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Bashir B, Sethi P, Panda S, Manikyam HK, Vishwas S, Singh SK, Singh K, Jain D, Chaitanya MVNL, Coutinho HDM. Unravelling the epigenetic based mechanism in discovery of anticancer phytomedicine: Evidence based studies. Cell Signal 2025; 131:111743. [PMID: 40107479 DOI: 10.1016/j.cellsig.2025.111743] [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: 01/15/2025] [Revised: 03/10/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
Epigenetic mechanisms play a crucial role in the normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of these processes can result in changes to gene function and the transformation of cells into a malignant state. Cancer is characterized by widespread alterations in the epigenetic landscape, revealing that it involves not only genetic mutations but also epigenetic abnormalities. Recent progress in the field of cancer epigenetics has demonstrated significant reprogramming of various components of the epigenetic machinery in cancer, such as DNA methylation, modifications to histones, positioning of nucleosomes, and the expression of non-coding RNAs, particularly microRNAs. The ability to reverse epigenetic abnormalities has given rise to the hopeful field of epigenetic therapy, which has shown advancement with the recent approval by the FDA of three drugs targeting epigenetic mechanisms for the treatment of cancer. In the present manuscript, a comprehensive review has been presented about the role of understanding the epigenetic link between cancer and mechanisms by which phytomedicine offers treatment avenues. Further, this review deciphers the significance of natural products in the identification of epigenetic therapeutics, the diversity of their molecular targets, the use of nanotechnology, and the creation of new strategies for overcoming the inherent clinical challenges associated with developing these drug leads.
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Affiliation(s)
- Bushra Bashir
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Pranshul Sethi
- Department of Pharmacology, College of Pharmacy, Shri Venkateshwara University, Gajraula, Uttar Pradesh, India
| | - Satyajit Panda
- Department of Pharmaceutics, Institute of Pharmacy and Technology, Salipur, Cuttack, Odisha 754202, India
| | - Hemanth Kumar Manikyam
- Department of Chemistry, Faculty of science, North East Frontier Technical University, Arunachal Pradesh 791001, India
| | - Sukriti Vishwas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Kuldeep Singh
- Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
| | - Divya Jain
- Department of Microbiology, School of Applied and Life sciences, Uttaranchal University, Dehradun, Uttarakhand 248007, India.
| | - M V N L Chaitanya
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India.
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2
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Liu L, Dai J, Yang Q, Lv L. A comprehensive review on anti-allergic natural bioactive compounds for combating food allergy. Food Res Int 2025; 201:115565. [PMID: 39849714 DOI: 10.1016/j.foodres.2024.115565] [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: 07/20/2024] [Revised: 11/18/2024] [Accepted: 12/28/2024] [Indexed: 01/25/2025]
Abstract
Food allergy poses a great challenge to food safety and public health worldwide. Currently, clinical symptoms are primarily managed with medications, which can lead to drug resistance, adverse effects, and disruptions in gut flora balance. As a result, there has been a focus on researching safe and effective anti-allergic natural ingredients. This paper provides a comprehensive overview of food allergy mechanisms, methods of assessment of anti-food allergy studies, and a classification of natural substances with anti-allergic properties. It also examines the anti-allergic effects of these substances on food allergies and investigates gut microbiota changes induced by these natural bioactives, highlighting their significance to food allergies.Natural actives with anti-food allergic properties may alleviate allergic reactions through multiple targets and pathways. These mechanisms include promoting a shift in the Th1/Th2 balance, reducting IgE synthesis, preventing cellular degranulation and reducing the release of allergic mediator. The gut environment is closely related to food allergy and there is a significant interaction between the two. By targeting the intestinal flora, we can adopt dietary interventions to effectively address and control food allergies. This provides valuable insights for the future development of functional foods targeting the alleviation of food allergies.
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Affiliation(s)
- Lu Liu
- School of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, PR China
| | - Jing Dai
- School of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, PR China
| | - Qingli Yang
- School of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, PR China
| | - Liangtao Lv
- School of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, PR China.
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3
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Togni A, Piermartiri T, Tasca CI, Nedel CB. The intricate relationship between SUMOylation and gliomas: a review with a perspective on natural compounds. Nat Prod Res 2025:1-12. [PMID: 39849680 DOI: 10.1080/14786419.2025.2456093] [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: 09/20/2023] [Revised: 12/31/2024] [Accepted: 01/16/2025] [Indexed: 01/25/2025]
Abstract
Gliomas are tumours that affect the nervous system, with glioblastoma, also known as grade IV astrocytoma, being the most aggressive type, associated with poor prognosis. Glioblastoma is characterised by its highly invasive nature, rapid growth, and resistance to conventional chemotherapy and radiation treatments, resulting in a median survival of about 14 months. To improve patient outcomes, novel therapeutic approaches are needed. Targeting SUMOylation, a post-translational modification involving the attachment of Small Ubiquitin-like Modifier (SUMO) proteins to lysine residues in target proteins, is emerging as a promising strategy. SUMOylation regulates various biological processes, including the cell cycle, apoptosis, and senescence. Dysregulation of this pathway has been linked to glioblastoma tumorigenesis, as well as the invasion and proliferation of glioblastoma cells. Therefore, focusing on the SUMOylation pathway offers the potential for developing innovative therapeutic strategies, including the use of natural compounds as adjuvant therapies, to address glioblastoma more effectively.
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Affiliation(s)
- Anderson Togni
- Programa de Pós-Graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Tetsade Piermartiri
- Programa de Pós-Graduação em Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Carla Inês Tasca
- Programa de Pós-Graduação em Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Cláudia Beatriz Nedel
- Programa de Pós-Graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, Brazil
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4
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Zhu JW, Wang HM, Aisikaer M, Zhou WJ, Yang TT, Aximujiang K. Application of Chinese Medicine in Treatment of Ulcerative Colitis and Elucidation of Relevant Mechanisms. Chin J Integr Med 2025:10.1007/s11655-025-3824-y. [PMID: 39821880 DOI: 10.1007/s11655-025-3824-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2024] [Indexed: 01/19/2025]
Abstract
Ulcerative colitis (UC) is a chronic, non-specific intestinal disease of unknown etiology, with high incidence rates worldwide. At present, Western medicine treatments have been associated with more adverse effects and poor efficacy. Chinese medicine (CM) is commonly used as an adjuvant treatment for the unique advantages in regulating immune function, repairing intestinal mucosa, and alleviating intestinal inflammation. At the same time, network pharmacology is also providing new ideas and innovations about CM and development of new drugs. This review systematically discusses the progress of research regarding UC treatment using CM, with a main focus on intestinal flora balance, intestinal mucosal barrier, CM enema, acupuncture therapy, and acupoint embedding. This study provides new ideas that clarify the therapeutic targets of UC.
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Affiliation(s)
- Ji-Wei Zhu
- Xinjiang Medical University, Urumqi, 830017, China
| | | | | | - Wen-Jun Zhou
- Xinjiang Medical University, Urumqi, 830017, China
| | | | - Kasimujiang Aximujiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China.
- Xinjiang Key Laboratory of Molecular Biology for Endemic Disease, Urumqi, 830017, China.
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Campagna R, Cecati M, Vignini A. The Multifaceted Role of the Polyphenol Curcumin: A Focus on Type 2 Diabetes Mellitus. Curr Diabetes Rev 2025; 21:e15733998313402. [PMID: 39620334 DOI: 10.2174/0115733998313402240726080637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 06/18/2024] [Accepted: 06/26/2024] [Indexed: 04/23/2025]
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia, which often co-exists with other metabolic impairments. This condition can damage various tissues and organs, resulting in the development of severe complications, both microvascular, such as retinopathy, nephropathy, and neuropathy, and macrovascular, responsible for an increased risk of cardiovascular diseases. Curcumin is the main bioactive molecule found in the rhizomes of turmeric. Many studies have reported curcumin to exhibit antioxidant, anti-inflammatory, anti-infectious, and anti-cancer properties; thus, there is an increasing interest in exploiting these properties in order to prevent the rise or the progression of T2DM, as well as its possible associated conditions. In this review, we have presented the current state-ofart regarding the clinical trials that have involved curcumin administration and analyzed the possible mechanisms by which curcumin might exert the beneficial effects observed in literature.
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Affiliation(s)
- Roberto Campagna
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Monia Cecati
- Scientific Direction, Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy
| | - Arianna Vignini
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
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Manoharan S, Perumal E. A strategic review of STAT3 signaling inhibition by phytochemicals for cancer prevention and treatment: Advances and insights. Fitoterapia 2024; 179:106265. [PMID: 39437855 DOI: 10.1016/j.fitote.2024.106265] [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: 05/29/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024]
Abstract
Cancer remains a significant global health concern. The dysregulation of signaling networks in tumor cells greatly affects their functions. This review intends to explore phytochemicals possessing potent anticancer properties that specifically target the STAT3 signaling pathway, elucidating strategies and emphasizing their potential as promising candidates for cancer therapy. The review comprehensively examines various STAT3 inhibitors designed to disrupt the signaling cascade, including those targeting upstream activation, SH2 domain phosphorylation, DNA binding domain (DBD), N-terminal domain (NTD), nuclear translocation, and enhancing endogenous STAT3 negative regulators. A literature review was conducted to identify phytochemicals with anticancer activity targeting the STAT3 signaling pathway. Popular research databases such as Google Scholar, PubMed, Science Direct, Scopus, Web of Science, and ResearchGate were searched from the years 1989 - 2023 based on the keywords "Cancer", "STAT3", "Phytochemicals", "Phytochemicals targeting STAT3 signaling", "upstream activation of STAT3", "SH2 domain of STAT3", "DBD of STAT3", "NTD of STAT3, "endogenous negative regulators of STAT3", or "nuclear translocation of STAT3", and their combinations. A total of 264 relevant studies were selected and analyzed based on the mechanisms of action and the efficacy of the phytocompounds. The majority of the discussed phytochemicals primarily focus on inhibiting upstream activation of STAT3. Additionally, flavonoid and terpenoid compounds exhibit multifaceted effects by targeting one or more checkpoints within the STAT3 pathway. Analysis reveals that phytochemicals targeting upstream activation predominantly belong to the classes of flavonoids and terpenoids, which hold significant promise as effective anticancer therapeutics. Future research in this field can be directed towards exploring and developing these scrutinized classes of phytochemicals to achieve desired therapeutic outcomes in cancer treatment.
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Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India.
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Eren E, Das J, Tollefsbol TO. Polyphenols as Immunomodulators and Epigenetic Modulators: An Analysis of Their Role in the Treatment and Prevention of Breast Cancer. Nutrients 2024; 16:4143. [PMID: 39683540 PMCID: PMC11644657 DOI: 10.3390/nu16234143] [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: 11/05/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Breast cancer poses a substantial health challenge for women globally. Recently, there has been a notable increase in scholarly attention regarding polyphenols, primarily attributed to not only the adverse effects associated with conventional treatments but also their immune-preventive impacts. Polyphenols, nature-derived substances present in vegetation, including fruits and vegetables, have received considerable attention in various fields of science due to their probable wellness merits, particularly in the treatment and hindrance of cancer. This review focuses on the immunomodulatory effects of polyphenols in breast cancer, emphasizing their capacity to influence the reaction of adaptive and innate immune cells within the tumor-associated environment. Polyphenols are implicated in the modulation of inflammation, the enhancement of antioxidant defenses, the promotion of epigenetic modifications, and the support of immune functions. Additionally, these compounds have been shown to influence the activity of critical immune cells, including macrophages and T cells. By targeting pathways involved in immune evasion, polyphenols may augment the capacity of the defensive system to detect and eliminate tumors. The findings suggest that incorporating polyphenol-rich foods into the diet could offer a promising, collaborative (integrative) approach to classical breast cancer remedial procedures by regulating how the defense mechanism interacts with the disease.
