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Tomsuk Ö, Kaçar S. Mechanistic Insights into Silymarin-Induced Apoptosis and Growth Inhibition in SPC212 Human Mesothelioma Cells. Cell Biochem Biophys 2025; 83:2405-2414. [PMID: 39747779 DOI: 10.1007/s12013-024-01650-w] [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: 12/17/2024] [Indexed: 01/04/2025]
Abstract
Silymarin, a flavonoid complex isolated from Silybum marianum, possesses various biological properties, including antioxidant, anti-inflammatory, anti-glycation, and hepatoprotective effects. In the present study, we investigated the effects of silymarin on the SPC212 human mesothelioma cell line. MTT and neutral red assays were performed to examine the cytotoxic effects of silymarin. The apoptotic effect was investigated using AO/EB and DAPI staining, and morphological changes were observed using H&E and May-Grünwald staining. Additionally, immunocytochemistry was performed to detect Bax, Bcl2, and PCNA. Our results indicated that silymarin has a dose-dependent cytotoxic effect on SPC212 cells, with an IC50 value of approximately 187.5 µM. Silymarin induces apoptotic hallmarks such as apoptotic bodies, cell shrinkage, and nuclear condensation. In conclusion, silymarin demonstrated cytotoxic and apoptotic effects as well as morphological changes in SPC212 human mesothelioma cells. Further detailed studies are warranted to explore the potential of silymarin as an anti-cancer agent.
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Affiliation(s)
- Özlem Tomsuk
- Graduate School of Natural and Applied Sciences, Biotechnology and Biosafety Department, Eskişehir Osmangazi University, Eskişehir, Türkiye.
- Cellular Therapy and Stem Cell Production Application and Research Center (ESTEM), Eskişehir Osmangazi University, Eskişehir, Türkiye.
- Faculty of Medicine, Department of Histology and Embryology, Eskişehir Osmangazi University, Eskişehir, Türkiye.
| | - Sedat Kaçar
- Faculty of Medicine, Department of Histology and Embryology, Eskişehir Osmangazi University, Eskişehir, Türkiye
- Vera Bradley Foundation Center for Breast Cancer Research, Department of Surgery & Division of Oncologic Surgery, Indiana University School of Medicine, Indianapolis, USA
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
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Nazir N, Khan S, Karim N, Nisar M, Aziz T, Shami A, Al-Asmari F, Alhhazmi AA, Al-Joufi FA, Alwethaynani MS. Elucidating the Phytochemical, Antibacterial, and Hepatoprotective Effects of Elaeagnus umbellata Leaf Extract Against Liver Injury in an Animal Model. Cell Biochem Biophys 2025:10.1007/s12013-025-01767-6. [PMID: 40310599 DOI: 10.1007/s12013-025-01767-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2025] [Indexed: 05/02/2025]
Abstract
Elaeagnus umbellata, commonly known as autumn olive, is considered a medicinal plant of high value and belongs to the Elaeagnaceae family. It exhibits anti-ulcer, antimutagenic, antimicrobial, and neuroprotective properties. The leaves of E. umbellata reportedly have pharmacological activities, including antibacterial, anti-inflammatory, and anticancer effects. However, no in vivo studies have evaluated this plant's hepatoprotective potential. In this study, the hepatoprotective potential of E. umbellata was determined using an in vivo model. Extraction from the leaves of E. umbellata was carried out using standard methods, which then were subjected to gas chromatography and mass spectroscopy for characterization. Fourteen compounds were identified in the crude methanolic extract (Met-Ext) of E. umbellata leaves. Total phenolic and total flavonoid contents were assessed, and the extract was tested for hepatoprotective potential against carbon tetrachloride (CCL4)-induced liver injury using rats as an experimental model. The samples exhibited antibacterial potential against bacterial strains such as Pseudomonas Aeruginosa 25619 (25 mm zone of inhibition) and Enterococcus faecalis 29212 (26 mm zone of inhibition). No inhibition was noted for Klebsiella pneumonia 43816 relative to the standard imipenem (34 mm zone of inhibition on average). A marked increase was observed in the levels of some serum liver biochemical parameters such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total cholesterol, serum creatinine, total serum bilirubin, total triglyceride, and low-density lipoprotein. By contrast, a reduction was observed in other parameters, such as high-density lipoprotein, in a group of animals treated with CCl4. The extract possessed substantial protective properties against CCl4-induced liver toxicity, thereby mitigating liver damage and restoring liver function. The results of this in vivo study indicate that the crude Met-Ext of E. umbellata leaves exhibits considerable hepatoprotective effects in a dose-dependent manner.
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Affiliation(s)
- Nausheen Nazir
- Department of Biochemistry, University of Malakand, Chakdara, Dir (Lower), Khyber Pakhtunkhwa, Pakistan.
| | - Sajid Khan
- Department of Biochemistry, University of Malakand, Chakdara, Dir (Lower), Khyber Pakhtunkhwa, Pakistan
| | - Nasiara Karim
- Department of Pharmacy, University of Peshawar, Khyber Pakhtunkhwa, Peshawar, Pakistan
| | - Mohammad Nisar
- Department of Botany, University of Malakand, Chakdara, Dir (Lower), Khyber Pakhtunkhwa, Pakistan
| | - Tariq Aziz
- Laboratory of Animal Health Food Hygiene and Quality, University of Ioannina, Arta, Greece.
| | - Ashwag Shami
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Fahad Al-Asmari
- Department of Food and Nutrition Sciences, College of Agricultural and Food Sciences, King Faisal University, Al Ahsa, Saudi Arabia
| | - Areej A Alhhazmi
- Clinical Laboratory Sciences Department. Applied Medical Sciences, Taibah University, Medina, Saudi Arabia
| | - Fakhria A Al-Joufi
- Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf, Saudi Arabia
| | - Maher S Alwethaynani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia
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Agarwal S, Kaushik S, Saha H, Paramanick D, Mazhar M, Basist P, Khan R, Alhalmi A. Therapeutic potential of traditional herbal plants and their polyphenols in alleviation of mercury toxicity. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03807-7. [PMID: 39912903 DOI: 10.1007/s00210-025-03807-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 01/09/2025] [Indexed: 02/07/2025]
Abstract
Mercury (Hg) is a major environmental contaminant significantly impacting human health. As a naturally occurring element, mercury has been extensively mobilized into aquatic and terrestrial ecosystems over thousands of years, largely due to anthropogenic activities such as mining and metal extraction. Acute mercury toxicity causes extensive physiological damage, affecting vital organs including the kidneys, heart, liver, brain, and skin. Phytochemicals, known for their diverse pharmacological properties, have shown promise in mitigating metal-induced toxicities, including mercury. These compounds exhibit protective effects against mercury-induced multi-organ damage through mechanisms such as reactive oxygen species (ROS) scavenging, cyclooxygenase (COX) inhibition, and anti-inflammatory activity. This review explores the therapeutic potential of traditional herbal plants and their phytoconstituents in alleviating mercury-induced toxicity. Key findings highlight several plants with hepatoprotective effects, mitigating necrosis and anatomical distortion in liver cells. Phytochemicals such as quercetin, rutin, salicylic acid, ferulic acid, 6-gingerol, and 6-shogaol play pivotal roles in downregulating molecular pathways activated by mercury exposure. Other bioactive compounds, including acetogenin and gallic acid, exhibit potent antioxidant properties, with mechanisms such as ROS scavenging and inhibition of lipid peroxidation. This review also highlights certain compounds, such as aloe-emodin and gentisic acid, which exhibit potential for mitigating mercury toxicity through mechanisms like inhibiting oxidative stress and enhancing cellular defense pathways. However, these compounds remain underexplored, with no significant studies conducted to evaluate their efficacy against mercury-induced toxicity, presenting a critical area for future research. These findings underscore the potential of phytochemicals as effective agents in combating mercury toxicity through antioxidant mechanisms, cellular signalling regulation, and heavy metal chelation.
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Affiliation(s)
- Saloni Agarwal
- School of Medical and Allied Sciences, K.R. Mangalam University, Sohna, Gurugram, 122103, India
| | - Swati Kaushik
- School of Medical and Allied Sciences, K.R. Mangalam University, Sohna, Gurugram, 122103, India
| | - Hiranmoy Saha
- School of Medical and Allied Sciences, K.R. Mangalam University, Sohna, Gurugram, 122103, India
| | - Debashish Paramanick
- School of Medical and Allied Sciences, K.R. Mangalam University, Sohna, Gurugram, 122103, India
| | - Mohd Mazhar
- School of Medical and Allied Sciences, K.R. Mangalam University, Sohna, Gurugram, 122103, India
| | - Parakh Basist
- School of Medical and Allied Sciences, K.R. Mangalam University, Sohna, Gurugram, 122103, India
| | - Rahmuddin Khan
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutics, Faculty of Pharmacy, University of Aden, 00967, Aden, Yemen.
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Sharma U, Sahni PK, Sharma B, Gupta M, Kaur D, Mathkor DM, Haque S, Khatoon S, Tuli HS, Mishra A, Ahmad F. Silymarin: a promising modulator of apoptosis and survival signaling in cancer. Discov Oncol 2025; 16:66. [PMID: 39836338 PMCID: PMC11751200 DOI: 10.1007/s12672-025-01800-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
Cancer, one of the deadliest diseases, has remained the epicenter of biological research for more than seven decades. Yet all the efforts for a perfect therapeutic cure come with certain limitations. The use of medicinal plants and their phytochemicals as therapeutics has received much attention in recent years. Silymarin, a polyphenolic flavonoid with a variety of anti-cancerous properties, was isolated from the plant Silybum marianum. The present review centres on the function of silymarin in controlling important signalling pathways related to apoptosis and survival, such as the JAK/STAT pathway, PI3K/Akt/mTOR, Bcl-2/Bax, and Fas/FasL. It is emphasised that silymarin's capacity to target these pathways is a key mechanism behind its anticancer effects against a variety of malignancies. By upregulating pro-apoptotic and downregulating anti-apoptotic proteins, silymarin controls a series of events that result in tumor suppression and cell death in a variety of cancer types. The low bioavailability and limited therapeutic efficacy of silymarin are improved by the application of various nano-delivery systems. As efficient carriers, liposomes, polymeric micelles, lipid- and metal-based nanoparticles, increase the solubility and distribution of silymarin in target tissues. Lastly, a number of preclinical studies that provide a basis for upcoming therapeutic interventions are highlighted in the review, providing encouraging directions for additional research and advancement.
