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Shin JH, Shin SH. A Comprehensive Review of Naringenin, a Promising Phytochemical with Therapeutic Potential. J Microbiol Biotechnol 2024; 34:2425-2438. [PMID: 39572023 PMCID: PMC11733549 DOI: 10.4014/jmb.2410.10006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/01/2024] [Accepted: 11/12/2024] [Indexed: 12/31/2024]
Abstract
Disorders, including cancer, metabolic disorders, and neurodegenerative diseases, can threaten human health; therefore, disease prevention is essential. Naringenin, a phytochemical with low toxicity, has been used in various disease prevention studies. This study aimed to comprehensively review the effects of naringenin on human health. First, we introduced the general characteristics of naringenin and its pharmacokinetic features when absorbed in the body. Next, we summarized the inhibitory effects of naringenin on colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers in preclinical studies. Lastly, we investigated the inhibitory effects of naringenin on metabolic disorders, including diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, steatosis, liver disease, and arteriosclerosis, as well as on neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In conclusion, naringenin may serve as a significant natural compound that benefits human health.
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Affiliation(s)
- Jun Hong Shin
- Department of Food and Nutrition, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Seung Ho Shin
- Department of Food and Nutrition, Gyeongsang National University, Jinju 52828, Republic of Korea
- Department of Bio & Medical Bigdata (BK4 Program), Gyeongsang National University, Jinju 52828, Republic of Korea
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2
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Asghariazar V, Karimi A, Adeli S, Kadkhodayi M, Zare E, Vajdi M, Nasimi Doost Azgoomi R, Asghari Vostakolaei M. Anticancer activity of naringenin on human liposarcoma: An experimental and bioinformatic study. Prostaglandins Other Lipid Mediat 2024; 174:106884. [PMID: 39154788 DOI: 10.1016/j.prostaglandins.2024.106884] [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: 06/25/2024] [Revised: 07/26/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
Naringenin (NAR) has shown potential as a cancer treatment, reducing cell proliferation and invasion in soft tissue sarcomas like liposarcoma (LPS). This study investigates NAR's role and molecular mechanism. Bioinformatic analysis was performed to assess the expression level of genes in LPS based on the GEO dataset. The heat map and PPI of genes were also analyzed. MTT, wound healing, DAPI staining, and flow cytometry evaluated the cell viability, migration, and apoptosis. Besides, real-time PCR was used to measure the NAR's impact on the expression levels of EMT, apoptosis, inflammation, and metastasis-related genes. The results showed that NAR reduces cell viability, proliferation, and migration but induces apoptosis in LPS cells. RT-PCR results revealed that NAR is capable of regulating the expression level of the apoptosis, EMT, migration, and Inflammation-related genes. This study demonstrated that NAR may play a crucial role in reducing cell viability, inducing apoptosis, and attenuating migration in Sw872 LPS cells. Consequently, NAR might be a promising and efficient factor in the treatment of LPS.
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Affiliation(s)
- Vahid Asghariazar
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Arash Karimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shaghayegh Adeli
- Department of Biochemistry and Diet Therapy, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahtab Kadkhodayi
- Immunology Research Center Tabriz University of Medical Sciences, Tabriz, Iran; Department of Animal Biology, Faculty of Natural Sciences, The University of Tabriz, Tabriz, Iran
| | - Erfan Zare
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mahdi Vajdi
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ramin Nasimi Doost Azgoomi
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mehdi Asghari Vostakolaei
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
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3
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Helen H, Gunawan MC, Halim P, Dinata MR, Ahmed A, Dalimunthe A, Marianne M, Ribeiro RIMDA, Hasibuan PAZ, Nurkolis F, Hey-Hawkins E, Park MN, Harahap U, Kim SH, Kim B, Syahputra RA. Flavonoids as modulators of miRNA expression in pancreatic cancer: Pathways, Mechanisms, And Therapeutic Potential. Biomed Pharmacother 2024; 179:117347. [PMID: 39241569 DOI: 10.1016/j.biopha.2024.117347] [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: 06/14/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/09/2024] Open
Abstract
Pancreatic cancer (PC) is a complex malignancy, distinguished by its aggressive characteristics and unfavorable prognosis. Recent developments in understanding the molecular foundations of this disease have brought attention to the noteworthy involvement of microRNAs (miRNAs) in disease development, advancement, and treatment resistance. The anticancer capabilities of flavonoids, which are a wide range of phytochemicals present in fruits and vegetables, have attracted considerable interest because of their ability to regulate miRNA expression. This review provides the effects of flavonoids on miRNA expression in PC, explains the underlying processes, and explores the possible therapeutic benefits of flavonoid-based therapies. Flavonoids inhibit PC cell proliferation, induce apoptosis, and enhance chemosensitivity via the modulation of miRNAs involved in carcinogenesis. Additionally, this review emphasizes the significance of certain miRNAs as targets of flavonoid action. These miRNAs have a role in regulating important signaling pathways such as the phosphoinositide-3-kinase-protein kinase B/Protein kinase B (Akt), mitogen activated protein kinase (MAPK), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Wnt/β-catenin pathways. This review aims to consolidate current knowledge on the interaction between flavonoids and miRNAs in PC, providing a comprehensive analysis of how flavonoid-mediated modulation of miRNA expression could influence cancer progression and therapy. It highlights the use of flavonoid nanoformulations to enhance stability, increase absorption, and maximize anti-PC activity, improving patient outcomes. The review calls for further research to optimize the use of flavonoid nanoformulations in clinical trials, leading to innovative treatment strategies and more effective approaches for PC.
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Affiliation(s)
- Helen Helen
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Mega Carensia Gunawan
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Princella Halim
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Muhammad Riza Dinata
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Amer Ahmed
- Department of Bioscience, Biotechnology and Environment, University of Bari, Bari, Italy
| | - Aminah Dalimunthe
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Marianne Marianne
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Rosy Iara Maciel De Azambuja Ribeiro
- Experimental Pathology Laboratory, Federal University of São João del Rei (UFSJ), 400, Sebastião Gonçalves Coelho, Chanadour, Divinópolis 35501-296, MG, Brazil
| | | | - Fahrul Nurkolis
- Biological Sciences, Faculty of Sciences and Technology, UIN Sunan Kalijaga, Yogyakarta, Indonesia
| | - Evamarie Hey-Hawkins
- Leipzig University, Faculty of Chemistry and Mineralogy, Centre for Biotechnology and Biomedicine (BBZ), Institute of Bioanalytical Chemistry, Deutscher Platz 5, 04103 Leipzig, Germany
| | - Moon Nyeo Park
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong, Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Urip Harahap
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Sung-Hoon Kim
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Bonglee Kim
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong, Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Rony Abdi Syahputra
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia.
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Niu C, Zhang J, Okolo PI. Harnessing Plant Flavonoids to Fight Pancreatic Cancer. Curr Nutr Rep 2024; 13:566-581. [PMID: 38700837 DOI: 10.1007/s13668-024-00545-9] [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] [Accepted: 04/24/2024] [Indexed: 08/16/2024]
Abstract
PURPOSE OF REVIEW This review draws on the last fifteen years (2009-2024) of published data to summarize the potential effect of plant flavonoids on pancreatic carcinogenesis and discuss the possible mechanisms of action to establish their applicability as anti-cancer agents. RECENT FINDINGS This review found that the plant flavonoids with anti-pancreatic cancer activity mainly include chalcones, dihydrochalcones, flavanols, flavanones, flavones, isoflavonoids, flavonols, isoflavones, and flavanonols. Most of these flavonoids have anti-proliferative, pro-apoptotic, cell cycle arrest, anti-angiogenic, anti-inflammatory, anti-epithelial-mesenchymal transition, and anti-metastatic properties. Some flavonoids can also regulate autophagy, immune and glucose uptake in the context of pancreatic cancer. Several molecules and signaling pathways are associated with the pharmacological activities of plant flavonoids, including AMP-activated protein kinase, mitogen-activated protein kinases, phosphatidylinositol-3-kinase/protein kinase B, nuclear factor-κB, signal transducer, and activator of transcription 3, Smad3, epidermal growth factor receptor, and vascular endothelial growth factor. This review provides strong evidence that plant flavonoids have potential against pancreatic carcinogenesis in experimental animals through various pharmacological mechanisms. They are a promising resource for use as adjuvant anti-cancer therapy. However, randomized controlled clinical trials with those flavonoids are needed.
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Affiliation(s)
- Chengu Niu
- Internal Medicine Residency Program, Rochester General Hospital, 1425 Portland Avenue, Rochester, NY, 14621, USA.
| | - Jing Zhang
- Rainier Springs Behavioral Health Hospital, 2805 NE 129th St, Vancouver, WA, 98686, USA
| | - Patrick I Okolo
- Division of Gastroenterology, Rochester General Hospital, Rochester, NY, 14621, USA
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Li X, Yang X, Guo W, Li H, Sun W, Lin X, Ma Z, Li X, Liu Z. Natural products as inhibitors against pancreatic cancer cell proliferation and invasion: possible mechanisms. Am J Cancer Res 2024; 14:2695-2713. [PMID: 39005683 PMCID: PMC11236794 DOI: 10.62347/xlzx8935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 05/24/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic cancer is one of the gastrointestinal tumors with the lowest survival rate and the worst prognosis. At the time of diagnosis, the majority of patients have missed the opportunity for radical surgical resection and opt for chemotherapy as their primary treatment choice. And drug resistance emerges during the application of the most widely used chemotherapeutic regimens such as modified FOLFIRINOX regimen, gemcitabine monotherapy or 5-Fluorouracil combination therapy, which further reduces the therapeutic efficacy. Therefore, it is urgent to explore better treatment strategies for pancreatic cancer. In recent years, more and more studies have found that natural products have significant anti-pancreatic cancer properties. In this paper, we reviewed the possible mechanisms by which natural products inhibit the proliferation and invasion of pancreatic cancer cells, including the possible mechanisms of targeting the inhibition of the growth and proliferation regulatory pathways of pancreatic cancer cells, inducing apoptosis and autophagy of pancreatic cancer cells, inhibiting the EMT process of pancreatic cancer cells, and inhibiting the angiogenesis of pancreatic cancer. Meanwhile, natural products have also hindered the progress of their basic and clinical research due to the complexity of their composition and the limitation of biological extraction technology. Further exploration of the specific molecular mechanisms of natural products to inhibit the proliferation and invasion of pancreatic cancer cells, optimization of purification and preparation techniques, and enrichment of basic and clinical trials to verify their efficacy and safety may be the future direction of natural products in the field of anti-pancreatic cancer research.