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Affiliation(s)
- Esmanur Eren
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.E.); (J.D.)
| | - Jyotirmoyee Das
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.E.); (J.D.)
| | - Trygve O. Tollefsbol
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.E.); (J.D.)
- Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Research, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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8
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Li Y, Xu C, Weng W, Goel A. Combined treatment with Aronia berry extract and oligomeric proanthocyanidins exhibit a synergistic anticancer efficacy through LMNB1-AKT signaling pathways in colorectal cancer. Mol Carcinog 2024; 63:2145-2157. [PMID: 39282961 DOI: 10.1002/mc.23800] [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: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 10/04/2024]
Abstract
Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.
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Affiliation(s)
- Yuan Li
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California, USA
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Caiming Xu
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California, USA
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Wenhao Weng
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California, USA
- City of Hope Comprehensive Cancer Center, Duarte, California, USA
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Nicoletti CF, Assmann TS, Souza LL, Martinez JA. DNA Methylation and Non-Coding RNAs in Metabolic Disorders: Epigenetic Role of Nutrients, Dietary Patterns, and Weight Loss Interventions for Precision Nutrition. Lifestyle Genom 2024; 17:151-165. [PMID: 39481358 DOI: 10.1159/000541000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 08/14/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Dysregulation of epigenetic processes and abnormal epigenetic profiles are associated with various metabolic disorders. Nutrition, as an environmental factor, can induce epigenetic changes through both direct exposure and transgenerational inheritance, continuously altering gene expression and shaping the phenotype. Nutrients consumed through food or supplementation, such as vitamin B12, folate, vitamin B6, and choline, play a pivotal role in DNA methylation, a critical process for gene regulation. Additionally, there is mounting evidence that the expression of non-coding RNAs (ncRNAs) can be modulated by the intake of specific nutrients and natural compounds, thereby influencing processes involved in the onset and progression of metabolic diseases. SUMMARY Evidence suggests that dietary patterns, weight loss interventions, nutrients and nutritional bioactive compounds can modulate the expression of various microRNA (miRNAs) and DNA methylation levels, contributing to the development of metabolic disorders such as obesity and type 2 diabetes. Furthermore, several studies have proposed that DNA methylation and miRNA expression could serve as biomarkers for the effects of weight loss programs. KEY MESSAGE Despite ongoing debate regarding the effects of nutrient supplementation on DNA methylation levels and the expression of ncRNAs, certain DNA methylation marks and ncRNA expressions might predict the risk of metabolic disorders and act as biomarkers for forecasting the success of therapies within the framework of precision medicine and nutrition. The role of DNA methylation and miRNA expression as potential mediators of the effects of weight loss underscores their potential as biomarkers for the outcomes of weight loss programs. This highlights the influence of dietary patterns and weight loss interventions on the regulation of miRNA expression and DNA methylation levels, suggesting an interaction between these epigenetic factors and the body's response to weight loss.
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Affiliation(s)
- Carolina F Nicoletti
- Applied Physiology and Nutrition Research Group - Center of Lifestyle Medicine, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Taís S Assmann
- Postgraduate Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Leticia L Souza
- Applied Physiology and Nutrition Research Group - Center of Lifestyle Medicine, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - José Alfredo Martinez
- Precision Nutrition and Cardiometabolic Health, IMDEA-Food Institute (Madrid Institute for Advanced Studies), Campus of International Excellence (CEI) UAM+CSIC, Madrid, Spain
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Hridayanka KSN, Duttaroy AK, Basak S. Bioactive Compounds and Their Chondroprotective Effects for Osteoarthritis Amelioration: A Focus on Nanotherapeutic Strategies, Epigenetic Modifications, and Gut Microbiota. Nutrients 2024; 16:3587. [PMID: 39519419 PMCID: PMC11547880 DOI: 10.3390/nu16213587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/20/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
In degenerative joint disease like osteoarthritis (OA), bioactive compounds like resveratrol, epigallocatechin gallate, curcumin, and other polyphenols often target various signalling pathways, including NFκB, TGFβ, and Wnt/β-catenin by executing epigenetic-modifying activities. Epigenetic modulation can target genes of disease pathophysiology via histone modification, promoter DNA methylation, and non-coding RNA expression, some of which are directly involved in OA but have been less explored. OA patients often seek options that can improve the quality of their life in addition to existing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Although bioactive and natural compounds exhibit therapeutic potential against OA, several disadvantages loom, like insolubility and poor bioavailability. Nanoformulated bioactive compounds promise a better way to alleviate OA since they also control systemic events, including metabolic, immunological, and inflammatory responses, by modulating host gut microbiota that can regulate OA pathogenesis. Recent data suggest gut dysbiosis in OA. However, limited evidence is available on the role of bioactive compounds as epigenetic and gut modulators in ameliorating OA. Moreover, it is not known whether the effects of polyphenolic bioactive compounds on gut microbial response are mediated by epigenetic modulatory activities in OA. This narrative review highlights the nanotherapeutic strategies utilizing bioactive compounds, reporting their effects on chondrocyte growth, metabolism, and epigenetic modifications in osteoarthritis amelioration.
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Affiliation(s)
- Kota Sri Naga Hridayanka
- Molecular Biology Division, National Institute of Nutrition, Indian Council of Medical Research, Hyderabad 500007, India;
| | - Asim K. Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway;
| | - Sanjay Basak
- Molecular Biology Division, National Institute of Nutrition, Indian Council of Medical Research, Hyderabad 500007, India;
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Tripathi S, Bhawana. Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic. Neurochem Res 2024; 49:2319-2335. [PMID: 38856890 DOI: 10.1007/s11064-024-04167-z] [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: 01/31/2024] [Revised: 04/23/2024] [Accepted: 05/22/2024] [Indexed: 06/11/2024]
Abstract
Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.
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Affiliation(s)
- Shweta Tripathi
- Department of Paramedical Sciences, Faculty of Allied Health Sciences, SGT University, Gurugram, 122505, Haryana, India.
| | - Bhawana
- Department of Paramedical Sciences, Faculty of Allied Health Sciences, SGT University, Gurugram, 122505, Haryana, India
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12
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Li Y, Xu C, Han H, Pascual-Sabater S, Fillat C, Goel A. Aronia Berry Extract Modulates MYD88/NF-kB/P-Glycoprotein Axis to Overcome Gemcitabine Resistance in Pancreatic Cancer. Pharmaceuticals (Basel) 2024; 17:911. [PMID: 39065761 PMCID: PMC11279572 DOI: 10.3390/ph17070911] [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: 06/09/2024] [Revised: 06/30/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor survival rates, primarily due to the limited effectiveness of gemcitabine (Gem)-based chemotherapy, as well as the acquisition of chemotherapeutic resistance. Aronia berry extracts (ABEs), abundant in phenolic constituents, have been recently recognized for their anticancer properties as well as their encouraging potential to help overcome chemoresistance in various cancers. In the present study, we explored ABE's potential to overcome Gem resistance in PDAC and identify specific growth regulatory pathways responsible for its anticancer activity. Through a series of in vitro experiments in gemcitabine-resistant (Gem-R) cells, we elucidated the synergistic interactions between Gem and ABE treatments. Using advanced transcriptomic analysis and network pharmacology, we revealed key molecular pathways linked to chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. Subsequently, the findings from cell culture studies were validated in patient-derived 3D tumor organoids (PDOs). The combination treatment of ABE and Gem demonstrated significant synergism and anticancer effects on cell viability, proliferation, migration, and invasion in Gem-R cells. Transcriptomic analysis revealed a correlation between the NF-Κb signaling pathway and Gem-R (p < 0.05), exhibiting a marked upregulation of MYD88. Additionally, MYD88 exhibited a significant correlation with the overall survival rates in patients with PDAC patients in the TCGA cohort (HR = 1.58, p < 0.05). The MYD88/NF-Κb pathway contributes to chemoresistance by potentially upregulating efflux transporters like P-glycoprotein (P-gp). Our findings revealed that the combined treatment with ABE suppressed the NF-Κb pathway by targeting MYD88 and reducing P-gp expression to overcome Gem resistance. Lastly, the combination therapy proved highly effective in PDOs in reducing both their number and size (p < 0.05). Our study offers previously unrecognized insights into the ability of ABE to overcome Gem resistance in PDAC cells through its targeting of the MYD88/NF-κb/P-gp axis, hence providing a safe and cost-effective adjunctive therapeutic strategy to improve treatment outcomes in PDAC.
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Affiliation(s)
- Yuan Li
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA; (Y.L.); (C.X.)
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Caiming Xu
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA; (Y.L.); (C.X.)
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116004, China
| | - Haiyong Han
- Division of Molecular Medicine, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA;
| | - Silvia Pascual-Sabater
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-S.); (C.F.)
| | - Cristina Fillat
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-S.); (C.F.)
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA; (Y.L.); (C.X.)
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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13
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Bahman F, Al-Roub A, Akhter N, Al Madhoun A, Wilson A, Almansour N, Al-Rashed F, Sindhu S, Al-Mulla F, Ahmad R. TNF-α/Stearate Induced H3K9/18 Histone Acetylation Amplifies IL-6 Expression in 3T3-L1 Mouse Adipocytes. Int J Mol Sci 2024; 25:6776. [PMID: 38928498 PMCID: PMC11203872 DOI: 10.3390/ijms25126776] [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: 05/08/2024] [Revised: 06/11/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Extensive evidence supports the connection between obesity-induced inflammation and the heightened expression of IL-6 adipose tissues. However, the mechanism underlying the IL-6 exacerbation in the adipose tissue remains unclear. There is general agreement that TNF-α and stearate concentrations are mildly elevated in adipose tissue in the state of obesity. We hypothesize that TNF-α and stearate co-treatment induce the increased expression of IL-6 in mouse adipocytes. We therefore aimed to determine IL-6 gene expression and protein production by TNF-α/stearate treated adipocytes and investigated the mechanism involved. To test our hypothesis, 3T3-L1 mouse preadipocytes were treated with TNF-α, stearate, or TNF-α/stearate. IL-6 gene expression was assessed by quantitative real-time qPCR. IL-6 protein production secreted in the cell culture media was determined by ELISA. Acetylation of histone was analyzed by Western blotting. Il6 region-associated histone H3 lysine 9/18 acetylation (H3K9/18Ac) was determined by ChIP-qPCR. 3T3-L1 mouse preadipocytes were co-challenged with TNF-α and stearate for 24 h, which led to significantly increased IL-6 gene expression (81 ± 2.1 Fold) compared to controls stimulated with either TNF-α (38 ± 0.5 Fold; p = 0.002) or stearate (56 ± 2.0 Fold; p = 0.013). As expected, co-treatment of adipocytes with TNF-α and stearate significantly increased protein production (338 ± 11 pg/mL) compared to controls stimulated with either TNF-α (28 ± 0.60 pg/mL; p = 0.001) or stearate (53 ± 0.20 pg/mL, p = 0.0015). Inhibition of histone acetyltransferases (HATs) with anacardic acid or curcumin significantly reduced the IL-6 gene expression and protein production by adipocytes. Conversely, TSA-induced acetylation substituted the stimulatory effect of TNF-α or stearate in their synergistic interaction for driving IL-6 gene expression and protein production. Mechanistically, TNF-α/stearate co-stimulation increased the promoter-associated histone H3 lysine 9/18 acetylation (H3K9/18Ac), rendering a transcriptionally permissive state that favored IL-6 expression at the transcriptional and translational levels. Our data represent a TNF-α/stearate cooperativity model driving IL-6 expression in 3T3-L1 cells via the H3K9/18Ac-dependent mechanism, with implications for adipose IL-6 exacerbations in obesity.
