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Unal Kocabas G, Kisim Blatti A, Berdeli A, Ozgen AG, Sarer Yurekli B. MAPK pathway and NIS in B-CPAP human papillary thyroid carcinoma cells treated with resveratrol. Pathol Res Pract 2024; 263:155623. [PMID: 39405802 DOI: 10.1016/j.prp.2024.155623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 11/10/2024]
Abstract
BACKGROUND Resveratrol, a herbal phytoalexin, is known to have anti-tumor effects in several tumors including thyroid cancer cells. AIM The aim of this study was to determine the effects of resveratrol on the expression of BRAF, ERK and NIS mRNA levels and protein expression in B-CPAP human thyroid papillary cancer cell line. METHODS B-CPAP cells were treated with resveratrol at concentrations of 10-100 μM for 24-48-72 h. Cell viability was assessed by XTT Cell Proliferation Assay. BRAF, ERK and NIS mRNA levels were evaluated by rt-PCR method. Protein expressions were evaluated by Western Blot method. RESULTS Resveratrol was found to inhibit cell proliferation in a time and dose dependent manner. The IC50 values of resveratrol were 18.7 μM and 56.8 μM after 48 h and 72 h respectively. Resveratrol treatment of B-CPAP cells resulted in up to 1.5-fold reduction in BRAF mRNA and up to 5.5 fold reduction in ERK mRNA levels. NIS mRNA levels showed up to 3-fold increase. Western Blot studies confirmed the rt- PCR results with a decrease in BRAF and ERK, and increase in NIS protein expressions. CONCLUSION This study demonstrated that resveratrol inhibits thyroid papillary carcinoma cell proliferation and reduces poor prognostic BRAF and ERK mRNA and protein expressions, while increasing NIS mRNA and protein expression suggesting a redifferentiating effect. More studies are needed to evaluate resveratrol as a novel therapeutic agent in the treatment of papillary thyroid cancer.
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Affiliation(s)
- Gokcen Unal Kocabas
- Department of Endocrinology and Metabolism, Ege University School of Medicine, Izmir, Turkey.
| | - Asli Kisim Blatti
- Department of Molecular Biology and Genetics,Izmir Institute of Technology, Izmir, Turkey.
| | - Afig Berdeli
- Molecular Medicine Laboratory,Department of Pediatrics,Ege University School of Medicine, Izmir, Turkey.
| | - Ahmet Gokhan Ozgen
- Department of Endocrinology and Metabolism, Ege University School of Medicine, Izmir, Turkey.
| | - Banu Sarer Yurekli
- Department of Endocrinology and Metabolism, Ege University School of Medicine, Izmir, Turkey.
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Mariano N, Wolf H, Vivekanand P. Isoginkgetin exerts apoptotic effects on A375 melanoma cells. MICROPUBLICATION BIOLOGY 2024; 2024:10.17912/micropub.biology.001324. [PMID: 39381637 PMCID: PMC11461025 DOI: 10.17912/micropub.biology.001324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/02/2024] [Accepted: 09/17/2024] [Indexed: 10/10/2024]
Abstract
Many plants produce secondary metabolites, known as flavonoids, which are thought to exhibit anti-cancer properties. Ginkgo biloba , a plant traditionally used in Chinese herbal medicine, is known to produce over 40 different secondary metabolites. Isoginkgetin, a biflavanoid from this species, has been demonstrated to be cytotoxic to different cancer cell lines. In this study, the anti-cancer effects of isoginkgetin were tested on A375 melanoma cells. XTT cell viability analysis revealed that isoginkgetin treatment resulted in a concentration dependent decrease in cell viability. To investigate whether apoptosis was induced in A375 cell treated with isoginkgetin, a western blot analysis was performed to detect PARP cleavage which is indicative of apoptosis. PARP cleavage was detected at all concentrations tested, with more pronounced cleavage observed with increasing isoginkgetin concentrations. To obtain insight into the potential mechanism of isoginkgetin induced apoptosis, we examined the involvement of the MAPK signaling pathway. We detected phosphorylated ERK in A375 cells treated with isoginkgetin which suggests that isoginkgetin might induce apoptosis of A375 cells through activation of the MAPK signaling pathway.
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Affiliation(s)
- Nina Mariano
- Biology Department, Susquehanna University, Selinsgrove, Pennsylvania, United States
| | - Hunter Wolf
- Biology Department, Susquehanna University, Selinsgrove, Pennsylvania, United States
| | - Pavithra Vivekanand
- Biology Department, Susquehanna University, Selinsgrove, Pennsylvania, United States
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Cordella F, Dragone N, D'Orsi R, Saponaro C, Vergara D, Lessi M, Angelici G. A Structure-Activity Relationship Study of Amino Acid Derivatives of Pterostilbene Analogues Toward Human Breast Cancer. ChemMedChem 2024; 19:e202300727. [PMID: 38346281 DOI: 10.1002/cmdc.202300727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/02/2024] [Indexed: 07/16/2024]
Abstract
Pterostilbene is the dimethylated analogue of Resveratrol, a compound with well-known biological activities, such as antioxidant, chemopreventive, anti-diabetic, anti-obesity, and cardioprotective. Despite many studies on the general effect of such polyphenolic molecules and their derivatives, a deep comprehension of their action and systematic structure-activity relationship studies are still rare. Herein, three different analogues of functionalizable Pterostilbene were efficiently synthesized and derivatized with a selected library of antioxidant amino acids, allowing for a highly diversified exploration of the chemical space. The library was analyzed towards cancer cells. Collectively, our data demonstrated the enhanced anti-proliferative activity of Tryptophan-conjugated compounds. In breast cancer cells, the treatment with Tryptophan-conjugated analogues induced the activation of cellular stress pathways, including autophagy signaling.
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Affiliation(s)
- Fabiana Cordella
- Dipartimento di Chimica e Chimica Industriale - Università di Pisa, Via Giuseppe Moruzzi 13, 56124, - Pisa, Italy
| | - Nicola Dragone
- Dipartimento di Chimica e Chimica Industriale - Università di Pisa, Via Giuseppe Moruzzi 13, 56124, - Pisa, Italy
| | - Rosarita D'Orsi
- Dipartimento di Chimica e Chimica Industriale - Università di Pisa, Via Giuseppe Moruzzi 13, 56124, - Pisa, Italy
| | - Concetta Saponaro
- Pathology Department, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy
| | - Daniele Vergara
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DISTEBA)-, Università del Salento Strada prov. Monteroni-Lecce, 73100, - Lecce, Italy
| | - Marco Lessi
- Dipartimento di Chimica e Chimica Industriale - Università di Pisa, Via Giuseppe Moruzzi 13, 56124, - Pisa, Italy
| | - Gaetano Angelici
- Dipartimento di Chimica e Chimica Industriale - Università di Pisa, Via Giuseppe Moruzzi 13, 56124, - Pisa, Italy
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Bhal S, Das B, Sinha S, Das C, Acharya SS, Maji J, Kundu CN. Resveratrol nanoparticles induce apoptosis in oral cancer stem cells by disrupting the interaction between β-catenin and GLI-1 through p53-independent activation of p21. Med Oncol 2024; 41:167. [PMID: 38831079 DOI: 10.1007/s12032-024-02405-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 05/06/2024] [Indexed: 06/05/2024]
Abstract
Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/β-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/β-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53-/-p21+/+, SCC9-PEMT p53+/+p21-/- and SCC9-PEMT p53-/-p21-/-), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the β-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model.
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Affiliation(s)
- Subhasmita Bhal
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Biswajit Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Saptarshi Sinha
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Chinmay Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Sushree Subhadra Acharya
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India
| | - Joydeb Maji
- Department of Botany, Siliguri College, Siliguri, Darjeeling, 734001, West Bengal, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, 751024, Odisha, India.
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Kaczmarzyk I, Nowak-Perlak M, Woźniak M. Promising Approaches in Plant-Based Therapies for Thyroid Cancer: An Overview of In Vitro, In Vivo, and Clinical Trial Studies. Int J Mol Sci 2024; 25:4463. [PMID: 38674046 PMCID: PMC11050626 DOI: 10.3390/ijms25084463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/22/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Thyroid cancer, particularly undifferentiated tumors, poses a significant challenge due to its limited response to standard therapies. The incidence of thyroid cancer, predominantly differentiated carcinomas, is on the rise globally. Anaplastic thyroid carcinoma (ATC), though rare, is highly aggressive and challenging to treat. Therefore, this study aimed to collect data and explore alternative treatments, focusing on the efficacy of photodynamic therapy (PDT) combined with natural compounds as well as the potential role of phytochemicals, including quercetin, kaempferol, apigenin, genistein, daidzein, naringenin, hesperitin, anthocyanidins, epigallocatechin gallate (EGCG), resveratrol, ellagic acid, ferulic acid, caffeic acid, curcumin, saponins, ursolic acid, indole-3-carbinol (I3C), capsaicin, and piperine in thyroid cancer treatment. PDT, utilizing sensitizers activated by tumor-directed light, demonstrates promising specificity compared to traditional treatments. Combining PDT with natural photosensitizers, such as hypericin and genistein, enhances cytotoxicity against thyroid carcinoma cells. This literature review summarizes the current knowledge on phytochemicals and their anti-proliferative effects in in vitro and in vivo studies, emphasizing their effectiveness and mechanism of action as a novel therapeutic approach for thyroid cancers, especially those refractory to standard treatments.
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Affiliation(s)
| | | | - Marta Woźniak
- Department of Clinical and Experimental Pathology, Division of General and Experimental Pathology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.K.); (M.N.-P.)
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Podgrajsek R, Ban Frangez H, Stimpfel M. Molecular Mechanism of Resveratrol and Its Therapeutic Potential on Female Infertility. Int J Mol Sci 2024; 25:3613. [PMID: 38612425 PMCID: PMC11011890 DOI: 10.3390/ijms25073613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/19/2024] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
Resveratrol is a polyphenol present in various plant sources. Studies have reported numerous potential health benefits of resveratrol, exhibiting anti-aging, anti-inflammatory, anti-microbial, and anti-carcinogenic activity. Due to the reported effects, resveratrol is also being tested in reproductive disorders, including female infertility. Numerous cellular, animal, and even human studies were performed with a focus on the effect of resveratrol on female infertility. In this review, we reviewed some of its molecular mechanisms of action and summarized animal and human studies regarding resveratrol and female infertility, with a focus on age-related infertility, polycystic ovary syndrome, and endometriosis.