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Affiliation(s)
- Xiang Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Xu Yang
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Hao Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Weiqing Sun
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Xingda Lin
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
| | - Zuoxin Ma
- Medical Laboratory, Liaoning Province Hospital Shenyang 110001, Liaoning, China
| | - Xuan Li
- Department of Orthopedics, Liaoning Province Hospital Shenyang 110001, Liaoning, China
| | - Zhe Liu
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University Shenyang 110001, Liaoning, China
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Rajendran P. Unveiling the power of flavonoids: A dynamic exploration of their impact on cancer through matrix metalloproteinases regulation. Biomedicine (Taipei) 2024; 14:12-28. [PMID: 38939095 PMCID: PMC11204124 DOI: 10.37796/2211-8039.1447] [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: 09/29/2023] [Revised: 11/15/2023] [Accepted: 12/22/2023] [Indexed: 06/29/2024] Open
Abstract
Cancer stands as a significant contributor to global mortality rates, primarily driven by its progression and widespread dissemination. Despite notable strides in cancer therapy, the efficacy of current treatment strategies is compromised due to their inherent toxicity and the emergence of chemoresistance. Consequently, there is a critical need to evaluate alternative therapeutic approaches, with natural compounds emerging as promising candidates, showcasing demonstrated anticancer capabilities in various research models. This review manuscript presents a comprehensive examination of the regulatory mechanisms governing the expression of matrix metalloproteinases (MMPs) and delves into the potential therapeutic role of flavonoids as agents exhibiting specific anticancer activity against MMPs. The primary aim of this study is to elucidate the diverse functions associated with MMP production in cancer and to investigate the potential of flavonoids in modulating MMP expression to inhibit metastasis.
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Affiliation(s)
- Peramaiyan Rajendran
- Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, Tamil Nadu, India
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Gu M, Liu Y, Xin P, Guo W, Zhao Z, Yang X, Ma R, Jiao T, Zheng W. Fundamental insights and molecular interactions in pancreatic cancer: Pathways to therapeutic approaches. Cancer Lett 2024; 588:216738. [PMID: 38401887 DOI: 10.1016/j.canlet.2024.216738] [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: 01/08/2024] [Revised: 02/08/2024] [Accepted: 02/18/2024] [Indexed: 02/26/2024]
Abstract
The gastrointestinal tract can be affected by a number of diseases that pancreatic cancer (PC) is a malignant manifestation of them. The prognosis of PC patients is unfavorable and because of their diagnosis at advanced stage, the treatment of this tumor is problematic. Owing to low survival rate, there is much interest towards understanding the molecular profile of PC in an attempt in developing more effective therapeutics. The conventional therapeutics for PC include surgery, chemotherapy and radiotherapy as well as emerging immunotherapy. However, PC is still incurable and more effort should be performed. The molecular landscape of PC is an underlying factor involved in increase in progression of tumor cells. In the presence review, the newest advances in understanding the molecular and biological events in PC are discussed. The dysregulation of molecular pathways including AMPK, MAPK, STAT3, Wnt/β-catenin and non-coding RNA transcripts has been suggested as a factor in development of tumorigenesis in PC. Moreover, cell death mechanisms such as apoptosis, autophagy, ferroptosis and necroptosis demonstrate abnormal levels. The EMT and glycolysis in PC cells enhance to ensure their metastasis and proliferation. Furthermore, such abnormal changes have been used to develop corresponding pharmacological and nanotechnological therapeutics for PC.
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Affiliation(s)
- Ming Gu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Yang Liu
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Peng Xin
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Zimo Zhao
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Xu Yang
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Ruiyang Ma
- Department of Otorhinolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Taiwei Jiao
- Department of Gastroenterology and Endoscopy, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Wenhui Zheng
- Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
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Gu YY, Liu XS, Lan HY. Therapeutic potential for renal fibrosis by targeting Smad3-dependent noncoding RNAs. Mol Ther 2024; 32:313-324. [PMID: 38093516 PMCID: PMC10861968 DOI: 10.1016/j.ymthe.2023.12.009] [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: 06/14/2023] [Revised: 09/13/2023] [Accepted: 12/11/2023] [Indexed: 01/26/2024] Open
Abstract
Renal fibrosis is a characteristic hallmark of chronic kidney disease (CKD) that ultimately results in renal failure, leaving patients with few therapeutic options. TGF-β is a master regulator of renal fibrosis and mediates progressive renal fibrosis via both canonical and noncanonical signaling pathways. In the canonical Smad signaling, Smad3 is a key mediator in tissue fibrosis and mediates renal fibrosis via a number of noncoding RNAs (ncRNAs). In this regard, targeting Smad3-dependent ncRNAs may offer a specific therapy for renal fibrosis. This review highlights the significance and innovation of TGF-β/Smad3-associated ncRNAs as biomarkers and therapeutic targets in renal fibrogenesis. In addition, the underlying mechanisms of these ncRNAs and their future perspectives in the treatment of renal fibrosis are discussed.
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Affiliation(s)
- Yue-Yu Gu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Departments of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong; Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Departments of Nephrology and Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xu-Sheng Liu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Hui-Yao Lan
- Departments of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong; Departments of Nephrology and Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
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Park MN. Therapeutic Strategies for Pancreatic-Cancer-Related Type 2 Diabetes Centered around Natural Products. Int J Mol Sci 2023; 24:15906. [PMID: 37958889 PMCID: PMC10648679 DOI: 10.3390/ijms242115906] [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: 08/25/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a highly malignant neoplasm, is classified as one of the most severe and devastating types of cancer. PDAC is a notable malignancy that exhibits a discouraging prognosis and a rising occurrence. The interplay between diabetes and pancreatic cancer exhibits a reciprocal causation. The identified metabolic disorder has been observed to possess noteworthy consequences on health outcomes, resulting in elevated rates of morbidity. The principal mechanisms involve the suppression of the immune system, the activation of pancreatic stellate cells (PSCs), and the onset of systemic metabolic disease caused by dysfunction of the islets. From this point forward, it is important to recognize that pancreatic-cancer-related diabetes (PCRD) has the ability to increase the likelihood of developing pancreatic cancer. This highlights the complex relationship that exists between these two physiological states. Therefore, we investigated into the complex domain of PSCs, elucidating their intricate signaling pathways and the profound influence of chemokines on their behavior and final outcome. In order to surmount the obstacle of drug resistance and eliminate PDAC, researchers have undertaken extensive efforts to explore and cultivate novel natural compounds of the next generation. Additional investigation is necessary in order to comprehensively comprehend the effect of PCRD-mediated apoptosis on the progression and onset of PDAC through the utilization of natural compounds. This study aims to examine the potential anticancer properties of natural compounds in individuals with diabetes who are undergoing chemotherapy, targeted therapy, or immunotherapy. It is anticipated that these compounds will exhibit increased potency and possess enhanced pharmacological benefits. According to our research findings, it is indicated that naturally derived chemical compounds hold potential in the development of PDAC therapies that are both safe and efficacious.
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Affiliation(s)
- Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Republic of Korea
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10
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Khaled SS, Soliman HA, Abdel-Gabbar M, Ahmed NA, El-Nahass ES, Ahmed OM. Naringin and naringenin counteract taxol-induced liver injury in Wistar rats via suppression of oxidative stress, apoptosis and inflammation. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:90892-90905. [PMID: 37466839 PMCID: PMC10439847 DOI: 10.1007/s11356-023-28454-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/22/2023] [Indexed: 07/20/2023]
Abstract
This research aimed to evaluate the preventing effects of naringin, naringenin, and their combination on liver injury induced by Taxol (paclitaxel) in Wistar rats. Male Wistar rats received 2 mg/kg Taxol intraperitoneal injections twice weekly on the second and fifth days of each week for 6 weeks. During the same period as Taxol administration, rats were given naringin, naringenin, or a combination of the two (10 mg/kg b.wt) every other day. Treatment with naringin and/or naringenin reduced the abnormally high serum levels of total bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma-glutamyl transferase in Taxol-treated rats. It also significantly increased the level of serum albumin, indicating an improvement in the liver. The perturbed histological liver changes were markedly improved due to the naringin and/or naringenin treatment in Taxol-administered rats. Additionally, the treatments reduced high hepatic lipid peroxidation and increased liver glutathione content as well as the activities of superoxide dismutase and glutathione peroxidase. Furthermore, the treatments reduced the levels of alpha-fetoprotein and caspase-3, a pro-apoptotic mediator. The naringin and naringenin mixture appeared more effective in improving organ function and structural integrity. In conclusion, naringin and naringenin are suggested to employ their hepatoprotective benefits via boosting the body's antioxidant defense system, reducing inflammation, and suppressing apoptosis.
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Affiliation(s)
- Shimaa S. Khaled
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Hanan A. Soliman
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Mohammed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Noha A. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - El-Shaymaa El-Nahass
- Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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11
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Liu S, Li L, Ren D. Anti-Cancer Potential of Phytochemicals: The Regulation of the Epithelial-Mesenchymal Transition. Molecules 2023; 28:5069. [PMID: 37446730 DOI: 10.3390/molecules28135069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
A biological process called epithelial-mesenchymal transition (EMT) allows epithelial cells to change into mesenchymal cells and acquire some cancer stem cell properties. EMT contributes significantly to the metastasis, invasion, and development of treatment resistance in cancer cells. Current research has demonstrated that phytochemicals are emerging as a potential source of safe and efficient anti-cancer medications. Phytochemicals could disrupt signaling pathways related to malignant cell metastasis and drug resistance by suppressing or reversing the EMT process. In this review, we briefly describe the pathophysiological properties and the molecular mechanisms of EMT in the progression of cancers, then summarize phytochemicals with diverse structures that could block the EMT process in different types of cancer. Hopefully, these will provide some guidance for future research on phytochemicals targeting EMT.
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Affiliation(s)
- Shuangyu Liu
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China
| | - Lingyu Li
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China
| | - Dongmei Ren
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China
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12
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Zhang F, Zheng Z, Wang L, Zeng W, Wei W, Zhang C, Zhao Z, Liang W. PKC-ζ mediated reduction of the extracellular vesicles-associated TGF-β1 overcomes radiotherapy resistance in breast cancer. Breast Cancer Res 2023; 25:38. [PMID: 37029374 PMCID: PMC10082517 DOI: 10.1186/s13058-023-01641-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 03/20/2023] [Indexed: 04/09/2023] Open
Abstract
BACKGROUND Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-β1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-β1 is secreted in an extracellular vesicles-associated form (TGF-β1EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-β1EV will pave a way for overcoming the radiotherapy resistance in cancer treatment. METHODS The superoxide-Zinc-PKC-ζ-TGF-β1EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student's t test or two-way ANOVA with correction was used for comparisons of groups. RESULTS The radiotherapy resulted in an increased expression of the intratumoral TGF-β1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-β1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-β1EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-β1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-β1EV pathway. CONCLUSIONS The superoxide-zinc-PKC-ζ-TGF-β1EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-β1EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers. TRIAL REGISTRATION The using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).