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Affiliation(s)
- Fatemah Bahman
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
| | - Areej Al-Roub
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
| | - Nadeem Akhter
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
| | - Ashraf Al Madhoun
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Ajit Wilson
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
| | - Nourah Almansour
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
| | - Fatema Al-Rashed
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
| | - Sardar Sindhu
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Fahd Al-Mulla
- Translational Research Department, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Rasheed Ahmad
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (F.B.); (A.A.-R.); (N.A.); (A.W.); (N.A.); (F.A.-R.); (S.S.)
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14
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Bártová E. Epigenetic and gene therapy in human and veterinary medicine. ENVIRONMENTAL EPIGENETICS 2024; 10:dvae006. [PMID: 38751572 PMCID: PMC11095531 DOI: 10.1093/eep/dvae006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 04/12/2024] [Accepted: 05/08/2024] [Indexed: 05/18/2024]
Abstract
Gene therapy is a focus of interest in both human and veterinary medicine, especially in recent years due to the potential applications of CRISPR/Cas9 technology. Another relatively new approach is that of epigenetic therapy, which involves an intervention based on epigenetic marks, including DNA methylation, histone post-translational modifications, and post-transcription modifications of distinct RNAs. The epigenome results from enzymatic reactions, which regulate gene expression without altering DNA sequences. In contrast to conventional CRISP/Cas9 techniques, the recently established methodology of epigenetic editing mediated by the CRISPR/dCas9 system is designed to target specific genes without causing DNA breaks. Both natural epigenetic processes and epigenetic editing regulate gene expression and thereby contribute to maintaining the balance between physiological functions and pathophysiological states. From this perspective, knowledge of specific epigenetic marks has immense potential in both human and veterinary medicine. For instance, the use of epigenetic drugs (chemical compounds with therapeutic potential affecting the epigenome) seems to be promising for the treatment of cancer, metabolic, and infectious diseases. Also, there is evidence that an epigenetic diet (nutrition-like factors affecting epigenome) should be considered as part of a healthy lifestyle and could contribute to the prevention of pathophysiological processes. In summary, epigenetic-based approaches in human and veterinary medicine have increasing significance in targeting aberrant gene expression associated with various diseases. In this case, CRISPR/dCas9, epigenetic targeting, and some epigenetic nutrition factors could contribute to reversing an abnormal epigenetic landscape to a healthy physiological state.
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Affiliation(s)
- Eva Bártová
- Department of Cell Biology and Epigenetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, 612 00, the Czech Republic
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15
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Pozzo LD, Xu Z, Lin S, Wang J, Wang Y, Enechojo OS, Abankwah JK, Peng Y, Chu X, Zhou H, Bian Y. Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight. Biomed Pharmacother 2024; 174:116592. [PMID: 38615608 DOI: 10.1016/j.biopha.2024.116592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/07/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024] Open
Abstract
Multiple epigenetic factors play a regulatory role in maintaining the homeostasis of cutaneous components and are implicated in the aging process of the skin. They have been associated with the activation of the senescence program, which is the primary contributor to age-related decline in the skin. Senescent species drive a series of interconnected processes that impact the immediate surroundings, leading to structural changes, diminished functionality, and heightened vulnerability to infections. Geroprotective medicines that may restore the epigenetic balance represent valid therapeutic alliances against skin aging. Most of them are well-known Western medications such as metformin, nicotinamide adenine dinucleotide (NAD+), rapamycin, and histone deacetylase inhibitors, while others belong to Traditional Chinese Medicine (TCM) remedies for which the scientific literature provides limited information. With the help of the Geroprotectors.org database and a comprehensive analysis of the referenced literature, we have compiled data on compounds and formulae that have shown potential in preventing skin aging and have been identified as epigenetic modulators.
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Affiliation(s)
- Lisa Dal Pozzo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Zhe Xu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shan Lin
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jida Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ying Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ogbe Susan Enechojo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Joseph Kofi Abankwah
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yanfei Peng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiaoqian Chu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Huifang Zhou
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Yuhong Bian
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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16
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Kmail A. Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds. Open Life Sci 2024; 19:20220857. [PMID: 38645751 PMCID: PMC11032100 DOI: 10.1515/biol-2022-0857] [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: 11/11/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 04/23/2024] Open
Abstract
This study explores the effects of the Mediterranean diet, herbal remedies, and their phytochemicals on various gastrointestinal conditions and reviews the global use of medicinal plants for common digestive problems. The review highlights key plants and their mechanisms of action and summarizes the latest findings on how plant-based products influence the digestive system and how they work. We searched various sources of literature and databases, including Google Scholar, PubMed, Science Direct, and MedlinePlus. Our focus was on gathering relevant papers published between 2013 and August 2023. Certain plants exhibit potential in preventing or treating digestive diseases and cancers. Notable examples include Curcuma longa, Zingiber officinale, Aloe vera, Calendula officinalis, Lavandula angustifolia, Thymus vulgaris, Rosmarinus officinalis, Ginkgo biloba, Cynodon dactylon, and Vaccinium myrtillus. The phytochemical analysis of the plants showed that compounds such as quercetin, anthocyanins, curcumin, phenolics, isoflavones glycosides, flavonoids, and saponins constitute the main active substances within these plants. These natural remedies have the potential to enhance the digestive system and alleviate pain and discomfort in patients. However, further research is imperative to comprehensively evaluate the benefits and safety of herbal medicines to use their active ingredients for the development of natural and effective drugs.
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Affiliation(s)
- Abdalsalam Kmail
- Faculty of Sciences, Arab American University Jenin, P. O. Box 240, Jenin, Palestine
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17
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Castillo-Ordoñez WO, Cajas-Salazar N, Velasco-Reyes MA. Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents. Neural Regen Res 2024; 19:846-854. [PMID: 37843220 PMCID: PMC10664119 DOI: 10.4103/1673-5374.382232] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/15/2023] [Accepted: 07/18/2023] [Indexed: 10/17/2023] Open
Abstract
Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer's disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer's disease, known as familial Alzheimer's disease (onset < 65 years) and late-onset or sporadic Alzheimer's disease (onset ≥ 65 years). Patients with familial Alzheimer's disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer's disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer's disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer's disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer's disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer's disease-related genes.
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Affiliation(s)
- Willian Orlando Castillo-Ordoñez
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
- Departamento de Estudios Psicológicos, Universidad Icesi, Cali, Colombia
| | - Nohelia Cajas-Salazar
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
| | - Mayra Alejandra Velasco-Reyes
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
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18
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Tang Q, Ojiro R, Ozawa S, Zou X, Nakahara J, Nakao T, Koyanagi M, Jin M, Yoshida T, Shibutani M. DNA methylation-altered genes in the rat hippocampal neurogenic niche after continuous exposure to amorphous curcumin. J Chem Neuroanat 2024; 137:102414. [PMID: 38490283 DOI: 10.1016/j.jchemneu.2024.102414] [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: 11/05/2023] [Revised: 03/09/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
Rat offspring who are exposed to an amorphous formula of curcumin (CUR) from the embryonic stage have anti-anxiety-like behaviors, enhanced fear extinction learning, and increased synaptic plasticity in the hippocampal dentate gyrus (DG). In the present study, we investigated the links between genes with altered methylation status in the neurogenic niche and enhanced neural functions after CUR exposure. We conducted methylation and RNA sequencing analyses of the DG of CUR-exposed rat offspring on day 77 after delivery. Methylation status and transcript levels of candidate genes were validated using methylation-sensitive high-resolution melting and real-time reverse-transcription PCR, respectively. In the CUR group, we confirmed the hypermethylation and downregulation of Gpr150, Mmp23, Rprml, and Pcdh8 as well as the hypomethylation and upregulation of Ppm1j, Fam222a, and Opn3. Immunohistochemically, reprimo-like+ hilar cells and protocadherin-8+ granule cells were decreased and opsin-3+ hilar cells were increased by CUR exposure. Both reprimo-like and opsin-3 were partially expressed on subpopulations of glutamic acid decarboxylase 67+ γ-aminobutyric acid-ergic interneurons. Furthermore, the transcript levels of genes involved in protocadherin-8-mediated N-cadherin endocytosis were altered with CUR exposure; this was accompanied by Ctnnb1 and Syp upregulation and Mapk14, Map2k3, and Grip1 downregulation, suggesting that CUR-induced enhanced synaptic plasticity is associated with cell adhesion. Together, our results indicate that functionally different genes have altered methylation and expression in different neuronal populations of the hippocampal neurogenic niche, thus enhancing synaptic plasticity after CUR exposure.
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Affiliation(s)
- Qian Tang
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Ryota Ojiro
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Shunsuke Ozawa
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Xinyu Zou
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Junta Nakahara
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Tomohiro Nakao
- Emulsion Laboratory, San-Ei Gen F.F.I., Inc., 1-1-11 Sanwa-cho, Toyonaka-shi, Osaka 561-8588, Japan
| | - Mihoko Koyanagi
- Global Scientific and Regulatory Affairs, San-Ei Gen F.F.I., Inc., 1-1-11 Sanwa-cho, Toyonaka-shi, Osaka 561-8588, Japan
| | - Meilan Jin
- Laboratory of Veterinary Pathology, College of Veterinary Medicine, Southwest University, No. 2 Tiansheng Road, BeiBei District, Chongqing 400715, PR China
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
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19
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Burenkova OV, Grigorenko EL. The role of epigenetic mechanisms in the long-term effects of early-life adversity and mother-infant relationship on physiology and behavior of offspring in laboratory rats and mice. Dev Psychobiol 2024; 66:e22479. [PMID: 38470450 PMCID: PMC10959231 DOI: 10.1002/dev.22479] [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: 09/15/2023] [Revised: 01/23/2024] [Accepted: 02/16/2024] [Indexed: 03/13/2024]
Abstract
Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal-child relationships modeling early-life adversity (ELA) in laboratory rats and mice have a strong long-term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother-infant relationship, with a focus on the regulation of hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research.
