33258 staining, and western bolt were used to detect cell viability, levels of intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (△ψ m), cell apoptosis, and expressions of mitochondrial pathway proteins, respectively. Meanwhile, xenograft tumor models in nude mice were made to evaluate the effect of hesperetin on gastric cancer in vivo. RESULTS Compared with the control group, the proliferation of gastric cancer cells in hesperetin groups was significantly inhibited (P < 0.05), and dose- and time-dependent effects were observed. Pretreatment with H2O2 (1 mM) or N-acetyl-L-cysteine (5 mM) enhanced or attenuated the hesperetin-induced inhibition of cell viability (P < 0.05). Percentages of apoptotic cells, levels of intracellular ROS, and △ψ m varied with the dose and treatment time of hesperetin (P < 0.05), and hesperetin caused an increase in the levels of AIF, Apaf-1, Cyt C, caspase-3, caspase-9, and Bax and a decrease in Bcl-2 levels (P < 0.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors (P < 0.05). CONCLUSION Our study suggests that hesperetin could inhibit the proliferation and induce the apoptosis of gastric cancer cells via activating the mitochondrial pathway by increasing the ROS.
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Pereira-Caro G, Oliver CM, Weerakkody R, Singh T, Conlon M, Borges G, Sanguansri L, Lockett T, Roberts SA, Crozier A, Augustin MA. Chronic administration of a microencapsulated probiotic enhances the bioavailability of orange juice flavanones in humans. Free Radic Biol Med 2015; 84:206-214. [PMID: 25801290 DOI: 10.1016/j.freeradbiomed.2015.03.010] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 03/04/2015] [Accepted: 03/11/2015] [Indexed: 11/18/2022]
Abstract
Orange juice (OJ) flavanones are bioactive polyphenols that are absorbed principally in the large intestine. Ingestion of probiotics has been associated with favorable changes in the colonic microflora. The present study examined the acute and chronic effects of orally administered Bifidobacterium longum R0175 on the colonic microflora and bioavailability of OJ flavanones in healthy volunteers. In an acute study volunteers drank OJ with and without the microencapsulated probiotic, whereas the chronic effects were examined when OJ was consumed after daily supplementation with the probiotic over 4 weeks. Bioavailability, assessed by 0-24h urinary excretion, was similar when OJ was consumed with and without acute probiotic intake. Hesperetin-O-glucuronides, naringenin-O-glucuronides, and hesperetin-3'-O-sulfate were the main urinary flavanone metabolites. The overall urinary excretion of these metabolites after OJ ingestion and acute probiotic intake corresponded to 22% of intake, whereas excretion of key colon-derived phenolic and aromatic acids was equivalent to 21% of the ingested OJ (poly)phenols. Acute OJ consumption after chronic probiotic intake over 4 weeks resulted in the excretion of 27% of flavanone intake, and excretion of selected phenolic acids also increased significantly to 43% of (poly)phenol intake, corresponding to an overall bioavailability of 70%. Neither the probiotic bacterial profiles of stools nor the stool moisture, weight, pH, or levels of short-chain fatty acids and phenols differed significantly between treatments. These findings highlight the positive effect of chronic, but not acute, intake of microencapsulated B. longum R0175 on the bioavailability of OJ flavanones.
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Affiliation(s)
- Gema Pereira-Caro
- Department of Technology, Postharvest and Food Industry, IFAPA-Alameda del Obispo, Córdoba, Spain
| | | | | | - Tanoj Singh
- CSIRO Food & Nutrition Flagship, Werribee, VIC, Australia
| | - Michael Conlon
- CSIRO Food & Nutrition Flagship, Adelaide, SA, Australia
| | - Gina Borges
- Department of Nutrition, University of California at Davis, Davis, CA 95616, USA
| | - Luz Sanguansri
- CSIRO Food & Nutrition Flagship, Werribee, VIC, Australia
| | - Trevor Lockett
- CSIRO Food & Nutrition Flagship, North Ryde, NSW, Australia
| | - Susan A Roberts
- Global Scientific and Regulatory Affairs, The Coca-Cola Company, Atlanta, GA 30313, USA
| | - Alan Crozier
- Department of Nutrition, University of California at Davis, Davis, CA 95616, USA
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Zhang J, Song J, Wu D, Wang J, Dong W. Hesperetin induces the apoptosis of hepatocellular carcinoma cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species, ATP and calcium. Med Oncol 2015; 32:101. [PMID: 25737432 DOI: 10.1007/s12032-015-0516-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 02/13/2015] [Indexed: 01/08/2023]
Abstract
Hesperetin, a flavonoid from citrus fruits, has been proved to possess biological activity on various types of human cancers. However, few related studies on hepatocellular carcinoma are available. In this study, we aimed to investigate the effect of hesperetin on hepatocellular carcinoma cells in vitro and in vivo and clarify its potentially specific mechanism. Compared with the control group, the proliferations of hepatocellular carcinoma cells in hesperetin groups were significantly inhibited (P < 0.05), and a dose- and time-dependent inhibition of cell viability was observed. When pretreated with H2O2 (1 mM) or N-acetyl-L-cysteine (5 mM), the inhibition of cell viability by hesperetin was enhanced or reduced, respectively (P < 0.05). Similarly, the levels of intracellular ROS, ATP and Ca(2+) changed in different groups (P < 0.05). The results of Hoechst 33258 staining showed that the percentages of apoptotic cells in hesperetin groups are remarkably higher than that in control group (P < 0.05). And the results of Western blot showed that hesperetin caused an increase in the levels of cytosolic AIF, cytosolic Apaf-1, cytosolic Cyt C, caspase-3, caspase-9 and Bax and a decrease in that of Bcl-2, mitochondrial AIF, mitochondrial Apaf-1 and mitochondrial Cyt C (P < 0.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors. Our study suggests that hesperetin could inhibit the proliferation and induce the apoptosis of hepatocellular carcinoma via triggering the activation of the mitochondrial pathway by increasing the levels of intracellular ROS, ATP and Ca(2+).
