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Kubatka P, Bojkova B, Nosalova N, Huniadi M, Samuel SM, Sreenesh B, Hrklova G, Kajo K, Hornak S, Cizkova D, Bubnov R, Smokovski I, Büsselberg D, Golubnitschaja O. Targeting the MAPK signaling pathway: implications and prospects of flavonoids in 3P medicine as modulators of cancer cell plasticity and therapeutic resistance in breast cancer patients. EPMA J 2025. [DOI: 10.1007/s13167-025-00407-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 03/24/2025] [Indexed: 04/21/2025]
Abstract
Abstract
Cancer drug resistance poses a significant challenge in oncology, primarily driven by cancer cell plasticity, which promotes tumor initiation, progression, metastasis, and therapeutic evasion in many different cancers. Breast cancers (BCs) are a prominent example of that, with an estimated 2.3 million new cases and 670,000 BC-related deaths registered worldwide annually. Triple-negative BC is especially challenging for treatments demonstrating particularly aggressive disease course, an early manifestation of metastatic disease, frequent drug-resistant cancer types, and poor individual outcomes. Although chemosensitizing agents have been developed, their clinical utility in oncology remains unproven. The mitogen-activated protein kinase (MAPK) pathway is considered a critical regulator of intracellular and extracellular signaling highly relevant for both — genetic and epigenetic modifications. Dysregulation of the MAPK signaling pathways plays a significant role in conferring chemoresistance in BC. Contextually, targeting the MAPK pathway represents a promising strategy for overcoming drug resistance and enhancing the therapeutic efficacy of anticancer agents in BC treatment. On the other hand, flavonoids, a prominent class of phytochemicals, are key modulators of MAPK signaling. Flavonoids interact with the ERK, JNK, p38, and ERK5 pathways of the MAPK signaling cascade and present a promising avenue for developing novel anti-cancer therapies and re-sensitizing agents for the treatment of BC. Compounds such as quercetin, kaempferol, genistein, luteolin, myricetin, EGCG, baicalein, baicalin, nobiletin, morin, delphinidin, acacetin, isorhamnetin, apigenin, silymarin, among others, have been identified as specific modulators of MAPK signaling, exerting complex downstream effects in BC cells increasing therewith drug efficacy and suppressing tumor growth and aggressivity. These properties reflect mechanisms of great clinical relevance to overcome therapeutic resistance in overall BC management. This article highlights corresponding mechanisms and provides clinically relevant illustrations in the framework of 3P medicine for primary (protection of individuals at high risk against health-to-disease transition) and secondary care (protection against metastatic BC progression). 3PM novelty makes good use of patient phenotyping and stratification, predictive multi-level diagnostics, and application of Artificial Intelligence (AI) tools to the individualized interpretation of big data — all proposed for cost-effective treatments tailored to individualized patient profiles with clear benefits to patients and advanced BC management.
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Hu L, Luo Y, Yang J, Cheng C. Botanical Flavonoids: Efficacy, Absorption, Metabolism and Advanced Pharmaceutical Technology for Improving Bioavailability. Molecules 2025; 30:1184. [PMID: 40076406 PMCID: PMC11902153 DOI: 10.3390/molecules30051184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/04/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Flavonoids represent a class of natural plant secondary metabolites with multiple activities including antioxidant, antitumor, anti-inflammatory, and antimicrobial properties. However, due to their structural characteristics, they often exhibit low bioavailability in vivo. In this review, we focus on the in vivo study of flavonoids, particularly the effects of gut microbiome on flavonoids, including common modifications such as methylation, acetylation, and dehydroxylation, etc. These modifications aim to change the structural characteristics of the original substances to enhance absorption and bioavailability. In order to improve the bioavailability of flavonoids, we discuss two feasible methods, namely dosage form modification and chemical modification, and hope that these approaches will offer new insights into the application of flavonoids for human health. In this article, we also introduce the types, plant sources, and efficacy of flavonoids. In conclusion, this is a comprehensive review on how to improve the bioavailability of flavonoids.
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Affiliation(s)
- Lei Hu
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
| | - Yiqing Luo
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
| | - Jiaxin Yang
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
| | - Chunsong Cheng
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
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Oliveira AMS, Santos AM, Nascimento Júnior JAC, Júnior CCS, Brito JRLR, dos Santos JS, Shanmugam S, dos Passos Menezes P, Frank LA, Serafini MR. Pharmaceutical technological trends containing flavonoids: a patent review. Future Med Chem 2025; 17:363-379. [PMID: 39835701 PMCID: PMC11792795 DOI: 10.1080/17568919.2025.2453408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025] Open
Abstract
Flavonoids such as silibinin, hesperetin, and phloretin exhibit well-documented biological activities, including anti-inflammatory, cytoprotective, anticarcinogenic, and antioxidant effects. However, their clinical application remains limited due to challenges such as poor aqueous solubility, low bioavailability, and restricted intestinal absorption, which can significantly reduce their pharmacological efficacy. This review analyzed patents related to innovative pharmaceutical technologies for flavonoids. The analysis used databases from the World Intellectual Property Organization and the European Patent Office. Following a comprehensive screening process, 38 patents were selected for detailed examination. These patents highlighted numerous studies on novel formulations, characterizations, and proprietary conditions. This review highlights technologies, such as nanocapsules, nanoemulsions, solid dispersions, phospholipid carriers, inclusion complexes, microemulsions, and other advanced systems, which enhance bioactive molecules' water solubility and stability. Consequently, these technologies improve permeability and absorption through the intended administration route, demonstrating the potential of flavonoids as promising candidates for various treatments, particularly when integrated into pharmaceutical technologies.
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Affiliation(s)
- Ana Maria Santos Oliveira
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Brazil
| | | | | | | | | | | | - Saravanan Shanmugam
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Brazil
| | | | - Luiza Abrahão Frank
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
- Núcleo de Terapias Nanotecnológicas (NTnano), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Mairim Russo Serafini
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Brazil
- Postgraduate Program in Health Sciences, Federal University of Sergipe, Aracaju, Brazil
- Department of Pharmacy, Federal University of Sergipe, São Cristóvão, Brazil
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Chaudhary S, Sharma S, Fuloria S, Sharma PK. Anti-Inflammatory and Anti-Arthritis Activity of Quercetin: A Comprehensive Review. Curr Rheumatol Rev 2025; 21:144-159. [PMID: 38808723 DOI: 10.2174/0115733971280645240415101912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 01/11/2024] [Accepted: 01/24/2024] [Indexed: 05/30/2024]
Abstract
This comprehensive exploration delves into the multifaceted attributes of quercetin, a flavonoid with extensive health-promoting potential. The review navigates through its fundamental properties, encompassing its chemical structure, classification as a flavonoid, and its natural prevalence in various sources. Addressing solubility, stability, and bioavailability challenges, the investigation delves into innovative isolation techniques, including solvent extraction, solid-phase extraction, natural deep eutectic solvents, supercritical fluid extraction, microwave-assisted extraction, column chromatography, and high-performance thin-layer chromatography. Transitioning into pharmacological implications, the study unveils quercetin's roles in anti-inflammatory pathways, antioxidant effects, and immune modulation, reflecting its versatile significance in health management. The review highlights its impact on wound healing processes and its potential to mitigate arthritis, elucidating its holistic contributions. Culminating in an exploration of recent studies, the analysis underscores quercetin's remarkable anti-inflammatory and anti-arthritis activities, reflecting its substantial potential across various ailments. The review concludes by projecting future trajectories, emphasizing prospects for an advanced understanding of quercetin's mechanisms, sustainable extraction techniques, clinical integration, and exploration of synergistic combinations. Collectively, this review investigation underscores quercetin's dynamic role at the intersection of natural compounds and medicinal applications, offering profound implications for well- being and health enhancement.
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Affiliation(s)
- Shikha Chaudhary
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Uttar Pradesh, India
| | - Shaweta Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Uttar Pradesh, India
| | - Shivkanya Fuloria
- Faculty of Pharmacy, AIMST University, Semeling Campus, Bedong, Kedah Aman, Malaysia
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Uttar Pradesh, India
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Zhang X, Yi R, Liu Y, Ma J, Xu J, Tian Q, Yan X, Wang S, Yang G. Resveratrol: potential application in safeguarding testicular health. EPMA J 2024; 15:643-657. [PMID: 39635023 PMCID: PMC11612077 DOI: 10.1007/s13167-024-00377-1] [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: 07/16/2024] [Accepted: 08/14/2024] [Indexed: 12/07/2024]
Abstract
Factors such as increasing mental pressure and poor living habits in modern society have led to an increase in the incidence of male reproductive diseases, including poor semen quality, testicular malignancy, and congenital developmental defects. The decline of male fertility deserves our attention. Resveratrol (3,4', 5-trihydroxy-trans-Stilbene, 3,4',5-trihydroxy), a polyphenol widely found in plant foods, is expected to enhance testicular function and promote breakthroughs in the treatment of diseases related to the male reproductive system. A large number of studies have shown that in male animals, resveratrol can enhance testicular function and spermatogenesis by activating SIRT1 expression and resist the damage of the testicular system by adverse factors. This article reviews the basic protective pathways of resveratrol against testicular and sperm damage, which involve oxidative stress, cell apoptosis, inflammatory damage, and mitochondrial function. The healthcare framework of predictive, preventive, and personalized medicine (PPPM/3PM) is by far the most beneficial for healthcare and is suitable for the management of chronic diseases. This review also summarizes the health benefits of resveratrol on male reproduction in the context of PPPM/3PM by comprehensively collecting and reviewing the available evidence, thus leading to a working hypothesis that resveratrol can personalize prevention and protection of male reproductive function. It provides a new perspective and direction for future research on the health effects of resveratrol in improving male reproductive function.
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Affiliation(s)
- Xu Zhang
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
| | - Ruhan Yi
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
| | - Yun Liu
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
| | - Jiaxuan Ma
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
| | - Jiawei Xu
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
| | - Qing Tian
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
| | - Xinyu Yan
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
| | - Shaopeng Wang
- Department of Cardiology, the First Affiliated Hospital of Dalian Medical University, No. 193, Lianhe Road, Dalian, 116011 China
| | - Guang Yang
- Department of Food Nutrition and Safety, Dalian Medical University, No. 9W, Lushun South Road, Dalian, 116044 China
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Liu GH, Yao ZQ, Chen GQ, Li YL, Liang B. Potential Benefits of Green Tea in Prostate Cancer Prevention and Treatment: A Comprehensive Review. Chin J Integr Med 2024; 30:1045-1055. [PMID: 38561489 DOI: 10.1007/s11655-024-4100-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2023] [Indexed: 04/04/2024]
Abstract
Prostate cancer is a prevalent and debilitating disease that necessitates effective prevention and treatment strategies. Green tea, a well-known beverage derived from the Camellia sinensis plant, contains bioactive compounds with potential health benefits, including catechins and polyphenols. This comprehensive review aims to explore the potential benefits of green tea in prostate cancer prevention and treatment by examining existing literature. Green tea possesses antioxidant, anti-inflammatory, and anti-carcinogenic properties attributed to its catechins, particularly epigallocatechin gallate. Epidemiological studies have reported an inverse association between green tea consumption and prostate cancer risk, with potential protection against aggressive forms of the disease. Laboratory studies demonstrate that green tea components inhibit tumor growth, induce apoptosis, and modulate signaling pathways critical to prostate cancer development and progression. Clinical trials and human studies further support the potential benefits of green tea. Green tea consumption has been found to be associated with a reduction in prostate-specific antigen levels, tumor markers, and played a potential role in slowing disease progression. However, challenges remain, including optimal dosage determination, formulation standardization, and conducting large-scale, long-term clinical trials. The review suggests future research should focus on combinatorial approaches with conventional therapies and personalized medicine strategies to identify patient subgroups most likely to benefit from green tea interventions.