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Affiliation(s)
- Rebeka Podgrajsek
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
| | - Helena Ban Frangez
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
- Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Martin Stimpfel
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
- Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
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Brockmueller A, Sajeev A, Koklesova L, Samuel SM, Kubatka P, Büsselberg D, Kunnumakkara AB, Shakibaei M. Resveratrol as sensitizer in colorectal cancer plasticity. Cancer Metastasis Rev 2024; 43:55-85. [PMID: 37507626 PMCID: PMC11016130 DOI: 10.1007/s10555-023-10126-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause of cancer deaths worldwide. Chemotherapy as monotherapy can lead to significant side effects and chemoresistance that can be linked to several resistance-activating biological processes, including an increase in inflammation, cellular plasticity, multidrug resistance (MDR), inhibition of the sentinel gene p53, and apoptosis. As a consequence, tumor cells can escape the effectiveness of chemotherapeutic agents. This underscores the need for cross-target therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Resveratrol, a natural polyphenolic phytoalexin found in various fruits and vegetables such as peanuts, berries, and red grapes, is one of the most effective natural chemopreventive agents. Abundant in vitro and in vivo studies have shown that resveratrol, in interaction with standard drugs, is an effective chemosensitizer for CRC cells to chemotherapeutic agents and thus prevents drug resistance by modulating multiple pathways, including transcription factors, epithelial-to-mesenchymal transition-plasticity, proliferation, metastasis, angiogenesis, cell cycle, and apoptosis. The ability of resveratrol to modify multiple subcellular pathways that may suppress cancer cell plasticity and reversal of chemoresistance are critical parameters for understanding its anti-cancer effects. In this review, we focus on the chemosensitizing properties of resveratrol in CRC and, thus, its potential importance as an additive to ongoing treatments.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Lenka Koklesova
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 03601, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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8
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Du Q, Shen W. Research progress of plant-derived natural products in thyroid carcinoma. Front Chem 2024; 11:1279384. [PMID: 38268761 PMCID: PMC10806030 DOI: 10.3389/fchem.2023.1279384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 12/15/2023] [Indexed: 01/26/2024] Open
Abstract
Thyroid carcinoma (TC) is a prevalent malignancy of the endocrine system, with a notable rise in its detection rate in recent decades. The primary therapeutic approaches for TC now encompass thyroidectomy and radioactive iodine therapy, yielding favorable prognoses for the majority of patients. TC survivors may necessitate ongoing surveillance, remedial treatment, and thyroid hormone supplementation, while also enduring the adverse consequences of thyroid hormone fluctuations, surgical complications, or side effects linked to radioactive iodine administration, and encountering enduring physical, psychosocial, and economic hardships. In vitro and in vivo studies of natural products against TC are demonstrating the potential of these natural products as alternatives to the treatment of thyroid cancer. This therapy may offer greater convenience, affordability, and acceptability than traditional therapies. In the early screening of natural products, we mainly use a combination of database prediction and literature search. The pharmacological effects on TC of selected natural products (quercetin, genistein, apigenin, luteolin, chrysin, myricetin, resveratrol, curcumin and nobiletin), which hold promise for therapeutic applications in TC, are reviewed in detail in this article through most of the cell-level evidence, animal-level evidence, and a small amount of human-level evidence. In addition, this article explores possible issues, such as bioavailability, drug safety.
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Affiliation(s)
- Qiujing Du
- The Affiliated Jiangyin People’s Hospital of Nantong University, Jiangyin, China
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Weidong Shen
- The Affiliated Jiangyin People’s Hospital of Nantong University, Jiangyin, China
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Shen H, Zhu R, Liu Y, Hong Y, Ge J, Xuan J, Niu W, Yu X, Qin JJ, Li Q. Radioiodine-refractory differentiated thyroid cancer: Molecular mechanisms and therapeutic strategies for radioiodine resistance. Drug Resist Updat 2024; 72:101013. [PMID: 38041877 DOI: 10.1016/j.drup.2023.101013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 12/04/2023]
Abstract
Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells for iodine uptake. This is usually due to the mutation or rearrangement of genes and the aberrant activation of signal pathways, which result in abnormal expression of thyroid-specific genes, leading to resistance of differentiated thyroid cancer cells to radioiodine therapy. Therefore, inhibiting the proliferation and growth of RAIR-DTC with multikinase inhibitors and other drugs or restoring its differentiation and then carrying out radioiodine therapy have become the first-line treatment strategies and main research directions. The drugs that regulate these kinases or signaling pathways have been studied in clinical and preclinical settings. In this review, we summarized the major gene mutations, gene rearrangements and abnormal activation of signaling pathways that led to radioiodine resistance of RAIR-DTC, as well as the medicine that have been tested in clinical and preclinical trials.
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Affiliation(s)
- Huize Shen
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Rui Zhu
- Department of stomatology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Yanyang Liu
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yangjian Hong
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jiaming Ge
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jie Xuan
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wenyuan Niu
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xuefei Yu
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Jiang-Jiang Qin
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
| | - Qinglin Li
- Zhejiang Cancer Hospital, Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China.
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10
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Macvanin MT, Gluvic Z, Zafirovic S, Gao X, Essack M, Isenovic ER. The protective role of nutritional antioxidants against oxidative stress in thyroid disorders. Front Endocrinol (Lausanne) 2023; 13:1092837. [PMID: 36686463 PMCID: PMC9846570 DOI: 10.3389/fendo.2022.1092837] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/12/2022] [Indexed: 01/06/2023] Open
Abstract
An imbalance between pro-oxidative and antioxidative cellular mechanisms is oxidative stress (OxS) which may be systemic or organ-specific. Although OxS is a consequence of normal body and organ physiology, severely impaired oxidative homeostasis results in DNA hydroxylation, protein denaturation, lipid peroxidation, and apoptosis, ultimately compromising cells' function and viability. The thyroid gland is an organ that exhibits both oxidative and antioxidative processes. In terms of OxS severity, the thyroid gland's response could be physiological (i.e. hormone production and secretion) or pathological (i.e. development of diseases, such as goitre, thyroid cancer, or thyroiditis). Protective nutritional antioxidants may benefit defensive antioxidative systems in resolving pro-oxidative dominance and redox imbalance, preventing or delaying chronic thyroid diseases. This review provides information on nutritional antioxidants and their protective roles against impaired redox homeostasis in various thyroid pathologies. We also review novel findings related to the connection between the thyroid gland and gut microbiome and analyze the effects of probiotics with antioxidant properties on thyroid diseases.
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Affiliation(s)
- Mirjana T. Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Clinic for Internal Medicine, Department of Endocrinology and Diabetes, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Sonja Zafirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Xin Gao
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Magbubah Essack
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Dual Inhibition of BRAF-MAPK and STAT3 Signaling Pathways in Resveratrol-Suppressed Anaplastic Thyroid Cancer Cells with BRAF Mutations. Int J Mol Sci 2022; 23:ijms232214385. [PMID: 36430869 PMCID: PMC9692422 DOI: 10.3390/ijms232214385] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/10/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
Anaplastic thyroid cancer is an extremely lethal malignancy without reliable treatment. BRAFV600E point mutation is common in ATCs, which leads to MAPK signaling activation and is regarded as a therapeutic target. Resveratrol inhibits ATC cell growth, while its impact on BRAF-MAPK signaling remains unknown. This study aims to address this issue by elucidating the statuses of BRAF-MAPK and STAT3 signaling activities in resveratrol-treated THJ-11T, THJ-16T, and THJ-21T ATC cells and Nthyori 3-1 thyroid epithelial cells. RT-PCR and Sanger sequencing revealed MKRN1-BRAF fusion mutation in THJ-16T, BRAF V600E point mutation in THJ-21T, and wild-type BRAF genes in THJ-11T and Nthyori 3-1 cells. Western blotting and immunocytochemical staining showed elevated pBRAF, pMEK, and pERK levels in THJ-16T and THJ-21T, but not in THJ-11T or Nthyori 3-1 cells. Calcein/PI, EdU, and TUNEL assays showed that compared with docetaxel and doxorubicin and MAPK-targeting dabrafenib and trametinib, resveratrol exerted more powerful inhibitory effects on mutant BRAF-harboring THJ-16T and THJ-21T cells, accompanied by reduced levels of MAPK pathway-associated proteins and pSTAT3. Trametinib- and dabrafenib-enhanced STAT3 activation was efficiently suppressed by resveratrol. In conclusion, resveratrol acts as dual BRAF-MAPK and STAT3 signaling inhibitor and a promising agent against ATCs with BRAF mutation.
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12
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Jang JY, Im E, Kim ND. Mechanism of Resveratrol-Induced Programmed Cell Death and New Drug Discovery against Cancer: A Review. Int J Mol Sci 2022; 23:13689. [PMID: 36430164 PMCID: PMC9697740 DOI: 10.3390/ijms232213689] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a polyphenol found in grapes, red wine, peanuts, and apples, has been reported to exhibit a wide range of biological and pharmacological properties. In addition, resveratrol has been reported to intervene in multiple stages of carcinogenesis. It has also been known to kill several human cancer cells through programmed cell death (PCD) mechanisms such as apoptosis, autophagy, and necroptosis. However, resveratrol has limitations in its use as an anticancer agent because it is susceptible to photoisomerization owing to its unstable double bond, short half-life, and is rapidly metabolized and eliminated. Trans-(E)-resveratrol is nontoxic, and has several biological and pharmacological activities. However, little is known about the pharmacological properties of the photoisomerized cis-(Z)-resveratrol. Therefore, many studies on resveratrol derivatives and analogues that can overcome the shortcomings of resveratrol and increase its anticancer activity are underway. This review comprehensively summarizes the literature related to resveratrol-induced PCD, such as apoptosis, autophagy, necroptosis, and the development status of synthetic resveratrol derivatives and analogues as novel anticancer drugs.
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Affiliation(s)
| | | | - Nam Deuk Kim
- Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan 46241, Korea
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13
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Kuo TJ, Jean YH, Shih PC, Cheng SY, Kuo HM, Lee YT, Lai YC, Tseng CC, Chen WF, Wen ZH. Stellettin B-Induced Oral Cancer Cell Death via Endoplasmic Reticulum Stress-Mitochondrial Apoptotic and Autophagic Signaling Pathway. Int J Mol Sci 2022; 23:ijms23158813. [PMID: 35955957 PMCID: PMC9368952 DOI: 10.3390/ijms23158813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/03/2022] [Accepted: 08/05/2022] [Indexed: 12/24/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) affects tens of thousands of people worldwide. Despite advances in cancer treatment, the 5-year survival rate of patients with late-stage OSCC is low at 50–60%. Therefore, the development of anti-OSCC therapy is necessary. We evaluated the effects of marine-derived triterpene stellettin B in human OC2 and SCC4 cells. Stellettin B dose-dependently decreased the viability of both cell lines, with a significant reduction in OC2 cells at ≥0.1 µM at 24 and 48 h, and in SCC4 cells at ≥1 µM at 24 and 48 h. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells were significantly observed at 20 µM of stellettin B at 48 h, with the overexpression of cleaved caspase3 and cleaved poly(ADP-ribose) polymerase (PARP). Moreover, mitochondrial respiratory functions were ablated by stellettin B. Autophagy-related LC3-II/LC3-I ratio and Beclin-1 proteins were increased, whereas p62 was decreased. At 20 µM at 48 h, the expression levels of the endoplasmic reticulum (ER) stress biomarkers calnexin and BiP/GRP78 were significantly increased and mitogen-activated protein kinase (MAPK) signaling pathways were activated. Further investigation using the autophagy inhibitor 3-methyladenine (3-MA) demonstrated that it alleviated stellettin B-induced cell death and autophagy. Overall, our findings show that stellettin B induces the ER stress, mitochondrial stress, apoptosis, and autophagy, causing cell death of OSCC cells.