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Affiliation(s)
- Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
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Kaur J, Kaur G. An insight into the role of citrus bioactives in modulation of colon cancer. J Funct Foods 2015. [DOI: 10.1016/j.jff.2014.12.043] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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Tao L, Yang JK, Gu Y, Zhou X, Zhao AG, Zheng J, Zhu YJ. Weichang’an and 5-fluorouracil suppresses colorectal cancer in a mouse model. World J Gastroenterol 2015; 21:1125-1139. [PMID: 25632185 PMCID: PMC4306156 DOI: 10.3748/wjg.v21.i4.1125] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the effect of Weichang’an (WCA) and 5-fluorouracil (5-FU) on colorectal tumor and hepatic metastasis in a mouse model.
METHODS: Quantitative determination of hesperidin, the effective component in WCA decoction, was performed using HPLC. In vitro cytotoxicity of WCA was determined by treating HCT-116 cells with WCA diluents or serum extracted from rats that received WCA by oral gavage for 1 wk and MTT assays. Forty-eight nude mice received cecum implantation with tumor blocks subcutaneously amplified from human colon cancer cell line HCT-116. Mice were randomly divided into four treatment groups: control (CON), WCA, 5-FU and combination (WCA + 5-FU). Pathological examination of tumors consisted of tissue sectioning and hematoxylin and eosin staining. Tumor weight and size were measured, and the number of metastatic lesions was counted. Serum carcinoembryonic antigen (CEA) level was determined by ELISA. The expression levels of tumor genesis and metastasis-related proteins β-catenin and matrix metalloproteinase (MMP)-7 were measured by real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry and immunoblotting. Cell fractionation was used to investigate intracellular distribution of β-catenin.
RESULTS: Parenchymal tumors were palpable in the abdomens of nude mice 2 wk post-implantation and orthotopic tumor formation rate was 100% in all groups. 5-FU treatment alone significantly decreased tumor weight compared to the CON group (1.203 ± 0.284 g vs 1.804 ± 0.649 g, P < 0.01). WCA treatment alone reduced the rate of metastasis (50% vs 100%, P < 0.05). Combination treatment of WCA + 5-FU was the most effective, reducing the tumor weight (1.140 ± 0.464 g vs 1.804 ± 0.649 g, P < 0.01) and size (1493.438 ± 740.906 mm3vs 2180.259 ± 816.556 mm3, P < 0.05), the rate of metastases (40% vs 100%, P < 0.01), and serum CEA levels (31.263 ± 7.421 μg/L vs 43.040 ± 11.273 μg/L, P < 0.05). Expression of β-catenin and MMP-7 was decreased in drug-treated groups compared to controls, as detected using real-time quantitative RT-PCR, immunohistochemistry and immunoblotting, respectively. Cell fractionation assays revealed that nuclear translocation of β-catenin was reduced by WCA and/or 5-FU treatments.
CONCLUSION: Combination of WCA with 5-FU significantly inhibited colon tumor growth and hepatic metastases. Decreased expression of β-catenin and MMP-7 may be important.