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Affiliation(s)
- Fayun Zhang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Zifeng Zheng
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Luoyang Wang
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Wenfeng Zeng
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wenjing Wei
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chunling Zhang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Ziran Zhao
- Thoracic Surgery Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Wei Liang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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13
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Dairo G, Ilesanmi A, Balogun T, Ward M, Soendergaard M, Determan J. Computational evaluation of bioactive compounds from Viscum album (mistletoe) as inhibitors of p63 for pancreatic cancer treatment. J Biomol Struct Dyn 2023; 41:15610-15624. [PMID: 36935102 DOI: 10.1080/07391102.2023.2191133] [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: 11/24/2022] [Accepted: 03/06/2023] [Indexed: 03/20/2023]
Abstract
Pancreatic ductal adenocarcinoma is an aggressive malignancy usually detectable at the advanced stage, with a 5-year survival rate of less than 8%. It has been reported that a gene called tumor-protein 63 (TP63) is expressed in an aggressive form of pancreatic cancer with a squamous signature. Thus, inhibiting the activity of p63 can be a means of treating and managing PDA. Different studies have shown that plant constituents are rich and can be a promising source for discovering drug candidates. The extract from mistletoe (Viscum album) is known to contain anticancer compounds; however, the specific molecular mechanism of the bioactive compounds is unknown. This study examines the pancreatic cancer therapeutic potential of the bioactive compounds in the flavonoid and phenolic acid constituents of mistletoe by adopting structural bioinformatics and advanced theoretical chemistry techniques via molecular docking, molecular dynamics simulation, molecular mechanics/generalized Born surface area (MM/GBSA) calculations, pharmacokinetic analysis, and density functional theory analysis. The six best compounds from the flavonoid constituent with the highest binding affinity ranging from -6.8 kcal/mol to -6.7 kcal/mol were selected with the control gemcitabine (-5.5 kcal/mol) for further computational analysis after molecular docking. Furthermore, MM/GBSA calculation showed the highest binding energy for the selected docked compounds, which validates their inhibitory potential. Hence, the molecular dynamics simulation, post-simulation analysis, pharmacokinetics model, and DFT results showed that mistletoe compounds are reliable due to their stable interaction with the target protein and drug-likeness properties.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Gbenga Dairo
- Department of Biological Sciences, Western Illinois University, Macomb, IL, USA
| | - Ayooluwa Ilesanmi
- Department of Chemistry, Mississippi University for Women, Columbus, MS, USA
| | - Toheeb Balogun
- Department of Biological Sciences, University of California, San Diego, CA, USA
| | - Matthew Ward
- Department of Chemistry, Western Illinois University, Macomb, IL, USA
| | | | - John Determan
- Department of Chemistry, Western Illinois University, Macomb, IL, USA
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14
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Dukel M. Combination of naringenin and epicatechin sensitizes colon carcinoma cells to anoikis via regulation of the epithelial–mesenchymal transition (EMT). Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00317-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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15
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Stabrauskiene J, Kopustinskiene DM, Lazauskas R, Bernatoniene J. Naringin and Naringenin: Their Mechanisms of Action and the Potential Anticancer Activities. Biomedicines 2022; 10:biomedicines10071686. [PMID: 35884991 PMCID: PMC9313440 DOI: 10.3390/biomedicines10071686] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/01/2022] [Accepted: 07/11/2022] [Indexed: 12/29/2022] Open
Abstract
Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health and has been practiced since ancient times. Numerous studies have reported these substances’ antioxidant and antiandrogenic properties, as well as their ability to protect from inflammation and cancer, in various in vitro and in vivo experimental models in animals and humans. Naringin and naringenin can suppress cancer development in various body parts, alleviating the conditions of cancer patients by acting as effective alternative supplementary remedies. Their anticancer activities are pleiotropic, and they can modulate different cellular signaling pathways, suppress cytokine and growth factor production and arrest the cell cycle. In this narrative review, we discuss the effects of naringin and naringenin on inflammation, apoptosis, proliferation, angiogenesis, metastasis and invasion processes and their potential to become innovative and safe anticancer drugs.
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Affiliation(s)
- Jolita Stabrauskiene
- Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
| | - Dalia M. Kopustinskiene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
| | - Robertas Lazauskas
- Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania;
| | - Jurga Bernatoniene
- Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
- Correspondence:
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16
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Motallebi M, Bhia M, Rajani HF, Bhia I, Tabarraei H, Mohammadkhani N, Pereira-Silva M, Kasaii MS, Nouri-Majd S, Mueller AL, Veiga FJB, Paiva-Santos AC, Shakibaei M. Naringenin: A potential flavonoid phytochemical for cancer therapy. Life Sci 2022; 305:120752. [PMID: 35779626 DOI: 10.1016/j.lfs.2022.120752] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/19/2022] [Accepted: 06/27/2022] [Indexed: 02/07/2023]
Abstract
Naringenin is an important phytochemical which belongs to the flavanone group of polyphenols, and is found mainly in citrus fruits like grapefruits and others such as tomatoes and cherries plus medicinal plants derived food. Available evidence demonstrates that naringenin, as herbal medicine, has important pharmacological properties, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, and anti-cancer activities. Collected data from in vitro and in vivo studies show the inactivation of carcinogens after treatment with pure naringenin, naringenin-loaded nanoparticles, and also naringenin in combination with anti-cancer agents in various malignancies, such as colon cancer, lung neoplasms, breast cancer, leukemia and lymphoma, pancreatic cancer, prostate tumors, oral squamous cell carcinoma, liver cancer, brain tumors, skin cancer, cervical and ovarian cancer, bladder neoplasms, gastric cancer, and osteosarcoma. Naringenin inhibits cancer progression through multiple mechanisms, like apoptosis induction, cell cycle arrest, angiogenesis hindrance, and modification of various signaling pathways including Wnt/β-catenin, PI3K/Akt, NF-ĸB, and TGF-β pathways. In this review, we demonstrate that naringenin is a natural product with potential for the treatment of different types of cancer, whether it is used alone, in combination with other agents, or in the form of the naringenin-loaded nanocarrier, after proper technological encapsulation.
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Affiliation(s)
- Mahzad Motallebi
- Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), Tehran 7616911319, Iran; Department of Biology, Yadegar-e-Imam Khomeini Shahr-e-Rey Branch, Islamic Azad University, Tehran 1815163111, Iran
| | - Mohammed Bhia
- Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), Tehran 7616911319, Iran; Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran 1996835113, Iran
| | - Huda Fatima Rajani
- Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E0T5, Canada
| | - Iman Bhia
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
| | - Hadi Tabarraei
- Department of Veterinary Biomedical Science, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon SKS7N 5B4, Canada
| | - Niloufar Mohammadkhani
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
| | - Miguel Pereira-Silva
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Maryam Sadat Kasaii
- Department of Nutrition Research, Department of Community Nutrition, National Nutrition and Food Technology Research Institute (WHO Collaborating Center); and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran 1981619573, Iran
| | - Saeedeh Nouri-Majd
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 14155-6117, Iran
| | - Anna-Lena Mueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilian-University Munich, 80336 Munich, Germany
| | - Francisco J B Veiga
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilian-University Munich, 80336 Munich, Germany.
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Naringenin induces intrinsic and extrinsic apoptotic signaling pathways in cancer cells: A systematic review and meta-analysis of in vitro and in vivo data. Nutr Res 2022; 105:33-52. [DOI: 10.1016/j.nutres.2022.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 05/13/2022] [Accepted: 05/20/2022] [Indexed: 12/24/2022]
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Rauf A, Shariati MA, Imran M, Bashir K, Khan SA, Mitra S, Emran TB, Badalova K, Uddin MS, Mubarak MS, Aljohani ASM, Alhumaydhi FA, Derkho M, Korpayev S, Zengin G. Comprehensive review on naringenin and naringin polyphenols as a potent anticancer agent. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:31025-31041. [PMID: 35119637 DOI: 10.1007/s11356-022-18754-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/14/2022] [Indexed: 06/14/2023]
Abstract
Though the incidence of several cancers in Western societies is regulated wisely, some cancers such as breast, lung, and colorectal cancer are currently rising in many low- and middle-income countries due to increased risk factors triggered by societal and development problems. Surgery, chemotherapy, hormone, radiation, and targeted therapies are examples of traditional cancer treatment approaches. However, multiple short- and long-term adverse effects may also significantly affect patient prognosis depending on treatment-associated clinical factors. More and more research has been carried out to find new therapeutic agents in natural products, among which the bioactive compounds derived from plants have been increasingly studied. Naringin and naringenin are abundantly found in citrus fruits, such as oranges and grapefruits. A variety of cell signaling pathways mediates their anti-carcinogenic properties. Naringin and naringenin were also documented to overcome multidrug resistance, one of the major challenges to clinical practice due to multiple defense mechanisms in cancer. The effective parameters underlying the anticancer effects of naringenin and naringin include GSK3β inactivation, suppression of the gene and protein activation of NF-kB and COX-2, JAK2/STAT3 downregulation, downregulation of intracellular adhesion molecules-1, upregulation of Notch1 and tyrocite-specific genes, and activation of p38/MAPK and caspase-3. Thus, this review outlines the potential of naringin and naringenin in managing different types of cancers.
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Affiliation(s)
- Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar, Swabi, 23561, Khyber Pakhtunkhwa, Pakistan
| | - Mohammad Ali Shariati
- K.G. Razumovsky Moscow State University of Technologies and Management, The First Cossack University), 73 Zemlyanoy Val, Moscow, 109004, Russia
| | - Muhammad Imran
- Department of food science and technology, University of Narowal-Pakistan, Pakistan
- Food, nutrition and lifestyle Unit, King Fahed Medical Research Center, Clinical Biochemistry Department, Faculty of Medicine, King Abdulaziz University, Saudi Arabia
| | - Kashif Bashir
- Department of Microbiology and Biotechnology, Abasyan University Peshawar, Peshawar, Pakistan
| | - Shahid Ali Khan
- Department of Chemistry, University of Swabi, Anbar, Swabi, 23561, Khyber Pakhtunkhwa, Pakistan
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh
| | - Kamala Badalova
- General Toxicological Chemistry Department, Azerbaijan Medical University Azerbaijan, Baku, Azerbaijan
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
| | | | - Abdullah S M Aljohani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Fahad A Alhumaydhi
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Marina Derkho
- Institute of Veterinary Medicine, South-Ural State Agrarian University, Chelyabinsk Region, 13 Gagarin St, Troitsk, 454700, Russian Federation
| | - Serdar Korpayev
- Biotechnology Institute, Ankara University, 06135, Ankara, Turkey
| | - Gokhan Zengin
- Department of Biology, Science Faculty, Selcuk University, Konya, Turkey.
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19
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Skelding KA, Barry DL, Theron DZ, Lincz LF. Targeting the two-pore channel 2 in cancer progression and metastasis. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:62-89. [PMID: 36046356 PMCID: PMC9400767 DOI: 10.37349/etat.2022.00072] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/02/2022] [Indexed: 11/19/2022] Open
Abstract
The importance of Ca2+ signaling, and particularly Ca2+ channels, in key events of cancer cell function such as proliferation, metastasis, autophagy and angiogenesis, has recently begun to be appreciated. Of particular note are two-pore channels (TPCs), a group of recently identified Ca2+-channels, located within the endolysosomal system. TPC2 has recently emerged as an intracellular ion channel of significant pathophysiological relevance, specifically in cancer, and interest in its role as an anti-cancer drug target has begun to be explored. Herein, an overview of the cancer-related functions of TPC2 and a discussion of its potential as a target for therapeutic intervention, including a summary of clinical trials examining the TPC2 inhibitors, naringenin, tetrandrine, and verapamil for the treatment of various cancers is provided.