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Affiliation(s)
- Tsu-Jen Kuo
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Yen-Hsuan Jean
- Section of Orthopedics, Department of Surgery, Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan
| | - Po-Chang Shih
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Shu-Yu Cheng
- Department of Environmental Protection, Green Technology Research Institute, CPC Corporation, No. 2, Zuonan Rd., Nan-Tzu District, Kaohsiung 81126, Taiwan
| | - Hsiao-Mei Kuo
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Yi-Ting Lee
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Yu-Cheng Lai
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Department of Orthopedics, Asia University Hospital, Taichung 41354, Taiwan
| | - Chung-Chih Tseng
- Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Wu-Fu Chen
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Correspondence: (W.-F.C.); (Z.-H.W.)
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Correspondence: (W.-F.C.); (Z.-H.W.)
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14
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Li Y, Zhang J, Zhou H, Du Z. Anticancer effects of natural phytochemicals in anaplastic thyroid cancer (Review). Oncol Rep 2022; 48:156. [PMID: 35856443 PMCID: PMC9471558 DOI: 10.3892/or.2022.8368] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Abstract
Anaplastic thyroid cancer (ATC) is an aggressive and lethal malignancy having a dismal prognosis. Phytochemicals are bioactive components obtained from plants that have been proven useful to treat numerous diseases. Phytochemicals are also an important source of novel anticancer drugs and an important area of research due to the numerous available candidates that can potentially treat cancers. This review discusses naturally occurring phytochemicals and their derivatives that show promising anticancer effects in anaplastic thyroid cancer. Anticancer effects include cell growth inhibition, induction of apoptosis, promoting cell cycle arrest, suppressing angiogenesis, modulating autophagy, and increasing the production of reactive oxygen species. Phytochemicals are not only prospective candidates in the therapy of anaplastic thyroid cancer but also exhibit potential as adjuvants to improve the anticancer effects of other drugs. Although some phytochemicals have excellent anticancer properties, drug resistance observed during the use of resveratrol and artemisinin in different anaplastic thyroid cancer cell lines is still a problem. Anaplastic thyroid cancer cells have several biological, clinical, and drug-resistance features that differ from differentiated thyroid cancer cells. Phytochemicals such as resveratrol and quercetin exhibit different biological effects in anaplastic thyroid cancer and differentiated thyroid cancer. Tumor cells depend on increased aerobic glycolysis by mitochondrial oxidative phosphorylation to provide energy for their rapid growth, invasiveness, and drug resistance. Phytochemicals can alter signaling cascades, modulate the metabolic properties of cancer cells, and influence the mitochondrial membrane potential of anaplastic thyroid cancer cells. These findings enrich our knowledge of the anticancer effects of phytochemicals and highlight alternative therapies to prevent drug resistance in anaplastic thyroid cancer.
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Affiliation(s)
- Yitian Li
- Department of Hygiene, Public Health College, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Jing Zhang
- Department of Hygiene, Public Health College, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Huihui Zhou
- Department of Hygiene, Public Health College, Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Zhen Du
- Department of Hygiene, Public Health College, Jining Medical University, Jining, Shandong 272067, P.R. China
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15
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Resveratrol as a modulatory of apoptosis and autophagy in cancer therapy. Clin Transl Oncol 2022; 24:1219-1230. [PMID: 35038152 DOI: 10.1007/s12094-021-02770-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/24/2021] [Indexed: 12/24/2022]
Abstract
Cancer is one of the leading causes of death, with a heavy socio-economical burden for countries. Despite the great advances that have been made in the treatment of cancer, chemotherapy is still the most common method of treatment. However, many side effects, including hepatotoxicity, renal toxicity, and cardiotoxicity, limit the efficacy of conventional chemotherapy. Over recent years, natural products have attracted attention as therapeutic agents against various diseases, such as cancer. Resveratrol (RES), a natural polyphenol occurring in grapes, nuts, wine, and berries, exhibited potential for preventing and treating various cancer types. RES also ameliorates chemotherapy-induced detrimental effects. Furthermore, RES could modulate apoptosis and autophagy as the main forms of cancer cell deaths by targeting various signaling pathways and up/downregulation of apoptotic and autophagic genes. This review will summarize the anti-cancer effects of RES and focus on the fundamental mechanisms and targets for modulating apoptosis and autophagy by RES.
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Almatroodi SA, A. Alsahli M, S. M. Aljohani A, Alhumaydhi FA, Babiker AY, Khan AA, Rahmani AH. Potential Therapeutic Targets of Resveratrol, a Plant Polyphenol, and Its Role in the Therapy of Various Types of Cancer. Molecules 2022; 27:2665. [PMID: 35566016 PMCID: PMC9101422 DOI: 10.3390/molecules27092665] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 12/17/2022] Open
Abstract
Cancer is among the most prominent causes of mortality worldwide. Different cancer therapy modes employed, including chemotherapy and radiotherapy, have been reported to be significant in cancer management, but the side effects associated with these treatment strategies are still a health problem. Therefore, alternative anticancer drugs based on medicinal plants or their active compounds have been generating attention because of their less serious side effects. Medicinal plants are an excellent source of phytochemicals that have been recognized to have health-prompting effects through modulating cell signaling pathways. Resveratrol is a well-known polyphenolic molecule with antioxidant, anti-inflammatory, and health-prompting effects among which its anticancer role has been best defined. Additionally, this polyphenol has confirmed its role in cancer management because it activates tumor suppressor genes, suppresses cell proliferation, induces apoptosis, inhibits angiogenesis, and modulates several other cell signaling molecules. The anticancer potential of resveratrol is recognized in numerous in vivo and in vitro studies. Previous experimental data suggested that resveratrol may be valuable in cancer management or improve the efficacy of drugs when given with anticancer drugs. This review emphasizes the potential role of resveratrol as an anticancer drug by modulating numerous cells signaling pathways in different types of cancer.
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Affiliation(s)
- Saleh A. Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Mohammed A. Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Abdullah S. M. Aljohani
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia;
| | - Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Ali Yousif Babiker
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
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17
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Marques MA, de Andrade GC, Silva JL, de Oliveira GAP. Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53. Front Mol Biosci 2022; 9:944955. [PMID: 36090037 PMCID: PMC9452956 DOI: 10.3389/fmolb.2022.944955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/18/2022] [Indexed: 12/30/2022] Open
Abstract
The p53 protein is a pleiotropic regulator working as a tumor suppressor and as an oncogene. Depending on the cellular insult and the mutational status, p53 may trigger opposing activities such as cell death or survival, senescence and cell cycle arrest or proliferative signals, antioxidant or prooxidant activation, glycolysis, or oxidative phosphorylation, among others. By augmenting or repressing specific target genes or directly interacting with cellular partners, p53 accomplishes a particular set of activities. The mechanism in which p53 is activated depends on increased stability through post-translational modifications (PTMs) and the formation of higher-order structures (HOS). The intricate cell death and metabolic p53 response are reviewed in light of gaining stability via PTM and HOS formation in health and disease.
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Affiliation(s)
- Mayra A. Marques
- *Correspondence: Mayra A. Marques, ; Guilherme A. P. de Oliveira,
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18
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Đuričić I, Todorović V, Dabetić N, Zrnić-Cirić M, Ivanović N, Vidović B. Dietary factors and thyroid dysfunction. ARHIV ZA FARMACIJU 2022. [DOI: 10.5937/arhfarm72-39624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Besides iodine deficiency, autoimmune Hashimoto thyroiditis is the leading cause of hypothyroidism globally, characterized by the increased titer of thyroid autoantibodies and destruction of thyroid cells. Graves' disease is the most common etiology of hyperthyroidism worldwide. Patients with thyroid dysfunction often require dietary modifications. Popular interventions include supplementation with certain vitamins and minerals, as well as trace elements such as iodine and selenium. The intake of food containing goitrogens should be limited. Goitrogens are substances of plant origin that interfere with the production of thyroid hormones, increasing the risk for goiter and hypothyroidism. The primary dietary sources of goitrogens are cruciferous vegetables, soy products, starchy plants, and some fruits. Beyond essential nutrients, there has been an increasing interest in using specific nutraceuticals, including myoinositol, Lcarnitine, melatonin, and resveratrol, as potential preventive and therapeutic agents in thyroid diseases. Even though current evidence promotes some beneficial outcomes of these nutraceuticals, further investigations are needed to clarify dose-dependent effects, duration of supplementation, combination in different clinical settings, and the exact mechanism of their action in thyroid disorders.
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19
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Mierziak J, Kostyn K, Boba A, Czemplik M, Kulma A, Wojtasik W. Influence of the Bioactive Diet Components on the Gene Expression Regulation. Nutrients 2021; 13:3673. [PMID: 34835928 PMCID: PMC8619229 DOI: 10.3390/nu13113673] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Diet bioactive components, in the concept of nutrigenetics and nutrigenomics, consist of food constituents, which can transfer information from the external environment and influence gene expression in the cell and thus the function of the whole organism. It is crucial to regard food not only as the source of energy and basic nutriments, crucial for living and organism development, but also as the factor influencing health/disease, biochemical mechanisms, and activation of biochemical pathways. Bioactive components of the diet regulate gene expression through changes in the chromatin structure (including DNA methylation and histone modification), non-coding RNA, activation of transcription factors by signalling cascades, or direct ligand binding to the nuclear receptors. Analysis of interactions between diet components and human genome structure and gene activity is a modern approach that will help to better understand these relations and will allow designing dietary guidances, which can help maintain good health.
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Affiliation(s)
- Justyna Mierziak
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Kamil Kostyn
- Department of Genetics, Plant Breeding & Seed Production, Faculty of Life Sciences and Technology, Wroclaw University of Environmental and Life Sciences, pl. Grunwaldzki 24A, 50-363 Wroclaw, Poland;
| | - Aleksandra Boba
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Magdalena Czemplik
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Anna Kulma
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Wioleta Wojtasik
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
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20
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Zhou Y, Li X, Morita Y, Hachimura S, Miyakawa T, Takahashi S, Tanokura M. Identification of the Effects of Chondroitin Sulfate on Inhibiting CDKs in Colorectal Cancer Based on Bioinformatic Analysis and Experimental Validation. Front Oncol 2021; 11:705939. [PMID: 34595111 PMCID: PMC8477652 DOI: 10.3389/fonc.2021.705939] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/23/2021] [Indexed: 11/18/2022] Open
Abstract
With a high occurrence rate and high mortality, the treatment of colorectal cancer (CRC) is increasingly attracting the attention of scholars. Hub genes that determine the phenotypes of CRC become essential for targeted therapy. In the present study, the importance of cyclin-dependent kinases (CDKs) on the occurrence of CRC was identified by data mining of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The results showed that the gene expression levels of CDK1, CDK4, and CDK6 were obviously changed in different stages of CRC. Among the CDKs, CDK4 was suggested as an independent risk factor for CRC based on Cox analysis. Furthermore, chondroitin sulfate (CS), a kind of dietary supplement to treat osteoarthritis, was predicted to treat CRC based on its chemical structure and GEO datasets. Cell assay experiments with the human CRC cell line HCT-116 also verified this prediction. CS inhibited the gene and protein expression levels of CDKs and increased the ratios of apoptotic or dead HCT-116 cells by regulating mitogen-activated protein (MAP) kinase pathways. Our data highlight the essential roles of CDKs in CRC carcinogenesis and the effects of CS on treating CRC, both of which will contribute to the future CRC treatment.