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Affiliation(s)
- Ujjawal Sharma
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India
| | - Praveen Kumar Sahni
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India
| | - Bunty Sharma
- Department of Biotechnology, Graphic Era (Deemed to Be University), Dehradun, Uttarakhand, India
| | - Madhu Gupta
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Damandeep Kaur
- University Center for Research & Development (UCRD), Chandigarh University, Gharuan, Mohali, Punjab, 140413, India
| | - Darin Mansor Mathkor
- Department of Nursing, College of Nursing and Health Sciences, Jazan University, 45142, Jazan, Saudi Arabia
| | - Shafiul Haque
- Department of Nursing, College of Nursing and Health Sciences, Jazan University, 45142, Jazan, Saudi Arabia
- Universidad Espiritu Santo, Samborondon, Ecuador
| | - Sabiha Khatoon
- University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, 133207, India
| | - Astha Mishra
- Department of Optometry, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, India
| | - Faraz Ahmad
- Department of Biotechnology, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore, 632014, India.
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Kangra K, Kakkar S, Mittal V, Kumar V, Aggarwal N, Chopra H, Malik T, Garg V. Incredible use of plant-derived bioactives as anticancer agents. RSC Adv 2025; 15:1721-1746. [PMID: 39835210 PMCID: PMC11744461 DOI: 10.1039/d4ra05089d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 12/31/2024] [Indexed: 01/22/2025] Open
Abstract
Cancer is a major global concern. Despite considerable advancements in cancer therapy and control, there are still large gaps and requirements for development. In recent years, various naturally occurring anticancer drugs have been derived from natural resources, such as alkaloids, glycosides, terpenes, terpenoids, flavones, and polyphenols. Plant-derived substances exhibit their anticancer potential through antiproliferative activity, cytotoxicity, apoptosis, angiogenesis and cell cycle arrest. Natural compounds can affect the molecular activity of cells through various signaling pathways, like the cell cycle pathway, STAT-3 pathway, PI3K/Akt, and Ras/MAP-kinase pathways. Capsaicin, ouabain, and lycopene show their anticancer potential through the STAT-3 pathway in breast, colorectal, pancreatic, lung, cervical, ovarian and colon cancers. Epigallocatechin gallate and emodin target the JNK protein in skin, breast, and lung cancers, while berberine, evodiamine, lycorine, and astragalin exhibit anticancer activity against breast, liver, prostate, pancreatic and skin cancers and leukemia through the PI3K/Akt and Ras/MAP-kinase pathways. In vitro/in vivo investigations revealed that secondary metabolites suppress cancer cells by causing DNA damage and activating apoptosis-inducing enzymes. After a meticulous literature review, the anti-cancer potential, mode of action, and clinical trials of 144 bioactive compounds and their synthetic analogues are included in the present work, which could pave the way for using plant-derived bioactives as anticancer agents.
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Affiliation(s)
- Kiran Kangra
- Department of Pharmaceutical Sciences, Maharshi Dayanand University Rohtak 124001 India
| | - Saloni Kakkar
- Department of Pharmaceutical Sciences, Maharshi Dayanand University Rohtak 124001 India
| | - Vineet Mittal
- Department of Pharmaceutical Sciences, Maharshi Dayanand University Rohtak 124001 India
| | - Virender Kumar
- College of Pharmacy, Pandit Bhagwat Dayal Sharma University of Health Sciences Rohtak 124001 India
| | - Navidha Aggarwal
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University) Mullana Ambala 133207 Haryana India
| | - Hitesh Chopra
- Department of Biosciences, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences Chennai 602105 Tamil Nadu India
| | - Tabarak Malik
- Department of Biomedical Sciences, Jimma University Jimma Ethiopia
- Division of Research & Development, Lovely Professional University Phagwara Punjab-144411 India
| | - Vandana Garg
- Department of Pharmaceutical Sciences, Maharshi Dayanand University Rohtak 124001 India
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6
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Liao Y, Lv F, Quan T, Wang C, Li J. Flavonoids in natural products for the therapy of liver diseases: progress and future opportunities. Front Pharmacol 2024; 15:1485065. [PMID: 39512816 PMCID: PMC11540641 DOI: 10.3389/fphar.2024.1485065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/17/2024] [Indexed: 11/15/2024] Open
Abstract
The liver is the largest, important organ and the site for essential biochemical reactions in the human body. It has the function to detoxify toxic substances and synthesize useful biomolecules. Liver diseases related complications represent a significant source of morbidity and mortality worldwide, creating a substantial economic burden. Oxidative stress, excessive inflammation, and dysregulated energy metabolism significantly contributed to liver diseases. Therefore, discovery of novel therapeutic drugs for the treatment of liver diseases are urgently required. For centuries, flavonoids and their preparations which have the beneficial health effects in chronic diseases have been used to treat various human illnesses. Flavonoids mainly include flavones, isoflavones, flavanols, dihydroflavones, dihydroflavonols, anthocyanins and chalcones. The primary objective of this review is to assess the efficacy and safety of flavonoids, mainly from a clinical point of view and considering clinically relevant end-points. We summarized the recent progress in the research of hepatoprotective and molecular mechanisms of different flavonoids bioactive ingredients and also outlined the networks of underlying molecular signaling pathways. Further pharmacology and toxicology research will contribute to the development of natural products in flavonoids and their derivatives as medicines with alluring prospect in the clinical application.
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Affiliation(s)
- Yanmei Liao
- Department of Pharmacy, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Fei Lv
- Department of Pharmacy, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Tianwen Quan
- Department of Pharmacy, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Chuan Wang
- Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Jike Li
- Scientific Research and Teaching Department, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
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Ashique S, Mohanto S, Kumar N, Nag S, Mishra A, Biswas A, Rihan M, Srivastava S, Bhowmick M, Taghizadeh-Hesary F. Unlocking the possibilities of therapeutic potential of silymarin and silibinin against neurodegenerative Diseases-A mechanistic overview. Eur J Pharmacol 2024; 981:176906. [PMID: 39154829 DOI: 10.1016/j.ejphar.2024.176906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 07/28/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
Silymarin, a bioflavonoid derived from the Silybum marianum plant, was discovered in 1960. It contains C25 and has been extensively used as a therapeutic agent against liver-related diseases caused by alcohol addiction, acute viral hepatitis, and toxins-inducing liver failure. Its efficacy stems from its role as a potent anti-oxidant and scavenger of free radicals, employed through various mechanisms. Additionally, silymarin or silybin possesses immunomodulatory characteristics, impacting immune-enhancing and immune-suppressive functions. Recently, silymarin has been recognized as a potential neuroprotective therapy for various neurological conditions, including Parkinson's and Alzheimer's diseases, along with conditions related to cerebral ischemia. Its hepatoprotective qualities, primarily due to its anti-oxidant and tissue-regenerating properties, are well-established. Silymarin also enhances health by modifying processes such as inflammation, β-amyloid accumulation, cellular estrogenic receptor mediation, and apoptotic machinery. While believed to reduce oxidative stress and support neuroprotective mechanisms, these effects represent just one aspect of the compound's multifaceted protective action. This review article further delves into the possibilities of potential therapeutic advancement of silymarin and silibinin for the management of neurodegenerative disorders via mechanics modules.
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Affiliation(s)
- Sumel Ashique
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India; Department of Pharmaceutics, Bengal College of Pharmaceutical Sciences & Research, Durgapur, 713212, West Bengal, India.
| | - Sourav Mohanto
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to Be University), Mangalore, Karnataka, 575018, India.
| | - Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to Be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh, 201204, India
| | - Sagnik Nag
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500, Bandar Sunway, Selangor, Malaysia.
| | - Anuradha Mishra
- Amity Institute of Pharmacy, Amity University Lucknow Campus, Uttar Pradesh, 226010, India
| | - Aritra Biswas
- Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College, Rahara Akhil Mukherjee Road, Khardaha, West Bengal, 700118, India; UNESCO Regional Centre for Biotechnology, Department of Biotechnology, Government of India, NCR Biotech Science Cluster, Faridabad, 121001, Haryana, India.
| | - Mohd Rihan
- Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, 160062, India
| | - Shriyansh Srivastava
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, 203201, India; Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), Sector 3 Pushp Vihar, New Delhi, 110017, India
| | - Mithun Bhowmick
- Department of Pharmaceutics, Bengal College of Pharmaceutical Sciences & Research, Durgapur, 713212, West Bengal, India
| | - Farzad Taghizadeh-Hesary
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Al-Haideri M. Silymarin suppresses proliferation and PD-L1 expression in colorectal cancer cells and increases inflammatory CD8+ cells in tumor-bearing mice. Clin Res Hepatol Gastroenterol 2024; 48:102425. [PMID: 39048076 DOI: 10.1016/j.clinre.2024.102425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/15/2024] [Accepted: 07/20/2024] [Indexed: 07/27/2024]
Abstract
INTRODUCTION Silymarin as an herbal medicine has shown anticancer effects on tumor cells, while having low toxicity in normal cells. In this study, the effects of Silymarin on proliferation and apoptosis of colorectal cancer cells and its impact on immune response against cancer cells were evaluated in vitro and in vivo. METHODS AND MATERIALS The effect of Silymarin on CT-26 and Caco-2 cells proliferation and apoptosis were demonstrated by MTT assay and PI staining. A subcutaneous tumor of colorectal cancer was developed. Silymarin and Doxorubicin were administrated by intravenous injection. qRT-PCR analyses was performed on blood samples and tumor tissues. Spleen tissue was used to evaluate CD8+ T cell immune responses. Histological study was carried out on tumor tissues. RESULTS Silymarin showed anti-proliferative effects on CT-26 and Caco-2 cells. The markers of immunogenic cell death (Calreticulin exposure, ATP secretion, and HMGB1 secretion) significantly increased in both cell lines in the presence of silymarin. The expression of genes related to cell proliferation particularly β-Catenin and Cycline D1, and also anti-apoptotic ones such as Bcl-2 significantly reduced in mice treated with Silymarin while the expression of pro-apoptotic Bax increased. The RNA level of PD-L1 decreased in tumor tissues exposed by Silymarin. Moreover, the number of CTLs increased in the spleen of mice treated with Silymarin in comparison with untreated mice. Decreased tumor size and also survival of colorectal cancer cells in Silymarin-treated mice were observed in histological analysis. CONCLUSION Silymarin treatment showed a suppressive role on colorectal cancer cells almost as much as Doxorubicin. Our study indicated that having a low toxicity profile, cost-effectiveness, and availability of raw materials, plant-derived Silymarin can be a good candidate for further investigation to treat CRC.