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Affiliation(s)
- Kathryn A. Skelding
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia
| | - Daniel L. Barry
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia
| | - Danielle Z. Theron
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia
| | - Lisa F. Lincz
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales 2308, Australia;Hunter Medical Research Institute, New Lambton Heights, New South Wales 2305, Australia;Hunter Hematology Research Group, Calvary Mater Newcastle Hospital, Waratah, New South Wales 2298, Australia
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Periyasamy L, Muruganantham B, Park WY, Muthusami S. Phyto-targeting the CEMIP Expression as a Strategy to Prevent Pancreatic Cancer Metastasis. Curr Pharm Des 2022; 28:922-946. [PMID: 35236267 DOI: 10.2174/1381612828666220302153201] [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: 04/08/2021] [Accepted: 12/16/2021] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Metastasis of primary pancreatic cancer (PC) to adjacent or distant organs is responsible for the poor survival rate of affected individuals. Chemotherapy, radiotherapy, and immunotherapy are currently being prescribed to treat PC in addition to surgical resection. Surgical resection is the preferred treatment for PC that leads to 20% of 5-year survival, but only less than 20% of patients are eligible for surgical resection because of the poor prognosis. To improve the prognosis and clinical outcome, early diagnostic markers need to be identified, and targeting them would be of immense benefit to increase the efficiency of the treatment. Cell migration-inducing hyaluronan-binding protein (CEMIP) is identified as an important risk factor for the metastasis of various cancers, including PC. Emerging studies have pointed out the crucial role of CEMIP in the regulation of various signaling mechanisms, leading to enhanced migration and metastasis of PC. METHODS The published findings on PC metastasis, phytoconstituents, and CEMIP were retrieved from Pubmed, ScienceDirect, and Cochrane Library. Computational tools, such as gene expression profiling interactive analysis (GEPIA) and Kaplan-Meier (KM) plotter, were used to study the relationship between CEMIP expression and survival of PC individuals. RESULTS Gene expression analysis using the GEPIA database identified a stupendous increase in the CEMIP transcript in PC compared to adjacent normal tissues. KM plotter analysis revealed the impact of CEMIP on the overall survival (OS) and disease-free survival (DFS) among PC patients. Subsequently, several risk factors associated with PC development were screened, and their ability to regulate CEMIP gene expression was analyzed using computational tools. CONCLUSION The current review is focused on gathering information regarding the regulatory role of phytocomponents in PC migration and exploring their possible impact on the CEMIP expression.
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Affiliation(s)
- Loganayaki Periyasamy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641 021, India
| | - Bharathi Muruganantham
- Karpagam Cancer Research Centre, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641 021, India
| | - Woo-Yoon Park
- Department of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea
| | - Sridhar Muthusami
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641 021, India
- Karpagam Cancer Research Centre, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641 021, India
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Yang Q, Gao L, Hu XW, Wang JN, Zhang Y, Dong YH, Lan HY, Meng XM. Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism. KIDNEY DISEASES 2021; 7:372-390. [PMID: 34604344 DOI: 10.1159/000512986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 11/11/2020] [Indexed: 12/30/2022]
Abstract
Background Transforming growth factor-β (TGF-β)/Smad signaling is the central mediator in renal fibrosis, yet its functional role in acute kidney injury (AKI) is not fully understood. Recent evidence showed that TGF-β/Smad3 may be involved in the pathogenesis of AKI, but its functional role and mechanism of action in cisplatin-induced AKI are unclear. Objectives Demonstrating that Smad3 may play certain roles in cisplatin nephropathy due to its potential effect on programmed cell death and inflammation. Methods Here, we established a cisplatin-induced AKI mouse model with Smad3 knockout mice and created stable in vitro models with Smad3 knockdown tubular epithelial cells. In addition, we tested the potential of Smad3-targeted therapy using 2 in vivo protocols - lentivirus-mediated Smad3 silencing in vivo and use of naringenin, a monomer used in traditional Chinese medicine and a natural inhibitor of Smad3. Results Disruption of Smad3 attenuated cisplatin-induced kidney injury, inflammation, and NADPH oxidase 4-dependent oxidative stress. We found that Smad3-targeted therapy protected against loss of renal function and alleviated apoptosis, RIPK-mediated necroptosis, renal inflammation, and oxidative stress in cisplatin nephropathy. Conclusions These findings show that Smad3 promotes cisplatin-induced AKI and Smad3-targeted therapy protects against this pathological process. These findings have substantial clinical relevance, as they suggest a therapeutic target for AKI.
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Affiliation(s)
- Qin Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Li Gao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Xiao-Wei Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Yao Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Yu-Hang Dong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Hui Yao Lan
- Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
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Gonçalves CFL, Hecht F, Cazarin J, Fortunato RS, Vaisman M, Carvalho DPD, Ferreira ACF. The flavonoid quercetin reduces cell migration and increases NIS and E-cadherin mRNA in the human thyroid cancer cell line BCPAP. Mol Cell Endocrinol 2021; 529:111266. [PMID: 33831503 DOI: 10.1016/j.mce.2021.111266] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 03/26/2021] [Accepted: 03/26/2021] [Indexed: 01/06/2023]
Abstract
Thyroid cancer is the most frequent cancer of the endocrine system. Most patients are treated with thyroidectomy followed by radioiodine therapy. However, in part of the patients, a reduction of the sodium-iodide symporter (NIS) occurs, rendering radioiodine therapy ineffective. Moreover, epithelial-mesenchymal transition (EMT) may occur, leading to more aggressive and invasive features. Herein, we evaluated the effect of the flavonoid quercetin on EMT and NIS expression in BCPAP, a papillary thyroid carcinoma cell line. BCPAP was treated with 100 μM quercetin for 24 h and cell viability, apoptosis, EMT markers and NIS were evaluated. Quercetin decreased cell viability by enhancing apoptosis. The flavonoid also reduced matrix metalloproteinase 9 and increased E-cadherin mRNA levels, inhibiting BCPAP adhesion and migration. Additionally, quercetin increased NIS expression and function. Thus, our results suggest that quercetin could be useful as adjuvant in thyroid cancer therapy, inducing apoptosis, reducing invasion and increasing the efficacy of radioiodine therapy.
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Affiliation(s)
- Carlos Frederico Lima Gonçalves
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
| | - Fabio Hecht
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
| | - Juliana Cazarin
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
| | - Rodrigo Soares Fortunato
- Laboratório de Fisiologia e Sinalização Redox, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
| | - Mario Vaisman
- Serviço de Endocrinologia do Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro (HUCFF/UFRJ), Rio de Janeiro, RJ, Brazil.
| | - Denise Pires de Carvalho
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
| | - Andrea Claudia Freitas Ferreira
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil; NUMPEX, Campus Duque de Caxias, Universidade Federal do Rio de Janeiro, Brazil.
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Precilla DS, Kuduvalli SS, Purushothaman M, Marimuthu P, Ramachandran MA, Anitha TS. Wnt/β-catenin Antagonists: Exploring New Avenues to Trigger Old Drugs in Alleviating Glioblastoma Multiforme. Curr Mol Pharmacol 2021; 15:338-360. [PMID: 33881978 DOI: 10.2174/1874467214666210420115431] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 12/24/2020] [Accepted: 01/30/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Glioblastoma multiforme is one of the most heterogenous primary brain tumor with high mortality. Nevertheless, of the current therapeutic approaches, survival rate remains poor with 12 to 15 months following preliminary diagnosis, this warrants the need for effective treatment modality. Wnt/β-catenin pathway is presumably the most noteworthy pathway up-regulated in almost 80% GBM cases contributing to tumor-initiation, progression and survival. Therefore, therapeutic strategies targeting key components of Wnt/β-catenin cascade using established genotoxic agents like temozolomide and pharmacological inhibitors would be an effective approach to modulate Wnt/β-catenin pathway. Recently, drug repurposing by means of effective combination therapy has gained importance in various solid tumors including GBM, by targeting two or more proteins in a single pathway, thereby possessing the ability to overcome the hurdle implicated by chemo-resistance in GBM. OBJECTIVE In this context, by employing computational tools, an attempt has been carried out to speculate the novel combinations against Wnt/β-catenin signaling pathway. METHODS We have explored the binding interactions of three conventional drugs namely temozolomide, metformin, chloroquine along with three natural compounds viz., epigallocatechin gallate, naringenin and phloroglucinol on the major receptors of Wnt/β-catenin signaling. RESULTS It was noted that all the experimental compounds possessed profound interaction with the two major receptors of Wnt/β-catenin pathway. CONCLUSION To the best of our knowledge, this study is the first of its kind to characterize the combined interactions of the afore-mentioned drugs on Wnt/β-catenin signaling in silico and this will putatively open up new avenues for combination therapies in GBM treatment.
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Affiliation(s)
- Daisy S Precilla
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Shreyas S Kuduvalli
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | | | - Parthiban Marimuthu
- Structural Bioinformatics Laboratory - Pharmacy, Faculty of Science and Engineering, Åbo Akademi University, Turku. Finland
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Guo H, Wang S, Ju M, Yan P, Sun W, Li Z, Wu S, Lin R, Xian S, Yang D, Wang J, Huang Z. Identification of Stemness-Related Genes for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma by Integrated Bioinformatics Analysis. Front Cell Dev Biol 2021; 9:642724. [PMID: 33842467 PMCID: PMC8027330 DOI: 10.3389/fcell.2021.642724] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/05/2021] [Indexed: 12/13/2022] Open
Abstract
Background Invasion and metastasis of cervical cancer are the main factors affecting the prognosis of patients with cervical squamous cell carcinoma (CESC). Therefore, it is of vital importance to find novel biomarkers that are associated with CESC invasion and metastasis, which will aid in the amelioration of individualized therapeutic methods for advanced patients. Methods The gene expression profiles of 10 metastatic and 116 non-metastatic samples were downloaded from The Cancer Genome Atlas (TCGA), where differentially expressed genes (DEGs) were defined. Weighted gene correlation network analysis (WGCNA) was employed to identify the stemness-related genes (SRGs). Univariate and multivariate regression analyses were used to identify the most significant prognostic key genes. Differential expression analysis of transcription factor (TF) and Gene Set Variation Analysis (GSVA) were utilized to explore the potential upstream regulation of TFs and downstream signaling pathways, respectively. Co-expression analysis was performed among significantly enriched TFs, key SRGs, and signaling pathways to construct a metastasis-specific regulation network in CESC. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for the network. Additionally, direct regulatory patterns of key genes were validated by ChIP-seq and ATAC-seq data. Results DEGs in yellow module acquired via WGCNA were defined as key genes which were most significantly related to mRNAsi. A multivariate Cox regression model was constructed and then utilized to explore the prognostic value of key SRGs by risk score. Area under curve (AUC) of the receiver operating characteristic (ROC) curve was 0.842. There was an obvious co expression pattern between the TF NR5A2 and the key gene VIM (R = 0.843, p < 0.001), while VIM was also significantly co-expressed with hallmark epithelial mesenchymal transition (EMT) signaling pathway (R = 0.318, p < 0.001). Naringenin was selected as the potential bioactive small molecule inhibitor for metastatic CESC based on CMap analysis. Conclusions VIM positively regulated by NR5A2 affected EMT signaling pathways in metastatic CESC, and naringenin was the inhibitor for the treatment of metastatic CESC via suppressing cancer stemness. This hypothetical signaling axis and potential inhibitors provide biomarkers and novel therapeutic targets for metastatic CESC.