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Affiliation(s)
- Yingyu Zhou
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Xuyang Li
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yuki Morita
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Department of Research, Medical Viara, Tokyo, Japan
- Department of Research, MAF Clinic, Tokyo, Japan
| | - Satoshi Hachimura
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Takuya Miyakawa
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Sachiko Takahashi
- Department of Research, Medical Viara, Tokyo, Japan
- Department of Research, MAF Clinic, Tokyo, Japan
| | - Masaru Tanokura
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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21
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Akter R, Rahman MH, Kaushik D, Mittal V, Uivarosan D, Nechifor AC, Behl T, Karthika C, Stoicescu M, Munteanu MA, Bustea C, Bungau S. Chemo-Preventive Action of Resveratrol: Suppression of p53-A Molecular Targeting Approach. Molecules 2021; 26:molecules26175325. [PMID: 34500758 PMCID: PMC8433711 DOI: 10.3390/molecules26175325] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 12/17/2022] Open
Abstract
Extensive experimental, clinical, and epidemiological evidence has explained and proven that products of natural origin are significantly important in preventing and/or ameliorating various disorders, including different types of cancer that researchers are extremely focused on. Among these studies on natural active substances, one can distinguish the emphasis on resveratrol and its properties, especially the potential anticancer role. Resveratrol is a natural product proven for its therapeutic activity, with remarkable anti-inflammatory properties. Various other benefits/actions have also been reported, such as cardioprotective, anti-ageing, antioxidant, etc. and its rapid digestion/absorption as well. This review aims to collect and present the latest published studies on resveratrol and its impact on cancer prevention, molecular signals (especially p53 protein participation), and its therapeutic prospects. The most recent information regarding the healing action of resveratrol is presented and concentrated to create an updated database focused on this topic presented above.
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Affiliation(s)
- Rokeya Akter
- Department of Pharmacy, Jagannath University, Sadarghat, Dhaka 1100, Bangladesh;
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
| | - Md. Habibur Rahman
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
- Department of Pharmacy, Southeast University, Banani, Dhaka 1213, Bangladesh
- Correspondence: (M.H.R.); (S.B.)
| | - Deepak Kaushik
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, India; (D.K.); (V.M.)
| | - Vineet Mittal
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, India; (D.K.); (V.M.)
| | - Diana Uivarosan
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Aurelia Cristina Nechifor
- Analytical Chemistry and Environmental Engineering Department, Polytechnic University of Bucharest, 011061 Bucharest, Romania;
| | - Tapan Behl
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India;
| | - Chenmala Karthika
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty 643001, India;
| | - Manuela Stoicescu
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (M.S.); (M.A.M.); (C.B.)
| | - Mihai Alexandru Munteanu
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (M.S.); (M.A.M.); (C.B.)
| | - Cristiana Bustea
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (M.S.); (M.A.M.); (C.B.)
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
- Correspondence: (M.H.R.); (S.B.)
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22
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Cyclometalated Ru(II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling. J Biol Inorg Chem 2021; 26:793-808. [PMID: 34459988 DOI: 10.1007/s00775-021-01894-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/17/2021] [Indexed: 10/20/2022]
Abstract
Two new cyclometalated Ru(II)-β-carboline complexes, [Ru(dmb)2(Cl-Ph-βC)](PF6) (dmb = 4,4'-dimethyl-2,2'-bipyridine; Cl-Ph-βC = Cl-phenyl-9H-pyrido[3,4-b]indole; RuβC-3) and [Ru(bpy)2(Cl-Ph-βC)](PF6) (bpy = 2,2'-bipyridine; RuβC-4) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC50 values of 3.2 ± 0.4 μM (RuβC-3) and 4.1 ± 0.6 μM (RuβC-4), which were considerably lower than that of non-cyclometalated Ru(II)-β-carboline complex [Ru(bpy)2(1-Py-βC)] (PF6)2 (61.2 ± 3.9 μM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RuβC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RuβC-3-induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RuβC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs.
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23
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NELL2 modulates cell proliferation and apoptosis via ERK pathway in the development of benign prostatic hyperplasia. Clin Sci (Lond) 2021; 135:1591-1608. [PMID: 34195782 DOI: 10.1042/cs20210476] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/16/2021] [Accepted: 06/28/2021] [Indexed: 01/01/2023]
Abstract
Benign prostatic hyperplasia (BPH) is a quite common illness but its etiology and mechanism remain unclear. Neural epidermal growth factor-like like 2 (NELL2) plays multifunctional roles in neural cell growth and is strongly linked to the urinary tract disease. Current study aims to determine the expression, functional activities and underlying mechanism of NELL2 in BPH. Human prostate cell lines and tissues from normal human and BPH patients were utilized. Immunohistochemical staining, immunofluorescent staining, RT-polymerase chain reaction (PCR) and Western blotting were performed. We further generated cell models with NELL2 silenced or overexpressed. Subsequently, proliferation, cycle, and apoptosis of prostate cells were determined by cell counting kit-8 (CCK-8) assay and flow cytometry analysis. The epithelial-mesenchymal transition (EMT) and fibrosis process were also analyzed. Our study revealed that NELL2 was up-regulated in BPH samples and localized in the stroma and the epithelium compartments of human prostate tissues. NELL2 deficiency induced a mitochondria-dependent cell apoptosis, and inhibited cell proliferation via phosphorylating extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Additionally, suppression of ERK1/2 with U0126 incubation could significantly reverse NELL2 deficiency triggered cell apoptosis. Consistently, overexpression of NELL2 promoted cell proliferation and inhibited cell apoptosis. However, NELL2 interference was observed no effect on EMT and fibrosis process. Our novel data demonstrated that up-regulation of NELL2 in the enlarged prostate could contribute to the development of BPH through enhancing cell proliferation and inhibited a mitochondria-dependent cell apoptosis via the ERK pathway. The NELL2-ERK system might represent an important target to facilitate the development of future therapeutic approaches in BPH.
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Yu P, Wang L, Tang F, Guo S, Liao H, Fan C, Yang Q. Resveratrol-mediated neurorestoration after cerebral ischemic injury - Sonic Hedgehog signaling pathway. Life Sci 2021; 280:119715. [PMID: 34116113 DOI: 10.1016/j.lfs.2021.119715] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 05/11/2021] [Accepted: 05/22/2021] [Indexed: 11/16/2022]
Abstract
AIMS Resveratrol pretreatment can decrease ischemic cerebral injury and enhance proliferation of neural stem cells via mediation of Sonic Hedgehog signaling. However, it is relatively little known about whether neurorestorative effects of resveratrol are mediated by Shh signaling in ischemic cerebral injury. The present study tests whether the Shh signaling pathway mediates resveratrol to promote neurorestoration of ischemic cerebral injury. MATERIALS AND METHODS Rats or neurons before middle cerebral artery occlusion/reperfusion (MCAO/R) or oxygen-glucose deprivation/reoxygenation (OGD/R) injury were pretreated with resveratrol. Immunohistochemistry is used to be determined BrdU+/DCX+, BrdU+/Nestin+ and BrdU+/NG2+ cell (markers of new proliferated neural stem/progenitor and oligodendrocyte precursor cell, respectively), BrdU+/MAP2+ and BrdU+/CNPase+ cell (markers of new mature neuron and oligodendrocyte, respectively), BrdU+/TUNEL+ cell (marker of apoptosis for new proliferated cell), SY, NF200, Iba-1 and GFAP (markers of synaptogenesis, axon, microglia and astrocyte, respectively). Shh and Gli-1 mRNAs were detected by RT-PCR assay. Iba-1, GFAP, Shh and Gli-1 proteins were detected by Western blot. KEY FINDINGS Resveratrol pretreatment significantly reduced neurological deficit scores, promoted proliferation, differentiation, migration and survival of neural stem/progenitor and oligodendrocyte precursor cells, inhibited astrocyte and microglia activation, strengthened synaptophysin and NF200 expression, at the same time, promoted neurite outgrowth of neurons. Meanwhile, expression levels of Shh and Gli-1 proteins were significantly increased and Gli-1 translocated into the nucleus. However, cyclopamine, a Smo inhibitor, canceled the above effects of resveratrol. CONCLUSIONS It may be mediated, at least partly, by the Shh signaling pathway that resveratrol pretreament promote neurorestoration of ischemic cerebral injury.
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Affiliation(s)
- Pingping Yu
- Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Physical Examination Center, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Wang
- Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fanren Tang
- Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuang Guo
- Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongyan Liao
- Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Cengceng Fan
- Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qin Yang
- Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Toupchian O, Abdollahi S, Salehi-Abargouei A, Heshmati J, Clark CCT, Sheikhha MH, Fallahzadeh H, Mozaffari-Khosravi H. The effects of resveratrol supplementation on PPARα, p16, p53, p21 gene expressions, and sCD163/sTWEAK ratio in patients with type 2 diabetes mellitus: A double-blind controlled randomized trial. Phytother Res 2021; 35:3205-3213. [PMID: 33580595 DOI: 10.1002/ptr.7031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 12/15/2022]
Abstract
The present study sought to evaluate the effect of resveratrol supplementation on mRNA expression levels of peroxisome proliferator-activated receptor alpha (PPARα), p53, p21, p16, and serum levels of cluster of differentiation 163 (CD163) to TNF-like weak inducer of apoptosis (TWEAK) ratio in patients with type 2 diabetes. In this double-blind randomized controlled trial, 71 patients were randomly assigned to receive either 1,000 mg of trans-resveratrol or placebo (methyl cellulose) for 8 weeks. Expression levels of genes of interest, and serum levels of sCD163 and sTWEAK were assessed at baseline and at the end of the study. Resveratrol supplementation significantly increased mRNA expression levels of p53 and p21 genes, compared with the placebo group (fold change of p53 = 1.29, p = .04; fold change of p21 = 1.46, p = .006). However, no significant effect on expression levels of PPARα and p16 genes was observed after supplementation. In addition, resveratrol significantly reduced serum levels of sCD163/sTWEAK ratio compared with the placebo group (p = .003). Resveratrol supplementation resulted in significant changes in p53 and p21 genes expression, while serum levels of sCD163/sTWEAK ratio also improved in the resveratrol group, without any significant change in adjusted sCD163 levels. More research is needed to confirm the beneficial effects of resveratrol for patients with diabetes.