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Affiliation(s)
- Maysoon Al-Haideri
- School of medicine, Pharmacy Department, University of Kurdistan Hawlêr, Erbil, Kurdistan, Iraq.
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9
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Hasan‐Abad A, Atapour A, Sobhani‐Nasab A, Motedayyen H, ArefNezhad R. Plant-Based Anticancer Compounds With a Focus on Breast Cancer. Cancer Rep (Hoboken) 2024; 7:e70012. [PMID: 39453820 PMCID: PMC11506041 DOI: 10.1002/cnr2.70012] [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: 10/18/2023] [Revised: 07/11/2024] [Accepted: 08/11/2024] [Indexed: 10/27/2024] Open
Abstract
Breast cancer is a common form of cancer among women characterized by the growth of malignant cells in the breast tissue. The most common treatments for this condition include chemotherapy, surgical intervention, radiation therapy, hormone therapy, and biological therapy. The primary issues associated with chemotherapy and radiation therapy are their adverse events and significant financial burden among patients in underdeveloped countries. This highlights the need to explore and develop superior therapeutic options that are less detrimental and more economically efficient. Plants provide an abundant supply of innovative compounds and present a promising new avenue for investigating cancer. Plants and their derivations are undergoing a revolution due to their reduced toxicity, expediency, cost-effectiveness, safety, and simplicity in comparison to conventional treatment methods. Natural products are considered promising candidates for the development of anticancer drugs, due perhaps to the diverse pleiotropic effects on target events. The effects of plant-derived products are limited to cancer cells while leaving healthy cells unaffected. Identification of compounds with strong anticancer properties and development of plant-based medications for cancer treatment might be crucial steps in breast cancer therapy. Although bioactive compounds have potent anticancer properties, they also have drawbacks that need to be resolved before their application in clinical trials and improved for the approved drugs. This study aims to give comprehensive information on known anticancer compounds, including their sources and molecular mechanisms of actions, along with opportunities and challenges in plant-based anticancer therapies.
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Affiliation(s)
| | - Amir Atapour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran
| | - Ali Sobhani‐Nasab
- Autoimmune Diseases Research CenterKashan University of Medical SciencesKashanIran
| | - Hossein Motedayyen
- Autoimmune Diseases Research CenterKashan University of Medical SciencesKashanIran
| | - Reza ArefNezhad
- Department of Anatomy, School of MedicineShiraz University of Medical SciencesShirazIran
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10
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Ashique S, Mohanto S, Kumar N, Nag S, Mishra A, Biswas A, Rihan M, Srivastava S, Bhowmick M, Taghizadeh-Hesary F. Unlocking the possibilities of therapeutic potential of silymarin and silibinin against neurodegenerative Diseases-A mechanistic overview. Eur J Pharmacol 2024; 981:176906. [DOI: https:/doi.org/10.1016/j.ejphar.2024.176906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
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11
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Iwaniec J, Niziołek K, Polanowski P, Słota D, Kosińska E, Sadlik J, Miernik K, Jampilek J, Sobczak-Kupiec A. Polyethylene Glycol/Pullulan-Based Carrier for Silymarin Delivery and Its Potential in Biomedical Applications. Int J Mol Sci 2024; 25:9972. [PMID: 39337459 PMCID: PMC11432400 DOI: 10.3390/ijms25189972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/11/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
Restoring the structures and functions of tissues along with organs in human bodies is a topic gathering attention nowadays. These issues are widely discussed in the context of regenerative medicine. Excipients/delivery systems play a key role in this topic, guaranteeing a positive impact on the effectiveness of the drugs or therapeutic substances supplied. Advances in materials engineering, particularly in the development of hydrogel biomaterials, have influenced the idea of creating an innovative material that could serve as a carrier for active substances while ensuring biocompatibility and meeting all the stringent requirements imposed on medical materials. This work presents the preparation of a natural polymeric material based on pullulan modified with silymarin, which belongs to the group of flavonoids and derives from a plant called Silybum marianum. Under UV light, matrices with a previously prepared composition were crosslinked. Before proceeding to the next stage of the research, the purity of the composition of the matrices was checked using Fourier-transform infrared (FT-IR) spectroscopy. Incubation tests lasting 19 days were carried out using incubation fluids such as simulated body fluid (SBF), Ringer's solution, and artificial saliva. Changes in pH, electrolytic conductivity, and weight were observed and then used to determine the sorption capacity. During incubation, SBF proved to be the most stable fluid, with a pH level of 7.6-7.8. Sorption tests showed a high sorption capacity of samples incubated in both Ringer's solution and artificial saliva (approximately 350%) and SBF (approximately 300%). After incubation, the surface morphology was analyzed using an optical microscope for samples demonstrating the greatest changes over time. The active substance, silymarin, was released using a water bath, and then the antioxidant capacity was determined using the Folin-Ciocâlteu test. The tests carried out proved that the material produced is active and harmless, which was shown by the incubation analysis. The continuous release of the active ingredient increases the biological value of the biomaterial. The material requires further research, including a more detailed assessment of its balance; however, it demonstrates promising potential for further experiments.
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Affiliation(s)
- Julia Iwaniec
- Cracow University of Technology, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Karina Niziołek
- Cracow University of Technology, CUT Doctoral School, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Patryk Polanowski
- Cracow University of Technology, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Dagmara Słota
- Cracow University of Technology, CUT Doctoral School, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Edyta Kosińska
- Cracow University of Technology, CUT Doctoral School, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Julia Sadlik
- Cracow University of Technology, CUT Doctoral School, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Krzysztof Miernik
- Cracow University of Technology, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Josef Jampilek
- Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
- Department of Chemical Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 783 71 Olomouc, Czech Republic
| | - Agnieszka Sobczak-Kupiec
- Cracow University of Technology, Faculty of Materials Engineering and Physics, Department of Materials Science, 37 Jana Pawła II Av., 31-864 Krakow, Poland
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Arghidash F, Javid-Naderi MJ, Gheybi F, Gholamhosseinian H, Kesharwani P, Sahebkar A. Exploring the multifaceted effects of silymarin on melanoma: Focusing on the role of lipid-based nanocarriers. J Drug Deliv Sci Technol 2024; 99:105950. [DOI: 10.1016/j.jddst.2024.105950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Zhang X, Liu M, Wang Z, Wang P, Kong L, Wu J, Wu W, Ma L, Jiang S, Ren W, Du L, Ma W, Liu X. A review of the botany, phytochemistry, pharmacology, synthetic biology and comprehensive utilization of Silybum marianum. Front Pharmacol 2024; 15:1417655. [PMID: 39055491 PMCID: PMC11269164 DOI: 10.3389/fphar.2024.1417655] [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: 04/15/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Silybum marianum (L.) Gaertn, a herbaceous plant with a long history in traditional medicine for the treatment of hepatobiliary diseases, particularly in Europe, which has attracted attention for its remarkable therapeutic effect. This review systematically summarizes the research progress in the botany, phytochemistry, pharmacology, comprehensive utilization and synthetic biology of S. marianum. Up to now, more than 20 types of flavonolignan components have been isolated from S. marianum. In addition, the rearch on fatty acids and triterpenoids is also constantly improving. Among them, silybin is the most active compound in flavonolignans components. Its pharmacological effects in vivo and in vitro include anti-inflammatory, antioxidant, anti-tumour, hypoglycaemic, neuroprotective and immunoregulatory properties. The use of coniferyl alcohol and taxifolin as substrates to produce silybin and isosilybin under the action of enzyme catalysis is the commonly used biosynthetic pathway of silymarin, which provides support for a comprehensive analysis of the synthetic pathway of silymarin. In addition to medicinal use, the extracts of plants also have broad application prospects in the production of food, healthcare products, cosmetics and other aspects. In addition, the chemical composition, pharmacological mechanism and synthetic biology of S. marianum need to be further studied, which is very important for its clinical efficacy and resource development.