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Affiliation(s)
- Hongjun Guo
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Siqiao Wang
- Tongji University School of Medicine, Shanghai, China
| | - Min Ju
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Penghui Yan
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenhuizi Sun
- Tongji University School of Medicine, Shanghai, China
| | - Zhenyu Li
- Tongji University School of Medicine, Shanghai, China
| | - Siyu Wu
- Tongji University School of Medicine, Shanghai, China
| | - Ruoyi Lin
- Tongji University School of Medicine, Shanghai, China
| | - Shuyuan Xian
- Tongji University School of Medicine, Shanghai, China
| | - Daoke Yang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jun Wang
- Department of Pediatric Rehabilitation, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zongqiang Huang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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LncRNA LINC00857 strengthens the malignancy behaviors of pancreatic adenocarcinoma cells by serving as a competing endogenous RNA for miR-340-5p to upregulate TGFA expression. PLoS One 2021; 16:e0247817. [PMID: 33661995 PMCID: PMC7932076 DOI: 10.1371/journal.pone.0247817] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 02/14/2021] [Indexed: 12/19/2022] Open
Abstract
Background Pancreatic adenocarcinoma (PAAD) is a pancreatic disease with a high mortality rate in the world. This present research intends to identify the function of lncRNA LINC00857/miR-340-5p/Transforming growth factor alpha (TGFA) in the progression of PAAD. Methods Bioinformatics analysis was used to explore the differentially expressed lncRNA/miRNA/mRNA and analyze the relationship between lncRNA/miRNA/mRNA expression and prognosis of PAAD by enquiring TCGA, GEO and GTEX. KEGG pathway analysis and GO enrichment analysis were implemented to annotate the crucial genes regulated by LINC00857. The biological behaviors of PAAD cells were detected by CCK-8, colony formation and transwell assays. Interactive associations between LINC00857 and miR-340-5p, as well as miR-340-5p and TGFA were analyzed by dual luciferase assay. Results By enquiring TCGA database, we got that LINC00857 was highly expressed in patients with PAAD and positively associated with worse prognosis in PAAD patients. Moreover, LINC00857 upregulation promoted the proliferation and clone formation abilities of PAAD cells. Afterwards, the downstream miRNA and mRNA targets of LINC00857 were picked up to construct a ceRNA network. Further study revealed that TGFA expression was positively regulated by LINC00857 and negatively regulated by miR-340-5p. Besides that, the inhibitory effect of miR-340-5p on PAAD cells growth and movement can be blocked by LINC00857 upregulation. While, the malignant behavior of PAAD cells induced by TGFA overexpression can be eliminated by LINC00857 knockdown. Conclusions Upregulation of LINC00857 improved growth, invasion and migration abilities of PAAD cells by modulation of miR-340-5p/TGFA, affording potential targets and biomarkers for the clinical diagnosis and treatment.
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Abdel Mouti M, Pauklin S. TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment. Mol Ther 2021; 29:920-936. [PMID: 33429081 PMCID: PMC7934636 DOI: 10.1016/j.ymthe.2021.01.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 10/17/2020] [Accepted: 01/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment.
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Affiliation(s)
- Mai Abdel Mouti
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Headington, University of Oxford, Oxford OX3 7LD, UK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Headington, University of Oxford, Oxford OX3 7LD, UK.
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Murti Y, Semwal BC, Goyal A, Mishra P. Naringenin Scaffold as a Template for Drug Designing. CURRENT TRADITIONAL MEDICINE 2021. [DOI: 10.2174/2215083805666190617144652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Natural products provide cornucopia of heterocyclic systems. The nucleus of 2-
phenyl chromane is one of the important and well-known heterocycles found in the natural
products. Naringenin, a plant-derived flavanone (2-phenyl chroman-4-one) belongs to the family
of flavanoids. It possesses diverse biologic activities such as antidiabetic, antiatherogenic,
antidepressant, antiandrogenic, antiestrogenic, immunomodulatory, antitumor, antimicrobial,
anti-inflammatory, antiviral, hypolipidemic, antihypertensive, antioxidant, neuroprotective,
anti-obesity, anti-Alzheimer, and memory enhancer activity. It has the potential to be used as
an active pharmacophore. There have been reports of a number of molecular mechanisms
underlying their beneficial activities. With emerging interest in traditional medicine and
exploiting their potential based on a variety of health care systems, naringenin literature was
thought to be explored. Further, this review aims to provide a new era of flavonoid-based
therapeutic agents with new insights into naringenin and its derivatives as a lead compound
in drug design.
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Affiliation(s)
- Yogesh Murti
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
| | - Bhupesh Chander Semwal
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
| | - Pradeep Mishra
- Institute of Pharmaceutical Research, GLA University, Mathura N.H.#2, Mathura-Delhi Road, P.O. Chaumuhan, Mathura-281 406, India
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Hermawan A, Ikawati M, Jenie RI, Khumaira A, Putri H, Nurhayati IP, Angraini SM, Muflikhasari HA. Identification of potential therapeutic target of naringenin in breast cancer stem cells inhibition by bioinformatics and in vitro studies. Saudi Pharm J 2021; 29:12-26. [PMID: 33603536 PMCID: PMC7873751 DOI: 10.1016/j.jsps.2020.12.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 12/03/2020] [Indexed: 12/15/2022] Open
Abstract
Cancer therapy is a strategic measure in inhibiting breast cancer stem cell (BCSC) pathways. Naringenin, a citrus flavonoid, was found to increase breast cancer cells' sensitivity to chemotherapeutic agents. Bioinformatics study and 3D tumorsphere in vitro modeling in breast cancer (mammosphere) were used in this study, which aims to explore the potential therapeutic targets of naringenin (PTTNs) in inhibiting BCSCs. Bioinformatic analyses identified direct target proteins (DTPs), indirect target proteins (ITPs), naringenin-mediated proteins (NMPs), BCSC regulatory genes, and PTTNs. The PTTNs were further analyzed for gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction (PPI) networks, and hub protein selection. Mammospheres were cultured in serum-free media. The effects of naringenin were measured by MTT-based cytotoxicity, mammosphere forming potential (MFP), colony formation, scratch wound-healing assay, and flow cytometry-based cell cycle analyses and apoptosis assays. Gene expression analysis was performed using real-time quantitative polymerase chain reaction (q-RT PCR). Bioinformatics analysis revealed p53 and estrogen receptor alpha (ERα) as PTTNs, and KEGG pathway enrichment analysis revealed that TGF-ß and Wnt/ß-catenin pathways are regulated by PTTNs. Naringenin demonstrated cytotoxicity and inhibited mammosphere and colony formation, migration, and epithelial to mesenchymal transition in the mammosphere. The mRNA of tumor suppressors P53 and ERα were downregulated in the mammosphere, but were significantly upregulated upon naringenin treatment. By modulating the P53 and ERα mRNA, naringenin has the potential of inhibiting BCSCs. Further studies on the molecular mechanism and formulation of naringenin in BCSCs would be beneficial for its development as a BCSC-targeting drug.
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Key Words
- BCSCs, Breast cancer stem cells
- Bioinformatics
- Breast cancer stem cells
- CSC, Cancer stem cell
- DAVID, Database for Annotation, Visualization, and Integrated Discovery
- DTPs, Direct target proteins
- DXR, Doxorubicin
- EGF, Epidermal growth factor
- EMT, Epithelial to mesenchymal transition
- ERα
- FITC, fluorescein isothiocyanate
- GO, Gene ontology
- ITPs, Indirect target proteins
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- MET, Metformin
- MFP, Mammosphere forming potential
- NAR, Naringenin
- NMPs, Naringenin-mediated proteins
- Naringenin
- P53
- PE, phycoerythrin
- PPI, Protein-protein interaction
- PTTN, Potential target of naringenin in inhibition of BCSCs
- ROS, Reactive oxygen species
- Targeted therapy
- q-RT PCR, Quantitative real-time polymerase chain reaction
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Affiliation(s)
- Adam Hermawan
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Muthi Ikawati
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Riris Istighfari Jenie
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Annisa Khumaira
- Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Herwandhani Putri
- Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Ika Putri Nurhayati
- Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Sonia Meta Angraini
- Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Haruma Anggraini Muflikhasari
- Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
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Martínez-Rodríguez OP, González-Torres A, Álvarez-Salas LM, Hernández-Sánchez H, García-Pérez BE, Thompson-Bonilla MDR, Jaramillo-Flores ME. Effect of naringenin and its combination with cisplatin in cell death, proliferation and invasion of cervical cancer spheroids. RSC Adv 2020; 11:129-141. [PMID: 35423031 PMCID: PMC8690252 DOI: 10.1039/d0ra07309a] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/30/2020] [Indexed: 01/17/2023] Open
Abstract
The main treatment alternative for cervical cancer is cisplatin chemotherapy. However, the resistance of tumor cells to cisplatin, in addition to side effects, limits its use. The flavonoid naringenin has shown cytotoxic effects on tumor cells and may be considered as a coadjuvant in the treatment of cervical cancer. In the present study, the effect of naringenin on cell viability, cytotoxicity, proliferation, apoptosis and invasion was evaluated in HeLa spheroid cultures. Naringenin impaired the cell viability as indicated by low ATP levels and caused concentration- and time-dependent cytotoxicity via the loss of cell membrane integrity. Furthermore, it did not activate caspases 3, 7, 8, and 9, suggesting that the cytotoxic effect was by necrotic cell death instead of apoptosis. Additionally, proliferation in the G0/G1 phase of the cell cycle was inhibited. Cell invasion also decreased as time progressed. Later, we determined if naringenin could improve the anti-tumor effect of cisplatin. The combination of naringenin with low concentrations of cisplatin improved the effect of the drug by significantly decreasing cell viability, potentiating the induction of cytotoxicity and decreasing the invasive capacity of the spheroids. Since these effects are regulated by some key proteins, molecular docking results indicated the interaction of naringenin with RIP3 and MLKL, cyclin B and with matrix metalloproteases 2 and 9. The results showed the anti-tumor effect of naringenin on the HeLa spheroids and improved effect of the cisplatin at low concentrations in combination with naringenin, placing flavonoids as a potential adjuvant in the therapy against cervical cancer.