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Affiliation(s)
- Omid Toupchian
- Department of Nutrition and Public Health, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Shima Abdollahi
- Department of Nutrition and Public Health, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran.,Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Amin Salehi-Abargouei
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Javad Heshmati
- Department of Nutritional Science, School of Nutritional Science and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Cain C T Clark
- Centre for Intelligent Healthcare, Coventry University, Coventry, UK
| | - Mohammad Hasan Sheikhha
- Department of Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Yazd Clinical and Research Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Fallahzadeh
- Department of Biostatistics and Epidemiology, Research Center of Prevention and Epidemiology of Non-Communicable Disease, School of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hassan Mozaffari-Khosravi
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Kolahi M, Saremi S, Tabandeh M, Hashemitabar M. Induction of apoptosis and suppression of Ras gene expression in MCF human breast cancer cells. J Cancer Res Ther 2021; 18:1052-1060. [DOI: 10.4103/jcrt.jcrt_624_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Yang F, Zhang J, Li B, Zhao Z, Liu Y, Zhao Z, Jing S, Wang G. Identification of Potential lncRNAs and miRNAs as Diagnostic Biomarkers for Papillary Thyroid Carcinoma Based on Machine Learning. Int J Endocrinol 2021; 2021:3984463. [PMID: 34335744 PMCID: PMC8318749 DOI: 10.1155/2021/3984463] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/06/2021] [Accepted: 07/12/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Papillary thyroid carcinoma (PTC) accounts for most of the proportion of thyroid cancer (TC). The objective of this study was to identify diagnostic, differentially expressed long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), contributing to understanding the epigenetics mechanism of PTC. METHODS The data of lncRNA, miRNA, and mRNA were downloaded from the Cancer Genome Atlas (TCGA) dataset, followed by functional analysis of differentially expressed mRNAs. Optimal diagnostic lncRNA and miRNA biomarkers were identified via random forest. The regulatory network between optimal diagnostic lncRNA and mRNAs and optimal diagnostic miRNA and mRNAs was identified, followed by the construction of ceRNA network of lncRNA-mRNA-miRNA. Expression validation and diagnostic analysis of lncRNAs, miRNAs, and mRNAs were performed. Overexpression of ADD3-AS1 was performed in PTC-UC3 cell lines, and cell proliferation and invasion assay were used for investigating the role of ADD3-AS1 in PTC. RESULTS A total of 107 differentially expressed lncRNAs, 81 differentially expressed miRNAs, and 515 differentially expressed mRNAs were identified. 11 lncRNAs and 6 miRNAs were regarded as the optimal diagnostic biomarkers for PTC. The epigenetic modifications via the above diagnostic lncRNAs and miRNAs were identified, including MIR181A2HG-FOXP2-hsa-miR-146b-3p, BLACAT1/ST7-AS1-RPS6KA5-hsa-miR-34a-5p, LBX2-AS1/MIR100HG-CDHR3-hsa-miR-34a-5p, ADD3-AS1-PTPRE-hsa-miR-9-5p, ADD3-AS1-TGFBR1-hsa-miR-214-3p, LINC00506-MMRN1-hsa-miR-4709-3p, and LOC339059-STK32A-hsa-miR-199b-5p. In the functional analysis, MMRN1 and TGFBR1 were involved in cell adhesion and endothelial cell migration, respectively. Overexpression of ADD3-AS1 inhibited cell growth and invasion in PTC cell lines. CONCLUSION The identified lncRNAs/miRNAs/mRNA were differentially expressed between normal and cancerous tissues. In addition, identified altered lncRNAs and miRNAs may be potential diagnostic biomarkers for PTC. Additionally, epigenetic modifications via the above lncRNAs and miRNAs may be involved in tumorigenesis of PTC.
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Affiliation(s)
- Fei Yang
- Department of Otolaryngology-Head and Neck Surgery, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Jie Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Baokun Li
- General Surgical Department, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Zhijun Zhao
- Department of Otolaryngology-Head and Neck Surgery, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Yan Liu
- Department of Otolaryngology-Head and Neck Surgery, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Zhen Zhao
- Department of Otolaryngology-Head and Neck Surgery, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Shanghua Jing
- Department of Otolaryngology-Head and Neck Surgery, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Guiying Wang
- General Surgical Department, The Fourth Hospital of Hebei Medical University, Hebei, China
- General Surgical Department, The Third Hospital of Hebei Medical University, Hebei, China
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Benedetti F, Sorrenti V, Buriani A, Fortinguerra S, Scapagnini G, Zella D. Resveratrol, Rapamycin and Metformin as Modulators of Antiviral Pathways. Viruses 2020; 12:v12121458. [PMID: 33348714 PMCID: PMC7766714 DOI: 10.3390/v12121458] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
Balanced nutrition and appropriate dietary interventions are fundamental in the prevention and management of viral infections. Additionally, accurate modulation of the inflammatory response is necessary to achieve an adequate antiviral immune response. Many studies, both in vitro with mammalian cells and in vivo with small animal models, have highlighted the antiviral properties of resveratrol, rapamycin and metformin. The current review outlines the mechanisms of action of these three important compounds on the cellular pathways involved with viral replication and the mechanisms of virus-related diseases, as well as the current status of their clinical use.
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Affiliation(s)
- Francesca Benedetti
- Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Vincenzo Sorrenti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy;
- Bendessere™ Study Center, Via Prima Strada 23/3, 35129 Padova, Italy
- Maria Paola Belloni Center for Personalized Medicine, Data Medica Group (Synlab Limited), 35100 Padova, Italy;
| | - Alessandro Buriani
- Maria Paola Belloni Center for Personalized Medicine, Data Medica Group (Synlab Limited), 35100 Padova, Italy;
| | | | - Giovanni Scapagnini
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
- Correspondence: (G.S.); (D.Z.)
| | - Davide Zella
- Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Correspondence: (G.S.); (D.Z.)
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Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway. Molecules 2020; 25:molecules25204619. [PMID: 33050597 PMCID: PMC7587212 DOI: 10.3390/molecules25204619] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 12/19/2022] Open
Abstract
Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1).
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Song Y, Sun X, Duan F, He C, Wu J, Huang X, Xing K, Sun S, Wang R, Xie F, Mao Y, Wang J, Li S. SYPL1 Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma via Suppression of ROS-Induced ERK Activation. Front Oncol 2020; 10:1482. [PMID: 33042794 PMCID: PMC7522464 DOI: 10.3389/fonc.2020.01482] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/10/2020] [Indexed: 12/19/2022] Open
Abstract
Synaptophysin-like 1 (SYPL1) is a neuroendocrine-related protein. The role of SYPL1 in pancreatic ductal adenocarcinoma (PDAC) and the underlying molecular mechanism remain unclarified. Here, after analyzing five datasets (GSE15471, GSE16515, GSE28735, TCGA, and PACA-AU) and 78 PDAC patients from Sun Yat-sen University Cancer Center, we demonstrated that SYPL1 was upregulated in PDAC and that a high level of SYPL1 indicated poor prognosis. Bioinformatics analysis implied that SYPL1 was related to cell proliferation and cell death. To validate these findings, gain-of-function and loss-of-function experiments were carried out, and we found that SYPL1 promoted cell proliferation in vitro and in vivo and that it protected cells from apoptosis. Mechanistic studies revealed that sustained extracellular-regulated protein kinase (ERK) activation was responsible for the cell death resulting from knockdown of SYPL1. In addition, bioinformatics analysis showed that the expression of SYPL1 positively correlated with antioxidant activity. Reactive oxygen species (ROS) were upregulated in cells with SYPL1 knockdown and vice versa. Upregulated ROS led to ERK activation and cell death. These results suggest that SYPL1 plays a vital role in PDAC and promotes cancer cell survival by suppressing ROS-induced ERK activation.
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Affiliation(s)
- Yunda Song
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xuesong Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fangting Duan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chaobin He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiali Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Kaili Xing
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuxin Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ruiqi Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fengxiao Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yize Mao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shengping Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
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Davis PJ, Lin HY, Hercbergs A, Mousa SA. Actions of L-thyroxine (T4) and Tetraiodothyroacetic Acid (Tetrac) on Gene Expression in Thyroid Cancer Cells. Genes (Basel) 2020; 11:genes11070755. [PMID: 32645835 PMCID: PMC7396989 DOI: 10.3390/genes11070755] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/26/2020] [Accepted: 07/01/2020] [Indexed: 12/19/2022] Open
Abstract
The clinical behavior of thyroid cancers is seen to reflect inherent transcriptional activities of mutated genes and trophic effects on tumors of circulating pituitary thyrotropin (TSH). The thyroid hormone, L-thyroxine (T4), has been shown to stimulate proliferation of a large number of different forms of cancer. This activity of T4 is mediated by a cell surface receptor on the extracellular domain of integrin αvβ3. In this brief review, we describe what is known about T4 as a circulating trophic factor for differentiated (papillary and follicular) thyroid cancers. Given T4′s cancer-stimulating activity in differentiated thyroid cancers, it was not surprising to find that genomic actions of T4 were anti-apoptotic. Transduction of the T4-generated signal at the integrin primarily involved mitogen-activated protein kinase (MAPK). In thyroid C cell-origin medullary carcinoma of the thyroid (MTC), effects of thyroid hormone analogues, such as tetraiodothyroacetic acid (tetrac), include pro-angiogenic and apoptosis-linked genes. Tetrac is an inhibitor of the actions of T4 at αvβ3, and it is assumed, but not yet proved, that the anti-angiogenic and pro-apoptotic actions of tetrac in MTC cells are matched by T4 effects that are pro-angiogenic and anti-apoptotic. We also note that papillary thyroid carcinoma cells may express the leptin receptor, and circulating leptin from adipocytes may stimulate tumor cell proliferation. Transcription was stimulated by leptin in anaplastic, papillary, and follicular carcinomas of genes involved in invasion, such as matrix metalloproteinases (MMPs). In summary, thyroid hormone analogues may act at their receptor on integrin αvβ3 in a variety of types of thyroid cancer to modulate transcription of genes relevant to tumor invasiveness, apoptosis, and angiogenesis. These effects are independent of TSH.