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Affiliation(s)
- Xiaozhuang Zhang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Meiqi Liu
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhen Wang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Panpan Wang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lingyang Kong
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jianhao Wu
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Wei Wu
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lengleng Ma
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shan Jiang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Weichao Ren
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Likun Du
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Wei Ma
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xiubo Liu
- College of Jiamusi, Heilongjiang University of Chinese Medicine, Jiamusi, China
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Zarei Shandiz S, Erfani B, Hashemy SI. Protective effects of silymarin in glioblastoma cancer cells through redox system regulation. Mol Biol Rep 2024; 51:723. [PMID: 38833199 DOI: 10.1007/s11033-024-09658-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 05/20/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND Glioblastoma multiforme, a deadly form of brain tumor, is characterized by aggressive growth and poor prognosis. Oxidative stress, a disruption in the balance between antioxidants and oxidants, is a crucial factor in its pathogenesis. Silymarin, a flavonoid extracted from milk thistle, has shown therapeutic potential in inhibiting cancer cell growth, promoting apoptosis, and reducing inflammation. It also regulates oxidative stress. This study aims to investigate the regulatory effects of silymarin on oxidative stress parameters, especially the transcription factor Nrf2 and its related enzymes in GBM cancer cells, to develop a new anti-cancer compound with low toxicity. METHODS AND RESULTS First, the cytotoxicity of silymarin on U-87 MG cells was investigated by MTT and the results showed an IC50 of 264.6 μM. Then, some parameters of the redox system were measured with commercial kits, and the obtained results showed that silymarin increased the activity of catalase and superoxide dismutase enzymes, as well as the total antioxidant capacity levels; while the malondialdehyde level that is an indicator of lipid peroxidation was decreased by this compound. The expression level of Nrf2 and HO-1 and glutaredoxin and thioredoxin enzymes were checked by real-time PCR method, and the expression level increased significantly after treatment. CONCLUSIONS Our findings suggest that silymarin may exert its cytotoxic and anticancer effects by enhancing the Nrf2/HO-1 pathway through antioxidant mechanisms in U-87 MG cells.
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Affiliation(s)
- Sara Zarei Shandiz
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Bahareh Erfani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Neelab, Zeb A, Jamil M. Milk thistle protects against non-alcoholic fatty liver disease induced by dietary thermally oxidized tallow. Heliyon 2024; 10:e31445. [PMID: 38818175 PMCID: PMC11137523 DOI: 10.1016/j.heliyon.2024.e31445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 05/10/2024] [Accepted: 05/15/2024] [Indexed: 06/01/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic condition caused by several factors including thermally oxidized tallow. Various strategies have been considered to ameliorate NAFLD. However, the role of milk thistle (MT) in ameliorating NAFLD caused by thermally oxidized tallow has not been reported. The purpose of this study was to evaluate the ability of milk thistle to protect rabbits from the toxicity of oxidized tallow (OT). The rabbits were given OT and an extract of MT. The composition of MT was analyzed using HPLC-DAD, and tallow samples were studied using GC-MS. The study also examined liver histology, antioxidant levels, liver-related inflammatory markers, and serum lipid profile. The results showed that the major components of the MT extract were silybin B, formononetin-glucuronic acid, proanthocyanidin B1, silychristin B, silydianin, and isosilybin A. The group given OT showed elevated lipid profiles, lower antioxidant status, higher levels of hepatic inflammatory markers, and lower levels of anti-inflammatory markers. This group also had higher fat storage in the liver compared to the control or treatment groups. However, when MT was supplemented, the pro-inflammatory cytokines (IL-1, IL-4, IL-6, and TNF-α) and antioxidant status (CAT, SOD, GSH-Px, GSH, and TBARS) of the liver returned to normal. This suggests that MT extract is an excellent source of hepatoprotective compounds. It protects the liver by increasing antioxidant enzymes, decreasing pro-inflammatory cytokines, and increasing anti-inflammatory markers.
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Affiliation(s)
- Neelab
- Department of Biotechnology, University of Malakand, Chakdara, Pakistan
| | - Alam Zeb
- The Bioactive Lab, Center for Desert Agriculture, King Abdullah University of Science and Technology, Thuwal, Kingdom of Saudi Arabia
- Department of Biochemistry, University of Malakand, Chakdara, Pakistan
| | - Muhammad Jamil
- Department of Surgery, Timergara Teaching Hospital, Timergara, Pakistan
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Roca E, Colloca G, Lombardo F, Bellieni A, Cucinella A, Madonia G, Martinelli L, Damiani ME, Zampieri I, Santo A. The importance of integrated therapies on cancer: Silibinin, an old and new molecule. Oncotarget 2024; 15:345-353. [PMID: 38781107 PMCID: PMC11115268 DOI: 10.18632/oncotarget.28587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024] Open
Abstract
In the landscape of cancer treatments, the efficacy of coadjuvant molecules remains a focus of attention for clinical research with the aim of reducing toxicity and achieving better outcomes. Most of the pathogenetic processes causing tumour development, neoplastic progression, ageing, and increased toxicity involve inflammation. Inflammatory mechanisms can progress through a variety of molecular patterns. As is well known, the ageing process is determined by pathological pathways very similar and often parallel to those that cause cancer development. Among these complex mechanisms, inflammation is currently much studied and is often referred to in the geriatric field as 'inflammaging'. In this context, treatments active in the management of inflammatory mechanisms could play a role as adjuvants to standard therapies. Among these emerging molecules, Silibinin has demonstrated its anti-inflammatory properties in different neoplastic types, also in combination with chemotherapeutic agents. Moreover, this molecule could represent a breakthrough in the management of age-related processes. Thus, Silibinin could be a valuable adjuvant to reduce drug-related toxicity and increase therapeutic potential. For this reason, the main aim of this review is to collect and analyse data presented in the literature on the use of Silibinin, to better understand the mechanisms of the functioning of this molecule and its possible therapeutic role.
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Affiliation(s)
- Elisa Roca
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
| | - Giuseppe Colloca
- Dipartimento di Scienze dell’invecchiamento, Neurologiche, Ortopediche e della testa-collo, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
| | - Fiorella Lombardo
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
| | - Andrea Bellieni
- Dipartimento di Scienze dell’invecchiamento, Neurologiche, Ortopediche e della testa-collo, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
| | - Alessandra Cucinella
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
| | - Giorgio Madonia
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
| | - Licia Martinelli
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
| | - Maria Elisa Damiani
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
| | - Ilaria Zampieri
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
| | - Antonio Santo
- Oncologia Toracica - Lung Unit, Ospedale P. Pederzoli - Via Monte Baldo, Peschiera del Garda (VR), Italy
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Gollapalli P, Ashok AK, G TS. System-level protein interaction network analysis and molecular dynamics study reveal interaction of ferulic acid with PTGS2 as a natural radioprotector. J Biomol Struct Dyn 2024; 42:2765-2781. [PMID: 37144749 DOI: 10.1080/07391102.2023.2208224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 04/20/2023] [Indexed: 05/06/2023]
Abstract
Ferulic acid is a crucial bioactive component of broccoli, wheat, and rice bran and is also an essential natural product that has undergone significant research. Ferulic acid's precise mode of action and effect on system-level protein networks have not been thoroughly investigated. An interactome was built using the STRING database and Cytoscape tools, utilizing 788 key proteins collected from PubMed literature to identify the ferulic acid-governed regulatory action on protein interaction network (PIN). The scale-free biological network of ferulic acid-rewired PIN is highly interconnected. We discovered 15 sub-modules using the MCODE tool for sub-modulization analysis and 153 enriched signaling pathways. Further, functional enrichment of top bottleneck proteins revealed the FoxO signaling pathway involved in enhancing cellular defense against oxidative stress. The selection of the critical regulatory proteins of the ferulic acid-rewired PIN was completed by performing analyses of topological characteristics such as GO term/pathways analysis, degree, bottleneck, molecular docking, and dynamics investigations. The current research derives a precise molecular mechanism for ferulic acid's action on the body. This in-depth in silico model would aid in understanding how ferulic acid origins its antioxidant and scavenging properties in the human body.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Pavan Gollapalli
- Center for Bioinformatics and Biostatistics, Nitte (Deemed to be University), Mangalore, Karnataka, India
| | - Avinash Karkada Ashok
- Department of Biotechnology, Siddaganga Institute of Technology, Tumakuru, Karnataka, India
| | - Tamizh Selvan G
- Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India
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El-Banna AA, Ibrahim RS. Metabolic profiling of milk thistle different organs using UPLC-TQD-MS/MS coupled to multivariate analysis in relation to their selective antiviral potential. BMC Complement Med Ther 2024; 24:115. [PMID: 38454377 PMCID: PMC10921647 DOI: 10.1186/s12906-024-04411-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 02/26/2024] [Indexed: 03/09/2024] Open
Abstract
INTRODUCTION Silybum marianum commonly known as milk thistle is one of the most imperative medicinal plants due to its remarkable pharmacological activities. Lately, the antiviral activities of S. marianum extract have been studied and it showed effectiveness against many viruses. OBJECTIVE Although most previous studies were concerned mainly with silymarin content of the fruit, the present study provides comprehensive comparative evaluation of S. marianum different organs' chemical profiles using UPLC-MS/MS coupled to chemometrics to unravel potentially selective antiviral compounds against human coronavirus (HCoV-229E). METHODOLOGY UPLC-ESI-TQD-MS/MS analysis was utilized to establish metabolic fingerprints for S. marianum organs namely fruits, roots, stems and seeds. Multivariate analysis, using OPLS-DA and HCA-heat map was applied to explore the main discriminatory phytoconstituents between organs. Selective virucidal activity of organs extracts against coronavirus (HCoV-229E) was evaluated for the first time using cytopathic effect (CPE) inhibition assay. Correlation coefficient analysis was implemented for detection of potential constituents having virucidal activity. RESULTS UPLC-MS/MS analysis resulted in 87 identified metabolites belonging to different classes. OPLS-DA revealed in-between class discrimination between milk thistle organs proving their significantly different metabolic profiles. The results of CPE assay showed that all tested organ samples exhibited dose dependent inhibitory activity in nanomolar range. Correlation analysis disclosed that caffeic acid-O-hexoside, gadoleic and linolenic acids were the most potentially selective antiviral phytoconstituents. CONCLUSION This study valorizes the importance of different S. marianum organs as wealthy sources of selective and effective antiviral candidates. This approach can be extended to unravel potentially active constituents from complex plant matrices.