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Affiliation(s)
- Gui-Hong Liu
- Department of Urology, Sanya Central Hospital (The Third People's Hospital of Hainan Province), Sanya City, Hainan Province, 572000, China
| | - Ze-Qin Yao
- Department of Urology, Sanya Central Hospital (The Third People's Hospital of Hainan Province), Sanya City, Hainan Province, 572000, China
| | - Guo-Qiang Chen
- Department of Urology, Sanya Central Hospital (The Third People's Hospital of Hainan Province), Sanya City, Hainan Province, 572000, China
| | - Ya-Lang Li
- Department of Urology, Yuzhou People's Hospital, Xuchang City, Henan Province, 461670, China
| | - Bing Liang
- Department of Urology, Sanya Central Hospital (The Third People's Hospital of Hainan Province), Sanya City, Hainan Province, 572000, China.
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Mansour H, Slika H, Nasser SA, Pintus G, Khachab M, Sahebkar A, Eid AH. Flavonoids, gut microbiota and cardiovascular disease: Dynamics and interplay. Pharmacol Res 2024; 209:107452. [PMID: 39383791 DOI: 10.1016/j.phrs.2024.107452] [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: 01/28/2024] [Revised: 09/11/2024] [Accepted: 10/04/2024] [Indexed: 10/11/2024]
Abstract
Cardiovascular disease (CVD) remains the leading cause of global morbidity and mortality. Extensive efforts have been invested to explicate mechanisms implicated in the onset and progression of CVD. Besides the usual suspects as risk factors (obesity, diabetes, and others), the gut microbiome has emerged as a prominent and essential factor in the pathogenesis of CVD. With its endocrine-like effects, the microbiome modulates many physiologic processes. As such, it is not surprising that dysbiosis-by generating metabolites, inciting inflammation, and altering secondary bile acid signaling- could predispose to or aggravate CVD. Nevertheless, various natural and synthetic compounds have been shown to modulate the microbiome. Prime among these molecules are flavonoids, which are natural polyphenols mainly present in fruits and vegetables. Accumulating evidence supports the potential of flavonoids in attenuating the development of CVD. The ascribed mechanisms of these compounds appear to involve mitigation of inflammation, alteration of the microbiome composition, enhancement of barrier integrity, induction of reverse cholesterol transport, and activation of farnesoid X receptor signaling. In this review, we critically appraise the methods by which the gut microbiome, despite being essential to the human body, predisposes to CVD. Moreover, we dissect the mechanisms and pathways underlying the cardioprotective effects of flavonoids.
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Affiliation(s)
- Hadi Mansour
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hasan Slika
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Gianfranco Pintus
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
| | - Maha Khachab
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Beirut, Lebanon
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar.
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Dvorska D, Mazurakova A, Lackova L, Sebova D, Kajo K, Samec M, Brany D, Svajdlenka E, Treml J, Mersakova S, Strnadel J, Adamkov M, Lasabova Z, Biringer K, Mojzis J, Büsselberg D, Smejkal K, Kello M, Kubatka P. Aronia melanocarpa L. fruit peels show anti-cancer effects in preclinical models of breast carcinoma: The perspectives in the chemoprevention and therapy modulation. Front Oncol 2024; 14:1463656. [PMID: 39435289 PMCID: PMC11491292 DOI: 10.3389/fonc.2024.1463656] [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: 07/12/2024] [Accepted: 09/17/2024] [Indexed: 10/23/2024] Open
Abstract
Introduction Within oncology research, there is a high effort for new approaches to prevent and treat cancer as a life-threatening disease. Specific plant species that adapt to harsh conditions may possess unique properties that may be utilized in the management of cancer. Hypothesis Chokeberry fruit is rich in secondary metabolites with anti-cancer activities potentially useful in cancer prevention and treatment. Aims of the study and Methods Based on mentioned hypothesis, the main goal of our study was to evaluate the antitumor effects of dietary administered Aronia melanocarpa L. fruit peels (in two concentrations of 0.3 and 3% [w/w]) in the therapeutic syngeneic 4T1 mouse adenocarcinoma model, the chemopreventive model of chemically induced mammary carcinogenesis in rats, a cell antioxidant assay, and robust in vitro analyses using MCF-7 and MDA-MB-231 cancer cells. Results The dominant metabolites in the A. melanocarpa fruit peel extract tested were phenolic derivatives classified as anthocyanins and procyanidins. In a therapeutic model, aronia significantly reduced the volume of 4T1 tumors at both higher and lower doses. In the same tumors, we noted a significant dose-dependent decrease in the mitotic activity index compared to the control. In the chemopreventive model, the expression of Bax was significantly increased by aronia at both doses. Additionally, aronia decreased Bcl-2 and VEGF levels, increasing the Bax/Bcl-2 ratio compared to the control group. The cytoplasmic expression of caspase-3 was significantly enhanced when aronia was administered at a higher dosage, in contrast to both the control group and the aronia group treated with a lower dosage. Furthermore, the higher dosage of aronia exhibited a significant reduction in the expression of the tumor stem cell marker CD133 compared to the control group. In addition, the examination of aronia`s epigenetic impact on tumor tissue through in vivo analyses revealed significant alterations in histone chemical modifications, specifically H3K4m3 and H3K9m3, miRNAs expression (miR155, miR210, and miR34a) and methylation status of tumor suppressor genes (PTEN and TIMP3). In vitro studies utilizing a methanolic extract of A.melanocarpa demonstrated significant anti-cancer properties in the MCF-7 and MDA-MB-231 cell lines. Various analyses, including Resazurin, cell cycle, annexin V/PI, caspase-3/7, Bcl-2, PARP, and mitochondrial membrane potential, were conducted in this regard. Additionally, the aronia extract enhanced the responsiveness to epirubicin in both cancer cell lines. Conclusion This study is the first to analyze the antitumor effect of A. melanocarpa in selected models of experimental breast carcinoma in vivo and in vitro. The utilization of the antitumor effects of aronia in clinical practice is still minimal and requires precise and long-term clinical evaluations. Individualized cancer-type profiling and patient stratification are crucial for effectively implementing plant nutraceuticals within targeted anti-cancer strategies in clinical oncology.
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Affiliation(s)
- Dana Dvorska
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Lenka Lackova
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dominika Sebova
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Karol Kajo
- Department of Pathology, St. Elisabeth Oncology Institute, Bratislava, Slovakia
| | - Marek Samec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dusan Brany
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Emil Svajdlenka
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Jakub Treml
- Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Sandra Mersakova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Strnadel
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Marian Adamkov
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Zora Lasabova
- Department of Molecular Biology and Genomics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Qatar Foundation, Doha, Qatar
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
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Herrera-Quintana L, Vázquez-Lorente H, Lopez-Garzon M, Cortés-Martín A, Plaza-Diaz J. Cancer and the Microbiome of the Human Body. Nutrients 2024; 16:2790. [PMID: 39203926 PMCID: PMC11357655 DOI: 10.3390/nu16162790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
Cancer remains a public health concern worldwide, with its incidence increasing worldwide and expected to continue growing during the next decades. The microbiome has emerged as a central factor in human health and disease, demonstrating an intricate relationship between the microbiome and cancer. Although some microbiomes present within local tissues have been shown to restrict cancer development, mainly by interacting with cancer cells or the host immune system, some microorganisms are harmful to human health and risk factors for cancer development. This review summarizes the recent evidence concerning the microbiome and some of the most common cancer types (i.e., lung, head and neck, breast, gastric, colorectal, prostate, and cervix cancers), providing a general overview of future clinical approaches and perspectives.
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Affiliation(s)
- Lourdes Herrera-Quintana
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Héctor Vázquez-Lorente
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Maria Lopez-Garzon
- Biomedical Group (BIO277), Department of Physical Therapy, Health Sciences Faculty, University of Granada, 18171 Granada, Spain;
| | - Adrián Cortés-Martín
- PROmoting FITness and Health through Physical Activity Research Group (PROFITH), Sport and Health University Research Institute (iMUDS), University of Granada, 18016 Granada, Spain;
- APC Microbiome Ireland, School of Microbiology, University College Cork, T12 YT20 Cork, Ireland
| | - Julio Plaza-Diaz
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
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Golubnitschaja O, Kapinova A, Sargheini N, Bojkova B, Kapalla M, Heinrich L, Gkika E, Kubatka P. Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care-clinically relevant 3PM innovation. EPMA J 2024; 15:163-205. [PMID: 38841620 PMCID: PMC11148002 DOI: 10.1007/s13167-024-00358-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 06/07/2024]
Abstract
Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.
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Affiliation(s)
- Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
| | - Andrea Kapinova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Nafiseh Sargheini
- Max Planck Institute for Plant Breeding Research, Carl-Von-Linne-Weg 10, 50829 Cologne, Germany
| | - Bianka Bojkova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, 040 01 Košice, Slovakia
| | - Marko Kapalla
- Negentropic Systems, Ružomberok, Slovakia
- PPPM Centre, s.r.o., Ruzomberok, Slovakia
| | - Luisa Heinrich
- Institute of General Medicine, University of Leipzig, Leipzig, Germany
| | - Eleni Gkika
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
| | - Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
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11
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Ma Y, Gou S, Zhu Z, Sun J, Shahbazi MA, Si T, Xu C, Ru J, Shi X, Reis RL, Kundu SC, Ke B, Nie G, Xiao B. Transient Mild Photothermia Improves Therapeutic Performance of Oral Nanomedicines with Enhanced Accumulation in the Colitis Mucosa. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2309516. [PMID: 38085512 DOI: 10.1002/adma.202309516] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/29/2023] [Indexed: 01/12/2024]
Abstract
The treatment outcomes of oral medications against ulcerative colitis (UC) have long been restricted by low drug accumulation in the colitis mucosa and subsequent unsatisfactory therapeutic efficacy. Here, high-performance pluronic F127 (P127)-modified gold shell (AuS)-polymeric core nanotherapeutics loading with curcumin (CUR) is constructed. Under near-infrared irradiation, the resultant P127-AuS@CURs generate transient mild photothermia (TMP; ≈42 °C, 10 min), which facilitates their penetration through colonic mucus and favors multiple cellular processes, including cell internalization, lysosomal escape, and controlled CUR release. This strategy relieves intracellular oxidative stress, improves wound healing, and reduces immune responses by polarizing the proinflammatory M1-type macrophages to the anti-inflammatory M2-type. Upon oral administration of hydrogel-encapsulating P127-AuS@CURs plus intestinal intralumen TMP, their therapeutic effects against acute and chronic UC are demonstrated to be superior to those of a widely used clinical drug, dexamethasone. The treatment of P127-AuS@CURs (+ TMP) elevates the proportions of beneficial bacteria (e.g., Lactobacillus and Lachnospiraceae), whose metabolites can also mitigate colitis symptoms by regulating genes associated with antioxidation, anti-inflammation, and wound healing. Overall, the intestinal intralumen TMP offers a promising approach to enhance the therapeutic outcomes of noninvasive medicines against UC.
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Affiliation(s)
- Ya Ma
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Shuangquan Gou
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Zhenhua Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Jianfeng Sun
- Botnar Research Centre, Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Headington, Oxford, OX3 7LD, UK
| | - Mohammad-Ali Shahbazi
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, Netherlands
| | - Tieyan Si
- School of Physics, Harbin Institute of Technology, Harbin, 150001, China
| | - Cheng Xu
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Jinlong Ru
- Chair of Prevention of Microbial Diseases, School of Life Sciences Weihenstephan, Technical University of Munich, 85354, Freising, Germany
| | - Xiaoxiao Shi
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Chongqing, 400715, China
| | - Rui L Reis
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimaraes, 4805-017, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimaraes, 4800-058, Portugal
| | - Subhas C Kundu
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimaraes, 4805-017, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimaraes, 4800-058, Portugal
| | - Bowen Ke
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Bo Xiao
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Chongqing, 400715, China
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12
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Kubatka P, Koklesova L, Mazurakova A, Brockmueller A, Büsselberg D, Kello M, Shakibaei M. Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling. Cancer Metastasis Rev 2024; 43:87-113. [PMID: 37789138 PMCID: PMC11016017 DOI: 10.1007/s10555-023-10134-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/31/2023] [Indexed: 10/05/2023]
Abstract
Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer.