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Affiliation(s)
- Paul J. Davis
- Department of Medicine, Albany Medical College, Albany, NY 12208, USA
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA;
- Correspondence:
| | - Hung-Yun Lin
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Aleck Hercbergs
- Department of Radiation Oncology, The Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA;
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Sharifi-Rad J, Rajabi S, Martorell M, López MD, Toro MT, Barollo S, Armanini D, Fokou PVT, Zagotto G, Ribaudo G, Pezzani R. Plant natural products with anti-thyroid cancer activity. Fitoterapia 2020; 146:104640. [PMID: 32474055 DOI: 10.1016/j.fitote.2020.104640] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/25/2020] [Accepted: 05/25/2020] [Indexed: 12/11/2022]
Abstract
Thyroid cancer is the most frequent endocrine malignancy, with more than 500,000 cases per year worldwide. Differentiated thyroid cancers are the most common forms with best prognosis, while poorly/undifferentiated ones are rare (2% of all thyroid cancer), aggressive, frequently metastasize and have a worse prognosis. For aggressive, metastatic and advanced thyroid cancer novel antitumor molecules are urgently needed and phytochemical products can be a rational and extensive source, since secondary plant metabolites can guarantee the necessary biochemical variability for therapeutic purpose. Among bioactive molecules that present biological activity on thyroid cancer, resveratrol, curcumin, isoflavones, glucosinolates are the most common and used in experimental model. Most of them have been studied both in vitro and in vivo on this cancer, but rarely in clinical trial. This review summarizes phytochemicals, phytotherapeutics and plant derived compounds used in thyroid cancer.
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Affiliation(s)
- Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Sadegh Rajabi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepcion, Concepcion, Chile; Centre for Healthy Living, University of Concepción, Concepción, Chile; Unidad de Desarrollo Tecnológico, Universidad de Concepción UDT, Concepcion, Chile.
| | - Maria Dolores López
- Department of Plant Production, Faculty of Agronomy, Universidad de Concepción, Avenida Vicente Mendez, 595, Chillán 3812120, Chile
| | - María Trinidad Toro
- Department of Plant Production, Faculty of Agronomy, Universidad de Concepción, Avenida Vicente Mendez, 595, Chillán 3812120, Chile.
| | - Susi Barollo
- Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via Ospedale 105, 35128 Padova, Italy
| | - Decio Armanini
- Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via Ospedale 105, 35128 Padova, Italy
| | | | - Giuseppe Zagotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy.
| | - Giovanni Ribaudo
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - Raffaele Pezzani
- Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via Ospedale 105, 35128 Padova, Italy; AIROB, Associazione Italiana per la Ricerca Oncologica di Base, Padova, Italy.
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Paunkov A, Chartoumpekis DV, Ziros PG, Chondrogianni N, Kensler TW, Sykiotis GP. Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway. Curr Pharm Des 2020; 25:1828-1846. [PMID: 31267862 DOI: 10.2174/1381612825666190701165821] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 06/20/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Natural compounds with potential antioxidant properties have been used in the form of food supplements or extracts with the intent to prevent or treat various diseases. Many of these compounds can activate the cytoprotective Nrf2 pathway. Besides, some of them are known to impact the thyroid gland, often with potential side-effects, but in other instances, with potential utility in the treatment of thyroid disorders. OBJECTIVE In view of recent data regarding the multiple roles of Nrf2 in the thyroid, this review summarizes the current bibliography on natural compounds that can have an effect on thyroid gland physiology and pathophysiology, and it discusses the potential implication of the Nrf2 system in the respective mechanisms. METHODS & RESULTS Literature searches for articles from 1950 to 2018 were performed in PubMed and Google Scholar using relevant keywords about phytochemicals, Nrf2 and thyroid. Natural substances were categorized into phenolic compounds, sulfur-containing compounds, quinones, terpenoids, or under the general category of plant extracts. For individual compounds in each category, respective data were summarized, as derived from in vitro (cell lines), preclinical (animal models) and clinical studies. The main emerging themes were as follows: phenolic compounds often showed potential to affect the production of thyroid hormones; sulfur-containing compounds impacted the pathogenesis of goiter and the proliferation of thyroid cancer cells; while quinones and terpenoids modified Nrf2 signaling in thyroid cell lines. CONCLUSION Natural compounds that modify the activity of the Nrf2 pathway should be evaluated carefully, not only for their potential to be used as therapeutic agents for thyroid disorders, but also for their thyroidal safety when used for the prevention and treatment of non-thyroidal diseases.
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Affiliation(s)
- Ana Paunkov
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
| | - Dionysios V Chartoumpekis
- Department of Internal Medicine, Endocrinology Unit, Patras University Medical School, Patras, Greece
| | - Panos G Ziros
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
| | - Niki Chondrogianni
- Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Thomas W Kensler
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Gerasimos P Sykiotis
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
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Abstract
Fruits come in a wide variety of colors, shapes, and flavors. This chapter will cover selected fruits that are known to be healthy and highly nutritious. These fruits were chosen due to their common usage and availability. Since it is not possible to cover all health benefits or essential nutrients and important phytochemicals of the fruit composition, this chapter will focus on the key valuable constituents and their potential health effects.
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Affiliation(s)
- Sawsan G Mohammed
- Qatar Research Leadership Program (QRLP), Qatar Foundation, Doha, Qatar.
| | - M Walid Qoronfleh
- Research & Policy Department, World Innovation Summit for Health (WISH), Qatar Foundation, Doha, Qatar.
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Oxidative Stress-Induced DNA Damage and Apoptosis in Clove Buds-Treated MCF-7 Cells. Biomolecules 2020; 10:biom10010139. [PMID: 31947708 PMCID: PMC7022383 DOI: 10.3390/biom10010139] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/10/2020] [Accepted: 01/12/2020] [Indexed: 02/07/2023] Open
Abstract
In recent decades, several spices have been studied for their potential in the prevention and treatment of cancer. It is documented that spices have antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. The main mechanisms of spices action included apoptosis induction, proliferation, migration and invasion of tumour inhibition, and sensitization of tumours to radiotherapy and chemotherapy. In this study, the ability of clove buds extract (CBE) to induce oxidative stress, DNA damage, and stress/survival/apoptotic pathways modulation were analysed in MCF-7 cells. We demonstrated that CBE treatment induced intrinsic caspase-dependent cell death associated with increased oxidative stress mediated by oxygen and nitrogen radicals. We showed also the CBE-mediated release of mitochondrial pro-apoptotic factors, signalling of oxidative stress-mediated DNA damage with modulation of cell antioxidant SOD (superoxide dismutase) system, and modulation activity of the Akt, p38 MAPK, JNK and Erk 1/2 pathways.
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Polyphenols: Major regulators of key components of DNA damage response in cancer. DNA Repair (Amst) 2019; 82:102679. [PMID: 31450085 DOI: 10.1016/j.dnarep.2019.102679] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 07/27/2019] [Accepted: 07/27/2019] [Indexed: 02/06/2023]
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Benvenga S, Feldt-Rasmussen U, Bonofiglio D, Asamoah E. Nutraceutical Supplements in the Thyroid Setting: Health Benefits beyond Basic Nutrition. Nutrients 2019; 11:E2214. [PMID: 31540254 PMCID: PMC6770945 DOI: 10.3390/nu11092214] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/03/2019] [Accepted: 09/09/2019] [Indexed: 12/13/2022] Open
Abstract
In recent years, there has been a growing interest in nutraceuticals, which may be considered as an efficient, preventive, and therapeutic tool in facing different pathological conditions, including thyroid diseases. Although iodine remains the major nutrient required for the functioning of the thyroid gland, other dietary components play important roles in clinical thyroidology-these include selenium, l-carnitine, myo-inositol, melatonin, and resveratrol-some of which have antioxidant properties. The main concern regarding the appropriate and effective use of nutraceuticals in prevention and treatment is due to the lack of clinical data supporting their efficacy. Another limitation is the discrepancy between the concentration claimed by the label and the real concentration. This paper provides a detailed critical review on the health benefits, beyond basic nutrition, of some popular nutraceutical supplements, with a special focus on their effects on thyroid pathophysiology and aims to distinguish between the truths and myths surrounding the clinical use of such nutraceuticals.
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Affiliation(s)
- Salvatore Benvenga
- Department of Clinical and Experimental Medicine-Endocrinology, University of Messina, via Consolare Valeria-Gazzi, 98125 Messina, Italy.
- Master Program on Childhood, Adolescent and Women's Endocrine Health, University of Messina, via Consolare Valeria-Gazzi, 98125 Messina, Italy.
- Interdepartmental Program on Molecular and Clinical Endocrinology and Women's Endocrine Health, AOU Policlinico G. Martino, via Consolare Valeria-Gazzi, 98125 Messina, Italy.
| | - Ulla Feldt-Rasmussen
- Medical Endocrinology and Metabolism PE 2132, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
| | - Ernest Asamoah
- Community Physicians Network, Diabetes & Endocrinology Care, 8435 Clearvista Place, Suite 101, Indianapolis, IN 46256, USA.
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Liu Z, Wu X, Lv J, Sun H, Zhou F. Resveratrol induces p53 in colorectal cancer through SET7/9. Oncol Lett 2019; 17:3783-3789. [PMID: 30881498 PMCID: PMC6403518 DOI: 10.3892/ol.2019.10034] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 09/04/2018] [Indexed: 12/26/2022] Open
Abstract
Resveratrol is one of the most promising phytoalexins for use as an anti-cancer agent, which is present in the skin of red grapes and berries. Resveratrol has been demonstrated to modulate a number of signalling pathways that are involved in carcinogenesis. In the present study, the function of resveratrol as a pro-apoptotic agent in colorectal cancer cell lines, including HCT116, CO115 and SW48, was investigated. The results revealed that resveratrol supressed cell viability. Additionally, resveratrol enhanced the expression of tumour protein p53 (p53) and p53 target genes, including Bcl2 associated X, apoptosis regulator and Bcl2 binding component 3 that have a pivotal role in p53-dependent apoptosis. Furthermore, treating cells with resveratrol upregulated SET domain containing lysine methyltransferase 7/9 (SET7/9) expression, which positively regulates p53 through its mono-methylation at lysine 372, compared with untreated cells. Furthermore, treating cells with resveratrol induced the expression of apoptotic markers including cleaved caspase-3 and poly (ADP-ribose) polymerases (PARP) compared with untreated cells. However, the genetic knockdown of SET7/9 by short hairpin RNA attenuated the resveratrol-driven overexpression of p53, cleaved caspase-3 and PARP. Collectively, these results reveal the molecular mechanisms by which resveratrol induces p53 stability in colon cancer that results in the activation of p53-mediated apoptosis.
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Affiliation(s)
- Zhonglun Liu
- Department of Clinical Laboratory, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, P.R. China
| | - Xiaohong Wu
- Department of General Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, P.R. China
| | - Jingjing Lv
- Department of Clinical Comprehensive Experiment Centre, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Hui Sun
- Department of Clinical Comprehensive Experiment Centre, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Feiqin Zhou
- Department of Medical Examination Centre, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, P.R. China
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Antitumor Effect of Various Phytochemicals on Diverse Types of Thyroid Cancers. Nutrients 2019; 11:nu11010125. [PMID: 30634497 PMCID: PMC6356543 DOI: 10.3390/nu11010125] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/24/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022] Open
Abstract
Thyroid cancers developed from the tissues of the thyroid gland are classified into papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic thyroid cancer (ATC). Although thyroid cancers have been generally known as mild forms of cancer, undifferentiated MTC and ATC have a more unfavorable prognosis than differentiated PTC and FTC because they are more aggressive and early metastatic. A variety of therapies such as surgery, radiotherapy, and chemotherapy have been currently used to treat thyroid cancer, but they still have limitations including drug resistance or unfavorable side effects. Phytochemicals are plant-derived chemicals having various physiological activities that are expected to be effective in cancer treatment. In this review, anticancer efficacy of phytochemicals, such as resveratrol, genistein, curcumin, and other substances in each type of thyroid cancer was introduced with their chemopreventive mechanisms. English articles related with thyroid cancer and anti-thyroid cancer of phytochemicals were searched from PubMed and Google Scholar. This article mainly focused on in vitro or animal studies on phytochemicals with anti-thyroid cancer activity. These various phytochemicals have been shown to induce apoptosis in all types of thyroid cancer cells, inhibit cell proliferation and invasion, and to be helpful in enhancing the effect of radioiodine therapy that is a typical therapy to thyroid cancer. These results suggest that thyroid cancer can be more effectively treated by the combinations of phytochemicals and the existing therapies or substances.