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Affiliation(s)
- Alaa A El-Banna
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Reham S Ibrahim
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
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19
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Hamed RA, Talib WH. Targeting cisplatin resistance in breast cancer using a combination of Thymoquinone and Silymarin: an in vitro and in vivo study. PHARMACIA 2024; 71:1-19. [DOI: 10.3897/pharmacia.71.e117997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Background: Breast cancer (BC) is considered the most diagnosed cancer among women globally. This is because of its high possibility of metastasis and high resistance to chemotherapy. Cisplatin is a platinum-based antitumor agent that is used to treat various types of cancer. However, the main obstacle to using this drug is drug resistance. Drug resistance is a cause of most relapses of cancer which eventually lead to death. Nowadays, combining natural products is a trend to overcome drug resistance. Thymoquinone (TQ) is a natural phytochemical that exists mainly in blackseed. It has been used in medicine for decades, especially as an anticancer agent. Silymarin is a milk thistle compound that exhibits anticancer, hepatoprotective, and neuroprotective activity. Hence, the combination of TQ and silymarin could be a probable solution to treat cancer and reduce chemoresistance.
Methods: This study tested this combination on cisplatin-sensitive (EMT6/P) and cisplatin-resistant (EMT6/CPR) mouse mammary cell lines. Apoptotic and antiproliferative activity was assessed for TQ and silymarin in vitro using caspase-3 and [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assays, respectively. An in vivo study was performed to evaluate the effect of TQ and silymarin combination in mice inoculated with EMT6/P and EMT6/CPR cells. The safety profile was also examined using creatinine and liver enzyme assays.
Results: In vitro, the TQ and silymarin combination synergized in both cell lines. Also, this combination caused apoptosis induction at a higher rate than the single treatment in both cell lines. In vivo, TQ and silymarin combination resulted in a remarkable reduction in tumor size and enhanced the cure rate in mice implanted with EMT6/P and EMT6/CPR cell lines. According to the safety profile results, TQ and silymarin combination was safe.
Conclusion: In conclusion, the combination of TQ and silymarin provides a promising solution in treating BC resistant to cisplatin by inducing apoptosis. Further studies are needed to define the exact anticancer mechanisms of this combination.
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Sharma AN, Dewangan HK, Upadhyay PK. Comprehensive Review on Herbal Medicine: Emphasis on Current Therapy and Role of Phytoconstituents for Cancer Treatment. Chem Biodivers 2024; 21:e202301468. [PMID: 38206170 DOI: 10.1002/cbdv.202301468] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 01/04/2024] [Accepted: 01/04/2024] [Indexed: 01/12/2024]
Abstract
INTRODUCTION Cancer poses a significant public health challenge in both developed and developing nations, with a rising global incidence of patients facing the threat of death due to abnormal cell proliferation. AIM Review explores the utilization of different parts of herbal medicinal plants and their active pharmaceutical constituents in the prevention and treatment of various types of cancer. METHODOLOGY Various anticancer medicinal plants have been identified, demonstrating their therapeutic effects by inhibiting cancer-stimulating enzymes and hormones, activating DNA repair processes, boosting the synthesis of protective stimulants, reducing the formation of free radicals, and enhancing individual immunity. Data for this study were gathered from diverse online bibliographic and databases, including Google, Google Scholar, Mendeley, Springer Link, Research Gate, and PubMed. RESULT Herbal drugs have a huge contribution to the inhibition of the progression of cancer.A large volume of clinical studies has reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL) of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. CONCLUSION The latest medicines for the clinical purpose (Above 50 %) are derived from herbal products. Furthermore, combination of these herbs with nanotechnology shows promise in treating specific carcinomas.
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Affiliation(s)
- Alok Nath Sharma
- Institute of Pharmaceutical Research(IPR), GLA University, NH-2 Mathura Delhi Road, P.O.-Chaumuhan, Mathura, 281406 (U.P.), India
- Faculty of Pharmacy, Raja Balwant Singh Engineering Technical Campus, Bichpuri, Agra, 283102
| | - Hitesh Kumar Dewangan
- University Institute of Pharma Sciences (UIPS), Chandigarh University, Panjab, NH-95 Mohali Ludhiana Road
| | - Prabhat Kumar Upadhyay
- Institute of Pharmaceutical Research(IPR), GLA University, NH-2 Mathura Delhi Road, P.O.-Chaumuhan, Mathura, 281406 (U.P.), India
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Salem MB, Mohammed DM, Hammam OA, Elzallat M. Mitigation of intrahepatic cholestasis induced by 17α-ethinylestradiol via nanoformulation of Silybum marianum L. BMC Complement Med Ther 2024; 24:51. [PMID: 38263002 PMCID: PMC10804614 DOI: 10.1186/s12906-024-04351-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 01/13/2024] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND Cholestasis is an important predisposing factor for hepatocyte damage, liver fibrosis, primary biliary cirrhosis, and even liver failure. Silybum marianum L. (SM) plant is used in teas or eaten in some countries due to its antioxidant and hepatoprotective properties. Because of its low and poor oral bioavailability, so we improve the therapeutic activity of Silybum marianum L. extract (SM) by studying the potential effects of nanoformulation of Silybum marianium L. extract (nano-SM) on 17α-ethinylestradiol (EE)-induced intrahepatic cholestasis. METHODS Thirty female Sprague-Dawley rats were divided into 5 groups (6 rats/group). Group I: Rats were received the treatment vehicle and served as normal group. Group II:Rats were injected daily with EE (10 mg/kg) for five successive days. Group III-V: Rats were injected daily with EE (10 mg/kg) and treated with either Ursodeoxycholic acid (UDCA) (40 mg/kg), SM (100 mg/kg) and nano-SM (100 mg/kg) orally once/day throughout the trialfor five successive days, respectively. RESULTS Nano-SM greatly dampened the increase in serum levels of total and direct bilirubin, alanine aminotransaminase, aspartate aminotransaminase, and alkaline phosphatase caused by EE. Furthermore, nano-SM increased the hepatic contents of reduced glutathione (GSH) and catalase (CAT) and also upregulated the relative hepatic gene expressions of Rho-kinase (ROCK-1), myosin light chain kinase (MLCK), and myosin phosphatase target subunit (MYPT1) compared to the EE-induced group. Administration of nano-SM reduced hepatic lipid peroxidation and downregulated the relative hepatic expressions of the nuclear factor-kappa B (NF-ҡB) and interleukin-1β (IL-1β). In addition, nano-SM improved the histopathological changes induced by EE. CONCLUSION Nano-SM possessed a superior effect over SM, which can be considered an effective protective modality against EE-induced cholestatic liver injury through its antioxidant, anti-inflammatory activities, and enhancing bile acid (BA) efflux.
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Affiliation(s)
- Maha B Salem
- Pharmacology Department, Theodor Bilharz Research Institute, P.O. box 30, Warrak El-Hadar, Giza, 12411, Imbaba, Egypt
| | - Dina Mostafa Mohammed
- Nutrition and Food Sciences Department, National Research Centre, Dokki, Giza, 12622, Egypt.
| | - Olfat A Hammam
- Pathology Department, Theodor Bilharz Research Institute, P.O. box 30, Warrak El-Hadar, Giza, 12411, Imbaba, Egypt
| | - Mohamed Elzallat
- Immunology Department, Theodor Bilharz Research Institute, P.O. box 30, Warrak El-Hadar, Giza, 12411, Imbaba, Egypt
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Jonnalagadda R, Rathinam S, Nagappan K, Chandrasekar V. Green HPLC Method for Simultaneous Analysis of Three Natural Antioxidants by Analytical Quality by Design. J AOAC Int 2024; 107:14-21. [PMID: 37701979 DOI: 10.1093/jaoacint/qsad105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/29/2023] [Accepted: 09/04/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND Glutathione, silybin, and curcumin are well-known potential antioxidants that are recommended as adjuvant therapy in cancer treatment. OBJECTIVE Based on the principles of Analytical Quality by Design (AQbD) and green analytical chemistry, a simple, robust, and environmentally benign HPLC method for the simultaneous estimation of glutathione, silybin, and curcumin in bulk and formulation was performed. METHOD Elution was achieved by an Agilent Eclipse XDB C18 (150 mm × 4.6 mm id, 3.5 μm) column using a gradient mobile phase composed of ethanol-water pH 6.7 (with 0.1%, v/v orthophosphoric acid) and 1.07 mL/min flow rate with PDA detection at 215 nm. Critical method variables were identified by risk assessment using an Ishikawa diagram, and multivariate optimization of the experimental conditions for the HPLC technique was accomplished by central composite design using design of experiments (DoE) software. RESULTS The separation was achieved within 15 min, where the retention time of glutathione, silybin, and curcumin were 3.3, 4.9, and 7.3 min, respectively. The standard curve was linear in the range of 3.75-26.25 µg/mL for glutathione, 62.50-437.50 µg/mL for silybin, and 12.5-87.50 µg/mL for curcumin. The developed method was validated as per ICH guidelines Q2 (R1), and all the parameters are within specified limits. CONCLUSIONS The proposed method is simple, precise, and robust, which can be employed for routine analysis and also concluded to be a greener approach according to AGREE, Green Analytical Procedure Index, and analytical eco-scale tools. HIGHLIGHTS The chosen antioxidants were evaluated for the very first time simultaneously using the chromatographic technique in bulk and dosage forms employing green solvents. The peak purity of all three compounds was studied using a PDA detector. Wastage was reduced in terms of time, cost, and solvents by employing AQbD elements and tools. Complete application of environmentally sustainable safe solvents were employed.