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Affiliation(s)
- Oswaldo Pablo Martínez-Rodríguez
- Laboratorio de Biopolímeros, Departamento de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional Av Wilfrido Masseiu Esq. Manuel Stampa S/N, Unidad Profesional Adolfo López Mateos CP 07738 Ciudad de México México
| | - Alejandro González-Torres
- Laboratorio de Biopolímeros, Departamento de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional Av Wilfrido Masseiu Esq. Manuel Stampa S/N, Unidad Profesional Adolfo López Mateos CP 07738 Ciudad de México México
| | - Luis Marat Álvarez-Salas
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del I.P.N. Av. I.P.N. 2508 CP 07360 Ciudad de México México
| | - Humberto Hernández-Sánchez
- Laboratorio de Biopolímeros, Departamento de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional Av Wilfrido Masseiu Esq. Manuel Stampa S/N, Unidad Profesional Adolfo López Mateos CP 07738 Ciudad de México México
| | - Blanca Estela García-Pérez
- Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional Carpio y Plan de Ayala. Casco de Santo Tomás CP 11340 Ciudad de México México
| | - María Del Rocío Thompson-Bonilla
- Laboratorio de Medicina Genómica, Hospital 1ro de Octubre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado Av. I.P.N. 1669 CP 07300 Ciudad de México México
| | - María Eugenia Jaramillo-Flores
- Laboratorio de Biopolímeros, Departamento de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional Av Wilfrido Masseiu Esq. Manuel Stampa S/N, Unidad Profesional Adolfo López Mateos CP 07738 Ciudad de México México
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Multi-Therapeutic Potential of Naringenin (4',5,7-Trihydroxyflavonone): Experimental Evidence and Mechanisms. PLANTS 2020; 9:plants9121784. [PMID: 33339267 PMCID: PMC7766900 DOI: 10.3390/plants9121784] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 12/12/2022]
Abstract
Extensive research has been carried out during the last few decades, providing a detailed account of thousands of discovered phytochemicals and their biological activities that have the potential to be exploited for a wide variety of medicinal purposes. These phytochemicals, which are pharmacologically important for clinical use, primarily consist of polyphenols, followed by terpenoids and alkaloids. There are numerous published reports indicating the primary role of phytochemicals proven to possess therapeutic potential against several diseases. However, not all phytochemicals possess significant medicinal properties, and only some of them exhibit viable biological effects. Naringenin, a flavanone found in citrus fruits, is known to improve immunity, repair DNA damage, and scavenge free radicals. Despite the very low bioavailability of naringenin, it is known to exhibit various promising biological properties of medicinal importance, including anti-inflammatory and antioxidant activities. This review focuses on the various aspects related to naringenin, particularly its physicochemical, pharmacokinetic, and pharmacodynamic properties. Furthermore, various pharmacological activities of naringenin, such as anticancer, antidiabetic, hepatoprotective, neuroprotective, cardioprotective, nephroprotective, and gastroprotective effects, have been discussed along with their mechanisms of action.
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Daisy Precilla S, Kuduvalli SS, Thirugnanasambandhar Sivasubramanian A. Disentangling the therapeutic tactics in GBM: From bench to bedside and beyond. Cell Biol Int 2020; 45:18-53. [PMID: 33049091 DOI: 10.1002/cbin.11484] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 10/04/2020] [Accepted: 10/11/2020] [Indexed: 12/15/2022]
Abstract
Glioblastoma multiforme (GBM) is one of the most common and malignant form of adult brain tumor with a high mortality rate and dismal prognosis. The present standard treatment comprising surgical resection followed by radiation and chemotherapy using temozolomide can broaden patient's survival to some extent. However, the advantages are not palliative due to the development of resistance to the drug and tumor recurrence following the multimodal treatment approaches due to both intra- and intertumoral heterogeneity of GBM. One of the major contributors to temozolomide resistance is O6 -methylguanine-DNA methyltransferase. Furthermore, deficiency of mismatch repair, base excision repair, and cytoprotective autophagy adds to temozolomide obstruction. Rising proof additionally showed that a small population of cells displaying certain stem cell markers, known as glioma stem cells, adds on to the resistance and tumor progression. Collectively, these findings necessitate the discovery of novel therapeutic avenues for treating glioblastoma. As of late, after understanding the pathophysiology and biology of GBM, some novel therapeutic discoveries, such as drug repurposing, targeted molecules, immunotherapies, antimitotic therapies, and microRNAs, have been developed as new potential treatments for glioblastoma. To help illustrate, "what are the mechanisms of resistance to temozolomide" and "what kind of alternative therapeutics can be suggested" with this fatal disease, a detailed history of these has been discussed in this review article, all with a hope to develop an effective treatment strategy for GBM.
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Affiliation(s)
- S Daisy Precilla
- Central Inter-Disciplinary Research Facility, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Shreyas S Kuduvalli
- Central Inter-Disciplinary Research Facility, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
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Memariani Z, Abbas SQ, Ul Hassan SS, Ahmadi A, Chabra A. Naringin and naringenin as anticancer agents and adjuvants in cancer combination therapy: Efficacy and molecular mechanisms of action, a comprehensive narrative review. Pharmacol Res 2020; 171:105264. [PMID: 33166734 DOI: 10.1016/j.phrs.2020.105264] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 10/10/2020] [Accepted: 10/19/2020] [Indexed: 12/24/2022]
Abstract
Although the rates of many cancers are controlled in Western countries, those of some cancers, such as lung, breast, and colorectal cancer are currently increasing in many low- and middle-income countries due to increases in risk factors caused by development and societal problems. Additionally, endogenous factors, such as inherited mutations, steroid hormones, insulin, and insulin-like growth factor systems, inflammation, oxidative stress, and exogenous factors (including tobacco, alcohol, infectious agents, and radiation), are believed to compromise cell functions and lead to carcinogenesis. Chemotherapy, surgery, radiation therapy, hormone therapy, and targeted therapies are some examples of the approaches used for cancer treatment. However, various short- and long-term side effects can also considerably impact patient prognosis based on clinical factors associated with treatments. Recently, increasing numbers of studies have been conducted to identify novel therapeutic agents from natural products, among which plant-derived bioactive compounds have been increasingly studied. Naringin (NG) and its aglycone naringenin (NGE) are abundantly present in citrus fruits, such as grapefruits and oranges. Their anti-carcinogenic activities have been shown to be exerted through several cell signal transduction pathways. Recently, different pharmacological strategies based on combination therapy, involving NG and NGE with the current anti-cancer agents have shown prodigious synergistic effects when compared to monotherapy. Besides, NG and NGE have been reported to overcome multidrug resistance, resulting from different defensive mechanisms in cancer, which is one of the major obstacles of clinical treatment. Thus, we comprehensively reviewed the inhibitory effects of NG and NGE on several types of cancers through different signal transduction pathways, the roles on sensitizing with the current anticancer medicines, and the efficacy of the cancer combination therapy.
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Affiliation(s)
- Zahra Memariani
- Traditional Medicine and History of Medical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
| | - Syed Qamar Abbas
- Department of Pharmacy, Sarhad University of Science and Technology, Peshawar, Pakistan.
| | - Syed Shams Ul Hassan
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
| | - Amirhossein Ahmadi
- Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Aroona Chabra
- Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
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Souza JM, Tuin SA, Robinson AG, de Souza JGO, Bianchini MA, Miguez PA. Effect of Flavonoid Supplementation on Alveolar Bone Healing-A Randomized Pilot Trial. Dent J (Basel) 2020; 8:E86. [PMID: 32759635 PMCID: PMC7560062 DOI: 10.3390/dj8030086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 02/07/2023] Open
Abstract
We investigated the effects of two common dietary supplements on bone healing in dental extraction sockets in humans. In this randomized pilot trial, male subjects took Grape Seed Extract [GSE] or Grapefruit Extract [GFE] starting two weeks prior to dental extraction and maintained this regimen for sixty days after surgery. Extraction sockets were filled with a collagen plug. After 24 h, a socket sample was collected and processed for quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and an 84-gene wound healing assay. Sixty days after tooth extraction, a core of newly formed bone was obtained prior to dental implant placement and processed for histology. qRT-PCR revealed that GFE led to a significant decrease in platelet-derived growth factor and interleukin (IL)1-β compared to GSE, and a significant decrease in IL-6 and CXCL2 compared to control. GSE led to a significant increase in coagulation factor Von Willebrand and inflammatory marker IL1-β compared to GFE. WISP1 and CXCL5 were upregulated in both groups. Overall, GFE showed a downregulation of inflammation and GSE led to a decrease in collagen density and increased osteoclasts. This pilot trial highlights the need for further investigation on the mechanism of action of such supplements on bone healing and oral health.
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Affiliation(s)
- Jose Moises Souza
- Centro de Ciências da Saúde, Departamento de Odontologia, Campus Reitor David Ferreira Lima, Universidade Federal de Santa Catarina, Bairro Trindade, Florianópolis 88040-970, Brazil; (J.M.S.J.); (J.G.O.d.S.); (M.A.B.)
| | - Stephen A. Tuin
- Oral and Craniofacial Health Sciences, Adams School of Dentistry, Koury Oral Health Sciences Building, Rm 4608, CB# 7455, University of North Carolina at Chapel Hill, 385 South Columbia Street, Chapel Hill, NC 27599-7455, USA; (S.A.T.); (A.G.R.)
| | - Adam G. Robinson
- Oral and Craniofacial Health Sciences, Adams School of Dentistry, Koury Oral Health Sciences Building, Rm 4608, CB# 7455, University of North Carolina at Chapel Hill, 385 South Columbia Street, Chapel Hill, NC 27599-7455, USA; (S.A.T.); (A.G.R.)
| | - Joao Gustavo Oliveira de Souza
- Centro de Ciências da Saúde, Departamento de Odontologia, Campus Reitor David Ferreira Lima, Universidade Federal de Santa Catarina, Bairro Trindade, Florianópolis 88040-970, Brazil; (J.M.S.J.); (J.G.O.d.S.); (M.A.B.)
| | - Marco Aurelio Bianchini
- Centro de Ciências da Saúde, Departamento de Odontologia, Campus Reitor David Ferreira Lima, Universidade Federal de Santa Catarina, Bairro Trindade, Florianópolis 88040-970, Brazil; (J.M.S.J.); (J.G.O.d.S.); (M.A.B.)
| | - Patricia A. Miguez
- Division of Comprehensive Oral Health, Adams School of Dentistry, Koury Oral Health Sciences Building, Rm 4610, CB# 7455, University of North Carolina at Chapel Hill, Chapel Hill, NC 77599-7455, USA
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Tan Z, Sun Y, Liu M, Xia L, Cao F, Qi Y, Song Y. Retracted: Naringenin Inhibits Cell Migration, Invasion, and Tumor Growth by Regulating circFOXM1/miR-3619-5p/SPAG5 Axis in Lung Cancer. Cancer Biother Radiopharm 2020; 35:e826-e838. [DOI: 10.1089/cbr.2019.3520] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Zhaofeng Tan
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuli Sun
- Department of Hepatology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Mei Liu
- Department of Obstetrics and Gynecology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Xia
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fang Cao
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuanfu Qi
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yonglei Song
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Wali AF, Rashid S, Rashid SM, Ansari MA, Khan MR, Haq N, Alhareth DY, Ahmad A, Rehman MU. Naringenin Regulates Doxorubicin-Induced Liver Dysfunction: Impact on Oxidative Stress and Inflammation. PLANTS 2020; 9:plants9040550. [PMID: 32344607 PMCID: PMC7238146 DOI: 10.3390/plants9040550] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/29/2020] [Accepted: 04/08/2020] [Indexed: 12/18/2022]
Abstract
Doxorubicin (Dox) is an operational and largely used anticancer drug, used to treat an array of malignancies. Nonetheless, its beneficial use is constrained due to its renal and hepatotoxicity dose dependently. Numerous research findings favor the use of antioxidants may impact Dox-induced liver injury/damage. In the current study, Wistar rats were given naringenin (50 and 100 mg/kg b.wt.) orally for 20 days as prophylactic dose, against the hepatotoxicity induced by single intraperitoneal injection of Dox (20 mg/kg b.wt.). Potency of naringenin against the liver damage caused by Dox was assessed by measuring malonyl aldehyde (MDA) as a by-product of lipid peroxidation, biochemical estimation of antioxidant enzyme system, reactive oxygen species (ROS) level, and inflammatory mediators. Naringenin-attenuated ROS production, ROS-induced lipid peroxidation, and replenished reduced antioxidant armory, namely, catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH). Naringenin similarly diminished expression of Cox-2 and levels of NF-κB and other inflammatory molecules induced by the Dox treatment. Histology added further evidence to the defensive effects of naringenin on Dox-induced liver damage. The outcomes of the current study reveal that oxidative stress and inflammation are meticulously linked with Dox-triggered damage, and naringenin illustrates the potential effect on Dox-induced hepatotoxicity probably through diminishing the oxidative stress and inflammation.