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Rehman A, Noreen A, Aftab S, Shakoori A. Antiproliferative effect of oxidative stress induced by tellurite in breast carcinoma cells. JOURNAL OF CANCER RESEARCH AND PRACTICE 2019. [DOI: 10.4103/jcrp.jcrp_5_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Sun C, Li C, Li X, Zhu Y, Su Z, Wang X, He Q, Zheng G, Feng B. Scutellarin induces apoptosis and autophagy in NSCLC cells through ERK1/2 and AKT Signaling Pathways in vitro and in vivo. J Cancer 2018; 9:3247-3256. [PMID: 30271483 PMCID: PMC6160677 DOI: 10.7150/jca.25921] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 08/13/2018] [Indexed: 12/23/2022] Open
Abstract
Curative molecular therapy for non-small cell lung cancer (NSCLC) is still lacking. Scutellarin, an active flavone extracted from Erigeron breviscapus Hand-Mazz, displays anti-tumor property in diverse cancer types, yet its tumor-suppressive effect on NSCLC is not reported. In this study, we found that scutellarin significantly inhibited the proliferation of NSCLC cells, induced cell apoptosis, and triggered autophagy. Notably, inhibition of autophagy with inhibitor HCQ attenuated the anti-proliferative activity of scutellarin, indicating that scutellarin-induced autophagy is antineoplastic. In addition, HCQ treatment reduced scutellarin-induced apoptosis. Further study demonstrated that scutellarin stimulated phosphorylation of ERK1/2, and inhibition of ERK1/2 with inhibitor U0126 markedly attenuated scutellarin-induced autophagy. Similarly, scutellarin downregulated the expression of p-AKT, and AKT inhibitor MK-2206 induced autophagy. Moreover, there also existed crosstalk between ERK and AKT pathways. Finally, in vivo xenograft nude mice experiment proved that scutellarin treatment significantly reduced tumor growth and increased the levels of LC3-II and p-ERK1/2, suppressed p-AKT in mice tumors. Thus, our study for the first time uncovered the anti-cancer function of scutellarin on NSCLC cells, and might provide a potential novel therapy for treatment of patients with NSCLC.
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Affiliation(s)
- ChaoYue Sun
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - CaiYun Li
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - XiaoFeng Li
- Clinical Medical College of Acupuncture and Rehabilitation, Guangzhou University of Chinese Medicine, no 232, Waihuandong Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China
| | - Ying Zhu
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - ZuQing Su
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - XieQi Wang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - QingLian He
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - GuangJuan Zheng
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Bing Feng
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
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Vanacore D, Messina G, Lama S, Bitti G, Ambrosio P, Tenore G, Messina A, Monda V, Zappavigna S, Boccellino M, Novellino E, Monda M, Stiuso P. Effect of restriction vegan diet's on muscle mass, oxidative status, and myocytes differentiation: A pilot study. J Cell Physiol 2018; 233:9345-9353. [PMID: 29319158 DOI: 10.1002/jcp.26427] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 01/05/2018] [Indexed: 01/17/2023]
Abstract
This study was conceived to evaluate the effects of three different diets on body composition, metabolic parameters, and serum oxidative status. We enrolled three groups of healthy men (omnivores, vegetarians, and vegans) with similar age, weight and BMI, and we observed a significant decrease in muscle mass index and lean body mass in vegan compared to vegetarian and omnivore groups, and higher serum homocysteine levels in vegetarians and vegans compared to omnivores. We studied whether serum from omnivore, vegetarian, and vegan subjects affected oxidative stress, growth and differentiation of both cardiomyoblast cell line H9c2 and H-H9c2 (H9c2 treated with H2 O2 to induce oxidative damage). We demonstrated that vegan sera treatment of both H9c2 and H-H9c2 cells induced an increase of TBARS values and cell death and a decrease of free NO2- compared to vegetarian and omnivorous sera. Afterwards, we investigated the protective effects of vegan, vegetarian, and omnivore sera on the morphological changes induced by H2 O2 in H9c2 cell line. We showed that the omnivorous sera had major antioxidant and differentiation properties compared to vegetarian and vegan sera. Finally, we evaluated the influence of the three different groups of sera on MAPKs pathway and our data suggested that ERK expression increased in H-H9c2 cells treated with vegetarian and vegan sera and could promote cell death. The results obtained in this study demonstrated that restrictive vegan diet could not prevent the onset of metabolic and cardiovascular diseases nor protect by oxidative damage.
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Affiliation(s)
- Daniela Vanacore
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giovanni Messina
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Stefania Lama
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Bitti
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pasqualina Ambrosio
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giancarlo Tenore
- Department of Pharmacy, University of Naples "Federico II", Napoli, Italy
| | - Antonietta Messina
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetic and Sport Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Vincenzo Monda
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetic and Sport Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Silvia Zappavigna
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Mariarosaria Boccellino
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ettore Novellino
- Department of Pharmacy, University of Naples "Federico II", Napoli, Italy
| | - Marcellino Monda
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetic and Sport Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Paola Stiuso
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Naples, Italy
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Pan J, Zhang L, Xu S, Cheng X, Yu H, Bao J, Lu R. Induction of Apoptosis in Human Papillary-Thyroid-Carcinoma BCPAP Cells by Diallyl Trisulfide through Activation of the MAPK Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:5871-5878. [PMID: 29786427 DOI: 10.1021/acs.jafc.8b02243] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
This study aimed to elucidate the potential effects of diallyl trisulfide (DATS) on human papillary-thyroid-carcinoma BCPAP cells and its underlying mechanisms. DATS is an organosulfur compound derived from garlic. In this study, we demonstrated that compared with the solvent control, DATS treatment at concentrations of 5, 10, and 20 μΜ decreased cell survival rates of BCPAP cells to 84.51 ± 2.67, 57.16 ± 1.18, and 41.22 ± 1.19% respectively. DATS also caused cell-cycle arrest at G0/G1 phase, and the proportion of cells arrested in G0/G1 phase rose from 68.8 ± 8.38 to 80.4 ± 8.38%, which eventually resulted in cell apoptosis through a mitochondrial apoptotic pathway in BCPAP cells. Further evidence showed that DATS activated ERK, JNK, and p38, members of the MAPK family. Moreover, ERK and JNK inhibitors partially reversed apoptosis in BCPAP cells induced by DATS treatment. Taken together, our results demonstrated that DATS exerted an apoptosis-inducing effect on papillary-thyroid-cancer cells via activation of the MAPK signaling pathway, which shed light on a prospective therapeutic target for thyroid-cancer treatment.
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Affiliation(s)
- Jie Pan
- School of Food Science and Technology , Jiangnan University , 1800 Lihu Avenue , Wuxi , Jiangsu 214122 , China
- Key Laboratory of Nuclear Medicine, Ministry of Health , Jiangsu Institute of Nuclear Medicine , 20 Qian Rong Road , Wuxi , Jiangsu 214063 , China
| | - Li Zhang
- Key Laboratory of Nuclear Medicine, Ministry of Health , Jiangsu Institute of Nuclear Medicine , 20 Qian Rong Road , Wuxi , Jiangsu 214063 , China
| | - Shichen Xu
- Key Laboratory of Nuclear Medicine, Ministry of Health , Jiangsu Institute of Nuclear Medicine , 20 Qian Rong Road , Wuxi , Jiangsu 214063 , China
| | - Xian Cheng
- Key Laboratory of Nuclear Medicine, Ministry of Health , Jiangsu Institute of Nuclear Medicine , 20 Qian Rong Road , Wuxi , Jiangsu 214063 , China
| | - Huixin Yu
- Key Laboratory of Nuclear Medicine, Ministry of Health , Jiangsu Institute of Nuclear Medicine , 20 Qian Rong Road , Wuxi , Jiangsu 214063 , China
| | - Jiandong Bao
- Key Laboratory of Nuclear Medicine, Ministry of Health , Jiangsu Institute of Nuclear Medicine , 20 Qian Rong Road , Wuxi , Jiangsu 214063 , China
| | - Rongrong Lu
- School of Food Science and Technology , Jiangnan University , 1800 Lihu Avenue , Wuxi , Jiangsu 214122 , China
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Wang J, He F, Chen L, Li Q, Jin S, Zheng H, Lin J, Zhang H, Ma S, Mei J, Yu J. Resveratrol inhibits pulmonary fibrosis by regulating miR-21 through MAPK/AP-1 pathways. Biomed Pharmacother 2018; 105:37-44. [PMID: 29843043 DOI: 10.1016/j.biopha.2018.05.104] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/16/2018] [Accepted: 05/21/2018] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE To explore the molecular mechanism of Res in regulation of pulmonary fibrosis (PF). METHODS Rats were injected with bleomycin (BLM) to establish a PF model and treated with resveratrol (Res) and/or miR-21 agomir. After 14 days, lung tissues were collected for Hematoxylin-eosin and Masson's staining, and real-time quantitative polymerase chain reaction and Western blot were performed to detect fibrosis-related protein expression and the activation of the TGF-β1/Smad pathway. In vitro, MRC-5 cells were pretreated with TGF-β1, Res, and/or miR-21 agomir. After 48 h, total soluble collagen was detected with a Sircol Soluble Collagen Assay. Subsequently, a miR-21 mimic was transfected into MRC-5 cells, and a luciferase reporter assay was employed to verify whether miR-21 targeted Smad7. RESULTS Res reversed the increased levels of miR-21 induced by BLM and alleviated serious PF symptoms, but agomiR-21 treatment effectively impaired the above manifestations. In vivo, miR-21 inhibited the decreases of TGF-β1 and p-Smad2/3 that were induced by Res. In vitro, miR-21 significantly disrupted the positive effect of Res on TGF-β-induced collagen deposition, as well as the levels of Fn, α-SMA, p-Smad2, and Smad7. In addition, Smad7 was found to be a direct target of miR-21-5p. TGF-β stimulation led to an enormous increase in p-c-Jun, c-Jun, and c-Fos, which were significantly reduced by Res. Finally, miR-21 sharply reduced the increased phosphorylation levels of ERK, JNK and p38 that were induced by Res. CONCLUSION Res inhibits BLM-induced PF by regulating miR-21 through MAPK/AP-1 pathways.