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Affiliation(s)
- Ramya Jonnalagadda
- Sri Ramachandra Institute of Higher Education and Research (DU), Department of Pharmaceutical Chemistry, Sri Ramachandra Faculty of Pharmacy, Chennai, Tamil Nadu 600116, India
| | - Seetharaman Rathinam
- SRM College of Pharmacy, SRM Institute of Science and Technology, Department of Pharmaceutical Analysis, Kattankulathur, Tamil Nadu 603203, India
| | - Krishnaveni Nagappan
- JSS College of Pharmacy, JSS Academy of Higher Education & Research, Department of Pharmaceutical Analysis, Ooty, The Nilgiris, Tamil Nadu 643001, India
| | - Vinodhini Chandrasekar
- Sri Ramachandra Institute of Higher Education and Research (DU), Department of Pharmaceutical Chemistry, Sri Ramachandra Faculty of Pharmacy, Chennai, Tamil Nadu 600116, India
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Kandhavelu J, Subramanian K, Naidoo V, Sebastianelli G, Doan P, Konda Mani S, Yapislar H, Haciosmanoglu E, Arslan L, Ozer S, Thiyagarajan R, Candeias NR, Penny C, Kandhavelu M, Murugesan A. A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer. Br J Pharmacol 2024; 181:107-124. [PMID: 37183661 PMCID: PMC10952184 DOI: 10.1111/bph.16141] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND AND PURPOSE Colorectal cancer (CRC) is the second most lethal disease, with high mortality due to its heterogeneity and chemo-resistance. Here, we have focused on the epidermal growth factor receptor (EGFR) as an effective therapeutic target in CRC and studied the effects of polyphenols known to modulate several key signalling mechanisms including EGFR signalling, associated with anti-proliferative and anti-metastatic properties. EXPERIMENTAL APPROACH Using ligand- and structure-based cheminformatics, we developed three potent, selective alkylaminophenols, 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), 2-[(1,2,3,4-tetrahydroquinolin-1-yl)(4-methoxyphenyl)methyl]phenol (THMPP) and N-[2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl]indoline (HNPMI). These alkylaminophenols were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and apoptosis induction, caspase activation and transcriptional and translational regulation. The lead compound HNPMI was evaluated in mice bearing xenografts of CRC cells. KEY RESULTS Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC50 in CRC cells and potential cytotoxic effects on other tumour cells. Modulation of EGFR pathway down-regulated protein levels of osteopontin, survivin and cathepsin S, leading to apoptosis. Cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered the mRNA for and protein levels of several apoptosis-related proteins including caspase 3, BCL-2 and p53. HNPMI down-regulated the proteins crucial to oncogenesis in CRC cells. Assays in mice bearing CRC xenografts showed that HNPMI reduced the relative tumour volume. CONCLUSIONS AND IMPLICATIONS HNPMI is a promising EGFR inhibitor for clinical translation. HNPMI regulated apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in CRC cell lines, showing potential as a therapeutic agent in the treatment of CRC.
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Affiliation(s)
- Jeyalakshmi Kandhavelu
- Division of Oncology, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Kumar Subramanian
- Division of Oncology, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Vivash Naidoo
- Division of Oncology, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Giulia Sebastianelli
- Molecular Signalling Lab, Faculty of Medicine and Health Technology, BioMediTechTampere University and Tays Cancer CentreTampereFinland
| | - Phuong Doan
- Molecular Signalling Lab, Faculty of Medicine and Health Technology, BioMediTechTampere University and Tays Cancer CentreTampereFinland
- BioMediTech Institute and Faculty of Medicine and Health TechnologyTampere UniversityTampereFinland
- Science CenterTampere University HospitalTampereFinland
| | - Saravanan Konda Mani
- Research and Publication WingBharath Institute of Higher Education and ResearchChennaiTamil NaduIndia
| | - Hande Yapislar
- Department of PhysiologyAcibadem University School of MedicineAtasehir, IstanbulTurkey
| | - Ebru Haciosmanoglu
- Department of BiophysicsBezmialem Vakıf University School of MedicineFatih, IstanbulTurkey
| | - Leman Arslan
- Department of PhysiologyBezmialem Vakıf University School of MedicineFatih, IstanbulTurkey
| | - Samed Ozer
- Department of PhysiologyAcibadem University School of MedicineAtasehir, IstanbulTurkey
| | - Ramesh Thiyagarajan
- Department of Basic Medical Sciences, College of MedicinePrince Sattam Bin Abdulaziz UniversityAl‐KharjKingdom of Saudi Arabia
| | - Nuno R. Candeias
- LAQV‐REQUIMTE, Department of ChemistryUniversity of AveiroAveiroPortugal
- Faculty of Engineering and Natural SciencesTampere UniversityTampereFinland
| | - Clement Penny
- Division of Oncology, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Meenakshisundaram Kandhavelu
- Molecular Signalling Lab, Faculty of Medicine and Health Technology, BioMediTechTampere University and Tays Cancer CentreTampereFinland
- BioMediTech Institute and Faculty of Medicine and Health TechnologyTampere UniversityTampereFinland
- Science CenterTampere University HospitalTampereFinland
| | - Akshaya Murugesan
- Molecular Signalling Lab, Faculty of Medicine and Health Technology, BioMediTechTampere University and Tays Cancer CentreTampereFinland
- Department of BiotechnologyLady Doak CollegeThallakulam, MaduraiIndia
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24
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Ghahfarrokhi SH, Heidari-Soureshjani S, Sherwin CMT, Azadegan-Dehkordi Z. Efficacy and Mechanisms of Silybum Marianum, Silymarin, and Silibinin on Rheumatoid Arthritis and Osteoarthritis Symptoms: A Systematic Review. Curr Rheumatol Rev 2024; 20:414-425. [PMID: 38314596 DOI: 10.2174/0115733971266397231122080247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/17/2023] [Accepted: 10/19/2023] [Indexed: 02/06/2024]
Abstract
BACKGROUND Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common forms of skeletal disease worldwide. OBJECTIVE The current systematic review investigated the mechanisms of Silybum marianum, silymarin, and silibinin on RA and OA symptoms. METHODS The PRISMA 2020 statement was used for reporting Items in this systematic review. The result was a list of five databases, including Web of Science, Cochrane Library, Embase, PubMed, and Scopus. After determining the inclusion and exclusion criteria, of 437 records identified, 21 studies were eligible. The data were extracted from the studies and imported into an Excel form, and finally, the effects, outcomes, and associated mechanisms were surveyed. RESULTS Silybum marianum and its main constituents revealed immunomodulatory, anti-inflammatory, antioxidant, and anti-apoptotic properties in humans and laboratory animals. Moreover, they protect the joints against the cartilage matrix's hypocellularity and fibrillation, reduce synovitis, and inhibit degeneration of aggrecan and collagen-II in human chondrocytes. They also, through reducing inflammatory cytokines, show an analgesic effect. Although silymarin and silibinin have low absorption, their bioavailability can be increased with nanoparticles. CONCLUSION In experimental studies, Silybum marianum, silymarin, and silibinin revealed promising effects on RA and OA symptoms. However, more clinical studies are needed in this field to obtain reliable results and clinical administration of these compounds.
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Affiliation(s)
- Shahrzad Habibi Ghahfarrokhi
- Department of Social Medicine, Modeling in Health Research Center, Shahrekord University of Medical Sciences, Social Determinants of Health Research Center, Shahrekord, Iran
| | | | - Catherine M T Sherwin
- Pediatric Clinical Pharmacology and Toxicology, Department of Pediatrics, Wright State University Boonshoft School of Medicine, Dayton Children's Hospital, One Children's Plaza, Dayton, Ohio, USA
| | - Zahra Azadegan-Dehkordi
- Oriented Nursing Midwifery Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
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El-Sapagh S, Allam NG, El-Sayed MNED, El-Hefnawy AA, Korbecka-Glinka G, Shala AY. Effects of Silybum marianum L. Seed Extracts on Multi Drug Resistant (MDR) Bacteria. Molecules 2023; 29:64. [PMID: 38202647 PMCID: PMC10779956 DOI: 10.3390/molecules29010064] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/14/2023] [Accepted: 12/16/2023] [Indexed: 01/12/2024] Open
Abstract
Wound infections became a great challenge, especially after the emergence of bacterial resistance to commonly used antibiotics. Medicinal plants can be the source of alternative antibacterial agents effective against multi drug resistant (MDR) bacteria. This research aimed to evaluate the effectiveness of different Silybum marianum seed extracts in fighting MDR bacteria that infect wounds. First, thirty purified bacterial cultures obtained from superficial, infected wounds were subjected to antibiotic sensitivity tests. The selected MDR isolates were then used to test the antimicrobial effects of different S. marianum seed extracts. The most potent extract was evaluated for its impact on the ultrastructure of the cells of sensitive bacterial isolates using transmission electron microscopy (TEM). The bioactive ingredients of this extract were analyzed by means of gas chromatography-mass spectroscopy (GC-MS). Then, in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted for the main components. The results indicated that four out of 30 bacterial isolates were considered MDR bacteria. Primary morphological features of colonies, secondary (automatic) identification using the Biomerieux Vitek 2 System, and 16S rRNA sequencing of the four isolates confirmed that they represent Staphylococcus aureus, Stenotrophomonas maltophilia, Klebsiella pneumoniae, and Escherichia coli. Among different extracts of S. marianum seeds, ethanol extract showed the strongest inhibitory effect on both Gram-positive and Gram-negative bacteria, with minimum inhibitory concentration (MIC) values between 9.375 and 1.172 mg/mL. However, at concentrations four times higher, this extract was unable to kill bacterial cells, indicating that it had a bacteriostatic effect on the tested MDR strains. TEM revealed denaturation and distorted cell ultrastructure in S. aureus and S. maltophilia after exposure to ethanol extract. In addition, GC-MS analysis of the ethanol extract identified nine compounds known to have important biological activities, and ADMET analysis showed good drug-likeness for two of these compounds. Consequently, S. marianum seeds could be a good source of alternative bacteriostatic agents effective against MDR bacterial strains that cause wound infections.