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Affiliation(s)
- Adil Farooq Wali
- RAK College of Pharmaceutical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, UAE;
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy Girls Section, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia;
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Shuhama, J&K 190006, India;
| | - Mushtaq Ahmad Ansari
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (M.A.A.); (M.R.K.); (D.Y.A.)
| | - Mohammad Rashid Khan
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (M.A.A.); (M.R.K.); (D.Y.A.)
| | - Nazrul Haq
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;
| | - Dhafer Yahya Alhareth
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (M.A.A.); (M.R.K.); (D.Y.A.)
| | - Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
- Correspondence: (A.A.); (M.U.R.); Tel.: +96-6114670765 (A.A. & M.U.R.)
| | - Muneeb U. Rehman
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Shuhama, J&K 190006, India;
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
- Correspondence: (A.A.); (M.U.R.); Tel.: +96-6114670765 (A.A. & M.U.R.)
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Ghalali A, Ye ZW, Högberg J, Stenius U. PTEN and PHLPP crosstalk in cancer cells and in TGFβ-activated stem cells. Biomed Pharmacother 2020; 127:110112. [PMID: 32294598 DOI: 10.1016/j.biopha.2020.110112] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/18/2020] [Accepted: 03/19/2020] [Indexed: 12/20/2022] Open
Abstract
Akt kinase regulates several cellular processes, among them growth, proliferation and survival, and has been correlated to neoplastic disease. We report here crosstalk between several Akt regulatory phosphatases that controls the level of the activated form (phosphorylated) of Akt and affects tumor cell aggressiveness. In prostate cancer cell lines, we observed that transient transfection of PTEN decreased the endogenous level of PHLPPs and in contrast, the transient transfection of PHLPPs decreased the endogenous level of PTEN. Furthermore, silencing of PTEN by siRNA resulted in increased PHLPP levels. This phenomenon was not seen in non-transformed cells or in prostate stem cells. This crosstalk promoted cancer cell invasion and was controlled by epigenetically regulated processes where activation of miRs (miR-190 and miR214), the polycomb group of proteins and DNA methylation were involved. The purinergic P2X4 receptor, which has been shown to have a role in wound healing, was identified to be the mediator of this crosstalk. We also studied prostate stem cells and found this crosstalk in the TGFβ1-activated epithelial-mesenchymal transition (EMT). The crosstalk seemed to be a natural part of EMT. In summary, we identify a crosstalk between Akt phosphatases which is not present in non-transformed prostate cells but occurs in cancer cells and stem cells transformed by TGFβ-1. This crosstalk is important for cellular invasion. BACKGROUND Phosphatases regulate the Akt oncogene. RESULTS Crosstalk between Akt phosphatases in prostate cancer cells and in TGF-β1 activated stem cells but not in non-transformed cells. CONCLUSION This back-up mechanism facilitates invasive migration of prostate stem and cancer cells. SIGNIFICANCE Characterization of Akt regulation may lead to a better understanding of tumor development and to novel strategies for treatment.
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Affiliation(s)
- Aram Ghalali
- Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
| | - Zhi-Wei Ye
- Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden; Department of Pharmacology, Medical University of South Carolina, United States
| | - Johan Högberg
- Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden
| | - Ulla Stenius
- Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden
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Wang W, Xing H, Huang C, Pan H, Li D. Identification of pancreatic cancer type related factors by Weighted Gene Co-Expression Network Analysis. Med Oncol 2020; 37:33. [PMID: 32200436 DOI: 10.1007/s12032-020-1339-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/22/2020] [Indexed: 12/12/2022]
Abstract
This study aims to identify the core modules associated with pancreatic cancer (PC) types and the ncRNAs and transcription factors (TFs) that regulate core module genes by weighted gene co-expression network analysis (WGCNA). WGCNA was used to analyze the union of genes related to PC in NCBI and OMIM databases and the differentially expressed genes screened by TCGA-PAAD database. Samples were clustered according to gene expression in gene modules and Fisher exact method was performed. GO and KEGG were used for enrichment analysis to visually display module genes and screen driver genes. Hypergeometric test method was used to calculate pivot nodes among ncRNAs, TFs and mRNA based on RAID 2.0 and TRRUST v2 databases. The blue and yellow modules were identified as the core modules associated with PC types. MST1R, TMPRSS, MIR198, SULF1, COL1A1 and FAP were the core genes in the modules. Hypergeometric test results showed that ANCR, miR-3134, MT1DP, LOC154449, LOC28329 and other ncRNAs were key factors driving blue module genes, while LINC-ROR, UCA1, SNORD114-4, HEIH, SNORD114-6 and other ncRNAs were key factors driving yellow module genes. TFs with significant regulatory effect on blue module included LCOR, PIAS4, ZEB1, SNAI2, SMARCA4, etc. and on yellow module included HOXC6, PER2, HOXD3, TWIST2, VHL, etc. The core modules associated with PC types were proved as yellow and blue modules, and important ncRNAs and TFs regulating yellow and blue modules were found. This study provides relevant evidence for further identification of PC types.
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Affiliation(s)
- Wei Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3# Eastern Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China
| | - Haibo Xing
- Department of ICU, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Xiasha Campus, 368# Xiasha Road, Hangzhou, 310019, Zhejiang, People's Republic of China
| | - Changxin Huang
- Department of Medical Oncology, Hangzhou Normal University Affiliated Hospital, Hangzhou, 310000, Zhejiang, People's Republic of China
| | - Hong Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Xiasha Campus, 368# Xiasha Road, Hangzhou, 310019, Zhejiang, People's Republic of China.
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3# Eastern Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China.
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Hsu LS, Kao TH, Chang YM, Lin MC, Hong LZ, Chen PN, Tsai YH, Hseu YC, Chen KM. Naringenin reduced migration in osteosarcoma cells through downregulation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and snail. Pharmacogn Mag 2020. [DOI: 10.4103/pm.pm_31_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] Open
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Hernández-Aquino E, Quezada-Ramírez MA, Silva-Olivares A, Casas-Grajales S, Ramos-Tovar E, Flores-Beltrán RE, Segovia J, Shibayama M, Muriel P. Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways. Eur J Pharmacol 2019; 865:172730. [PMID: 31618621 DOI: 10.1016/j.ejphar.2019.172730] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023]
Abstract
There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CCl4 was given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9-12 of the CCl4 treatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1β, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1β, IL-10, TGF-β, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced by naringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-β-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.
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Affiliation(s)
| | - Marco A Quezada-Ramírez
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Angélica Silva-Olivares
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Sael Casas-Grajales
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Erika Ramos-Tovar
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Rosa E Flores-Beltrán
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - José Segovia
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Mineko Shibayama
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Pablo Muriel
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico.
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Jiang X, Hou D, Wei Z, Zheng S, Zhang Y, Li J. Extracellular and intracellular microRNAs in pancreatic cancer: from early diagnosis to reducing chemoresistance. ACTA ACUST UNITED AC 2019. [DOI: 10.1186/s41544-019-0014-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Hu B, An HM, Yan X, Zheng JL, Huang XW, Li M. Traditional Chinese medicine formulation Yanggan Jiedu Sanjie inhibits TGF-β1-induced epithelial-mesenchymal transition and metastatic potential in human hepatocarcinoma Bel-7402 cells. Altern Ther Health Med 2019; 19:67. [PMID: 30876428 PMCID: PMC6420768 DOI: 10.1186/s12906-019-2477-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 03/10/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is a vital process in cancer progression and metastasis. Yanggan Jiedu Sanjie (YGJDSJ) is Traditional Chinese Medicine formulation for liver cancer treatment. In the present study, we evaluated the effects of YGJDSJ on TGF-β1-induced EMT in hepatocellular carcinoma Bel-7402 cells. METHODS Bel-7402 cells were treated with TGF-β1 and YGJDSJ. EMT was identified by morphological changes and expression of marker proteins. Cell morphology was observed under a microscope. Protein expression and phosphorylation was detected by western blotting. Cell migration was measured by the scratch assay. Cell adhesion and invasion was detected by a commercial kit. RESULTS YGJDSJ reversed TGF-β1-induced morphological changes, as well as the expression of the EMT markers E-cadherin and N-cadherin in Bel-7402 cells. YGJDSJ also inhibited TGF-β1 up-regulated Smad3 phosphorylation and Snail expression in Bel-7402 cells. Moreover, YGJDSJ inhibited TGF-β1-induced cell adhesion, migration and invasion in Bel-7402 cells. CONCLUSIONS YGJDSJ inhibited TGF-β1-induced EMT and mediated metastatic potential of Bel-7402 cells, which may be related to down-regulation of Smad3 phosphorylation and Snail expression. The present study provides a new basis for application of this herbal formula for prevention of liver cancer metastasis.
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Chen YY, Chang YM, Wang KY, Chen PN, Hseu YC, Chen KM, Yeh KT, Chen CJ, Hsu LS. Naringenin inhibited migration and invasion of glioblastoma cells through multiple mechanisms. ENVIRONMENTAL TOXICOLOGY 2019; 34:233-239. [PMID: 30431227 DOI: 10.1002/tox.22677] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/16/2018] [Accepted: 10/20/2018] [Indexed: 06/09/2023]
Abstract
Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 μM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 μM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.
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Affiliation(s)
- Yen-Yu Chen
- Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
| | - Yuh-Ming Chang
- Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, Taichung, Taiwan
- Department of Neurology, Division of Internal Medicine, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan
| | - Kuan-Yi Wang
- Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Pei-Ni Chen
- Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - You-Cheng Hseu
- Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Research Center of Chinese Herbal Medicine, China Medical University, Taichung, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
| | - Ke-Min Chen
- Department of Parasitology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Kun-Tu Yeh
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Jung Chen
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Li-Sung Hsu
- Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
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Sagandykova GN, Pomastowski PP, Kaliszan R, Buszewski B. Modern analytical methods for consideration of natural biological activity. Trends Analyt Chem 2018. [DOI: 10.1016/j.trac.2018.10.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Gumushan Aktas H, Akgun T. Naringenin inhibits prostate cancer metastasis by blocking voltage-gated sodium channels. Biomed Pharmacother 2018; 106:770-775. [DOI: 10.1016/j.biopha.2018.07.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 06/30/2018] [Accepted: 07/01/2018] [Indexed: 12/17/2022] Open
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Abstract
Naringenin, a citrus flavonoid that possesses various biological activities, has emerged as a potential therapeutic agent for the management of a variety of diseases. Studies using cell culture system have shown that naringenin can inhibit inflammatory response in diverse cell types. Moreover, research using various animal models has further demonstrated therapeutic potentials of naringenin in the treatment of several inflammation-related disorders, such as sepsis, fulminant hepatitis, fibrosis and cancer. The mechanism of action of naringenin is not completely understood but recent mechanistic studies revealed that naringenin suppresses inflammatory cytokine production through both transcriptional and post-transcriptional mechanisms. Surprisingly, naringenin not only inhibits cytokine mRNA expression but also promotes lysosome-dependent cytokine protein degradation. This unique property of naringenin stands in sharp contrast with some widely-studied natural products such as apigenin and curcumin, which regulate cytokine production essentially at the transcriptional level. Therefore, naringenin may provide modality for the development of novel anti-inflammatory agent. This review article summarizes our recent studies in understanding how naringenin acts in cells and animal models. Particularly, we will discuss the anti-inflammatory activities of naringenin in various disease context and its potential use, as an immunomodulator, in the treatment of inflammatory related disease.