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Affiliation(s)
- Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Qatar Foundation, Doha, Qatar
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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13
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Kubatka P, Mazurakova A, Koklesova L, Kuruc T, Samec M, Kajo K, Kotorova K, Adamkov M, Smejkal K, Svajdlenka E, Dvorska D, Brany D, Baranovicova E, Sadlonova V, Mojzis J, Kello M. Salvia officinalis L. exerts oncostatic effects in rodent and in vitro models of breast carcinoma. Front Pharmacol 2024; 15:1216199. [PMID: 38464730 PMCID: PMC10921418 DOI: 10.3389/fphar.2024.1216199] [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: 05/03/2023] [Accepted: 01/25/2024] [Indexed: 03/12/2024] Open
Abstract
Introduction: Based on extensive data from oncology research, the use of phytochemicals or plant-based nutraceuticals is considered an innovative tool for cancer management. This research aimed to analyze the oncostatic properties of Salvia officinalis L. [Lamiaceae; Salviae officinalis herba] using animal and in vitro models of breast carcinoma (BC). Methods: The effects of dietary administered S. officinalis in two concentrations (0.1%/SAL 0.1/and 1%/SAL 1/) were assessed in both syngeneic 4T1 mouse and chemically induced rat models of BC. The histopathological and molecular evaluations of rodent carcinoma specimens were performed after the autopsy. Besides, numerous in vitro analyses using two human cancer cell lines were performed. Results and Conclusion: The dominant metabolites found in S. officinalis propylene glycol extract (SPGE) were representatives of phenolics, specifically rosmarinic, protocatechuic, and salicylic acids. Furthermore, the occurrence of triterpenoids ursolic and oleanolic acid was proved in SPGE. In a mouse model, a non-significant tumor volume decrease after S. officinalis treatment was associated with a significant reduction in the mitotic activity index of 4T1 tumors by 37.5% (SAL 0.1) and 31.5% (SAL 1) vs. controls (set as a blank group with not applied salvia in the diet). In addition, salvia at higher doses significantly decreased necrosis/whole tumor area ratio by 46% when compared to control tumor samples. In a rat chemoprevention study, S. officinalis at a higher dose significantly lengthened the latency of tumors by 8.5 days and significantly improved the high/low-grade carcinomas ratio vs. controls in both doses. Analyses of the mechanisms of anticancer activities of S. officinalis included well-validated prognostic, predictive, and diagnostic biomarkers that are applied in both oncology practice and preclinical investigation. Our assessment in vivo revealed numerous significant changes after a comparison of treated vs. untreated cancer cells. In this regard, we found an overexpression in caspase-3, an increased Bax/Bcl-2 ratio, and a decrease in MDA, ALDH1, and EpCam expression. In addition, salvia reduced TGF-β serum levels in rats (decrease in IL-6 and TNF-α levels were with borderline significance). Evaluation of epigenetic modifications in rat cancer specimens in vivo revealed a decline in the lysine methylations of H3K4m3 and an increase in lysine acetylation in H4K16ac levels in treated groups. Salvia decreased the relative levels of oncogenic miR21 and tumor-suppressive miR145 (miR210, miR22, miR34a, and miR155 were not significantly altered). The methylation of ATM and PTEN promoters was decreased after S. officinalis treatment (PITX2, RASSF1, and TIMP3 promoters were not altered). Analyzing plasma metabolomics profile in tumor-bearing rats, we found reduced levels of ketoacids derived from BCAAs after salvia treatment. In vitro analyses revealed significant anti-cancer effects of SPGE extract in MCF-7 and MDA-MB-231 cell lines (cytotoxicity, caspase-3/-7, Bcl-2, Annexin V/PI, cell cycle, BrdU, and mitochondrial membrane potential). Our study demonstrates the significant chemopreventive and treatment effects of salvia haulm using animal or in vitro BC models.
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Affiliation(s)
- Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Lenka Koklesova
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Tomas Kuruc
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Marek Samec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Karol Kajo
- Department of Pathology, St. Elisabeth Oncology Institute, Bratislava, Slovakia
| | - Klaudia Kotorova
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Marian Adamkov
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Emil Svajdlenka
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Dana Dvorska
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dusan Brany
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Eva Baranovicova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Vladimira Sadlonova
- Department of Microbiology and Immunology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
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14
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Mazurakova A, Koklesova L, Csizmár SH, Samec M, Brockmueller A, Šudomová M, Biringer K, Kudela E, Pec M, Samuel SM, Kassayova M, Hassan STS, Smejkal K, Shakibaei M, Büsselberg D, Saso L, Kubatka P, Golubnitschaja O. Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells - A potential contribution to the predictive, preventive, and personalized medicine. J Adv Res 2024; 55:103-118. [PMID: 36871616 PMCID: PMC10770105 DOI: 10.1016/j.jare.2023.02.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. AIM OF REVIEW We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). KEY SCIENTIFIC CONCEPTS OF REVIEW The working hypothesis of the manuscript proposes HIF-1α - the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation.
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Affiliation(s)
- Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia.
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Sandra Hurta Csizmár
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Marek Samec
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
| | - Miroslava Šudomová
- Museum of Literature in Moravia, Klášter 1, 66461 Rajhrad, Czech Republic
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Monika Kassayova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, P. J. Safarik University, 04001 Kosice, Slovakia
| | - Sherif T S Hassan
- Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Kamýcká 129, 165 00 Prague, Czech Republic
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, 61242 Brno, Czech Republic
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, P.le Aldo Moro 5, 00185, Rome, Italy
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia.
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127, Bonn, Germany.
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Singh V, Singh R, Singh MP, Katrolia A. Therapeutic Role of Desmodium Species on its Isolated Flavonoids. Curr Mol Med 2024; 24:74-84. [PMID: 36515031 DOI: 10.2174/1566524023666221213111851] [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: 09/09/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 12/15/2022]
Abstract
Secondary metabolites are an important part to play a major role in society and it was isolated from plant flavonoids and useful in the treatment of various kinds of diseases in the human race. They are widely used as food and nutrition supplements as well as antioxidants. Traditionally, the Desmodium species are an important tool for the secondary metabolites to treat various diseases. Desmodium triquetrum (Fabaceae) one of the Indian medicinal plants is widely used in the treatment of asthma and inflammation. Three flavonoids isolated from Desmodium triquetrum Linn namely Baicalein, Naringin and Neohesperidin are useful as antioxidants, food and nutrition supplements, that help the body to function efficiently while protecting it against toxins as well stressors. The role of flavonoids may be due to the presence of the phenolic compound. Similarly, the flavonoids such as gangetin, gangetinin, desmocarpin and desmodin isolated from the species Desmodium gangeticum are responsible for antileishmanial, antioxidant, anti-arthritic, and immunomodulatory activities. Additionally, isolated flavanoids from the species Desmodium triflorum show antibacterial, antiepileptic, antifungal, and radioprotective activities. So, the aim of the present study, based on the literature miming from the desmodium species is to acknowledge the importance of flavonoids in human health as dietary food supplements and therapeutic uses.
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Affiliation(s)
- Vedpal Singh
- Department of Pharmacognosy, College of Pharmacy, JSS Academy of Technical Education, C-1/A sector 62 Noida, Uttar Pradesh, India
| | - Rohit Singh
- Department of Pharmaceutical Chemistry, College of Pharmacy, JSS Academy of Technical Education, C-1/A sector 62 Noida, Uttar Pradesh. India
| | - Manish Pal Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Punjab, India
| | - Archita Katrolia
- Department of Pharmaceutics, College of Pharmacy, JSS Academy of Technical Education, Noida, UP, India
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16
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Liang W, He J, Zhong N. Towards zero lung cancer. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2023; 1:195-197. [PMID: 39171283 PMCID: PMC11332822 DOI: 10.1016/j.pccm.2023.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Indexed: 08/23/2024]
Affiliation(s)
- Wenhua Liang
- The First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, Guangzhou, Guangdong 510120, China
| | - Jianxing He
- The First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, Guangzhou, Guangdong 510120, China
| | - Nanshan Zhong
- The First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, Guangzhou, Guangdong 510120, China
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Jia W, Gong X, Ye Z, Li N, Zhan X. Nitroproteomics is instrumental for stratification and targeted treatments of astrocytoma patients: expert recommendations for advanced 3PM approach with improved individual outcomes. EPMA J 2023; 14:673-696. [PMID: 38094577 PMCID: PMC10713973 DOI: 10.1007/s13167-023-00348-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 11/11/2023] [Indexed: 12/05/2024]
Abstract
Protein tyrosine nitration is a selectively and reversible important post-translational modification, which is closely related to oxidative stress. Astrocytoma is the most common neuroepithelial tumor with heterogeneity and complexity. In the past, the diagnosis of astrocytoma was based on the histological and clinical features, and the treatment methods were nothing more than surgery-assisted radiotherapy and chemotherapy. Obviously, traditional methods short falls an effective treatment for astrocytoma. In late 2021, the World Health Organization (WHO) adopted molecular biomarkers in the comprehensive diagnosis of astrocytoma, such as IDH-mutant and DNA methylation, which enabled the risk stratification, classification, and clinical prognosis prediction of astrocytoma to be more correct. Protein tyrosine nitration is closely related to the pathogenesis of astrocytoma. We hypothesize that nitroproteome is significantly different in astrocytoma relative to controls, which leads to establishment of nitroprotein biomarkers for patient stratification, diagnostics, and prediction of disease stages and severity grade, targeted prevention in secondary care, treatment algorithms tailored to individualized patient profile in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Nitroproteomics based on gel electrophoresis and tandem mass spectrometry is an effective tool to identify the nitroproteins and effective biomarkers in human astrocytomas, clarifying the biological roles of oxidative/nitrative stress in the pathophysiology of astrocytomas, functional characteristics of nitroproteins in astrocytomas, nitration-mediated signal pathway network, and early diagnosis and treatment of astrocytomas. The results finds that these nitroproteins are enriched in mitotic cell components, which are related to transcription regulation, signal transduction, controlling subcellular organelle events, cell perception, maintaining cell homeostasis, and immune activity. Eleven statistically significant signal pathways are identified in astrocytoma, including remodeling of epithelial adherens junctions, germ cell-sertoli cell junction signaling, 14-3-3-mediated signaling, phagosome maturation, gap junction signaling, axonal guidance signaling, assembly of RNA polymerase III complex, and TREM1 signaling. Furthermore, protein tyrosine nitration is closely associated with the therapeutic effects of protein drugs, and molecular mechanism and drug targets of cancer. It provides valuable data for studying the protein nitration biomarkers, molecular mechanisms, and therapeutic targets of astrocytoma towards PPPM (3P medicine) practice. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-023-00348-y.