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Affiliation(s)
- Shimaa El-Sapagh
- Botany and Microbiology Department, Faculty of Science Tanta University, Tanta 31527, Egypt; (S.E.-S.)
| | - Nanis G. Allam
- Botany and Microbiology Department, Faculty of Science Tanta University, Tanta 31527, Egypt; (S.E.-S.)
| | | | - Asmaa Ahmed El-Hefnawy
- Botany and Microbiology Department, Faculty of Science Tanta University, Tanta 31527, Egypt; (S.E.-S.)
| | - Grażyna Korbecka-Glinka
- Department of Plant Breeding and Biotechnology, Institute of Soil Science and Plant Cultivation—State Research Institute, Czartoryskich 8, 24-100 Puławy, Poland
| | - Awad Y. Shala
- Medicinal and Aromatic Plants Research Department, Horticulture Research Institute, Agricultural Research Center (ARC), Giza 12619, Egypt;
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Doagooyan M, Alavizadeh SH, Sahebkar A, Houshangi K, Khoddamipour Z, Gheybi F. Anti-tumor activity of silymarin nanoliposomes in combination with iron: In vitro and in vivo study. Int J Pharm X 2023; 6:100214. [PMID: 38024450 PMCID: PMC10660084 DOI: 10.1016/j.ijpx.2023.100214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/13/2023] [Accepted: 10/21/2023] [Indexed: 12/01/2023] Open
Abstract
Combination therapy represents a promising strategy in cancer management by reducing chemotherapy resistance and associated side effects. Silymarin (SLM) has been extensively investigated due to its potent antioxidant properties and demonstrated efficacy against cancer cells. Under certain conditions however, polyphenolic compounds may also exhibit prooxidant activity by elevating intracellular reactive oxygen species (ROS), which can harm the target cells. In this study, we hypothesized that the simultaneous administration of iron (Fe) could alter the antioxidant characteristic of SLM nanoliposomes (SLM Lip) to a prooxidant state. Hence, we first developed a SLM Lip preparation using lipid film method, and then investigated the anti-oxidant properties as well as the cytotoxicity of the liposomal preparation. We also explored the efficacy of concomitant administration of iron sucrose and SML Lip on the tumor growth and survival of mice bearing tumors. We observed that exposing cells to iron, and consecutive treatment with SLM Lip (Fe + SLM Lip) could induce greater toxicity to 4 T1 breast cancer cells compared to SLM Lip. Further, Fe + SLM Lip combination demonstrated a time-dependent effect on reducing the catalase activity compared to SLM Lip, while iron treatment did not alter cell toxicity and catalase activity. In a mouse breast cancer model, the therapeutic efficacy of Fe + SLM Lip was superior compared to SLM Lip, and the treated animals survived longer. The histopathological findings did not reveal a significant damage to the major organs, whereas the most significant tumor necrosis was evident with Fe + SLM Lip treatment. The outcomes of the present investigation unequivocally underscored the prospective use of Fe + SLM combination in the context of cancer therapy, which warrants further scrutiny.
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Affiliation(s)
- Maham Doagooyan
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Hoda Alavizadeh
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kebria Houshangi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Khoddamipour
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Gheybi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Wei F, Nian Q, Zhao M, Wen Y, Yang Y, Wang J, He Z, Chen X, Yin X, Wang J, Ma X, Chen Y, Feng P, Zeng J. Natural products and mitochondrial allies in colorectal cancer therapy. Biomed Pharmacother 2023; 167:115473. [PMID: 37713992 DOI: 10.1016/j.biopha.2023.115473] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/17/2023] Open
Abstract
Colorectal cancer (CRC) is a globally prevalent malignancy with a high potential for metastasis. Existing cancer treatments have limitations, including drug resistance and adverse effects. Researchers are striving to develop effective therapies to address these challenges. Impressively, contemporary research has discovered that many natural products derived from foods, plants, insects, and marine invertebrates can suppress the progression, metastasis, and invasion of CRC. In this review, we conducted a comprehensive search of the CNKI, PubMed, Embase, and Web of Science databases from inception to April 2023 to evaluate the efficacy of natural products targeting mitochondria to fight against CRC. Mitochondria are intracellular energy factories involved in cell differentiation, signal transduction, cell cycle regulation, apoptosis, and tumorigenesis. The identified natural products have been classified and summarized based on their mechanisms of action. These findings indicate that natural products can induce apoptosis in colorectal cancer cells by inhibiting the mitochondrial respiratory chain, ROS elevation, disruption of mitochondrial membrane potential, the release of pro-apoptotic factors, modulation of the Bcl-2 protein family to facilitate cytochrome c release, induction of apoptotic vesicle activity by activating the caspase protein family, and selective targeting of mitochondrial division. Furthermore, diverse apoptotic signaling pathways targeting mitochondria, such as the MAPK, p53, STAT3, JNK and AKT pathway, have been triggered by natural products. Natural products such as diosgenin, allopurinol, and clausenidin have demonstrated low toxicity, high efficacy, and multi-targeted properties. Mitochondria-targeting natural products have great potential for overcoming the challenges of CRC therapy.
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Affiliation(s)
- Feng Wei
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China
| | - Qing Nian
- Department of Blood Transfusion, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Maoyuan Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yi Yang
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Jundong Wang
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Zhelin He
- Endoscopy center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Xiaoyan Chen
- Endoscopy center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Xiang Yin
- Endoscopy center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Jian Wang
- Endoscopy center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yu Chen
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
| | - Peimin Feng
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
| | - Jinhao Zeng
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
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Huang RY, Chang HY, Chih SM, Dyke TV, Cheng CD, Sung CE, Weng PW, Shieh YS, Cheng WC. Silibinin alleviates inflammation-induced bone loss by modulating biological interaction between human gingival fibroblasts and monocytes. J Periodontol 2023; 94:905-918. [PMID: 36716169 DOI: 10.1002/jper.22-0535] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/21/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023]
Abstract
BACKGROUND Silibinin has shown various pharmacological effects that could be attributed to its antioxidant, anti-inflammatory, and immunoregulatory properties. However, the therapeutic potential of silibinin for periodontitis has not been investigated. METHODS The therapeutic effects of silibinin in ligation-induced experimental periodontitis were investigated using biochemical, histological, and immunohistochemical methods. The effects of silibinin on the osteoclastogenesis of RAW264.7 cells were investigated using TRAP staining, quantitative polymerase chain reaction (qPCR), pit formation, and immunoblotting. Moreover, its effects on inflammatory cytokine production, RANKL expression, and oxidative stress in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (HGFs) were evaluated using qPCR and flow cytometry. A coculture system was established to elucidate the effects of silibinin on the crosstalk between LPS-stimulated HGFs and undifferentiated monocytes. RESULTS Silibinin significantly reduced the alveolar bone loss, decreased the gingival inflammation and RANKL expression, and decreased the RANKL/osteoprotegerin ratio in gingival tissues in experimental periodontitis. The in vitro results showed that silibinin inhibited RANKL-induced osteoclast differentiation and function of RAW264.7 cells and suppressed RANKL-induced nuclear factor of activated T cells 1 (NFATc1) induction and translocation through the nuclear factor-κB and mitogen-activated protein kinase signaling pathways. Silibinin decreased the inflammatory cytokine level and oxidative stress production in LPS-stimulated HGFs; significantly suppressed membrane-bound RANKL expression on LPS-stimulated HGFs; and significantly disrupted TRAP+ cell differentiation in the coculture system. CONCLUSIONS Silibinin effectively inhibits inflammation-induced bone loss in experimental periodontitis based on the regulation of stimulated HGFs by inhibiting the expression of inflammatory and osteoclastogenic mediators. Collectively, targeting the inflamed HGF resolution that mediates osteogenesis may use silibinin as a potential drug-repurposing candidate for modulating alveolar bone destruction in periodontitis. SUMMARY Silibinin effectively inhibits inflammation-induced bone loss in experimental periodontitis based on the regulation of stimulated HGFs by inhibiting the expression of inflammatory and osteoclastogenic mediators.
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Affiliation(s)
- Ren-Yeong Huang
- Department of Periodontology, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
| | - Hua-Yang Chang
- Department of Periodontology, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Dental Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Shu-Mi Chih
- Department of Periodontology, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Dental Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Thomas Van Dyke
- Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA
- Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA
| | - Chia-Dan Cheng
- Department of Periodontology, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Dental Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-En Sung
- Department of Periodontology, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
| | - Pei-Wei Weng
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Orthopedics, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Shing Shieh
- Department of Operative Dentistry and Endodontics, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
| | - Wan-Chien Cheng
- Department of Periodontology, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
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Singh M, Kadhim MM, Turki Jalil A, Oudah SK, Aminov Z, Alsaikhan F, Jawhar ZH, Ramírez-Coronel AA, Farhood B. A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity. Cancer Cell Int 2023; 23:88. [PMID: 37165384 PMCID: PMC10173635 DOI: 10.1186/s12935-023-02936-4] [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: 01/17/2023] [Accepted: 05/03/2023] [Indexed: 05/12/2023] Open
Abstract
PURPOSE Although doxorubicin chemotherapy is commonly applied for treating different malignant tumors, cardiotoxicity induced by this chemotherapeutic agent restricts its clinical use. The use of silymarin/silibinin may mitigate the doxorubicin-induced cardiac adverse effects. For this aim, the potential cardioprotective effects of silymarin/silibinin against the doxorubicin-induced cardiotoxicity were systematically reviewed. METHODS In this study, we performed a systematic search in accordance with PRISMA guideline for identifying all relevant studies on "the role of silymarin/silibinin against doxorubicin-induced cardiotoxicity" in different electronic databases up to June 2022. Sixty-one articles were obtained and screened based on the predefined inclusion and exclusion criteria. Thirteen eligible papers were finally included in this review. RESULTS According to the echocardiographic and electrocardiographic findings, the doxorubicin-treated groups presented a significant reduction in ejection fraction, tissue Doppler peak mitral annulus systolic velocity, and fractional shortening as well as bradycardia, prolongation of QT and QRS interval. However, these echocardiographic abnormalities were obviously improved in the silymarin plus doxorubicin groups. As well, the doxorubicin administration led to induce histopathological and biochemical changes in the cardiac cells/tissue; in contrast, the silymarin/silibinin co-administration could mitigate these induced alterations (for most of the cases). CONCLUSION According to the findings, it was found that the co-administration of silymarin/silibinin alleviates the doxorubicin-induced cardiac adverse effects. Silymarin/silibinin exerts its cardioprotective effects via antioxidant, anti-inflammatory, anti-apoptotic activities, and other mechanisms.