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Affiliation(s)
- Jing Wang
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Fang He
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Lingqiang Chen
- Department of Orthopaedics, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Kunming 650032, Yunnan Province, China.
| | - Qin Li
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Song Jin
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Hongmei Zheng
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Jun Lin
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Hong Zhang
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Sha Ma
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Jian Mei
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
| | - Juan Yu
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650034, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650034, Yunnan Province, China
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Simabuco FM, Morale MG, Pavan IC, Morelli AP, Silva FR, Tamura RE. p53 and metabolism: from mechanism to therapeutics. Oncotarget 2018; 9:23780-23823. [PMID: 29805774 PMCID: PMC5955117 DOI: 10.18632/oncotarget.25267] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/06/2018] [Indexed: 11/25/2022] Open
Abstract
The tumor cell changes itself and its microenvironment to adapt to different situations, including action of drugs and other agents targeting tumor control. Therefore, metabolism plays an important role in the activation of survival mechanisms to keep the cell proliferative potential. The Warburg effect directs the cellular metabolism towards an aerobic glycolytic pathway, despite the fact that it generates less adenosine triphosphate than oxidative phosphorylation; because it creates the building blocks necessary for cell proliferation. The transcription factor p53 is the master tumor suppressor; it binds to more than 4,000 sites in the genome and regulates the expression of more than 500 genes. Among these genes are important regulators of metabolism, affecting glucose, lipids and amino acids metabolism, oxidative phosphorylation, reactive oxygen species (ROS) generation and growth factors signaling. Wild-type and mutant p53 may have opposing effects in the expression of these metabolic genes. Therefore, depending on the p53 status of the cell, drugs that target metabolism may have different outcomes and metabolism may modulate drug resistance. Conversely, induction of p53 expression may regulate differently the tumor cell metabolism, inducing senescence, autophagy and apoptosis, which are dependent on the regulation of the PI3K/AKT/mTOR pathway and/or ROS induction. The interplay between p53 and metabolism is essential in the decision of cell fate and for cancer therapeutics.
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Affiliation(s)
- Fernando M. Simabuco
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Mirian G. Morale
- Center for Translational Investigation in Oncology/LIM24, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
- Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Isadora C.B. Pavan
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Ana P. Morelli
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Fernando R. Silva
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Rodrigo E. Tamura
- Center for Translational Investigation in Oncology/LIM24, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
- Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Wang Y, Xu H, Lu Z, Yu X, Lv C, Tian Y, Sui D. Pseudo-Ginsenoside Rh2 induces A549 cells apoptosis via the Ras/Raf/ERK/p53 pathway. Exp Ther Med 2018; 15:4916-4924. [PMID: 29805515 PMCID: PMC5958631 DOI: 10.3892/etm.2018.6067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 02/22/2018] [Indexed: 12/18/2022] Open
Abstract
Ginsenoside Rh2, a major effective constituent of ginseng, has been suggested to have a pro-apoptotic effect in a variety of cancer cells. Pseudo-Ginsenside-Rh2 (pseudo-G-Rh2) is a novel derivative of ginsenoside Rh2. The aim of the present study was to evaluate the effect of pseudo-G-Rh2 on the apoptosis of lung adenocarcinoma A549 cells. The cytotoxicity of pseudo-G-Rh2 on A549 cells was evaluated using an MTT assay. Apoptosis was detected using DAPI staining and flow cytometry. The expression of apoptosis associated proteins was identified by western blot analysis. The results demonstrated that pseudo-G-Rh2 inhibits the proliferation of A549 cells in a dose-dependent manner. DAPI staining revealed topical morphological changes in apoptotic bodies following pseudo-G-Rh2 treatment. Flow cytometric analysis revealed that the percentage of Annexin V-fluorescein isothiocyanate-positive cells, which are apoptotic, increased with pseudo-G-Rh2 treatment in a dose-dependent manner. Furthermore, treatment with pseudo-G-Rh2 increased the level of reactive oxygen species in A549 cells as well as the activation of caspase-9, caspase-3 and poly ADP-ribose polymerase. Pseudo-G-Rh2 treatment was observed to induce mitochondrial membrane potential loss. Furthermore, the results of western blotting revealed that B-cell lymphoma 2 (Bcl-2) expression was significantly decreased while Bcl-2-associated X protein expression was significantly upregulated in A549 cells with pseudo-G-Rh2 treatment. Pseudo-G-Rh2-induced apoptosis was accompanied by sustained phosphorylation of Ras, Raf, extracellular signal-regulated kinase (ERK) and p53. In conclusion, the results of the present study suggest that pseudo-G-Rh2 induces mitochondrial apoptosis in A549 cells and is responsible for excessive activation of the Ras/Raf/ERK/p53 pathway.
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Affiliation(s)
- Yuchen Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.,School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Huali Xu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Zeyuan Lu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xiaofeng Yu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Chen Lv
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yuan Tian
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Dayun Sui
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
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Ciocci M, Iorio E, Carotenuto F, Khashoggi HA, Nanni F, Melino S. H2S-releasing nanoemulsions: a new formulation to inhibit tumor cells proliferation and improve tissue repair. Oncotarget 2018; 7:84338-84358. [PMID: 27741519 PMCID: PMC5356665 DOI: 10.18632/oncotarget.12609] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 10/07/2016] [Indexed: 12/16/2022] Open
Abstract
The improvement of solubility and/or dissolution rate of poorly soluble natural compounds is an ideal strategy to make them optimal candidates as new potential drugs. Accordingly, the allyl sulfur compounds and omega-3 fatty acids are natural hydrophobic compounds that exhibit two important combined properties: cardiovascular protection and antitumor activity. Here, we have synthesized and characterized a novel formulation of diallyl disulfide (DADS) and α-linolenic acid (ALA) as protein-nanoemulsions (BAD-NEs), using ultrasounds. BAD-NEs are stable over time at room temperature and show antioxidant and radical scavenging property. These NEs are also optimal H2S slow-release donors and show a significant anti-proliferative effect on different human cancer cell lines: MCF-7 breast cancer and HuT 78 T-cell lymphoma cells. BAD-NEs are able to regulate the ERK1/2 pathway, inducing apoptosis and cell cycle arrest at the G0/G1 phase. We have also investigated their effect on cell proliferation of human adult stem/progenitor cells. Interestingly, BAD-NEs are able to improve the Lin- Sca1+ human cardiac progenitor cells (hCPC) proliferation. This stem cell growth stimulation is combined with the expression and activation of proteins involved in tissue-repair, such as P-AKT, α-sma and connexin 43. Altogether, our results suggest that these antioxidant nanoemulsions might have potential application in selective cancer therapy and for promoting the muscle tissue repair.
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Affiliation(s)
- Matteo Ciocci
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Egidio Iorio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Felicia Carotenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Haneen A Khashoggi
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Nanni
- Department of Industrial Engineering, University of Rome Tor Vergata, Rome, Italy
| | - Sonia Melino
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy
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Abstract
Mammalian silent information regulator 1 (SIRT1) is reported to play a role in cancers of the secretory organs, including thyroid, pancreatic endocrine, and ovarian tumors [1, 2, 3, 4]. A recent meta-analysis conducted on 37 selected studies of human cancers analyzed the correlations of overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) with SIRT1 expression [5]. This study reported that SIRT1 overexpression was associated with a worse OS in liver and lung cancers, while it was not correlated with OS in breast cancer, colorectal cancer, or gastric carcinoma. Collectively, the meta-analysis revealed that an unfavorable OS was associated with SIRT1 expression for solid malignancies. Given the growing importance of this class of lysine/histone deacetylases in human endocrine malignancies, a rational and focused literature assessment is desirable in light of future clinical translations.
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Muscella A, Cossa LG, Vetrugno C, Antonaci G, Marsigliante S. Inhibition of ZL55 cell proliferation by ADP via PKC-dependent signalling pathway. J Cell Physiol 2017; 233:2526-2536. [PMID: 28777435 DOI: 10.1002/jcp.26128] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 08/01/2017] [Indexed: 11/09/2022]
Abstract
Extracellular nucleotides can regulate cell proliferation in both normal and tumorigenic tissues. Here, we studied how extracellular nucleotides regulate the proliferation of ZL55 cells, a mesothelioma-derived cell line obtained from bioptic samples of asbestos-exposed patients. ADP and 2-MeS-ADP inhibited ZL55 cell proliferation, whereas ATP, UTP, and UDP were inactive. The nucleotide potency profile and the blockade of the ADP-mediated inhibitory effect by the phospholipase C inhibitor U-73122 suggest that P2Y1 receptor controls ZL55 cell proliferation. The activation of P2Y1 receptor by ADP leads to activation of intracellular transduction pathways involving [Ca2+ ]i , PKC-δ/PKC-α, and MAPKs, ERK1/2 and JNK1/2. Cell treatment with ADP or 2-MeS-ADP also provokes the activation of p53, causing an accumulation of the G1 cyclin-dependent kinase inhibitors p21WAF1 and p27Kip . Inhibition of ZL55 cell proliferation by ADP was completely reversed by inhibiting MEK1/2, or JNK1/2, or PKC-δ, and PKC-α. Through the inhibition of ADP-activated transductional kinases it was found that PKC-δ was responsible for JNK1/2 activation. JNK1/2 has a role in transcriptional up-regulation of p53, p21WAF1/CIP1 , and p27kip1 . Conversely, the ADP-activated PKC-α provoked ERK1/2 phosphorylation. ERK1/2 increased p53 stabilization, required to G1 arrest of ZL55 cells. Concluding, the importance of the study is twofold: first, results shed light on the mechanism of cell cycle inhibition by ADP; second, results suggest that extracellular ADP may inhibit mesothelioma progression.
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Affiliation(s)
- Antonella Muscella
- Dipartimento di Scienze e Tecnologie Biologiche e Ambientali (Di.S.Te.B.A.), Universita' del Salento, Lecce, Italy
| | - Luca G Cossa
- Dipartimento di Scienze e Tecnologie Biologiche e Ambientali (Di.S.Te.B.A.), Universita' del Salento, Lecce, Italy
| | - Carla Vetrugno
- Dipartimento di Scienze e Tecnologie Biologiche e Ambientali (Di.S.Te.B.A.), Universita' del Salento, Lecce, Italy
| | - Giovanna Antonaci
- Dipartimento di Scienze e Tecnologie Biologiche e Ambientali (Di.S.Te.B.A.), Universita' del Salento, Lecce, Italy
| | - Santo Marsigliante
- Dipartimento di Scienze e Tecnologie Biologiche e Ambientali (Di.S.Te.B.A.), Universita' del Salento, Lecce, Italy
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50
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Mohamed SIA, Jantan I, Haque MA. Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action. Int Immunopharmacol 2017; 50:291-304. [PMID: 28734166 DOI: 10.1016/j.intimp.2017.07.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/13/2017] [Accepted: 07/12/2017] [Indexed: 01/08/2023]
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