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Affiliation(s)
- Olga V. Burenkova
- Department of Psychology, University of Houston, Houston, Texas, USA
- Texas Institute for Measurement, Evaluation, and Statistics, University of Houston, Houston, Texas, USA
- Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada
| | - Elena L. Grigorenko
- Department of Psychology, University of Houston, Houston, Texas, USA
- Texas Institute for Measurement, Evaluation, and Statistics, University of Houston, Houston, Texas, USA
- Center for Cognitive Sciences, Sirius University of Science and Technology, Sochi, Russia
- Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Child Study Center, Yale University, New Haven, Connecticut, USA
- Research Administration, Moscow State University for Psychology and Education, Moscow, Russia
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20
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Zhang H, Wang H, Qin L, Lin S. Garlic-derived compounds: Epigenetic modulators and their antitumor effects. Phytother Res 2024; 38:1329-1344. [PMID: 38194996 DOI: 10.1002/ptr.8108] [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: 10/15/2023] [Revised: 11/26/2023] [Accepted: 12/09/2023] [Indexed: 01/11/2024]
Abstract
Cancer is a highly heterogeneous disease that poses a serious threat to human health worldwide. Despite significant advances in the diagnosis and treatment of cancer, the prognosis and survival rate of cancer remain poor due to late diagnosis, drug resistance, and adverse reactions. Therefore, it is very necessary to study the development mechanism of cancer and formulate effective therapeutic interventions. As widely available bioactive substances, natural products have shown obvious anticancer potential, especially by targeting abnormal epigenetic changes. The main active part of garlic is organic sulfur compounds, of which diallyl trisulfide (DATS) content is the highest, accounting for more than 40% of the total composition. The garlic-derived compounds have been recognized as an antioxidant for cancer prevention and treatment. However, the molecular mechanism of the antitumor effect of garlic-derived compounds remains unclear. Recent studies have identified garlic-derived compound DATS that plays critical roles in enhancing CpG demethylation or promoting histone acetylation as an epigenetic inhibitor. Here, we review the therapeutic progress of garlic-derived compounds against cancer through epigenetic pathways.
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Affiliation(s)
- Huan Zhang
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Haichao Wang
- Institute of Resources and Environment, Beijing Academy of Science and Technology, Beijing, China
| | - Lin Qin
- Department of Endoscopic Diagnosis and Treatment, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Shuye Lin
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
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21
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Manoharan S, Saha S, Murugesan K, Santhakumar A, Perumal E. Natural bioactive compounds and STAT3 against hepatocellular carcinoma: An update. Life Sci 2024; 337:122351. [PMID: 38103726 DOI: 10.1016/j.lfs.2023.122351] [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: 09/17/2023] [Revised: 11/23/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences.
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Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Shreejit Saha
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Krishnasanthiya Murugesan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Aksayakeerthana Santhakumar
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India.
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22
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Islam MR, Rauf A, Akash S, Trisha SI, Nasim AH, Akter M, Dhar PS, Ogaly HA, Hemeg HA, Wilairatana P, Thiruvengadam M. Targeted therapies of curcumin focus on its therapeutic benefits in cancers and human health: Molecular signaling pathway-based approaches and future perspectives. Biomed Pharmacother 2024; 170:116034. [PMID: 38141282 DOI: 10.1016/j.biopha.2023.116034] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 12/08/2023] [Accepted: 12/14/2023] [Indexed: 12/25/2023] Open
Abstract
The curry powder spices turmeric (Curcuma longa L.), which contains curcumin (diferuloylmethane), an orange-yellow chemical. Polyphenols are the most commonly used sources of curcumin. It combats oxidative stress and inflammation in diseases, such as hyperlipidemia, metabolic syndrome, arthritis, and depression. Most of these benefits are due to their anti-inflammatory and antioxidant properties. Curcumin consumption leads to decreased bioavailability, resulting in limited absorption, quick metabolism, and quick excretion, which hinders health improvement. Numerous factors can increase its bioavailability. Piperine enhances bioavailability when combined with curcumin in a complex. When combined with other enhancing agents, curcumin has a wide spectrum of health benefits. This review evaluates the therapeutic potential of curcumin with a specific emphasis on its approach based on molecular signaling pathways. This study investigated its influence on the progression of cancer, inflammation, and many health-related mechanisms, such as cell proliferation, apoptosis, and metastasis. Curcumin has a significant potential for the prevention and treatment of various diseases. Curcumin modulates several biochemical pathways and targets involved in cancer growth. Despite its limited tissue accumulation and bioavailability when administered orally, curcumin has proven useful. This review provides an in-depth analysis of curcumin's therapeutic applications, its molecular signaling pathway-based approach, and its potential for precision medicine in cancer and human health.
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Affiliation(s)
- Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar 23561, Khyber Pakhtunkhwa, Pakistan.
| | - Shopnil Akash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Sadiya Islam Trisha
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Akram Hossain Nasim
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Muniya Akter
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Puja Sutro Dhar
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Hanan A Ogaly
- Chemistry Department, College of Science, King Khalid University, Abha 61421, Saudi Arabia
| | - Hassan A Hemeg
- Department of Medical Laboratory Technology, College of Applied Medical Sciences, Taibah University, Al-Medinah Al-Monawara, Saudi Arabia
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
| | - Muthu Thiruvengadam
- Department of Applied Bioscience, College of Life and Environmental Science, Konkuk University, Seoul 05029, Republic of Korea; Department of Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, India.
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Schatten H. The Impact of Centrosome Pathologies on Ovarian Cancer Development and Progression with a Focus on Centrosomes as Therapeutic Target. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1452:37-64. [PMID: 38805124 DOI: 10.1007/978-3-031-58311-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
The impact of centrosome abnormalities on cancer cell proliferation has been recognized as early as 1914 (Boveri, Zur Frage der Entstehung maligner Tumoren. Jena: G. Fisher, 1914), but vigorous research on molecular levels has only recently started when it became fully apparent that centrosomes can be targeted for new cancer therapies. While best known for their microtubule-organizing capabilities as MTOC (microtubule organizing center) in interphase and mitosis, centrosomes are now further well known for a variety of different functions, some of which are related to microtubule organization and consequential activities such as cell division, migration, maintenance of cell shape, and vesicle transport powered by motor proteins, while other functions include essential roles in cell cycle regulation, metabolic activities, signal transduction, proteolytic activity, and several others that are now heavily being investigated for their role in diseases and disorders (reviewed in Schatten and Sun, Histochem Cell Biol 150:303-325, 2018; Schatten, Adv Anat Embryol Cell Biol 235:43-50, 2022a; Schatten, Adv Anat Embryol Cell Biol 235:17-35, 2022b).Cancer cell centrosomes differ from centrosomes in noncancer cells in displaying specific abnormalities that include phosphorylation abnormalities, overexpression of specific centrosomal proteins, abnormalities in centriole and centrosome duplication, formation of multipolar spindles that play a role in aneuploidy and genomic instability, and several others that are highlighted in the present review on ovarian cancer. Ovarian cancer cell centrosomes, like those in other cancers, display complex abnormalities that in part are based on the heterogeneity of cells in the cancer tissues resulting from different etiologies of individual cancer cells that will be discussed in more detail in this chapter.Because of the critical role of centrosomes in cancer cell proliferation, several lines of research are being pursued to target centrosomes for therapeutic intervention to inhibit abnormal cancer cell proliferation and control tumor progression. Specific centrosome abnormalities observed in ovarian cancer will be addressed in this chapter with a focus on targeting such aberrations for ovarian cancer-specific therapies.
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Affiliation(s)
- Heide Schatten
- University of Missouri-Columbia Department of Veterinary Pathobiology, Columbia, MO, USA.
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Klotz LO, Carlberg C. Nutrigenomics and redox regulation: Concepts relating to the Special Issue on nutrigenomics. Redox Biol 2023; 68:102920. [PMID: 37839954 PMCID: PMC10624588 DOI: 10.1016/j.redox.2023.102920] [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: 08/17/2023] [Revised: 09/21/2023] [Accepted: 10/03/2023] [Indexed: 10/17/2023] Open
Abstract
During our whole lifespan, from conception to death, the epigenomes of all tissues and cell types of our body integrate signals from the environment. This includes signals derived from our diet and the uptake of macro- and micronutrients. In most cases, this leads only to transient changes, but some effects of this epigenome programming process are persistent and can even be transferred to the next generation. Both epigenetic programming and redox processes are affected by the individual choice of diet and other lifestyle decisions like physical activity. The nutrient-gene communication pathways have adapted during human evolution and are essential for maintaining health. However, when they are maladaptive, such as in long-term obesity, they significantly contribute to diseases like type 2 diabetes and cancer. The field of nutrigenomics investigates nutrition-related signal transduction pathways and their effect on gene expression involving interactions both with the genome and the epigenomes. Several of these diet-(epi)genome interactions and the involved signal transduction cascades are redox-regulated. Examples include the effects of the NAD+/NADH ratio, vitamin C levels and secondary metabolites of dietary molecules from plants on the acetylation and methylation state of the epigenome as well as on gene expression through redox-sensitive pathways via the transcription factors NFE2L2 and FOXO. In this review, we summarize and extend on these topics as well as those discussed in the articles of this Special Issue and take them into the context of redox biology.
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Affiliation(s)
- Lars-Oliver Klotz
- Institute of Nutritional Sciences, Nutrigenomics Section, Friedrich Schiller University Jena, Jena, Germany
| | - Carsten Carlberg
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, PL-10-748, Olsztyn, Poland; School of Medicine, Institute of Biomedicine, University of Eastern Finland, FI-70211, Kuopio, Finland.
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Castillo Ordoñez WO, Aristizabal-Pachon AF, Alves LB, Giuliatti S. Epigenetic regulation exerted by Caliphruria subedentata and galantamine: an in vitro and in silico approach for mimic Alzheimer's disease. J Biomol Struct Dyn 2023; 42:11215-11230. [PMID: 37814967 DOI: 10.1080/07391102.2023.2261034] [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: 04/18/2023] [Accepted: 09/13/2023] [Indexed: 10/11/2023]
Abstract
At the interface between genes and environment, epigenetic mechanisms, including DNA methylation and histone modification, regulate neurogenic processes such as differentiation, proliferation, and maturation of neural stem cells. However, these mechanisms are altered in Alzheimer's disease (AD), a neurodegenerative condition that mainly affects older adults. Since epigenetic mechanisms are known to be reversible, a number of molecules from natural sources are being studied as epigenetic regulators in AD. Recently, in vitro and in silico studies have shown that C. subedentata and its alkaloids modulated neurotoxicity. However, studies exploring the epigenetic activity of these alkaloids are limited. We conducted a set of bioassays to evaluate neuronal differentiation and the sensitivity of undifferentiated SH-SY5 cells against a neurotoxic stimulus. In addition, we analyzed the methylation profiles in genes such as APP, PSI, and BACE1 due to their role in amyloid processing. Docking and molecular dynamic analysis were used to explore the effect exerted by C. subedentata alkaloids on the regulation of histone deacetylases (HDAC2, HDAC3 and HDAC7). The results demonstrated that C. subedentata and galantamine induce neuronal differentiation and protect the undifferentiated SH-SY5Y cells against Aβ(1-42)-induced neurotoxicity. The methylation profiles of the studied genes show no statistically significant differences between C. subedentata, galantamine. However, these findings should be interpreted with caution, since small changes in methylation promoters in the brain could not be easily detected. Results from in silico approaches describe for the first time the potential promissing epigenetic effects of galantamine by regulating HDAC3 and HDAC7 modification.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Willian Orlando Castillo Ordoñez
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología, Universidad del Cauca, Popayán-Cauca, Colombia
- Departamento de Estudios Psicológicos, Universidad Icesi, Cali, Colombia
| | - Andrés F Aristizabal-Pachon
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Levy Bueno Alves
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo-USP, Brazil
| | - Silvana Giuliatti
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo-USP, Brazil
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Yaskolka Meir A, Yun H, Stampfer MJ, Liang L, Hu FB. Nutrition, DNA methylation and obesity across life stages and generations. Epigenomics 2023; 15:991-1015. [PMID: 37933548 DOI: 10.2217/epi-2023-0172] [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] [Indexed: 11/08/2023] Open
Abstract
Obesity is a complex multifactorial condition that often manifests in early life with a lifelong burden on metabolic health. Diet, including pre-pregnancy maternal diet, in utero nutrition and dietary patterns in early and late life, can shape obesity development. Growing evidence suggests that epigenetic modifications, specifically DNA methylation, might mediate or accompany these effects across life stages and generations. By reviewing human observational and intervention studies conducted over the past 10 years, this work provides a comprehensive overview of the evidence linking nutrition to DNA methylation and its association with obesity across different age periods, spanning from preconception to adulthood and identify future research directions in the field.