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Affiliation(s)
- Wenshuang Jia
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Xiaoxia Gong
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Zhen Ye
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Na Li
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Xianquan Zhan
- Medical Science and Technology Innovation Center, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
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18
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Karagülle OO, Yurttaş AG. Synergistic effects of ozone with doxorubicin on the proliferation, apoptosis and metastatic profile of luminal-B type human breast cancer cell line. Tissue Cell 2023; 85:102233. [PMID: 37866151 DOI: 10.1016/j.tice.2023.102233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/06/2023] [Accepted: 10/04/2023] [Indexed: 10/24/2023]
Abstract
OBJECTIVE Luminal-B type human breast cancer cell line (BT-474) to assess the synergistic effects of ozone applied after chemotherapeutic treatment with various dosages of doxorubicin, and compare the results with the effects on L929 fibroblast cell line. METHODS Doxorubicin (1-50 M) was added to each cell lines and left to sit for 24 h at 37 °C. Then, as combination groups, half of the groups were incubated with 30 g/mL ozone for 25 min. Tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), and matrix metalloproteinase-2 and - 9 (MMP-2 and MMP-9) levels were measured using the MTT test, flow cytometry, and immunocytochemistry, respectively. RESULTS When compared to simply doxorubicin-applied cells without ozone treatment, each dose of doxorubicin + ozone treatment considerably boosted L929 viability but significantly decreased BT-474 viability. Additionally, the combination increased the apoptotic impact of doxorubicin on BT-474 but not L929 (P < 0.001). TGF-, MMP-2, and MMP-9 levels of L929 after combination were substantially higher than those of the other groups (P < 0.01). Doxorubicin's effect on BT-474's protein levels, which had significantly decreased in comparison to those of the other groups, was reversed by the combination treatment (P < 0.05). CONCLUSION Doxorubicin's anti-proliferative and apoptotic effects were enhanced by ozone treatment in BT-474 cells, but it also repaired and healed healthy fibroblast cells that had been harmed by the cytotoxicity of the chemotherapy drug. If doxorubicin and ozone treatment are coupled, BT-474 cells may develop resistance to it through expressions of TNF-α, TGF-β, MMP-2, and MMP-9.
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Affiliation(s)
- Onur Olgaç Karagülle
- Department of General Surgery, Istanbul Education and Research Hospital, University of Health Sciences, Cerrahpaşa, Org. Abdurrahman Nafiz Gürman Cd. No:24 Fatih, 34098, İstanbul, Turkey.
| | - Asiye Gök Yurttaş
- Istanbul Health and Technology University, Faculty of Pharmacy, Biochemistry Department, İstanbul, Turkey.
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19
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Herrera-Rocha KM, Manjarrez-Juanes MM, Larrosa M, Barrios-Payán JA, Rocha-Guzmán NE, Macías-Salas A, Gallegos-Infante JA, Álvarez SA, González-Laredo RF, Moreno-Jiménez MR. The Synergistic Effect of Quince Fruit and Probiotics ( Lactobacillus and Bifidobacterium) on Reducing Oxidative Stress and Inflammation at the Intestinal Level and Improving Athletic Performance during Endurance Exercise. Nutrients 2023; 15:4764. [PMID: 38004161 PMCID: PMC10675360 DOI: 10.3390/nu15224764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/04/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Endurance exercise promotes damage at the intestinal level and generates a variety of symptoms related to oxidative stress processes, inflammatory processes, microbiota dysbiosis, and intestinal barrier damage. This study evaluated the effects of quince (Cydonia oblonga Mill.) and probiotics of the genera Lactobacillus and Bifidobacterium on intestinal protection and exercise endurance in an animal swimming model. Phytochemical characterization of the quince fruit demonstrated a total dietary fiber concentration of 0.820 ± 0.70 g/100 g and a fiber-bound phenolic content of 30,218 ± 104 µg/g in the freeze-dried fruit. UPLC-PDA-ESI-QqQ analyses identified a high content of polyphenol, mainly flavanols, hydroxycinnamic acids, hydroxybenzoic acids, flavonols, and, to a lesser extent, dihydrochalcones. The animal model of swimming was performed using C57BL/6 mice. The histological results determined that the consumption of the synbiotic generated intestinal protection and increased antioxidant (catalase and glutathione peroxidase enzymes) and anti-inflammatory (TNF-α and IL-6 and increasing IL-10) activities. An immunohistochemical analysis indicated mitochondrial biogenesis (Tom2) at the muscular level related to the increased swimming performance. These effects correlated mainly with the polyphenol content of the fruit and the effect of the probiotics. Therefore, this combination of quince and probiotics could be an alternative for the generation of a synbiotic product that improves exercise endurance and reduces the effects generated by the practice of high performance sports.
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Affiliation(s)
- Karen Marlenne Herrera-Rocha
- Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, TecNM/Instituto Tecnológico de Durango, Felipe Pescador 1830 Ote., Durango 34080, Mexico
| | - María Magdalena Manjarrez-Juanes
- Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, TecNM/Instituto Tecnológico de Durango, Felipe Pescador 1830 Ote., Durango 34080, Mexico
| | - Mar Larrosa
- Department of Nutrition and Food Science, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Jorge Alberto Barrios-Payán
- Laboratory of Experimental Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubirán (INCMNSZ), Vasco de Quiroga #15, Tlalpan, Ciudad de México 14080, Mexico
| | - Nuria Elizabeth Rocha-Guzmán
- Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, TecNM/Instituto Tecnológico de Durango, Felipe Pescador 1830 Ote., Durango 34080, Mexico
| | - Alejo Macías-Salas
- Hospital Santiago Ramón y Cajal, Departamento de Patología, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Durango 34079, Mexico
| | - José Alberto Gallegos-Infante
- Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, TecNM/Instituto Tecnológico de Durango, Felipe Pescador 1830 Ote., Durango 34080, Mexico
| | - Saul Alberto Álvarez
- Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, TecNM/Instituto Tecnológico de Durango, Felipe Pescador 1830 Ote., Durango 34080, Mexico
| | - Rubén Francisco González-Laredo
- Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, TecNM/Instituto Tecnológico de Durango, Felipe Pescador 1830 Ote., Durango 34080, Mexico
| | - Martha Rocío Moreno-Jiménez
- Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, TecNM/Instituto Tecnológico de Durango, Felipe Pescador 1830 Ote., Durango 34080, Mexico
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20
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Kaag S, Lorentz A. Effects of Dietary Components on Mast Cells: Possible Use as Nutraceuticals for Allergies? Cells 2023; 12:2602. [PMID: 37998337 PMCID: PMC10670325 DOI: 10.3390/cells12222602] [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: 09/29/2023] [Revised: 11/03/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023] Open
Abstract
Allergic diseases affect an estimated 30 percent of the world's population. Mast cells (MC) are the key effector cells of allergic reactions by releasing pro-inflammatory mediators such as histamine, lipid mediators, and cytokines/chemokines. Components of the daily diet, including certain fatty acids, amino acids, and vitamins, as well as secondary plant components, may have effects on MC and thus may be of interest as nutraceuticals for the prevention and treatment of allergies. This review summarizes the anti-inflammatory effects of dietary components on MC, including the signaling pathways involved, in in vitro and in vivo models. Butyrate, calcitriol, kaempferol, quercetin, luteolin, resveratrol, curcumin, and cinnamon extract were the most effective in suppressing the release of preformed and de novo synthesized mediators from MC or in animal models. In randomized controlled trials (RCT), vitamin D, quercetin, O-methylated epigallocatechin gallate (EGCG), resveratrol, curcumin, and cinnamon extract improved symptoms of allergic rhinitis (AR) and reduced the number of inflammatory cells in patients. However, strategies to overcome the poor bioavailability of these nutrients are an important part of current research.
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Affiliation(s)
| | - Axel Lorentz
- Institute of Nutritional Medicine, University of Hohenheim, D-70593 Stuttgart, Germany
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21
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Rarison RHG, Truong VL, Yoon BH, Park JW, Jeong WS. Antioxidant and Anti-Inflammatory Mechanisms of Lipophilic Fractions from Polyscias fruticosa Leaves Based on Network Pharmacology, In Silico, and In Vitro Approaches. Foods 2023; 12:3643. [PMID: 37835296 PMCID: PMC10573055 DOI: 10.3390/foods12193643] [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: 09/04/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Polyscias fruticosa leaf (PFL) has been used in food and traditional medicine for the treatment of rheumatism, ischemia, and neuralgia. However, the lipophilic components of PFL and their biological properties remain unknown. This study, integrating network pharmacology analysis with in silico and in vitro approaches, aimed to elucidate the antioxidant and anti-inflammatory capacities of lipophilic extracts from PFL. A total of 71 lipophilic compounds were identified in PFL using gas chromatography-mass spectrometry. Network pharmacology and molecular docking analyses showed that key active compounds, mainly phytosterols and sesquiterpenes, were responsible for regulating core target genes, such as PTGS2, TLR4, NFE2L2, PRKCD, KEAP1, NFKB1, NR1l2, PTGS1, AR, and CYP3A4, which were mostly enriched in oxidative stress and inflammation-related pathways. Furthermore, lipophilic extracts from PFL offered powerful antioxidant capacities, as evident in our cell-free antioxidant assays. These extracts also provided a protection against oxidative stress by inducing the expression of catalase and heme oxygenase-1 in lipopolysaccharide (LPS)-treated RAW 264.7 cells. Additionally, lipophilic fractions from PFL showed anti-inflammatory potential in downregulating the level of pro-inflammatory factors in LPS-treated macrophages. Overall, these findings provide valuable insights into the antioxidant and anti-inflammatory properties of lipophilic extracts from PFL, which can be used as a fundamental basis for developing nutraceuticals and functional foods.
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Affiliation(s)
- Razanamanana H. G. Rarison
- School of Food Science & Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Van-Long Truong
- School of Food Science & Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- Food and Bio-industry Research Institute, School of Food Science & Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea (V.-L.T.)
| | - Byoung-Hoon Yoon
- School of Food Science & Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Ji-Won Park
- School of Food Science & Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Woo-Sik Jeong
- School of Food Science & Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- Food and Bio-industry Research Institute, School of Food Science & Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea (V.-L.T.)
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22
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Halma MTJ, Tuszynski JA, Marik PE. Cancer Metabolism as a Therapeutic Target and Review of Interventions. Nutrients 2023; 15:4245. [PMID: 37836529 PMCID: PMC10574675 DOI: 10.3390/nu15194245] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/20/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.
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Affiliation(s)
- Matthew T. J. Halma
- Department of Physics and Astronomy, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- EbMC Squared CIC, Bath BA2 4BL, UK
| | - Jack A. Tuszynski
- Department of Physics, University of Alberta, 11335 Saskatchewan Dr NW, Edmonton, AB T6G 2M9, Canada
- Department of Data Science and Engineering, The Silesian University of Technology, 44-100 Gliwice, Poland
- DIMEAS, Politecnico di Torino, Corso Duca degli Abruzzi 24, I-1029 Turin, Italy
| | - Paul E. Marik
- Frontline COVID-19 Critical Care Alliance, Washington, DC 20036, USA
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23
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Proença C, Rufino AT, Santos I, Albuquerque HMT, Silva AMS, Fernandes E, Ferreira de Oliveira JMP. Gossypetin Is a Novel Modulator of Inflammatory Cytokine Production and a Suppressor of Osteosarcoma Cell Growth. Antioxidants (Basel) 2023; 12:1744. [PMID: 37760046 PMCID: PMC10525374 DOI: 10.3390/antiox12091744] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/01/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Osteosarcoma (OS) is a common childhood sarcoma, and its treatment is hindered by adverse effects, chemoresistance, and recurrence. Interleukin (IL)-6 production by tumors plays a significant role in inflammation, carcinogenesis, and metastasis. This study aimed to investigate the antiproliferative potential of luteolin derivatives in OS and to evaluate interleukin production. MG-63, Saos-2, HOS, and 143B human OS cell lines were incubated with luteolin and eight derivatives containing hydroxy, chlorine, or alkyl substitutions. The cell viability and growth were evaluated in the presence of these compounds. Apoptosis was also examined through the analysis of the Bax expression and caspase-3 activity. Finally, the gossypetin effects were measured regarding the production of proinflammatory cytokines interleukin (IL)-6, IL-1β, and IL-12p70. Our findings show that gossypetin was the most potent compound, with proliferation-suppressing activities that induced a series of critical events, including the inhibition of the cell viability and growth. Apoptosis was associated with enhanced caspase-3 activity and increased Bax expression, indicating the involvement of the intrinsic pathway of apoptosis. Moreover, pre-/co-treatment with gossypetin significantly reduced the autocrine production of proinflammatory cytokines. Further investigation is required; nevertheless, considering the link between inflammation, carcinogenesis, and metastasis in OS, our findings suggest that gossypetin exhibits anti-proliferative and anti-inflammatory properties that are potentially relevant in the clinical context.