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Wang L, Wang Y, Hu Q, Li S. Systematic analysis of new drug indications by drug-gene-disease coherent subnetworks. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2014; 3:e146. [PMID: 25390685 PMCID: PMC4259999 DOI: 10.1038/psp.2014.44] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 08/30/2014] [Indexed: 01/20/2023]
Abstract
Drug targets and disease genes may work as driver factors at the transcriptional level, which propagate signals through gene regulatory network and cause the downstream genes' differential expression. How to analyze transcriptional response data to identify meaningful gene modules shared by both drugs and diseases is still a critical issue for drug-disease associations and molecular mechanism. In this article, we propose the drug-gene-disease coherent subnetwork concept to group the biological function related drugs, diseases, and genes. It was defined as the subnetwork with drug, gene, and disease as nodes and their interactions coherently crossing three data layers as edges. Integrating differential expression profiles of 418 drugs and 84 diseases, we develop a computational framework and identify 13 coherent subnetworks such as inflammatory bowel disease and melanoma relevant subnetwork. The results demonstrate that our coherent subnetwork approach is able to identify novel drug indications and highlight their molecular basis.
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Affiliation(s)
- L Wang
- 1] School of Computer Science and Information Engineering, Tianjin University of Science and Technology, Tianjin, China [2] Department of Automation, MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST, Tsinghua University, Beijing, China
| | - Y Wang
- Academy of Mathematics and Systems Science, National Center for Mathematics and Interdisciplinary Sciences, Chinese Academy of Sciences, Beijing, China
| | - Q Hu
- School of Computer Science and Technology, Tianjin University, Tianjin, China
| | - S Li
- Department of Automation, MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST, Tsinghua University, Beijing, China
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Nagarajan S, Namasivayam N. Silibinin alleviates hyperlipidaemia, restores mucin content, modulates TGF-β and fosters apoptosis in experimental rat colon carcinogenesis. J Funct Foods 2014. [DOI: 10.1016/j.jff.2014.10.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Vuong QV, Hirun S, Phillips PA, Chuen TLK, Bowyer MC, Goldsmith CD, Scarlett CJ. Fruit-derived phenolic compounds and pancreatic cancer: perspectives from Australian native fruits. JOURNAL OF ETHNOPHARMACOLOGY 2014; 152:227-242. [PMID: 24463158 DOI: 10.1016/j.jep.2013.12.023] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 12/09/2013] [Accepted: 12/11/2013] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pancreatic cancer is a devastating cancer that presents late, is rapidly progressive and has current therapeutics with only limited efficacy. Bioactive compounds are ubiquitously present in fruits and numerous studies in vitro are addressing the activity of these compounds against pancreatic cancer, thus studies of specific bioactive compounds could lead to new anti-pancreatic cancer strategies. Australian native fruits have been used as foods and medicines by Australian Aboriginals for thousands of years, and preliminary studies have found these fruits to contain rich and diversified bioactive components with high antioxidant activity. Thus, Australian native fruits may possess key components for preventing or delaying the onset of tumorigenesis, or for the treatment of existing cancers, including pancreatic cancer. MATERIALS AND METHODS Numerous databases including PubMed, SciFinder, Web of Knowledge, Scopus, and Sciencedirect were analysed for correlations between bioactive components from fruits and pancreatic cancer, as well as studies concerning Australian native fruits. RESULTS In this review, we comprehensively highlight the proposed mechanisms of action of fruit bioactives as anti-cancer agents, update the potential anti-pancreatic cancer activity of various major classes of bioactive compounds derived from fruits, and discuss the existence of bioactive compounds identified from a selection Australian native fruits for future studies. CONCLUSION Bioactive compounds derived from fruits possess the potential for the discovery of new anti-pancreatic cancer strategies. Further, Australian native fruits are rich in polyphenols including some flora that contain unique phenolic compounds, thereby warranting further investigations into their anti-cancer properties.