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Affiliation(s)
- Anat Yaskolka Meir
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Huan Yun
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Meir J Stampfer
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Department of Medicine, Channing Division of Network Medicine, Brigham & Women's Hospital & Harvard Medical School, Boston, MA 02115, USA
| | - Liming Liang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Frank B Hu
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Department of Medicine, Channing Division of Network Medicine, Brigham & Women's Hospital & Harvard Medical School, Boston, MA 02115, USA
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Mahmoudi Z, Jahani M, Nekouian R. Role of curcumin on miR-26a and its effect on DNMT1, DNMT3b, and MEG3 expression in A549 lung cancer cell. J Cancer Res Ther 2023; 19:1788-1793. [PMID: 38376279 DOI: 10.4103/jcrt.jcrt_2181_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 12/28/2021] [Indexed: 02/21/2024]
Abstract
CONTEXT Most of the patients diagnosed with non-small cell lung cancer (NSCLC) are in their advanced stages and as a result might not be cured in spite of the advances in aimed therapy. In the recent years, the role of noncoding RNAs (ncRNAs) has been expanded to cancer as potential targets for RNA-based epigenetic therapies. Curcumin, as an active ingredient, is associated with epigenetic alterations, and it might modulate the expression of tumor suppressor and oncogenic microRNAs. MATERIALS AND METHODS In this study, we investigated the RNA-based epigenetic effects of curcumin on NSCLC, and the effect of curcumin on A549 cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The expression of miR-26a, MEG3, DNA methyltransferase 1 (DNMT1), and DNMT3 beta (DNMT3b) was assessed by quantitative polymerase chain reaction. STATISTICAL ANALYSIS USED Data analysis was done using Prism®6 software (GraphPad Software, Inc., La Jolla, CA, USA), and statistical analysis was performed using t-test between control and vitality samples. RESULTS The results showed a significant increase (P < 0.05) of miR-26a expression which in turn was associated with a significant decrease (P < 0.05) in expression of DNMTs and subsequently a significant increase in MEG3 expression (P < 0.05) in A549 cell line after adding curcumin in the media. CONCLUSION Considering all the data together, we could speculate the role of curcumin in ceasing the progression of cancer in its early stages and might be considered a potential drug for the treatment of NSCLC-derived lung cancer by establishing a meaningful relationship between epigenetic mechanisms and ncRNAs.
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Affiliation(s)
- Zahra Mahmoudi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Jahani
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Nekouian
- Department of Medical Biotechnology, School of Allied Medicine, Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
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Baharara H, Kesharwani P, Johnston TP, Sahebkar A. Therapeutic potential of phytochemicals for cystic fibrosis. Biofactors 2023; 49:984-1009. [PMID: 37191383 DOI: 10.1002/biof.1960] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 05/01/2023] [Indexed: 05/17/2023]
Abstract
The aim of this review was to review and discuss various phytochemicals that exhibit beneficial effects on mutated membrane channels, and hence, improve transmembrane conductance. These therapeutic phytochemicals may have the potential to decrease mortality and morbidity of CF patients. Four databases were searched using keywords. Relevant studies were identified, and related articles were separated. Google Scholar, as well as gray literature (i.e., information that is not produced by commercial publishers), were also checked for related articles to locate/identify additional studies. The relevant databases were searched a second time to ensure that recent studies were included. In conclusion, while curcumin, genistein, and resveratrol have demonstrated effectiveness in this regard, it should be emphasized that coumarins, quercetin, and other herbal medicines also have beneficial effects on transporter function, transmembrane conductivity, and overall channel activity. Additional in vitro and in vivo studies should be conducted on mutant CFTR to unequivocally define the mechanism by which phytochemicals alter transmembrane channel function/activity, since the results of the studies evaluated in this review have a high degree of heterogenicity and discrepancy. Finally, continued research be undertaken to clearly define the mechanism(s) of action and the therapeutic effects that therapeutic phytochemicals have on the symptoms observed in CF patients in an effort to reduce mortality and morbidity.
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Affiliation(s)
- Hamed Baharara
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai, India
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - AmirHossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Okuno K, Pratama MY, Li J, Tokunaga M, Wang X, Kinugasa Y, Goel A. Ginseng mediates its anticancer activity by inhibiting the expression of DNMTs and reactivating methylation-silenced genes in colorectal cancer. Carcinogenesis 2023; 44:394-403. [PMID: 37137336 PMCID: PMC10414140 DOI: 10.1093/carcin/bgad025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/26/2023] [Accepted: 05/01/2023] [Indexed: 05/05/2023] Open
Abstract
Developing safe and effective therapeutic modalities remains a critical challenge for improving the prognosis of patients with colorectal cancer (CRC). In this regard, targeting epigenetic regulation in cancers has recently emerged as a promising therapeutic approach. Since several natural compounds have recently been shown to be important epigenetic modulators, we hypothesized that Ginseng might exert its anticancer activity by regulating DNA methylation alterations in CRC. In this study, a series of cell culture studies were conducted, followed by their interrogation in patient-derived 3D organoid models to evaluate Ginseng's anticancer activity in CRC. Genome-wide methylation alterations were interrogated by undertaking MethylationEpic BeadChip microarrays. First, 50% inhibitory concentrations (IC50) were determined by cell viability assays, and subsequent Ginseng treatment demonstrated a significant anticancer effect on clonogenicity and cellular migration in CRC cells. Treatment with Ginseng potentiated cellular apoptosis through regulation of apoptosis-related genes in CRC cells. Furthermore, Ginseng treatment downregulated the expression of DNA methyltransferases (DNMTs) and decreased the global DNA methylation levels in CRC cells. The genome-wide methylation profiling identified Ginseng-induced hypomethylation of transcriptionally silenced tumor suppressor genes. Finally, cell culture-based findings were successfully validated in patient-derived 3D organoids. In conclusion, we demonstrate that Ginseng exerts its antitumorigenic potential by regulating cellular apoptosis via the downregulation of DNMTs and reversing the methylation status of transcriptionally silenced genes in CRC.
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Affiliation(s)
- Keisuke Okuno
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Muhammad Yogi Pratama
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
| | - Jiang Li
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, SAR, 518057, China
| | - Masanori Tokunaga
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Xin Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, SAR, 518057, China
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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Abubakar B, Usman D, Sanusi KO, Azmi NH, Imam MU. Preventive Epigenetic Mechanisms of Functional Foods for Type 2 Diabetes. DIABETOLOGY 2023; 4:259-277. [DOI: 10.3390/diabetology4030023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
Type 2 diabetes (T2D) is a growing global health problem that requires new and effective prevention and management strategies. Recent research has highlighted the role of epigenetic changes in the development and progression of T2D, and the potential of functional foods as a complementary therapy for the disease. This review aims to provide an overview of the current state of knowledge on the preventive epigenetic mechanisms of functional foods in T2D. We provide background information on T2D and its current treatment approaches, an explanation of the concept of epigenetics, and an overview of the different functional foods with demonstrated preventive epigenetic effects in T2D. We also discuss the epigenetic mechanisms by which these functional foods prevent or manage T2D, and the studies that have investigated their preventive epigenetic effects. In addition, we revisit works on the beneficial influence of functional foods against the programming and complications of parentally-triggered offspring diabetes. We also suggest, albeit based on scarce data, that epigenetic inheritance mechanistically mediates the impacts of functional nutrition against the metabolic risk of diabetes in offspring. Finally, our review highlights the importance of considering the preventive epigenetic mechanisms of functional foods as a potential avenue for the development of new prevention and management strategies for T2D.
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Affiliation(s)
- Bilyaminu Abubakar
- Department of Pharmacology and Toxicology, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Dawoud Usman
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
- Department of Physiology, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Kamaldeen Olalekan Sanusi
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
- Department of Physiology, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Nur Hanisah Azmi
- Faculty of Food Science and Nutrition, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia
| | - Mustapha Umar Imam
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
- Department of Medical Biochemistry, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
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Galkin F, Kovalchuk O, Koldasbayeva D, Zhavoronkov A, Bischof E. Stress, diet, exercise: Common environmental factors and their impact on epigenetic age. Ageing Res Rev 2023; 88:101956. [PMID: 37211319 DOI: 10.1016/j.arr.2023.101956] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/13/2023] [Accepted: 05/15/2023] [Indexed: 05/23/2023]
Abstract
Epigenetic aging clocks have gained significant attention as a tool for predicting age-related health conditions in clinical and research settings. They have enabled geroscientists to study the underlying mechanisms of aging and assess the effectiveness of anti-aging therapies, including diet, exercise and environmental exposures. This review explores the effects of modifiable lifestyle factors' on the global DNA methylation landscape, as seen by aging clocks. We also discuss the underlying mechanisms through which these factors contribute to biological aging and provide comments on what these findings mean for people willing to build an evidence-based pro-longevity lifestyle.
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Affiliation(s)
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Canada
| | | | - Alex Zhavoronkov
- Deep Longevity, Hong Kong; Insilico Medicine, Hong Kong; Buck Institute for Research on Aging, Novato, CA, USA
| | - Evelyne Bischof
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Shanghai University of Medicine and Health Sciences, Shanghai, China; Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Via S. Pansini, 580131, Naples, Italy
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Miyazaki K, Xu C, Shimada M, Goel A. Curcumin and Andrographis Exhibit Anti-Tumor Effects in Colorectal Cancer via Activation of Ferroptosis and Dual Suppression of Glutathione Peroxidase-4 and Ferroptosis Suppressor Protein-1. Pharmaceuticals (Basel) 2023; 16:383. [PMID: 36986483 PMCID: PMC10055708 DOI: 10.3390/ph16030383] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 02/24/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. The limitations of current chemotherapeutic drugs in CRC include their toxicity, side effects, and exorbitant costs. To assess these unmet needs in CRC treatment, several naturally occurring compounds, including curcumin and andrographis, have gained increasing attention due to their multi-targeted functionality and safety vs. conventional drugs. In the current study, we revealed that a combination of curcumin and andrographis exhibited superior anti-tumor effects by inhibiting cell proliferation, invasion, colony formation, and inducing apoptosis. Genome-wide transcriptomic expression profiling analysis revealed that curcumin and andrographis activated the ferroptosis pathway. Moreover, we confirmed the gene and protein expression of glutathione peroxidase 4 (GPX-4) and ferroptosis suppressor protein 1 (FSP-1), the two major negative regulators of ferroptosis, were downregulated by this combined treatment. With this regimen, we also observed that intracellular accumulation of reactive oxygen species and lipid peroxides were induced in CRC cells. These cell line findings were validated in patient-derived organoids. In conclusion, our study revealed that combined treatment with curcumin and andrographis exhibited anti-tumorigenic effects in CRC cells through activation of ferroptosis and by dual suppression of GPX-4 and FSP-1, which have significant potential implications for the adjunctive treatment of CRC patients.