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Affiliation(s)
- Carina Proença
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (C.P.); (A.T.R.); (I.S.); (E.F.)
| | - Ana Teresa Rufino
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (C.P.); (A.T.R.); (I.S.); (E.F.)
| | - Isabela Santos
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (C.P.); (A.T.R.); (I.S.); (E.F.)
| | - Hélio M. T. Albuquerque
- LAQV, REQUIMTE, Department of Chemistry, Campus Universitario de Santiago, University of Aveiro, 3810-193 Aveiro, Portugal; (H.M.T.A.); (A.M.S.S.)
| | - Artur M. S. Silva
- LAQV, REQUIMTE, Department of Chemistry, Campus Universitario de Santiago, University of Aveiro, 3810-193 Aveiro, Portugal; (H.M.T.A.); (A.M.S.S.)
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (C.P.); (A.T.R.); (I.S.); (E.F.)
| | - José Miguel P. Ferreira de Oliveira
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (C.P.); (A.T.R.); (I.S.); (E.F.)
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24
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Bi Q, Wu JY, Qiu XM, Li YQ, Yan YY, Sun ZJ, Wang W. Identification of potential necroinflammation-associated necroptosis-related biomarkers for delayed graft function and renal allograft failure: a machine learning-based exploration in the framework of predictive, preventive, and personalized medicine. EPMA J 2023; 14:307-328. [PMID: 37275548 PMCID: PMC10141843 DOI: 10.1007/s13167-023-00320-w] [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: 01/06/2023] [Accepted: 04/07/2023] [Indexed: 06/07/2023]
Abstract
Delayed graft function (DGF) is one of the key post-operative challenges for a subset of kidney transplantation (KTx) patients. Graft survival is significantly lower in recipients who have experienced DGF than in those who have not. Assessing the risk of chronic graft injury, predicting graft rejection, providing personalized treatment, and improving graft survival are major strategies for predictive, preventive, and personalized medicine (PPPM/3PM) to promote the development of transplant medicine. However, since PPPM aims to accurately identify disease by integrating multiple omics, current methods to predict DGF and graft survival can still be improved. Renal ischemia/reperfusion injury (IRI) is a pathological process experienced by all KTx recipients that can result in varying occurrences of DGF, chronic rejection, and allograft failure depending on its severity. During this process, a necroinflammation-mediated necroptosis-dependent secondary wave of cell death significantly contributes to post-IRI tubular cell loss. In this article, we obtained the expression matrices and corresponding clinical data from the GEO database. Subsequently, nine differentially expressed necroinflammation-associated necroptosis-related genes (NiNRGs) were identified by correlation and differential expression analysis. The subtyping of post-KTx IRI samples relied on consensus clustering; the grouping of prognostic risks and the construction of predictive models for DGF (the area under the receiver operating characteristic curve (AUC) of the internal validation set and the external validation set were 0.730 and 0.773, respectively) and expected graft survival after a biopsy (the internal validation set's 1-year AUC: 0.770; 2-year AUC: 0.702; and 3-year AUC: 0.735) were based on the least absolute shrinkage and selection operator regression algorithms. The results of the immune infiltration analysis showed a higher infiltration abundance of myeloid immune cells, especially neutrophils, macrophages, and dendritic cells, in the cluster A subtype and prognostic high-risk groups. Therefore, in the framework of PPPM, this work provides a comprehensive exploration of the early expression landscape, related pathways, immune features, and prognostic impact of NiNRGs in post-KTx patients and assesses their capabilities as.predictors of post-KTx DGF and graft loss,targets of the vicious loop between regulated tubular cell necrosis and necroinflammation for targeted secondary and tertiary prevention, andreferences for personalized immunotherapy. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-023-00320-w.
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Affiliation(s)
- Qing Bi
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Ji-Yue Wu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Xue-Meng Qiu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
- Third Clinical Medical College, Capital Medical University, Beijing, China
| | - Yu-Qing Li
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Yu-Yao Yan
- Department of Anesthesiology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Ze-Jia Sun
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
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25
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Nabil-Adam A, E. Elnosary M, L. Ashour M, M. Abd El-Moneam N, A. Shreadah M. Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning Pharmacodynamics and Pharmacokinetic Properties. FLAVONOID METABOLISM - RECENT ADVANCES AND APPLICATIONS IN CROP BREEDING 2023. [DOI: 10.5772/intechopen.108637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Flavonoids are a major class of secondary metabolites that comprises more than 6000 compounds that have been identified. They are biosynthesized via the phenylpropanoid metabolic pathway that involves groups of enzymes such as isomerases, hydroxylases, and reductases that greatly affect the determination of the flavonoid skeleton. For example, transferase enzymes responsible for the modification of sugar result in changes in the physiological activity of the flavonoids and changes in their physical properties, such as solubility, reactivity, and interaction with cellular target molecules, which affect their pharmacodynamics and pharmacokinetic properties. In addition, flavonoids have diverse biological activities such as antioxidants, anticancer, and antiviral in managing Alzheimer’s disease. However, most marine flavonoids are still incompletely discovered because marine flavonoid biosynthesis is produced and possesses unique substitutions that are not commonly found in terrestrial bioactive compounds. The current chapter will illustrate the importance of flavonoids’ role in metabolism and the main difference between marine and terrestrial flavonoids.
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26
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Al-Ishaq RK, Samuel SM, Büsselberg D. The Influence of Gut Microbial Species on Diabetes Mellitus. Int J Mol Sci 2023; 24:ijms24098118. [PMID: 37175825 PMCID: PMC10179351 DOI: 10.3390/ijms24098118] [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: 03/13/2023] [Revised: 04/16/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder with an alarming incidence rate and a considerable burden on the patient's life and health care providers. An increase in blood glucose level and insulin resistance characterizes it. Internal and external factors such as urbanization, obesity, and genetic mutations could increase the risk of DM. Microbes in the gut influence overall health through immunity and nutrition. Recently, more studies have been conducted to evaluate and estimate the role of the gut microbiome in diabetes development, progression, and management. This review summarizes the current knowledge addressing three main bacterial species: Bifidobacterium adolescentis, Bifidobacterium bifidum, and Lactobacillus rhamnosus and their influence on diabetes and its underlying molecular mechanisms. Most studies illustrate that using those bacterial species positively reduces blood glucose levels and activates inflammatory markers. Additionally, we reported the relationship between those bacterial species and metformin, one of the commonly used antidiabetic drugs. Overall, more research is needed to understand the influence of the gut microbiome on the development of diabetes. Furthermore, more efforts are required to standardize the model used, concentration ranges, and interpretation tools to advance the field further.
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Affiliation(s)
- Raghad Khalid Al-Ishaq
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
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27
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Xie L, Zhao YX, Zheng Y, Li XF. The pharmacology and mechanisms of platycodin D, an active triterpenoid saponin from Platycodon grandiflorus. Front Pharmacol 2023; 14:1148853. [PMID: 37089949 PMCID: PMC10117678 DOI: 10.3389/fphar.2023.1148853] [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: 01/20/2023] [Accepted: 03/28/2023] [Indexed: 04/09/2023] Open
Abstract
Chinese doctors widely prescribed Platycodon grandiflorus A. DC. (PG) to treat lung carbuncles in ancient China. Modern clinical experiences have demonstrated that PG plays a crucial role in treating chronic pharyngitis, plum pneumonia, pneumoconiosis, acute and chronic laryngitis, and so forth. Additionally, PG is a food with a long history in China, Japan, and Korea. Furthermore, Platycodin D (PLD), an oleanane-type triterpenoid saponin, is one of the active substances in PG. PLD has been revealed to have anti-inflammatory, anti-viral, anti-oxidation, anti-obesity, anticoagulant, spermicidal, anti-tumor etc., activities. And the mechanism of the effects draws lots of attention, with various signaling pathways involved in these processes. Additionally, research on PLD's pharmacokinetics and extraction processes is under study. The bioavailability of PLD could be improved by being prescribed with Glycyrrhiza uralensis Fisch. or by creating a new dosage form. PLD has been recently considered to have the potential to be a solubilizer or an immunologic adjuvant. Meanwhile, PLD was discovered to have hemolytic activity correlated. PLD has broad application prospects and reveals practical pharmacological activities in pre-clinical research. The authors believe that these activities of PLD contribute to the efficacy of PG. What is apparent is that the clinical translation of PLD still has a long way to go. With the help of modern technology, the scope of clinical applications of PLD is probable to be expanded from traditional applications to new fields.
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Affiliation(s)
| | | | | | - Xiao-Fang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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28
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Mazurakova A, Koklesova L, Vybohova D, Samec M, Kudela E, Biringer K, Šudomová M, Hassan STS, Kello M, Büsselberg D, Golubnitschaja O, Kubatka P. Therapy-resistant breast cancer in focus: Clinically relevant mitigation by flavonoids targeting cancer stem cells. Front Pharmacol 2023; 14:1160068. [PMID: 37089930 PMCID: PMC10115970 DOI: 10.3389/fphar.2023.1160068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/27/2023] [Indexed: 04/09/2023] Open
Abstract
Significant limitations of the reactive medical approach in breast cancer management are clearly reflected by alarming statistics recorded worldwide. According to the WHO updates, breast malignancies become the leading cancer type. Further, the portion of premenopausal breast cancer cases is permanently increasing and demonstrates particularly aggressive patterns and poor outcomes exemplified by young patients with triple-negative breast cancer that lacks targeted therapy. Accumulating studies suggest the crucial role of stem cells in tumour biology, high metastatic activity, and therapy resistance of aggressive breast cancer. Therefore, targeting breast cancer stem cells is a promising treatment approach in secondary and tertiary breast cancer care. To this end, naturally occurring substances demonstrate high potential to target cancer stem cells which, however, require in-depth analysis to identify effective anti-cancer agents for cost-effective breast cancer management. The current article highlights the properties of flavonoids particularly relevant for targeting breast cancer stem cells to mitigate therapy resistance. The proposed approach is conformed with the principles of 3P medicine by applying predictive diagnostics, patient stratification and treatments tailored to the individualised patient profile. Expected impacts are very high, namely, to overcome limitations of reactive medical services improving individual outcomes and the healthcare economy in breast cancer management. Relevant clinical applications are exemplified in the paper.