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Zhang C, Zeng W, Yao Y, Xu B, Wei X, Wang L, Yin X, Barman AK, Zhang F, Zhang C, Song Q, Liang W. Naringenin Ameliorates Radiation-Induced Lung Injury by Lowering IL-1 β Level. J Pharmacol Exp Ther 2018; 366:341-348. [PMID: 29866791 DOI: 10.1124/jpet.118.248807] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
Radiation-induced lung injury (RILI) is the main complication of radiotherapy for thoracic malignancies. Since naringenin, a potent immune-modulator, has been found to relieve bleomycin-induced lung fibrosis by restoring the balance of disordered cytokines, we sought to determine whether naringenin would mitigate RILI and to investigate the underlying mechanism. Animals received fractionated irradiation in the thoracic area to induce RILI. Enzyme-linked immunosorbent assay and MILLIPLEX assays were used for serum and bronchoalveolar lavage fluid for cytokine analyses, hematoxylin and eosin staining for pathologic changes, and Masson trichrome staining for determination of lung fibrosis. Interleukin (IL)-1β was found significantly elevated after thoracic irradiation and it triggered production of profibrotic tumor growth factor β both in vivo and in vitro, suggesting the vital role of in IL-1β in the development of RILI. Furthermore, we found that naringenin was able to ameliorate RILI through downregulation of IL-1β and restoration of the homeostasis of inflammatory factors. Our results demonstrated that naringenin could serve as a potent immune-modulator to ameliorate RILI. More importantly, we suggest that a new complementary strategy of maintaining the homeostasis of inflammatory factors combined with radiation could improve the efficacy of thoracic radiotherapy.
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Affiliation(s)
- Chao Zhang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Wenfeng Zeng
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Yi Yao
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Bin Xu
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Xiuli Wei
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Luoyang Wang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Xiaozhe Yin
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Apurba Kumar Barman
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Fayun Zhang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Chunling Zhang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Qibin Song
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
| | - Wei Liang
- Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (Cha.Z., W.Z., X.W., L.W., X.Y., A.K.B., F.Z., Chu.Z., W.L.); University of Chinese Academy of Sciences, Beijing, China (Cha.Z., L.W., X.Y., A.K.B.); and Department of Oncology I (Y.Y., B.X., Q.S.) and Cancer Center (Y.Y., Q.S.), Wuhan University Renmin Hospital, Wuhan, China
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An Array of Bioactive Compounds From Australian Eucalypts and Their Relevance in Pancreatic Cancer Therapeutics. Pancreas 2018; 47:690-707. [PMID: 29894418 DOI: 10.1097/mpa.0000000000001074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer (PC) is one of the most devastating human cancers, and despite the significant advances in the current therapeutic options, the overall survival rate for PC has remained static for the past 50 years. Plant-derived bioactive compounds play a vital role in cancer therapeutics by providing new lead compounds for future drug development. Therefore, the isolation, characterization, and identification of new bioactive compounds for the prevention and treatment of cancer continue to be an important aspect of natural product research. Many in vitro and in vivo studies published in the last few decades have established strong links between the phytochemical profile of eucalypts and anticancer activity. However, only a small number of these reports have attempted to demonstrate a relationship between the biological activity of eucalypt extracts and PC. This review focuses on potential anti-PC effects of an array of bioactive compounds present in various species of eucalypts. It also highlights the necessity for further in vitro and in vivo studies to develop a complete understanding of the potential this group of plants has for the development of potent and specific chemotherapeutic drugs for PC.
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Lian GY, Wang QM, Tang PMK, Zhou S, Huang XR, Lan HY. Combination of Asiatic Acid and Naringenin Modulates NK Cell Anti-cancer Immunity by Rebalancing Smad3/Smad7 Signaling. Mol Ther 2018; 26:2255-2266. [PMID: 30017880 DOI: 10.1016/j.ymthe.2018.06.016] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 06/13/2018] [Accepted: 06/16/2018] [Indexed: 01/01/2023] Open
Abstract
Transforming growth factor β1 (TGF-β1) plays a promoting role in tumor growth via a mechanism associated with hyperactive Smad3 and suppressed Smad7 signaling in the tumor microenvironment. We report that retrieving the balance between Smad3 and Smad7 signaling with asiatic acid (AA, a Smad7 inducer) and naringenin (NG, a Smad3 inhibitor) effectively inhibited tumor progression in mouse models of invasive melanoma (B16F10) and lung carcinoma (LLC) by promoting natural killer (NK) cell development and cytotoxicity against cancer. Mechanistically, we found that Smad3 physically bound Id2 and IRF2 to suppress NK cell production and NK cell-mediated cytotoxicity against cancer. Treatment with AA and NG greatly inhibited Smad3 translation and phosphorylation while it restored Smad7 expression, and, therefore, it largely promoted NK cell differentiation, maturation, and cytotoxicity against cancer via Id2/IRF2-associated mechanisms. In contrast, silencing Id2 or IRF2 blunted the protective effects of AA and NG on NK cell-dependent anti-cancer activities. Thus, treatment with AA and NG produced an additive effect on inactivating TGF-β1/Smad3 signaling, and, therefore, it suppressed melanoma and lung carcinoma growth by promoting NK cell immunity against cancer via a mechanism associated with Id2 and IRF2.
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Affiliation(s)
- Guang-Yu Lian
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Qing-Ming Wang
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shuang Zhou
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao-Ru Huang
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hui-Yao Lan
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Bhuyan DJ, Vuong QV, Bond DR, Chalmers AC, Bowyer MC, Scarlett CJ. Eucalyptus microcorys leaf extract derived HPLC-fraction reduces the viability of MIA PaCa-2 cells by inducing apoptosis and arresting cell cycle. Biomed Pharmacother 2018; 105:449-460. [PMID: 29879629 DOI: 10.1016/j.biopha.2018.05.150] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 12/22/2022] Open
Abstract
New therapeutic strategies such as the development of novel drugs and combinatorial therapies with existing chemotherapeutic agents are urgently needed to improve the clinical prognosis of pancreatic cancer. We have previously reported the antiproliferative properties of aqueous crude Eucalyptus microcorys extract against pancreatic cancer cell lines. In this study, bioassay-guided fractionation of the aqueous crude E. microcorys extract using RP-HPLC and subsequent assessment of the resultant fractions (F1-F5) for their antioxidant activity and cytotoxicity against pancreatic cancer cell lines were performed. The molecular mechanisms associated with the cytotoxicity was characterised by studying the effects of the most potent fraction-1 (F1) on apoptosis and cell cycle profiles as well as its phytochemical constituents by LC-ESI/MS/MS. F1 displayed significantly greater antioxidant activity in three different assays (p < 0.05). Moreover, F1 exhibited significantly greater antiproliferative activity (IC50 = 93.11 ± 3.43 μg/mL) against MIA PaCa-2 cells compared to the other four fractions (p < 0.05). F1 induced apoptosis by regulating key apoptotic proteins- Bcl-2, Bak, Bax, cleaved PARP, procaspase-3 and cleaved caspase-3 in MIA PaCa-2 cells, suggesting the involvement of intrinsic mitochondrial apoptotic pathway and arrested cells at G2/M phase. A combination of gemcitabine and F1 exerted a greater effect on apoptosis and cell cycle arrest than F1 or gemcitabine alone (p < 0.05). LC-ESI/MS/MS revealed the tentative identities of phytochemicals present in F1 and their similarities with the phenolic compounds previously reported in Eucalyptus with antipancreatic cancer activity. Our study shows that the polyphenol and antioxidant-rich fraction of E. microcorys extract is a promising candidate for developing mono or combination therapies against pancreatic cancer.
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Affiliation(s)
- Deep Jyoti Bhuyan
- Pancreatic Cancer Research Group, School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia.
| | - Quan V Vuong
- Pancreatic Cancer Research Group, School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia
| | - Danielle R Bond
- Pancreatic Cancer Research Group, School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia
| | - Anita C Chalmers
- School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia
| | - Michael C Bowyer
- Pancreatic Cancer Research Group, School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia
| | - Christopher J Scarlett
- Pancreatic Cancer Research Group, School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, Australia
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50
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Saenz J, Santa-María C, Reyes-Quiroz ME, Geniz I, Jiménez J, Sobrino F, Alba G. Grapefruit Flavonoid Naringenin Regulates the Expression of LXRα in THP-1 Macrophages by Modulating AMP-Activated Protein Kinase. Mol Pharm 2018; 15:1735-1745. [PMID: 29140707 DOI: 10.1021/acs.molpharmaceut.7b00797] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The present work investigates the modulation of grapefruit flavonoid naringenin over liver X receptor alpha (LXRα) and its target genes in THP-1 macrophages, focusing on AMP-activated protein kinase (AMPK) implication. Naringenin induced LXRα at mRNA and protein levels besides influencing the expression of LXRα target genes ABCA1, ABCG1 (ATP-binding cassette A1 and G1), and SREBP1c (sterol response element binding protein 1c) in THP-1 macrophages. The increased LXRα mRNA and protein expression was reverted when AMPK was inhibited by its chemical inhibitor, compound C or by transfection with AMPK α1 and α2 siRNA. Naringenin treatments were also able to promote reverse cholesterol transport in THP-1 cells, which is in line with the increase in the ABCA1 and ABCG1 expression found. Treatments with this flavonoid also inhibited cell migration in THP-1 cells. In conclusion, LXRα and its target genes are up-regulated by naringenin in an AMPK dependent manner in human macrophages. The enhancement in the expression of genes involved in cholesterol efflux may reveal a new mechanism by which this polyphenol can prevent atherosclerosis and foam cell progression.
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Affiliation(s)
- Javier Saenz
- Departamento de Bioquímica Médica y Biología Molecular , Universidad de Sevilla , 41004 Sevilla , Spain
| | - Consuelo Santa-María
- Departamento de Bioquímica y Biología Molecular , Universidad de Sevilla , 41004 Sevilla , Spain
| | - María Edith Reyes-Quiroz
- Departamento de Bioquímica Médica y Biología Molecular , Universidad de Sevilla , 41004 Sevilla , Spain
| | - Isabel Geniz
- Hospital Nuestra Señora de Valme , Servicio Andaluz de Salud , 41001 Sevilla , Spain
| | - Juan Jiménez
- Departamento de Bioquímica Médica y Biología Molecular , Universidad de Sevilla , 41004 Sevilla , Spain
| | - Francisco Sobrino
- Departamento de Bioquímica Médica y Biología Molecular , Universidad de Sevilla , 41004 Sevilla , Spain
| | - Gonzalo Alba
- Departamento de Bioquímica Médica y Biología Molecular , Universidad de Sevilla , 41004 Sevilla , Spain
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