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Affiliation(s)
- Katsuki Miyazaki
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA 91016, USA
- Department of Surgery, Tokushima University, Tokushima 770-0042, Japan
| | - Caiming Xu
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA 91016, USA
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116004, China
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima 770-0042, Japan
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA 91016, USA
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Ramakrishnan J, Magudeeswaran S, Suresh S, Poomani K. Investigation of intermolecular interactions and binding mechanism of PU139 and PU141 molecules with p300 HAT enzyme via molecular docking, molecular dynamics simulations and binding free energy analysis. J Biomol Struct Dyn 2023; 41:1351-1365. [PMID: 34974819 DOI: 10.1080/07391102.2021.2020164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The p300 histone acetyltransferase (HAT) enzyme acetylates the lysine residue of histone promotes the transcription reaction. The abnormal function of p300 HAT enzyme causes various diseases such as Cancer, Asthma, Alzheimer, Diabetics, and AIDS. In the recent years, several studies have been conducted to design potential drug to inhibit this enzyme. Recently, an in vitro study has been performed on the synthetic molecules PU139 and PU141 to inhibit the p300 HAT enzyme. The present study aims to understand the binding affinity, intermolecular interactions, conformational stability and binding energy of PU139 and PU141 molecules in the active site of p300 HAT enzyme from the in silico studies. The molecular docking and molecular dynamics (MD) simulations were carried out for both ligands with the p300 HAT enzyme. The molecular docking and MD simulations reveals that both molecules forms expected interactions with the catalytic site key residues of p300 enzyme. The MD simulation shows the maximum RMSD value for the PU141 is 2.3 Å, whereas for PU139 is 3.3 Å; these low RMSD values indicate that both molecules are highly stable in the active site of p300. The calculated binding free energy of PU141 (-20.62 kcal/mol) is higher than the molecule PU139 (-17.67 kcal/mol). Among the results, PU141 shows the high binding affinity with p300 while comparing with PU139. The results of this in-silico study coupled with the findings reported in the in vitro study confirm that PU141 may be suitable for clinical study.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Jaganathan Ramakrishnan
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Sivanandam Magudeeswaran
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Suganya Suresh
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Kumaradhas Poomani
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
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Kour S, Biswas I, Sheoran S, Arora S, Sheela P, Duppala SK, Murthy DK, Pawar SC, Singh H, Kumar D, Prabhu D, Vuree S, Kumar R. Artificial intelligence and nanotechnology for cervical cancer treatment: Current status and future perspectives. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
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Martínez-Iglesias O, Naidoo V, Carrera I, Corzo L, Cacabelos R. Natural Bioactive Products as Epigenetic Modulators for Treating Neurodegenerative Disorders. Pharmaceuticals (Basel) 2023; 16:216. [PMID: 37259364 PMCID: PMC9967112 DOI: 10.3390/ph16020216] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/26/2023] [Accepted: 01/28/2023] [Indexed: 08/27/2023] Open
Abstract
Neurodegenerative disorders (NDDs) are major health issues in Western countries. Despite significant efforts, no effective therapeutics for NDDs exist. Several drugs that target epigenetic mechanisms (epidrugs) have been recently developed for the treatment of NDDs, and several of these are currently being tested in clinical trials. Furthermore, various bioproducts have shown important biological effects for the potential prevention and treatment of these disorders. Here, we review the use of natural products as epidrugs to treat NDDs in order to explore the epigenetic effects and benefits of functional foods and natural bioproducts on neurodegeneration.
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Affiliation(s)
- Olaia Martínez-Iglesias
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
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Kang D, Khan MA, Song P, Liu Y, Wu Y, Ai P, Li Z, Wang Z. Comparative analysis of the chrysanthemum transcriptome with DNA methylation inhibitors treatment and silencing MET1 lines. BMC PLANT BIOLOGY 2023; 23:47. [PMID: 36670371 PMCID: PMC9862865 DOI: 10.1186/s12870-023-04036-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 01/02/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND As one of the ten most famous flowers in China, the chrysanthemum has rich germplasm with a variety of flowering induction pathways, most of which are photoperiod-induced. After treatment with DNA methylation inhibitors, it was found that DNA methylation plays an important role in flowering regulation, but the mechanism of action remains unclear. Therefore, in this study, curcumin, 5-azaC, their mixed treatment, and MET1-RNAi lines were used for transcriptome sequencing to find out how different treatments affected gene expression in chrysanthemums at different stages of flowering. RESULTS Genomic DNA methylation levels were measured using HPLC technology. The methylation level of the whole genome in the vegetative growth stage was higher than that in the flowering stage. The methylation level of DNA in the vegetative growth stage was the lowest in the curcumin and mixed treatment, and the methylation level of DNA in the transgenic line, mixed treatment, and curcumin treatment was the lowest in the flowering stage. The flowering rate of mixed treatment and curcumin treatment was the lowest. Analysis of differentially expressed genes in transcriptomes showed that 5-azaC treatment had the most differentially expressed genes, followed by curcumin and transgenic lines, and mixed treatment had the fewest. In addition, 5-azaC treatment resulted in the differential expression of multiple DNA methylation transferases, which led to the differential expression of many genes. Analysis of differentially expressed genes in different treatments revealed that different treatments had gene specificity. However, the down-regulated GO pathway in all 4 treatments was involved in the negative regulation of the reproductive process, and post-embryonic development, and regulation of flower development. Several genes associated with DNA methylation and flowering regulation showed differential expression in response to various treatments. CONCLUSIONS Both DNA methylase reagent treatment and targeted silencing of the MET1 gene can cause differential expression of the genes. The operation of the exogenous application is simple, but the affected genes are exceedingly diverse and untargeted. Therefore, it is possible to construct populations with DNA methylation phenotypic diversity and to screen genes for DNA methylation regulation.
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Affiliation(s)
- Dongru Kang
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
| | - Muhammad Ayoub Khan
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
| | - Pan Song
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
| | - Yvru Liu
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
| | - Yifei Wu
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
| | - Penghui Ai
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
| | - Zhongai Li
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
| | - Zicheng Wang
- State Key Laboratory of Crop Stress Adaptation and Improvement, Plant Germplasm Resources and Genetic Laboratory, Kaifeng Key Laboratory of Chrysanthemum Biology, School of Life Sciences, Henan University. Jinming Road, Kaifeng, 475004 Henan China
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Okuno K, Xu C, Pascual-Sabater S, Tokunaga M, Takayama T, Han H, Fillat C, Kinugasa Y, Goel A. Andrographis Reverses Gemcitabine Resistance through Regulation of ERBB3 and Calcium Signaling Pathway in Pancreatic Ductal Adenocarcinoma. Biomedicines 2023; 11:119. [PMID: 36672630 PMCID: PMC9855441 DOI: 10.3390/biomedicines11010119] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, primarily due to intrinsic or acquired resistance to chemotherapy, such as Gemcitabine (Gem). Naturally occurring botanicals, including Andrographis (Andro), can help enhance the anti-tumorigenic therapeutic efficacy of conventional chemotherapy through time-tested safety and cost-effectiveness. Accordingly, we hypothesized that Andro might reverse Gem resistance in PDAC. The critical regulatory pathways associated with Gem resistance in PDAC were identified by analyzing publicly available transcriptomic profiling and PDAC tissue specimens. A series of systematic in vitro experiments were performed using Gem-resistant (Gem-R) PDAC cells and patient-derived 3D-organoids to evaluate the Andro-mediated reversal of Gem resistance in PDAC. Transcriptomic profiling identified the calcium signaling pathway as a critical regulator of Gem-resistance (Fold enrichment: 2.8, p = 0.002). Within this pathway, high ERBB3 expression was significantly associated with poor prognosis in PDAC patients. The combination of Andro and Gem exhibited superior anti-cancer potential in Gem-R PDAC cells through potentiating cellular apoptosis. The combined treatment down-regulated ERBB3 and decreased intracellular calcium concentration in Gem-R PDAC cells. Finally, these findings were successfully interrogated in patient-derived 3D-organoids. In conclusion, we demonstrate novel evidence for Andro-mediated reversal of chemoresistance to Gem in PDAC cells through the regulation of ERBB3 and calcium signaling.
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Affiliation(s)
- Keisuke Okuno
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Caiming Xu
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116004, China
| | - Silvia Pascual-Sabater
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Masanori Tokunaga
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Haiyong Han
- Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | - Cristina Fillat
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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Rodrigues-Costa M, Fernandes MSDS, Jurema-Santos GC, Gonçalves LVDP, Andrade-da-Costa BLDS. Nutrigenomics in Parkinson's disease: diversity of modulatory actions of polyphenols on epigenetic effects induced by toxins. Nutr Neurosci 2023; 26:72-84. [PMID: 36625764 DOI: 10.1080/1028415x.2021.2017662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Although the pathogenesis of Parkinson's Disease (PD) is not completely understood, there is a consensus that it can be caused by multifactorial mechanisms involving genetic susceptibility, epigenetic modifications induced by toxins and mitochondrial dysfunction. In the past 20 years, great efforts have been made in order to clarify molecular mechanisms that are risk factors for this disease, as well as to identify bioactive agents for prevention and slowing down of its progression. Nutraceutical products have received substantial interest due to their nutritional, safe and therapeutic effects on several chronic diseases. The aim of this review was to gather the main evidence of the epigenetic mechanisms involved in the neuroprotective effects of phenolic compounds currently under investigation for the treatment of toxin-induced PD. These studies confirm that the neuroprotective actions of polyphenols involve complex epigenetic modulations, demonstrating that the intake of these natural compounds can be a promising, low-cost, pharmacogenomic strategy against the development of PD.
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Affiliation(s)
- Moara Rodrigues-Costa
- Programa de Neuropsiquiatria e Ciências do Comportamento, Universidade Federal de Pernambuco, Recife, Brazil.,Departamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco, Recife, Brazil
| | - Matheus Santos de Sousa Fernandes
- Programa de Neuropsiquiatria e Ciências do Comportamento, Universidade Federal de Pernambuco, Recife, Brazil.,Departamento de Educação Física, Universidade Federal de Pernambuco, Recife, Brazil
| | | | | | - Belmira Lara da Silveira Andrade-da-Costa
- Programa de Neuropsiquiatria e Ciências do Comportamento, Universidade Federal de Pernambuco, Recife, Brazil.,Departamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco, Recife, Brazil
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Mirza S, Penny C, Jain NK, Rawal RM. Curcumin mediated dendritic cell maturation by modulating cancer associated fibroblasts-derived exosomal miRNA-146a. J Cancer Res Ther 2023; 19:S649-S657. [PMID: 38384034 DOI: 10.4103/jcrt.jcrt_1286_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 07/20/2022] [Indexed: 02/23/2024]
Abstract
BACKGROUND Though cancer associated fibroblasts (CAFs), being a main component of tumor microenvironment (TME), are known to modulate immune response through secretion of various growth hormones, exosomes carrying miRNAs and cytokines; their effect on dendritic cells (DCs) are yet to be elucidated. Thus, aim of this study was to assess the effect of miRNAs and cytokines released by lung-CAFs and to evaluate immunomodulatory potential of curcumin on DC maturation through modulating their TME. MATERIAL AND METHODS To check the effect of CAFs derived exosomes on DC maturation, we cultured imDCs in the presence of CAFs derived conditioned media (CAFs-CM) and characterized by the presence of maturation markers CD80, CD83, CD86 and CTLA4 using qRT-PCR. Additionally, expression of miR-221, miR-222, miR-155, miR-142-3p and miR-146a was assessed to evaluate the role of epigenetic regulators on DC maturation. Likewise, cytokine profiling of CAFs-CM as well as CAFs-CM treated with curcumin was also conducted using ELISA. RESULTS Results revealed the generation of regulatory DCs which were characterized by decreased expression of maturation markers in the presence of CAFs-CM. In addition, such DCs showed higher expression of epigenetic regulator miR-146a which was positively correlated with increased expression of anti-inflammatory cytokines like IL-6, IL-10, TGF-β and decreased expression of TNF-α (pro-inflammatory). Moreover, curcumin had the potential to convert regulatory DCs generated by CAFs into mDCs, which were characterized by high expression of co-stimulatory molecules, low expression of CTLA4, lower levels of immune suppressive cytokines production and lower levels of miR-146a. CONCLUSION Collectively, these findings provide insight into understanding the immunomodulatory role of curcumin in targeting CAFs and modulating TME, thus enhancing antitumor immune response in DC based therapy.