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Affiliation(s)
- Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
- *Correspondence: Peter Kubatka, ; Alena Mazurakova,
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Desanka Vybohova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Marek Samec
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | | | - Sherif T. S. Hassan
- Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Prague, Czechia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Qatar Foundation, Doha, Qatar
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
- *Correspondence: Peter Kubatka, ; Alena Mazurakova,
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Brockmueller A, Samuel SM, Mazurakova A, Büsselberg D, Kubatka P, Shakibaei M. Curcumin, calebin A and chemosensitization: How are they linked to colorectal cancer? Life Sci 2023; 318:121504. [PMID: 36813082 DOI: 10.1016/j.lfs.2023.121504] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 02/10/2023] [Accepted: 02/12/2023] [Indexed: 02/22/2023]
Abstract
Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds. Calebin A and curcumin, two polyphenolic turmeric ingredients derived from the Asian Curcuma longa plant, demonstrate versatile anti-inflammatory and cancer-reducing abilities, including CRC-combating capacity. After an insight into their epigenetics-modifying holistic health-promoting effects, this review compares functional anti-CRC mechanisms of multi-targeting turmeric-derived compounds with mono-target classical chemotherapeutic agents. Furthermore, the reversal of resistance to chemotherapeutic drugs was presented by focusing on calebin A's and curcumin's capabilities to chemosensitize or re-sensitize CRC cells to 5-FU, oxaliplatin, cisplatin, and irinotecan. Both polyphenols enhance the receptiveness of CRC cells to standard cytostatic drugs converting them from chemoresistant into non-chemoresistant CRC cells by modulating inflammation, proliferation, cell cycle, cancer stem cells, and apoptotic signaling. Therefore, calebin A and curcumin can be tested for their ability to overcome cancer chemoresistance in preclinical and clinical trials. The future perspective of involving turmeric-ingredients curcumin or calebin A as an additive treatment to chemotherapy for patients with advanced metastasized CRC is explained.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany.
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar.
| | - Alena Mazurakova
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 036 01 Martin, Slovakia; Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia.
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar.
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 036 01 Martin, Slovakia.
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany.
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Koklesova L, Jakubikova J, Cholujova D, Samec M, Mazurakova A, Šudomová M, Pec M, Hassan STS, Biringer K, Büsselberg D, Hurtova T, Golubnitschaja O, Kubatka P. Phytochemical-based nanodrugs going beyond the state-of-the-art in cancer management-Targeting cancer stem cells in the framework of predictive, preventive, personalized medicine. Front Pharmacol 2023; 14:1121950. [PMID: 37033601 PMCID: PMC10076662 DOI: 10.3389/fphar.2023.1121950] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
Cancer causes many deaths worldwide each year, especially due to tumor heterogeneity leading to disease progression and treatment failure. Targeted treatment of heterogeneous population of cells - cancer stem cells is still an issue in protecting affected individuals against associated multidrug resistance and disease progression. Nanotherapeutic agents have the potential to go beyond state-of-the-art approaches in overall cancer management. Specially assembled nanoparticles act as carriers for targeted drug delivery. Several nanodrugs have already been approved by the US Food and Drug Administration (FDA) for treating different cancer types. Phytochemicals isolated from plants demonstrate considerable potential for nanomedical applications in oncology thanks to their antioxidant, anti-inflammatory, anti-proliferative, and other health benefits. Phytochemical-based NPs can enhance anticancer therapeutic effects, improve cellular uptake of therapeutic agents, and mitigate the side effects of toxic anticancer treatments. Per evidence, phytochemical-based NPs can specifically target CSCs decreasing risks of tumor relapse and metastatic disease manifestation. Therefore, this review focuses on current outlook of phytochemical-based NPs and their potential targeting CSCs in cancer research studies and their consideration in the framework of predictive, preventive, and personalized medicine (3PM).
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Affiliation(s)
- Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jana Jakubikova
- Cancer Research Institute, Department of Tumor Immunology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Dana Cholujova
- Cancer Research Institute, Department of Tumor Immunology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Marek Samec
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | | | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Sherif T. S. Hassan
- Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Prague, Czech Republic
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, Qatar
| | - Tatiana Hurtova
- Department of Dermatology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital Martin, Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
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Samec M, Mazurakova A, Lucansky V, Koklesova L, Pecova R, Pec M, Golubnitschaja O, Al-Ishaq RK, Caprnda M, Gaspar L, Prosecky R, Gazdikova K, Adamek M, Büsselberg D, Kruzliak P, Kubatka P. Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2. Eur J Pharmacol 2023; 949:175655. [PMID: 36921709 DOI: 10.1016/j.ejphar.2023.175655] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/20/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023]
Abstract
Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.
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Affiliation(s)
- Marek Samec
- Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Comenius University in Bratislava, Martin, Slovakia
| | - Vincent Lucansky
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Renata Pecova
- Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | | | - Martin Caprnda
- 1(st) Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Ludovit Gaspar
- Faculty of Health Sciences, University of Ss. Cyril and Methodius in Trnava, Trnava, Slovakia
| | - Robert Prosecky
- 2(nd) Department of Internal Medicine, Faculty of Medicine, Masaryk University and St. Anne´s University Hospital, Brno, Czech Republic; International Clinical Research Centre, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic
| | - Katarina Gazdikova
- Department of Nutrition, Faculty of Nursing and Professional Health Studies, Slovak Medical University, Bratislava, Slovakia; Department of General Medicine, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia.
| | - Mariusz Adamek
- Department of Thoracic Surgery, Medical University of Silesia, Katowice, Poland
| | | | - Peter Kruzliak
- 2(nd) Department of Surgery, Faculty of Medicine, Masaryk University and St. Anne´s University Hospital, Brno, Czech Republic.
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
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Kropp M, De Clerck E, Vo TTKS, Thumann G, Costigliola V, Golubnitschaja O. Short communication: unique metabolic signature of proliferative retinopathy in the tear fluid of diabetic patients with comorbidities - preliminary data for PPPM validation. EPMA J 2023; 14:43-51. [PMID: 36845280 PMCID: PMC9944425 DOI: 10.1007/s13167-023-00318-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 02/08/2023] [Indexed: 02/24/2023]
Abstract
Type 2 diabetes (T2DM) defined as the adult-onset type that is primarily not insulin-dependent, comprises over 95% of all diabetes mellitus (DM) cases. According to global records, 537 million adults aged 20-79 years are affected by DM that means at least 1 out of 15 persons. This number is projected to grow by 51% by the year 2045. One of the most common complications of T2DM is diabetic retinopathy (DR) with an overall prevalence over 30%. The total number of the DR-related visual impairments is on the rise, due to the growing T2DM population. Proliferative diabetic retinopathy (PDR) is the progressing DR and leading cause of preventable blindness in working-age adults. Moreover, PDR with characteristic systemic attributes including mitochondrial impairment, increased cell death and chronic inflammation, is an independent predictor of the cascading DM-complications such as ischemic stroke. Therefore, early DR is a reliable predictor appearing upstream of this "domino effect". Global screening, leading to timely identification of DM-related complications, is insufficiently implemented by currently applied reactive medicine. A personalised predictive approach and cost-effective targeted prevention shortly - predictive, preventive and personalised medicine (PPPM / 3PM) could make a good use of the accumulated knowledge, preventing blindness and other severe DM complications. In order to reach this goal, reliable stage- and disease-specific biomarker panels are needed characterised by an easy way of the sample collection, high sensitivity and specificity of analyses. In the current study, we tested the hypothesis that non-invasively collected tear fluid is a robust source for the analysis of ocular and systemic (DM-related complications) biomarker patterns suitable for differential diagnosis of stable DR versus PDR. Here, we report the first results of the comprehensive ongoing study, in which we correlate individualised patient profiles (healthy controls versus patients with stable D as well as patients with PDR with and without co-morbidities) with their metabolic profiles in the tear fluid. Comparative mass spectrometric analysis performed has identified following metabolic clusters which are differentially expressed in the groups of comparison: acylcarnitines, amino acid & related compounds, bile acids, ceramides, lysophosphatidyl-choline, nucleobases & related compounds, phosphatidyl-cholines, triglycerides, cholesterol esters, and fatty acids. Our preliminary data strongly support potential clinical utility of metabolic patterns in the tear fluid indicating a unique metabolic signature characteristic for the DR stages and PDR progression. This pilot study creates a platform for validating the tear fluid biomarker patterns to stratify T2DM-patients predisposed to the PDR. Moreover, since PDR is an independent predictor of severe T2DM-related complications such as ischemic stroke, our international project aims to create an analytical prototype for the "diagnostic tree" (yes/no) applicable to healthrisk assessment in diabetes care.
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Affiliation(s)
- Martina Kropp
- Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Eline De Clerck
- Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Trong-Tin Kevin Steve Vo
- Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Gabriele Thumann
- Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | | | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
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Kropp M, Golubnitschaja O, Mazurakova A, Koklesova L, Sargheini N, Vo TTKS, de Clerck E, Polivka J, Potuznik P, Polivka J, Stetkarova I, Kubatka P, Thumann G. Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications-risks and mitigation. EPMA J 2023; 14:21-42. [PMID: 36866156 PMCID: PMC9971534 DOI: 10.1007/s13167-023-00314-8] [Citation(s) in RCA: 116] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 01/15/2023] [Indexed: 02/17/2023]
Abstract
Proliferative diabetic retinopathy (PDR) the sequel of diabetic retinopathy (DR), a frequent complication of diabetes mellitus (DM), is the leading cause of blindness in the working-age population. The current screening process for the DR risk is not sufficiently effective such that often the disease is undetected until irreversible damage occurs. Diabetes-associated small vessel disease and neuroretinal changes create a vicious cycle resulting in the conversion of DR into PDR with characteristic ocular attributes including excessive mitochondrial and retinal cell damage, chronic inflammation, neovascularisation, and reduced visual field. PDR is considered an independent predictor of other severe diabetic complications such as ischemic stroke. A "domino effect" is highly characteristic for the cascading DM complications in which DR is an early indicator of impaired molecular and visual signaling. Mitochondrial health control is clinically relevant in DR management, and multi-omic tear fluid analysis can be instrumental for DR prognosis and PDR prediction. Altered metabolic pathways and bioenergetics, microvascular deficits and small vessel disease, chronic inflammation, and excessive tissue remodelling are in focus of this article as evidence-based targets for a predictive approach to develop diagnosis and treatment algorithms tailored to the individual for a cost-effective early prevention by implementing the paradigm shift from reactive medicine to predictive, preventive, and personalized medicine (PPPM) in primary and secondary DR care management.
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Affiliation(s)
- Martina Kropp
- Division of Experimental Ophthalmology, Department of Clinical Neurosciences, University of Geneva University Hospitals, 1205 Geneva, Switzerland ,Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
| | - Alena Mazurakova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Nafiseh Sargheini
- Max Planck Institute for Plant Breeding Research, Carl-Von-Linne-Weg 10, 50829 Cologne, Germany
| | - Trong-Tin Kevin Steve Vo
- Division of Experimental Ophthalmology, Department of Clinical Neurosciences, University of Geneva University Hospitals, 1205 Geneva, Switzerland ,Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Eline de Clerck
- Division of Experimental Ophthalmology, Department of Clinical Neurosciences, University of Geneva University Hospitals, 1205 Geneva, Switzerland ,Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Jiri Polivka
- Department of Histology and Embryology, and Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Prague, Czech Republic
| | - Pavel Potuznik
- Department of Neurology, University Hospital Plzen, and Faculty of Medicine in Plzen, Charles University, 100 34 Prague, Czech Republic
| | - Jiri Polivka
- Department of Neurology, University Hospital Plzen, and Faculty of Medicine in Plzen, Charles University, 100 34 Prague, Czech Republic
| | - Ivana Stetkarova
- Department of Neurology, University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Gabriele Thumann
- Division of Experimental Ophthalmology, Department of Clinical Neurosciences, University of Geneva University Hospitals, 1205 Geneva, Switzerland ,Ophthalmology Department, University Hospitals of Geneva, 1205 Geneva, Switzerland
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Mahboob A, Senevirathne DKL, Paul P, Nabi F, Khan RH, Chaari A. An investigation into the potential action of polyphenols against human Islet Amyloid Polypeptide aggregation in type 2 diabetes. Int J Biol Macromol 2023; 225:318-350. [PMID: 36400215 DOI: 10.1016/j.ijbiomac.2022.11.038] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/24/2022] [Accepted: 11/04/2022] [Indexed: 11/17/2022]
Abstract
Type 2 diabetes (T2D), a chronic metabolic disease characterized by hyperglycemia, results in significant disease burden and financial costs globally. Whilst the majority of T2D cases seem to have a genetic basis, non-genetic modifiable and non-modifiable risk factors for T2D include obesity, diet, physical activity and lifestyle, smoking, age, ethnicity, and mental stress. In healthy individuals, insulin secretion from pancreatic islet β-cells is responsible for keeping blood glucose levels within normal ranges. T2D patients suffer from multifactorial onset of β-cell dysfunction and/or loss of β-cell mass owing to reactive oxygen species (ROS) production, mitochondrial dysfunction, autophagy, and endoplasmic reticulum (ER) stress. Most predominantly however, and the focus of this review, it is the aggregation and misfolding of human Islet Amyloid Polypeptide (hIAPP, also known as amylin), which is detrimental to β-cell function and health. Whilst hIAPP is found in healthy individuals, its misfolded version is cytotoxic and able to induce β-cell dysfunction and/or death through various mechanisms including membrane changes in β-cell causing influx of calcium ions, arresting complete granule membrane recovery and ER stress. There are several existing therapeutics for T2D. However, there is a need for alternative or adjunct therapies for T2D with milder adverse effects and greater availability. Foremost among the potential natural therapeutics are polyphenols. Extensive data from studies evaluating the potential of polyphenols to inhibit hIAPP aggregation and disassemble aggregated hIAPP are promising. Moreover, in-vivo, and in-silico studies also highlight the potential effects of polyphenols against hIAPP aggregation and mitigation of larger pathological effects of T2D. Whilst there have been some promising clinical studies on the therapeutic potential of polyphenols, extensive further clinical studies and in-vitro studies evaluating the mechanisms of action and ideal doses for many of these compounds are required. The need for these studies is made more important by the postulated link between Alzheimer's disease (AD) and T2D pathophysiology given the similar aggregation process of their respective amyloid proteins, which evokes thoughts of cross-reactive polyphenols which can be effective for both AD and T2D patients.