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Affiliation(s)
- Q V Vuong
- Pancreatic Cancer Research, Nutrition Food & Health Research Group, Australia; School of Environmental and Life Sciences, University of Newcastle, NSW, Australia
| | - S Hirun
- Pancreatic Cancer Research, Nutrition Food & Health Research Group, Australia; School of Environmental and Life Sciences, University of Newcastle, NSW, Australia
| | - P A Phillips
- Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia
| | - T L K Chuen
- Pancreatic Cancer Research, Nutrition Food & Health Research Group, Australia; School of Environmental and Life Sciences, University of Newcastle, NSW, Australia
| | - M C Bowyer
- Pancreatic Cancer Research, Nutrition Food & Health Research Group, Australia; School of Environmental and Life Sciences, University of Newcastle, NSW, Australia
| | - C D Goldsmith
- Pancreatic Cancer Research, Nutrition Food & Health Research Group, Australia; School of Environmental and Life Sciences, University of Newcastle, NSW, Australia
| | - C J Scarlett
- Pancreatic Cancer Research, Nutrition Food & Health Research Group, Australia; School of Environmental and Life Sciences, University of Newcastle, NSW, Australia; Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
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Antiproliferative and apoptotic-inducing potential of ellagic acid against 1,2-dimethyl hydrazine-induced colon tumorigenesis in Wistar rats. Mol Cell Biochem 2013; 388:157-72. [PMID: 24281858 DOI: 10.1007/s11010-013-1907-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 11/15/2013] [Indexed: 02/06/2023]
Abstract
Colon cancer remains one of the major worldwide causes of cancer-related morbidity and mortality in Western countries and is increasingly common in Asia. Ellagic acid (EA), a major component of polyphenol possesses attractive remedial features. The aim of this study is to divulge the potential effect of EA during 1,2-dimethyl hydrazine (DMH)-induced colon cancer in male Wistar albino rats. The rats were segregated into four groups: group I, control rats; group II, rats received EA (60 mg/kg b.wt./day, orally); rats in group III, induced with DMH (20 mg/kg b.wt.) subcutaneously for 15 weeks; DMH-induced group IV rats were initiated with EA treatment. Colon of the rats treated with DMH exhibited higher glycoconjugates and proliferation index such as elevated expressions of argyrophilic nucleolar organizing regions (AgNORs), proliferating cell nuclear antigen (PCNA), cyclin D1, matrix metalloproteins (MMP-2 and -9), and mast cells. DMH induction also increased phase I-metabolizing enzymes with simultaneous decrease in the phase II detoxifying enzymes. In contrast, dietary administration of EA significantly (p < 0.05) down regulated the proliferation index and restored back the levels of biotransformation enzymes. The carcinogenic insult also altered the expression of pro-apoptotic protein p53, whereas dietary EA administration significantly (p < 0.01) up regulates p53 expression to further induce apoptotic pathway. Ultrastructural changes in colon were also in accord with the above aberrations. Overall findings suggested that the suppression of colon cancer by EA in vivo involves inhibition of cell proliferation, activation of apoptosis, and efficient detoxification.
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Romano B, Pagano E, Montanaro V, Fortunato AL, Milic N, Borrelli F. Novel Insights into the Pharmacology of Flavonoids. Phytother Res 2013; 27:1588-96. [DOI: 10.1002/ptr.5023] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 05/15/2013] [Indexed: 01/23/2023]
Affiliation(s)
- Barbara Romano
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
| | - Ester Pagano
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
| | - Vittorino Montanaro
- Department of Pharmacy; University of Naples Federico II; via Pansini 5 80131 Naples Italy
| | - Alfonso L. Fortunato
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
| | - Natasa Milic
- Department of Pharmacy; Faculty of Medicine, University of Novi Sad; Hajduk Veljkova, 3 21000 Novi Sad Serbia
| | - Francesca Borrelli
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
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Kim HY, Jung SK, Byun S, Son JE, Oh MH, Lee J, Kang MJ, Heo YS, Lee KW, Lee HJ. Raf and PI3K are the molecular targets for the anti-metastatic effect of luteolin. Phytother Res 2012; 27:1481-8. [PMID: 23172826 DOI: 10.1002/ptr.4888] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 10/12/2012] [Accepted: 10/22/2012] [Indexed: 01/25/2023]
Abstract
Metastases are the primary cause of human cancer deaths. Luteolin, a naturally occurring phytochemical, has chemopreventive and/or anticancer properties in several cancer cell lines. However, anti-metastatic effects of luteolin in vivo and the underlying molecular mechanisms and target(s) remain unknown. Luteolin suppresses matrix metalloproteinase (MMP)-2 and -9 activities and invasion in murine colorectal cancer CT-26 cells. Western blot and kinase assay data revealed that luteolin inhibited Raf and phosphatidylinositol 3-kinase (PI3K) activities and subsequently attenuated phosphorylation of MEK and Akt. A pull-down assay indicated that luteolin non-competitively bound with ATP to suppress Raf activity and competitively bound with ATP to inhibit PI3K activity. GW5074, a Raf inhibitor, and LY294002, a PI3K inhibitor, inhibited MMP-2 and -9 activities and invasion in CT-26 cells. An in vivo mouse study showed that oral administration (10 or 50 mg/kg) of luteolin significantly inhibited tumor nodules and tumor volume of lung metastasis induced by intravenous injection of CT-26 cells. Luteolin also inhibited MMP-9 expression and activity in CT-26-induced mouse lung tissue. These results suggest that luteolin may have considerable potential for development as an anti-metastatic agent.
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Affiliation(s)
- Ho Young Kim
- WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea; Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
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