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Affiliation(s)
- Sheefa Mirza
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
- Division of Medicinal Chemistry and Pharmacogenomics, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Clement Penny
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Nayan K Jain
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Rakesh M Rawal
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
- Division of Medicinal Chemistry and Pharmacogenomics, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
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40
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Curcumin: An epigenetic regulator and its application in cancer. Biomed Pharmacother 2022; 156:113956. [DOI: 10.1016/j.biopha.2022.113956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
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Sawesi S, Malkaram SA, Abd Elmageed ZY, Fandy TE. Modulation of the activity of histone lysine methyltransferases and demethylases by curcumin analog in leukaemia cells. J Cell Mol Med 2022; 26:5624-5633. [PMID: 36300880 PMCID: PMC9667515 DOI: 10.1111/jcmm.17589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/24/2022] [Accepted: 10/05/2022] [Indexed: 12/03/2022] Open
Abstract
Curcumin is a known epigenetic modifier that demonstrated antitumor effect in different types of cancer. The poor solubility and metabolic stability are major drawbacks that limit its development as an antitumor agent. Dimethoxycurcumin (DMC) is a more soluble and stable curcumin analog. In this study, we compared the effect of both drugs on a variety of histone posttranslational modifications and on the activity of histone lysine methyltransferase (HKMTs) and demethylase (HKDMTs) enzymes that target the H3K4, H3K9 and H3K27 epigenetic marks. Mass spectrometry was used to quantitate the changes in 95 histone posttranslational modifications induced by curcumin or DMC. The effect of both drugs on the enzymatic activity of HKMTs and HKDMs was measured using an antibody‐based assay. Mass spectrometry analysis showed that curcumin and DMC modulated several histone modifications. Histone changes were not limited to lysine methylation and acetylation but included arginine and glutamine methylation. Only few histone modifications were similarly changed by both drugs. On the contrary, the effect of both drugs on the activity of HKMTs and HKDMs was very similar. Curcumin and DMC inhibited the HKMTs enzymes that target the H3K4, H3K9 and H3K27 marks and increased the activity of the HKDMs enzymes LSD1, JARID and JMJD2. In conclusion, we identified novel enzymatic targets for both curcumin and DMC that support their use and development as epigenetic modifiers in cancer treatment. The multiple targets modulated by both drugs could provide a therapeutic advantage by overcoming drug resistance development.
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Affiliation(s)
- Suhila Sawesi
- Department of Pharmaceutical & Administrative Sciences, School of Pharmacy University of Charleston Charleston West Virginia USA
| | - Sridhar A. Malkaram
- Department of Mathematics & Computer Science West Virginia State University Institute West Virginia USA
| | - Zakaria Y. Abd Elmageed
- Department of Biomedical Sciences Edward Via College of Osteopathic Medicine (VCOM) Monroe Louisiana USA
| | - Tamer E. Fandy
- Department of Pharmaceutical & Administrative Sciences, School of Pharmacy University of Charleston Charleston West Virginia USA
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Okuno K, Xu C, Pascual-Sabater S, Tokunaga M, Han H, Fillat C, Kinugasa Y, Goel A. Berberine Overcomes Gemcitabine-Associated Chemoresistance through Regulation of Rap1/PI3K-Akt Signaling in Pancreatic Ductal Adenocarcinoma. Pharmaceuticals (Basel) 2022; 15:1199. [PMID: 36297310 PMCID: PMC9611392 DOI: 10.3390/ph15101199] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
Gemcitabine (Gem)-based chemotherapy is one of the first-line treatments for pancreatic ductal adenocarcinoma (PDAC). However, its clinical effect is limited due to development of chemoresistance. Various naturally occurring compounds, including Berberine (BBR), provide an anti-cancer efficacy with time-tested safety, individually and in combination with chemotherapeutic drugs. Accordingly, we hypothesized that BBR might enhance the chemosensitivity to Gem in PDAC. In this study, cell culture studies using MIA PaCa-2 and BxPC-3 cells, followed by analysis in patient-derived organoids were performed to evaluate the anti-cancer effects of BBR in PDAC. Considering that cancer is a significant manifestation of increased chronic inflammatory stress, systems biology approaches are prudent for the identification of molecular pathways and networks responsible for phytochemical-induced anti-cancer activity, we used these approaches for BBR-mediated chemosensitization to Gem. Firstly, Gem-resistant (Gem-R) PDAC cells were established, and the combination of BBR and Gem revealed superior anti-cancer efficacy in Gem-R cells. Furthermore, the combination treatment induced cell cycle arrest and apoptosis in Gem-R PDAC cells. Transcriptomic profiling investigated the Rap1 and PI3K-Akt signaling pathway as a key regulator of Gem-resistance and was a key mediator for BBR-mediated chemosensitization in PDAC cells. All cell culture-based findings were successfully validated in patient-derived organoids. In conclusion, we demonstrate that BBR-mediated reversal of chemoresistance to Gem manifests through Rap1/PI3K-Akt signaling in PDAC.
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Affiliation(s)
- Keisuke Okuno
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Caiming Xu
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116004, China
| | - Silvia Pascual-Sabater
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Masanori Tokunaga
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Haiyong Han
- Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | - Cristina Fillat
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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Vrânceanu M, Galimberti D, Banc R, Dragoş O, Cozma-Petruţ A, Hegheş SC, Voştinaru O, Cuciureanu M, Stroia CM, Miere D, Filip L. The Anticancer Potential of Plant-Derived Nutraceuticals via the Modulation of Gene Expression. PLANTS 2022; 11:plants11192524. [PMID: 36235389 PMCID: PMC9571524 DOI: 10.3390/plants11192524] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/07/2022] [Accepted: 09/22/2022] [Indexed: 11/17/2022]
Abstract
Current studies show that approximately one-third of all cancer-related deaths are linked to diet and several cancer forms are preventable with balanced nutrition, due to dietary compounds being able to reverse epigenetic abnormalities. An appropriate diet in cancer patients can lead to changes in gene expression and enhance the efficacy of therapy. It has been demonstrated that nutraceuticals can act as powerful antioxidants at the cellular level as well as anticarcinogenic agents. This review is focused on the best studies on worldwide-available plant-derived nutraceuticals: curcumin, resveratrol, sulforaphane, indole-3-carbinol, quercetin, astaxanthin, epigallocatechin-3-gallate, and lycopene. These compounds have an enhanced effect on epigenetic changes such as histone modification via HDAC (histone deacetylase), HAT (histone acetyltransferase) inhibition, DNMT (DNA methyltransferase) inhibition, and non-coding RNA expression. All of these nutraceuticals are reported to positively modulate the epigenome, reducing cancer incidence. Furthermore, the current review addresses the issue of the low bioavailability of nutraceuticals and how to overcome the drawbacks related to their oral administration. Understanding the mechanisms by which nutraceuticals influence gene expression will allow their incorporation into an “epigenetic diet” that could be further capitalized on in the therapy of cancer.
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Affiliation(s)
- Maria Vrânceanu
- Department of Toxicology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Damiano Galimberti
- Italian Association of Anti-Ageing Physicians, Via Monte Cristallo, 1, 20159 Milan, Italy
| | - Roxana Banc
- Department of Bromatology, Hygiene, Nutrition, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
- Correspondence: (R.B.); (O.D.); Tel.: +40-744-367-958 (R.B.); +40-733-040-917 (O.D.)
| | - Ovidiu Dragoş
- Department of Kinetotheraphy and Special Motricity, “1 Decembrie 1918” University of Alba Iulia, 510009 Alba Iulia, Romania
- Correspondence: (R.B.); (O.D.); Tel.: +40-744-367-958 (R.B.); +40-733-040-917 (O.D.)
| | - Anamaria Cozma-Petruţ
- Department of Bromatology, Hygiene, Nutrition, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Simona-Codruţa Hegheş
- Department of Drug Analysis, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Oliviu Voştinaru
- Department of Pharmacology, Physiology and Physiopathology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Magdalena Cuciureanu
- Department of Pharmacology, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 16 Universităţii Street, 700115 Iași, Romania
| | - Carmina Mariana Stroia
- Department of Pharmacy, Oradea University, 1 Universităţii Street, 410087 Oradea, Romania
| | - Doina Miere
- Department of Bromatology, Hygiene, Nutrition, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Lorena Filip
- Department of Bromatology, Hygiene, Nutrition, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
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Effects of Resveratrol, Curcumin and Quercetin Supplementation on Bone Metabolism—A Systematic Review. Nutrients 2022; 14:nu14173519. [PMID: 36079777 PMCID: PMC9459740 DOI: 10.3390/nu14173519] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/15/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Phenolic compounds are natural phytochemicals that have recently reported numerous health benefits. Resveratrol, curcumin, and quercetin have recently received the most attention among these molecules due to their documented antioxidant effects. The review aims to investigate the effects of these molecules on bone metabolism and their role in several diseases such as osteopenia and osteoporosis, bone tumours, and periodontitis. The PubMed/Medline, Web of Science, Google Scholar, Scopus, Cochrane Library, and Embase electronic databases were searched for papers in line with the study topic. According to an English language restriction, the screening period was from January 2012 to 3 July 2022, with the following Boolean keywords: (“resveratrol” AND “bone”); (“curcumin” AND “bone”); (“quercetin” AND “bone”). A total of 36 papers were identified as relevant to the purpose of our investigation. The studies reported the positive effects of the investigated phenolic compounds on bone metabolism and their potential application as adjuvant treatments for osteoporosis, bone tumours, and periodontitis. Furthermore, their use on the titanium surfaces of orthopaedic prostheses could represent a possible application to improve the osteogenic processes and osseointegration. According to the study findings, resveratrol, curcumin, and quercetin are reported to have a wide variety of beneficial effects as supplement therapies. The investigated phenolic compounds seem to positively mediate bone metabolism and osteoclast-related pathologies.
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Lisi S, Trovato M, Vitaloni O, Fantini M, Chirichella M, Tognini P, Cornuti S, Costa M, Groth M, Cattaneo A. Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression. Int J Mol Sci 2022; 23:ijms23168892. [PMID: 36012156 PMCID: PMC9408029 DOI: 10.3390/ijms23168892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 11/29/2022] Open
Abstract
Among Histone post-translational modifications (PTMs), lysine acetylation plays a pivotal role in the epigenetic regulation of gene expression, mediated by chromatin modifying enzymes. Due to their activity in physiology and pathology, several chemical compounds have been developed to inhibit the function of these proteins. However, the pleiotropy of these classes of proteins represents a weakness of epigenetic drugs. Ideally, a new generation of epigenetic drugs should target with molecular precision individual acetylated lysines on the target protein. We exploit a PTM-directed interference, based on an intrabody (scFv-58F) that selectively binds acetylated lysine 9 of histone H3 (H3K9ac), to test the hypothesis that targeting H3K9ac yields more specific effects than inhibiting the corresponding HAT enzyme that installs that PTM. In yeast scFv-58F modulates, gene expression in a more specific way, compared to two well-established HAT inhibitors. This PTM-specific interference modulated expression of genes involved in ribosome biogenesis and function. In mammalian cells, the scFv-58F induces exclusive changes in the H3K9ac-dependent expression of specific genes. These results suggest the H3K9ac-specific intrabody as the founder of a new class of molecules to directly target histone PTMs, inverting the paradigm from inhibiting the writer enzyme to acting on the PTM.