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Affiliation(s)
- Anns Mahboob
- Premedical Division Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | | | - Pradipta Paul
- Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | - Faisal Nabi
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202001, India
| | - Rizwan Hasan Khan
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202001, India
| | - Ali Chaari
- Premedical Division Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar.
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Manthalkar L, Ajazuddin, Bhattacharya S. Evidence-based capacity of natural cytochrome enzyme inhibitors to increase the effectivity of antineoplastic drugs. Discov Oncol 2022; 13:142. [PMID: 36571647 PMCID: PMC9792636 DOI: 10.1007/s12672-022-00605-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 12/14/2022] [Indexed: 12/27/2022] Open
Abstract
Cytochrome (CYP) enzymes catalyze the metabolism of numerous exogenous and endogenous substrates in cancer therapy leading to significant drug interactions due to their metabolizing effect. CYP enzymes play an important role in the metabolism of essential anticancer medications. They are shown to be overexpressed in tumor cells at numerous locations in the body. This overexpression could be a result of lifestyle factors, presence of hereditary variants of CYP (Bio individuality) and multi-drug resistance. This finding has sparked an interest in using CYP inhibitors to lower their metabolizing activity as a result facilitating anti-cancer medications to have a therapeutic impact. As a result of the cytotoxic nature of synthetic enzyme inhibitors and the increased prevalence of herbal medication, natural CYP inhibitors have been identified as an excellent way to inhibit overexpression sighting their tendency to show less cytotoxicity, lesser adverse drug reactions and enhanced bioavailability. Nonetheless, their effect of lowering the hindrance caused in chemotherapy due to CYP enzymes remains unexploited to its fullest. It has been observed that there is a substantial decrease in first pass metabolism and increase in intestinal absorption of chemotherapeutic drugs like paclitaxel when administered along with flavonoids which help suppress certain specific cytochrome enzymes which play a role in paclitaxel metabolism. This review elaborates on the role and scope of phytochemicals in primary, secondary and tertiary care and how targeted prevention of cancer could be a breakthrough in the field of chemotherapy and oncology. This opens up a whole new area of research for delivery of these natural inhibitors along with anticancer drugs with the help of liposomes, micelles, nanoparticles, the usage of liquid biopsy analysis, artificial intelligence in medicine, risk assessment tools, multi-omics and multi-parametric analysis. Further, the site of action, mechanisms, metabolites involved, experimental models, doses and observations of two natural compounds, quercetin & thymoquinone, and two plant extracts, liquorice & garlic on CYP enzymes have been summarized.
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Affiliation(s)
- Laxmi Manthalkar
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, 425405, Maharashtra, India
| | - Ajazuddin
- Department of Pharmaceutics, Rungta College of Pharmaceutical Sciences & Research, Khoka-Kurud Road, Bhilai, 490024, Chhattisgarh, India.
| | - Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, 425405, Maharashtra, India.
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Flavonoids' Dual Benefits in Gastrointestinal Cancer and Diabetes: A Potential Treatment on the Horizon? Cancers (Basel) 2022; 14:cancers14246073. [PMID: 36551558 PMCID: PMC9776408 DOI: 10.3390/cancers14246073] [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: 11/13/2022] [Revised: 12/08/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetes and gastrointestinal cancers (GI) are global health conditions with a massive burden on patients' lives worldwide. The development of both conditions is influenced by several factors, such as diet, genetics, environment, and infection, which shows a potential link between them. Flavonoids are naturally occurring phenolic compounds present in fruits and vegetables. Once ingested, unabsorbed flavonoids reaching the colon undergo enzymatic modification by the gut microbiome to facilitate absorption and produce ring fission products. The metabolized flavonoids exert antidiabetic and anti-GI cancer properties, targeting major impaired pathways such as apoptosis and cellular proliferation in both conditions, suggesting the potentially dual effects of flavonoids on diabetes and GI cancers. This review summarizes the current knowledge on the impact of flavonoids on diabetes and GI cancers in four significant pathways. It also addresses the synergistic effects of selected flavonoids on both conditions. While this is an intriguing approach, more studies are required to better understand the mechanism of how flavonoids can influence the same impaired pathways with different outcomes depending on the disease.
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Rašková M, Lacina L, Kejík Z, Venhauerová A, Skaličková M, Kolář M, Jakubek M, Rosel D, Smetana K, Brábek J. The Role of IL-6 in Cancer Cell Invasiveness and Metastasis-Overview and Therapeutic Opportunities. Cells 2022; 11:3698. [PMID: 36429126 PMCID: PMC9688109 DOI: 10.3390/cells11223698] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression.
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Affiliation(s)
- Magdalena Rašková
- Department of Cell Biology, Faculty of Science, Charles University, 120 00 Prague, Czech Republic
- BIOCEV, Faculty of Science, Charles University, 252 50 Vestec, Czech Republic
| | - Lukáš Lacina
- Centre for Tumour Ecology, First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Institute of Anatomy, First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic
- Department of Dermatovenereology, First Faculty of Medicine, Charles University and General University Hospital, 120 00 Prague, Czech Republic
| | - Zdeněk Kejík
- Centre for Tumour Ecology, First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, 120 00 Prague, Czech Republic
| | - Anna Venhauerová
- BIOCEV, Faculty of Science, Charles University, 252 50 Vestec, Czech Republic
| | - Markéta Skaličková
- BIOCEV, Faculty of Science, Charles University, 252 50 Vestec, Czech Republic
| | - Michal Kolář
- Centre for Tumour Ecology, First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics, Czech Academy of Sciences, 140 00 Prague, Czech Republic
| | - Milan Jakubek
- Centre for Tumour Ecology, First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, 120 00 Prague, Czech Republic
| | - Daniel Rosel
- Department of Cell Biology, Faculty of Science, Charles University, 120 00 Prague, Czech Republic
- BIOCEV, Faculty of Science, Charles University, 252 50 Vestec, Czech Republic
| | - Karel Smetana
- Centre for Tumour Ecology, First Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department of Dermatovenereology, First Faculty of Medicine, Charles University and General University Hospital, 120 00 Prague, Czech Republic
| | - Jan Brábek
- Department of Cell Biology, Faculty of Science, Charles University, 120 00 Prague, Czech Republic
- BIOCEV, Faculty of Science, Charles University, 252 50 Vestec, Czech Republic
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Qi X, Jha SK, Jha NK, Dewanjee S, Dey A, Deka R, Pritam P, Ramgopal K, Liu W, Hou K. Antioxidants in brain tumors: current therapeutic significance and future prospects. Mol Cancer 2022; 21:204. [PMID: 36307808 PMCID: PMC9615186 DOI: 10.1186/s12943-022-01668-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 09/27/2022] [Indexed: 11/23/2022] Open
Abstract
Brain cancer is regarded among the deadliest forms of cancer worldwide. The distinct tumor microenvironment and inherent characteristics of brain tumor cells virtually render them resistant to the majority of conventional and advanced therapies. Oxidative stress (OS) is a key disruptor of normal brain homeostasis and is involved in carcinogenesis of different forms of brain cancers. Thus, antioxidants may inhibit tumorigenesis by preventing OS induced by various oncogenic factors. Antioxidants are hypothesized to inhibit cancer initiation by endorsing DNA repair and suppressing cancer progression by creating an energy crisis for preneoplastic cells, resulting in antiproliferative effects. These effects are referred to as chemopreventive effects mediated by an antioxidant mechanism. In addition, antioxidants minimize chemotherapy-induced nonspecific organ toxicity and prolong survival. Antioxidants also support the prooxidant chemistry that demonstrate chemotherapeutic potential, particularly at high or pharmacological doses and trigger OS by promoting free radical production, which is essential for activating cell death pathways. A growing body of evidence also revealed the roles of exogenous antioxidants as adjuvants and their ability to reverse chemoresistance. In this review, we explain the influences of different exogenous and endogenous antioxidants on brain cancers with reference to their chemopreventive and chemotherapeutic roles. The role of antioxidants on metabolic reprogramming and their influence on downstream signaling events induced by tumor suppressor gene mutations are critically discussed. Finally, the review hypothesized that both pro- and antioxidant roles are involved in the anticancer mechanisms of the antioxidant molecules by killing neoplastic cells and inhibiting tumor recurrence followed by conventional cancer treatments. The requirements of pro- and antioxidant effects of exogenous antioxidants in brain tumor treatment under different conditions are critically discussed along with the reasons behind the conflicting outcomes in different reports. Finally, we also mention the influencing factors that regulate the pharmacology of the exogenous antioxidants in brain cancer treatment. In conclusion, to achieve consistent clinical outcomes with antioxidant treatments in brain cancers, rigorous mechanistic studies are required with respect to the types, forms, and stages of brain tumors. The concomitant treatment regimens also need adequate consideration.
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Affiliation(s)
- Xuchen Qi
- Department of Neurosurgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China.,Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310020, Zhejiang, China
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India. .,Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India. .,Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India.
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, 700032, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700032, India
| | - Rahul Deka
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Pingal Pritam
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Kritika Ramgopal
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Weiting Liu
- School of Nursing, Anhui University of Chinese Medicine, Hefei, 230001, Anhui, China.
| | - Kaijian Hou
- School of Nursing, Anhui University of Chinese Medicine, Hefei, 230001, Anhui, China. .,School of Public Health, Shantou University, Shantou, 515000, Guangdong, China.
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Kubatka P, Mazurakova A, Koklesova L, Samec M, Sokol J, Samuel SM, Kudela E, Biringer K, Bugos O, Pec M, Link B, Adamkov M, Smejkal K, Büsselberg D, Golubnitschaja O. Antithrombotic and antiplatelet effects of plant-derived compounds: a great utility potential for primary, secondary, and tertiary care in the framework of 3P medicine. EPMA J 2022; 13:407-431. [PMID: 35990779 PMCID: PMC9376584 DOI: 10.1007/s13167-022-00293-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/03/2022] [Indexed: 12/29/2022]
Abstract
Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both - the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.