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Affiliation(s)
- Simonetta Lisi
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
| | - Matteo Trovato
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
- European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany
| | | | - Marco Fantini
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
| | | | - Paola Tognini
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Sara Cornuti
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
| | - Mario Costa
- Institute of Neurosciences, Consiglio Nazionale Delle Ricerche, 56124 Pisa, Italy
| | - Marco Groth
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Antonino Cattaneo
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
- Correspondence: ; Tel.: +39-050-509320
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Munnik C, Xaba MP, Malindisa ST, Russell BL, Sooklal SA. Drosophila melanogaster: A platform for anticancer drug discovery and personalized therapies. Front Genet 2022; 13:949241. [PMID: 36003330 PMCID: PMC9393232 DOI: 10.3389/fgene.2022.949241] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/06/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer is a complex disease whereby multiple genetic aberrations, epigenetic modifications, metabolic reprogramming, and the microenvironment contribute to the development of a tumor. In the traditional anticancer drug discovery pipeline, drug candidates are usually screened in vitro using two-dimensional or three-dimensional cell culture. However, these methods fail to accurately mimic the human disease state. This has led to the poor success rate of anticancer drugs in the preclinical stages since many drugs are abandoned due to inefficacy or toxicity when transitioned to whole-organism models. The common fruit fly, Drosophila melanogaster, has emerged as a beneficial system for modeling human cancers. Decades of fundamental research have shown the evolutionary conservation of key genes and signaling pathways between flies and humans. Moreover, Drosophila has a lower genetic redundancy in comparison to mammals. These factors, in addition to the advancement of genetic toolkits for manipulating gene expression, allow for the generation of complex Drosophila genotypes and phenotypes. Numerous studies have successfully created Drosophila models for colorectal, lung, thyroid, and brain cancers. These models were utilized in the high-throughput screening of FDA-approved drugs which led to the identification of several compounds capable of reducing proliferation and rescuing phenotypes. More noteworthy, Drosophila has also unlocked the potential for personalized therapies. Drosophila ‘avatars’ presenting the same mutations as a patient are used to screen multiple therapeutic agents targeting multiple pathways to find the most appropriate combination of drugs. The outcomes of these studies have translated to significant responses in patients with adenoid cystic carcinoma and metastatic colorectal cancers. Despite not being widely utilized, the concept of in vivo screening of drugs in Drosophila is making significant contributions to the current drug discovery pipeline. In this review, we discuss the application of Drosophila as a platform in anticancer drug discovery; with special focus on the cancer models that have been generated, drug libraries that have been screened and the status of personalized therapies. In addition, we elaborate on the biological and technical limitations of this system.
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Affiliation(s)
- Chamoné Munnik
- Department of Life and Consumer Sciences, University of South Africa, Pretoria, South Africa
| | - Malungi P. Xaba
- Department of Life and Consumer Sciences, University of South Africa, Pretoria, South Africa
| | - Sibusiso T. Malindisa
- Department of Life and Consumer Sciences, University of South Africa, Pretoria, South Africa
| | - Bonnie L. Russell
- Department of Life and Consumer Sciences, University of South Africa, Pretoria, South Africa
- Buboo (Pty) Ltd, The Innovation Hub, Pretoria, South Africa
| | - Selisha A. Sooklal
- Department of Life and Consumer Sciences, University of South Africa, Pretoria, South Africa
- *Correspondence: Selisha A. Sooklal,
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Shanaki M, Omidifar A, Shabani P, Toolabi K. Association between HDACs and pro-inflammatory cytokine gene expressions in obesity. Arch Physiol Biochem 2022; 128:880-886. [PMID: 32238064 DOI: 10.1080/13813455.2020.1734843] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Histone deacetylases (HDACs) are important players in a variety of physiological and pathological conditions. Few studies have addressed HDAC expressions in human adipose tissue in obese individuals, and their association with pro-inflammatory cytokines. Here, we compared 20 non-obese and 20 obese women to investigate possible changes in gene expressions of HDAC2, 4, 5, and 6 in the subcutaneous adipose tissues (SAT) and visceral adipose tissues (VAT) of these individuals. Our findings showed decreased HDAC5 expression in SAT and elevated HDAC4 expression in VAT from the obese group compared with the non-obese group. Our analyses showed negative correlations between HDAC2, 5, and 6 and the obesity indices and positive correlations between HDAC4 and obesity indices. HDAC2 showed a positive correlation with pro-inflammatory cytokines whereas HDAC4, 5, and 6 were negatively correlated with pro-inflammatory cytokines. Our findings provide new evidence that implicates the important roles of HDACs in obesity and obesity-associated inflammation.
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Affiliation(s)
- Mehrnoosh Shanaki
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Omidifar
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Shabani
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Karamollah Toolabi
- Department of Surgery, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Erichsen L, Thimm C, Santourlidis S. Methyl Group Metabolism in Differentiation, Aging, and Cancer. Int J Mol Sci 2022; 23:8378. [PMID: 35955511 PMCID: PMC9369357 DOI: 10.3390/ijms23158378] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 12/04/2022] Open
Abstract
Methyl group metabolism belongs to a relatively understudied field of research. Its importance lies in the fact that methyl group metabolic pathways are crucial for the successful conversion of dietary nutrients into the basic building blocks to carry out any cellular methylation reaction. Methyl groups play essential roles in numerous cellular functions such as DNA methylation, nucleotide- and protein biosynthesis. Especially, DNA methylation is responsible for organizing the genome into transcriptionally silent and active regions. Ultimately, it is this proper annotation that determines the quality of expression patterns required to ensure and shape the phenotypic integrity and function of a highly specialized cell type. Life is characterized by constantly changing environmental conditions, which are addressed by changes in DNA methylation. This relationship is increasingly coming into focus as it is of fundamental importance for differentiation, aging, and cancer. The stability and permanence of these metabolic processes, fueling the supplementation of methyl groups, seem to be important criteria to prevent deficiencies and erosion of the methylome. Alterations in the metabolic processes can lead to epigenetic and genetic perturbations, causative for diverse disorders, accelerated aging, and various age-related diseases. In recent decades, the intake of methyl group compounds has changed significantly due to, e.g., environmental pollution and food additives. Based on the current knowledge, this review provides a brief overview of the highly interconnected relationship between nutrition, metabolism, changes in epigenetic modifications, cancer, and aging. One goal is to provide an impetus to additionally investigate changes in DNA methylation as a possible consequence of an impaired methyl group metabolism.
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Affiliation(s)
- Lars Erichsen
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Chantelle Thimm
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany;
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49
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Antony B, Benny M, Kuruvilla BT, Gupta NK, Jacob S. Acute and sub chronic toxicity studies with herbal pain relieving formula (Rhuleave-K™) in rats. Regul Toxicol Pharmacol 2022; 133:105214. [PMID: 35781033 DOI: 10.1016/j.yrtph.2022.105214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/17/2022] [Accepted: 06/28/2022] [Indexed: 11/19/2022]
Abstract
Rhuleave-K™ is a proprietary combination of Curcuma longa extract, Boswellia serrata extract and black sesame seed oil. Acute toxicity was evaluated as per OECD guidelines 423. Rhuleave-K™ was fed at 2000 mg/kg to overnight fasted female rats. Clinical signs of abnormality and mortality was observed daily for 14 days. Sub-chronic toxicity was studied by feeding Rhuleave-K™ at 100, 500 and 1000 mg/kg/day to rats as per OECD guidelines 408. After 90 days feeding, heamatological and biochemical parameters were analyzed. Histopathology of all the major organs was also studied. In the acute toxicity study, there was no clinical sign of toxicity in any of the rat at maximum dose of 2000 mg/kg. The LD50 was computed as >2000 mg/kg in rats. The repeated dosing of Rhuleave-K™ at the maximum dose level of 1000 mg/kg for 90 days did not induce any observable toxic effects in rats, when compared to its corresponding control. The hematology and biochemistry profile of treated rats was similar to control animals and difference was non-significant (p > 0.05). The histopathology of major organs of all the control and treated animals was normal. In this study the NOAEL for Rhuleave-K™ was calculated as 1000 mg/kg daily in rats.
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Affiliation(s)
- Benny Antony
- Research and Development Laboratory, Arjuna Natural Private Ltd., Erumathala PO, Aluva, Kerala, 683112, India
| | - Merina Benny
- Research and Development Laboratory, Arjuna Natural Private Ltd., Erumathala PO, Aluva, Kerala, 683112, India.
| | - Binu T Kuruvilla
- Research and Development Laboratory, Arjuna Natural Private Ltd., Erumathala PO, Aluva, Kerala, 683112, India
| | - Nishant Kumar Gupta
- Research and Development Laboratory, Arjuna Natural Private Ltd., Erumathala PO, Aluva, Kerala, 683112, India
| | - Sherina Jacob
- Research and Development Laboratory, Arjuna Natural Private Ltd., Erumathala PO, Aluva, Kerala, 683112, India
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Zhao Y, Wang C, Goel A. A combined treatment with melatonin and andrographis promotes autophagy and anticancer activity in colorectal cancer. Carcinogenesis 2022; 43:217-230. [PMID: 35089340 PMCID: PMC9036994 DOI: 10.1093/carcin/bgac008] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/31/2021] [Accepted: 01/25/2022] [Indexed: 01/30/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent malignancies worldwide and remains one of the leading causes of cancer-related deaths in the USA. The high degree of morbidity and mortality associated with this disease is largely due to the inadequate efficacy of current treatments as well the development of chemoresistance. In recent years, several pharmaceutical agents screened from natural products have shown the promise to offer a safe, inexpensive and synergistically multi-targeted treatment option in various cancers. Given the growing evidence of anti-carcinogenic properties of two natural compounds, melatonin (MLT) and andrographis (Andro), we aimed to evaluate their synergistic anticancer effects in CRC. We demonstrate that indeed these two compounds possessed a synergistic anticancer effect in terms of their ability to inhibit cell viability, suppression of colony-formation and induction of apoptosis (P < 0.05). In line with our in vitro findings, we were able to validate this combinatorial anticancer activity in xenograft animal models (P < 0.001) as well as tumor-derived 3D organoids (P < 0.01). RNA-sequencing analysis revealed candidate pathways and genes that mediated antitumor efficacy of MLT and Andro in CRC, among which autophagy pathway and related genes, including NR4A1, CTSL and Atg12, were found to be primarily responsible for the increased anticancer effect by the two natural products. In conclusion, our data reveal a potent and synergistic therapeutic effect of MLT and Andro in the treatment of CRC and provides a rationale for suppressing autophagy in cancer cells as a potential therapeutic strategy for CRC.
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Affiliation(s)
- Yinghui Zhao
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA, USA
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, China
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA, USA
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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