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Affiliation(s)
- Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Alena Mazurakova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Marek Samec
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Juraj Sokol
- Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, 24144 Doha, Qatar
| | - Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | | | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Barbara Link
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
| | - Marian Adamkov
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, 61200 Brno, Czech Republic
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, 24144 Doha, Qatar
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
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Sevastre AS, Manea EV, Popescu OS, Tache DE, Danoiu S, Sfredel V, Tataranu LG, Dricu A. Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy. Int J Mol Sci 2022; 23:ijms23179943. [PMID: 36077338 PMCID: PMC9456420 DOI: 10.3390/ijms23179943] [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: 07/26/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022] Open
Abstract
Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.
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Affiliation(s)
- Ani-Simona Sevastre
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Elena Victoria Manea
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Oana Stefana Popescu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Daniela Elise Tache
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Suzana Danoiu
- Department of Pathophysiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Veronica Sfredel
- Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Ligia Gabriela Tataranu
- Neurosurgical Department, Clinical Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania
- Correspondence: ; Tel.: +40-21-334-30-25
| | - Anica Dricu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
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Evsevieva M, Sergeeva O, Mazurakova A, Koklesova L, Prokhorenko-Kolomoytseva I, Shchetinin E, Birkenbihl C, Costigliola V, Kubatka P, Golubnitschaja O. Pre-pregnancy check-up of maternal vascular status and associated phenotype is crucial for the health of mother and offspring. EPMA J 2022; 13:351-366. [PMID: 36061831 PMCID: PMC9437153 DOI: 10.1007/s13167-022-00294-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/04/2022] [Indexed: 12/15/2022]
Abstract
Abstract Cardiovascular disease remains the leading cause of disease burden globally with far-reaching consequences including enormous socio-economic burden to healthcare and society at large. Cardiovascular health is decisive for reproductive function, healthy pregnancy and postpartum. During pregnancy, maternal cardiovascular system is exposed to highly increased haemodynamic stress that significantly impacts health status of the mother and offspring. Resulting from sub-optimal maternal health conditions overlooked in pre-pregnancy time, progressive abnormalities can be expected during pregnancy and postpartum. Contextually, there are two main concepts to follow in the framework of predictive, preventive and personalised medicine, namely to develop: 1. advanced screening of sub-optimal health conditions in young populations to predict and prevent individual health risks prior to planned pregnancies 2. in-depth companion diagnostics during pregnancy to predict and prevent long-lasting postpartum health risks of the mother and offspring. Data collected in the current study demonstrate group-specific complications to health of the mother and offspring and clinical relevance of the related phenotyping in pre-pregnant mothers. Diagnostic approach proposed in this study revealed its great clinical utility demonstrating important synergies between cardiovascular maladaptation and connective tissue dysfunction. Co-diagnosed pre-pregnancy low BMI of the mother, connective tissue dysfunction, increased stiffness of peripheral vessels and decreased blood pressure are considered a highly specific maternal phenotype useful for innovative screening programmes in young populations to predict and prevent severe risks to health of the mother and offspring. This crucial discovery brings together systemic effects characteristic, for example, for individuals with Flammer syndrome predisposed to the phenotype-specific primary vascular dysregulation, pregnancy-associated risks, normal tension glaucoma, ischemic stroke at young age, impaired wound healing and associated disorders. Proposed maternal phenotyping is crucial to predict and effectively protect both the mother and offspring against health-to-disease transition. Pre-pregnancy check-up focused on sub-optimal health and utilising here described phenotypes is pivotal for advanced health policy. Plain English abstract Cardiovascular health is decisive for reproductive function and healthy pregnancy. During pregnancy, maternal cardiovascular system may demonstrate health-to-disease transition relevant for the affected mother and offspring. Overlooked in pre-pregnancy time, progressive abnormalities can be expected during pregnancy and lifelong. Here we co-diagnosed maternal pre-pregnancy low bodyweight with systemic effects which may increase risks of pregnancy, eye and heart disorders and ischemic stroke at young age, amongst others. Innovative screening programmes focused on sub-optimal health in young populations to predict and to mitigate individual health risks prior to pregnancy is an essential innovation for health policy proposed.
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Affiliation(s)
- Maria Evsevieva
- Stavropol State Medical University, Stavropol, Russian Federation
| | - Oksana Sergeeva
- Stavropol State Medical University, Stavropol, Russian Federation
| | - Alena Mazurakova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | | | | | | | | | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
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A Dietary Antioxidant Formulation Ameliorates DNA Damage Caused by γ-Irradiation in Normal Human Bronchial Epithelial Cells In Vitro. Antioxidants (Basel) 2022; 11:antiox11071407. [PMID: 35883898 PMCID: PMC9311589 DOI: 10.3390/antiox11071407] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/12/2022] [Accepted: 07/18/2022] [Indexed: 12/10/2022] Open
Abstract
Antioxidants can be used as radioprotectants to reduce DNA damage due to exposure to radiation that could result in malignancies, including lung cancer. Mortality rates are consistently higher in lung cancer, which is usually diagnosed at later stages of cancer development and progression. In this preliminary study, we examined the potential of an antioxidant formulation (AOX2) to reduce DNA damage using a cell model of human normal bronchial epithelial cells (BEAS-2B). Cells were exposed to γ-irradiation or smoke-related hydrocarbon 4[(acetoxymethyl)nitrosamino]-1 (3-pyridyl) 1-butanone (NNKOAc) to induce DNA damage. We monitored intracellular reactive oxygen species (ROS) levels and evidence of genotoxic damage including DNA fragmentation ELISA, γ-H2AX immunofluorescence, and comet assays. Pre-incubation of the cells with AOX2 before exposure to γ-irradiation and NNKOAc significantly reduced DNA damage. The dietary antioxidant preparation AOX2 significantly reduced the induction of the tumor suppressor protein p53 and DNA damage-associated γ-H2AX phosphorylation by radiation and the NNKOAc treatment. Thus, AOX2 has the potential to act as a chemoprotectant by lowering ROS levels and DNA damage caused by exposure to radiation or chemical carcinogens.
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Li X, Liu C, Liang J, Zhou L, Li J, Chen H, Jiang T, Guan Y, Eng Khoo H. Antioxidative mechanisms and anticolitic potential of Desmodium styracifolium (Osb.) Merr. in DSS-induced colitic mice. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Flavonoids as Potential Anti-Inflammatory Molecules: A Review. Molecules 2022; 27:molecules27092901. [PMID: 35566252 PMCID: PMC9100260 DOI: 10.3390/molecules27092901] [Citation(s) in RCA: 335] [Impact Index Per Article: 111.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/22/2022] Open
Abstract
Hydroxylated polyphenols, also called flavonoids, are richly present in vegetables, fruits, cereals, nuts, herbs, seeds, stems, and flowers of numerous plants. They possess numerous medicinal properties such as antioxidant, anti-cancer, anti-microbial, neuroprotective, and anti-inflammation. Studies show that flavonoids activate antioxidant pathways that render an anti-inflammatory effect. They inhibit the secretions of enzymes such as lysozymes and β-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions. Flavonoids such as quercetin, genistein, apigenin, kaempferol, and epigallocatechin 3-gallate modulate the expression and activation of a cytokine such as interleukin-1beta (IL-1β), Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); regulate the gene expression of many pro-inflammatory molecules such s nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and E-selectins; and also inhibits inducible nitric oxide (NO) synthase, cyclooxygenase-2, and lipoxygenase, which are pro-inflammatory enzymes. Understanding the anti-inflammatory action of flavonoids provides better treatment options, including coronavirus disease 2019 (COVID-19)-induced inflammation, inflammatory bowel disease, obstructive pulmonary disorder, arthritis, Alzheimer’s disease, cardiovascular disease, atherosclerosis, and cancer. This review highlights the sources, biochemical activities, and role of flavonoids in enhancing human health.
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Mazurakova A, Koklesova L, Samec M, Kudela E, Kajo K, Skuciova V, Csizmár SH, Mestanova V, Pec M, Adamkov M, Al-Ishaq RK, Smejkal K, Giordano FA, Büsselberg D, Biringer K, Golubnitschaja O, Kubatka P. Anti-breast cancer effects of phytochemicals: primary, secondary, and tertiary care. EPMA J 2022; 13:315-334. [PMID: 35437454 PMCID: PMC9008621 DOI: 10.1007/s13167-022-00277-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 03/21/2022] [Indexed: 02/07/2023]
Abstract
Breast cancer incidence is actually the highest one among all cancers. Overall breast cancer management is associated with challenges considering risk assessment and predictive diagnostics, targeted prevention of metastatic disease, appropriate treatment options, and cost-effectiveness of approaches applied. Accumulated research evidence indicates promising anti-cancer effects of phytochemicals protecting cells against malignant transformation, inhibiting carcinogenesis and metastatic spread, supporting immune system and increasing effectiveness of conventional anti-cancer therapies, among others. Molecular and sub-/cellular mechanisms are highly complex affecting several pathways considered potent targets for advanced diagnostics and cost-effective treatments. Demonstrated anti-cancer affects, therefore, are clinically relevant for improving individual outcomes and might be applicable to the primary (protection against initial cancer development), secondary (protection against potential metastatic disease development), and tertiary (towards cascading complications) care. However, a detailed data analysis is essential to adapt treatment algorithms to individuals’ and patients’ needs. Consequently, advanced concepts of patient stratification, predictive diagnostics, targeted prevention, and treatments tailored to the individualized patient profile are instrumental for the cost-effective application of natural anti-cancer substances to improve overall breast cancer management benefiting affected individuals and the society at large.
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Holubekova V, Kolkova Z, Kasubova I, Samec M, Mazurakova A, Koklesova L, Kubatka P, Rokos T, Kozubik E, Biringer K, Kudela E. Interaction of cervical microbiome with epigenome of epithelial cells: Significance of inflammation to primary healthcare. Biomol Concepts 2022; 13:61-80. [PMID: 35245973 DOI: 10.1515/bmc-2022-0005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
One pillar of the predictive, preventive, and personalized medicine framework strategies is the female health. The evaluation of women's lifestyle and dietary habits in context with genetic and modifiable risk factors may reflect the prevention of cervical cancer before the occurrence of clinical symptoms and prediction of cervical lesion behavior. The main aim of this review is to analyze publications in the field of precision medicine that allow the use of research knowledge of cervical microbiome, epigenetic modifications, and inflammation in potential application in clinical practice. Personalized approach in evaluating patient's risk of future development of cervical abnormality should consider the biomarkers of the local microenvironment characterized by the microbial composition, epigenetic pattern of cervical epithelium, and presence of chronic inflammation. Novel sequencing techniques enable a more detailed characterization of actual state in cervical epithelium. Better understanding of all changes in multiomics level enables a better assessment of disease prognosis and selects the eligible targeted therapy in personalized medicine. Restoring of healthy vaginal microflora and reversing the outbreak of cervical abnormality can be also achieved by dietary habits as well as uptake of prebiotics, probiotics, synbiotics, microbial transplantation, and others.
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Affiliation(s)
- Veronika Holubekova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, SK-03601, Slovakia
| | - Zuzana Kolkova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, SK-03601, Slovakia
| | - Ivana Kasubova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, SK-03601, Slovakia
| | - Marek Samec
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, SK-03601, Slovakia
| | - Alena Mazurakova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin University Hospital, Martin, SK-03601, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin University Hospital, Martin, SK-03601, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, SK-03601, Slovakia
| | - Tomas Rokos
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin University Hospital, Martin, SK-03601, Slovakia
| | - Erik Kozubik
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin University Hospital, Martin, SK-03601, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin University Hospital, Martin, SK-03601, Slovakia
| | - Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin University Hospital, Martin, SK-03601, Slovakia
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