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Affiliation(s)
- Mandeep Singh
- Department of Physical Education, University of Jammu, Srinagar, Jammu, India
| | - Mustafa M Kadhim
- Department of Dentistry, Kut University College, Kut, Wasit, 52001, Iraq
- Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad, 10022, Iraq
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq.
| | | | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, 103 Makhtumkuli Str., Tashkent, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | - Zanko Hassan Jawhar
- Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Erbil, Kurdistan Region, Iraq
- Clinical Biochemistry Department, College of Health Sciences, Hawler Medical University, Erbil, Kurdistan Region, Iraq
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Cuenca, Ecuador
- Epidemiology and Biostatistics Research Group, CES University, Medellín, Colombia
- Educational Statistics Research Group (GIEE), National University of Education, Cuenca, Ecuador
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Parsa L, Motafakkerazad R, Soheyli ST, Haratian A, Kosari-Nasab M, Mahdavi M. Silymarin in combination with ATRA enhances apoptosis induction in human acute promyelocytic NB4 cells. Toxicon 2023; 228:107127. [PMID: 37085055 DOI: 10.1016/j.toxicon.2023.107127] [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: 12/22/2022] [Revised: 03/30/2023] [Accepted: 04/13/2023] [Indexed: 04/23/2023]
Abstract
Although all-trans retinoic acid (ATRA) is an efficient pattern in acute promyelocytic leukemia (APL) therapy, further studies are required due to the extant clinical limitations of ATRA. It has been reported that Silymarin, an anti-cancer herbal substance extracted from milk thistle (Silybum marianum), is able to regulate apoptosis in various types of cancer cells through different mechanisms of action. This study investigated the apoptosis-inducing effect of Silymarin (SM) alone and in combination with ATRA on human acute promyelocytic NB4 cells. Examination using MTT assay indicated that SM treatment leads to growth inhibition in NB4 cells in a dose-dependent manner. The IC50 values of SM and ATRA were calculated 90 μM and 2 μM, respectively. Cell cycle analysis by flow cytometry revealed that a more increase in the sub-G1 phase (a sign of apoptosis) when cells were exposed to SM in combination with ATRA. The incidence of apoptosis was confirmed through Hoechst 33258 staining and Annexin V-FITC analysis. The results showed that Silymarin enhances ATRA-induced apoptosis. The flow cytometric analysis also indicated an enhancement in levels of ROS in the treated cells with both compounds. The real-time PCR illustrated that SM targets apoptosis by down-regulation in Survivin and Bcl-2 while up-regulation in Bax. The findings showed that the combination of the two compounds is more effective in the induction of apoptosis in NB4 cells. Molecular docking studies indicated that Sylibin, as a primary compound of the SM, binds to the BH3 domain of Bcl-2 and the BIR domain of Survivin with various affinities. Based on the findings, it seems that SM used alone and in combination with ATRA may be beneficial for inducing apoptosis in APL cells.
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Affiliation(s)
- Leila Parsa
- Department of Plant Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Sarvin Taleb Soheyli
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Amin Haratian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Morteza Kosari-Nasab
- Department of Plant Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Mahdavi
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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Hassani S, Maghsoudi H, Fattahi F, Malekinejad F, Hajmalek N, Sheikhnia F, Kheradmand F, Fahimirad S, Ghorbanpour M. Flavonoids nanostructures promising therapeutic efficiencies in colorectal cancer. Int J Biol Macromol 2023; 241:124508. [PMID: 37085076 DOI: 10.1016/j.ijbiomac.2023.124508] [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: 01/23/2023] [Revised: 04/07/2023] [Accepted: 04/14/2023] [Indexed: 04/23/2023]
Abstract
Colorectal cancer is among the frequently diagnosed cancers with high mortality rates around the world. Polyphenolic compounds such as flavonoids are secondary plant metabolites which exhibit anti-cancer activities along with anti-inflammatory effects. However, due to their hydrophobicity, sensitivity to degradation and low bioavailability, therapeutic effects have shown poor therapeutic effect. Nano delivery systems such as nanoliposomes, nanomicelles, silica nanoparticles have been investigated to overcome these difficulties. This review provides a summary of the efficiency of certain flavonoids and polyphenols (apigenin, genistein, resveratrol, quercetin, silymarin, catechins, luteolin, fisetin, gallic acid, rutin, and curcumin) on colorectal cancer models. It comprehensively discusses the influence of nano-formulation of flavonoids on their biological functions, including cellular uptake rate, bioavailability, solubility, and cytotoxicity, as well as their potential for reducing colorectal cancer tumor size under in vivo situations.
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Affiliation(s)
- Sepideh Hassani
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Hossein Maghsoudi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fahimeh Fattahi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran; Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
| | - Faezeh Malekinejad
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Nooshin Hajmalek
- Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Shohreh Fahimirad
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran.
| | - Mansour Ghorbanpour
- Department of Medicinal Plants, Faculty of Agriculture and Natural Resources, Arak University, Arak 38156-8-8349, Iran.
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Elmowafy M, Shalaby K, Elkomy MH, Alsaidan OA, Gomaa HAM, Abdelgawad MA, Mostafa EM. Polymeric Nanoparticles for Delivery of Natural Bioactive Agents: Recent Advances and Challenges. Polymers (Basel) 2023; 15:1123. [PMID: 36904364 PMCID: PMC10007077 DOI: 10.3390/polym15051123] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/16/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
In the last few decades, several natural bioactive agents have been widely utilized in the treatment and prevention of many diseases owing to their unique and versatile therapeutic effects, including antioxidant, anti-inflammatory, anticancer, and neuroprotective action. However, their poor aqueous solubility, poor bioavailability, low GIT stability, extensive metabolism as well as short duration of action are the most shortfalls hampering their biomedical/pharmaceutical applications. Different drug delivery platforms have developed in this regard, and a captivating tool of this has been the fabrication of nanocarriers. In particular, polymeric nanoparticles were reported to offer proficient delivery of various natural bioactive agents with good entrapment potential and stability, an efficiently controlled release, improved bioavailability, and fascinating therapeutic efficacy. In addition, surface decoration and polymer functionalization have opened the door to improving the characteristics of polymeric nanoparticles and alleviating the reported toxicity. Herein, a review of the state of knowledge on polymeric nanoparticles loaded with natural bioactive agents is presented. The review focuses on frequently used polymeric materials and their corresponding methods of fabrication, the needs of such systems for natural bioactive agents, polymeric nanoparticles loaded with natural bioactive agents in the literature, and the potential role of polymer functionalization, hybrid systems, and stimuli-responsive systems in overcoming most of the system drawbacks. This exploration may offer a thorough idea of viewing the polymeric nanoparticles as a potential candidate for the delivery of natural bioactive agents as well as the challenges and the combating tools used to overcome any hurdles.
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Affiliation(s)
- Mohammed Elmowafy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Khaled Shalaby
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Mohammed H. Elkomy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Omar Awad Alsaidan
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Hesham A. M. Gomaa
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Mohamed A. Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
| | - Ehab M. Mostafa
- Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia
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Effects of Dietary Milk Thistle ( Silybum marianum) Supplementation in Ducks Fed Mycotoxin-Contaminated Diets. Vet Sci 2023; 10:vetsci10020100. [PMID: 36851404 PMCID: PMC9967284 DOI: 10.3390/vetsci10020100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/15/2023] [Accepted: 01/28/2023] [Indexed: 02/01/2023] Open
Abstract
The medicinal plant milk thistle (Silybum marianum) has been widely used due to its hepatoprotective properties. The main objective of our study was to investigate the health protective effects of dietary milk thistle seed (MS), oil (MO), and seed cake (MSC) in ducks fed diets naturally contaminated with deoxynivalenol (DON; 3.43-3.72 mg/kg feed) and zearalenone (ZEN; 0.46-0.50 mg/kg feed). Female White Hungarian ducks were randomly allocated to four dietary treatments consisting of the control diet (C), the control diet supplemented with 0.5% MS, 0.5% MSC, or 0.1% MO. The feeding of experimental diets did not result in mortality cases, clinical signs of mycotoxicosis, or in differences of clinical chemistry values of blood serum. The positive effect of MO on vacuolar hepatocyte degeneration exceeded that of the MSC on d14 and both MS and MSC on d42. Each treatment was equally effective in the decrease of the severity of solitary cell death and infiltration of lympho- and histiocytes in the liver on d28 as well as in the prevention of lymphocyte depletion in the spleen and bursa of Fabricius on d14. In conclusion, the applied treatments have been proven effective in the prevention of histopathological changes caused by DON and ZEN.
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In Vitro Antioxidant Capacity of Purified Bioactive Compounds in Milk Thistle Seed (Silybum marianum) Along with Phenolic Profile. FOOD ANAL METHOD 2023. [DOI: 10.1007/s12161-023-02449-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Ghodousi M, Karbasforooshan H, Arabi L, Elyasi S. Silymarin as a preventive or therapeutic measure for chemotherapy and radiotherapy-induced adverse reactions: a comprehensive review of preclinical and clinical data. Eur J Clin Pharmacol 2023; 79:15-38. [PMID: 36450892 DOI: 10.1007/s00228-022-03434-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/21/2022] [Indexed: 12/03/2022]
Abstract
PURPOSE Thus far, silymarin has been examined in several studies for prevention or treatment of various chemotherapy or radiotherapy-induced adverse reactions. In this review, we try to collect all available human, animal, and pre-clinical data in this field. METHODS The search was done in Scopus, PubMed, Medline, and systematic reviews in the Cochrane database, using the following keywords: "Cancer," "Chemotherapy," "Radiotherapy," "Mucositis," "Nephrotoxicity," "Dermatitis," "Ototoxicity," "Cardiotoxicity," "Nephrotoxicity," "Hepatotoxicity," "Reproductive system," "Silybum marianum," "Milk thistle," and "Silymarin" and "Silybin." We included all relevant in vitro, in vivo, and human studies up to the date of publication. RESULTS Based on 64 included studies in this review, silymarin is considered a safe and well-tolerated compound, with no known clinical drug interaction. Notably, multiple adverse reactions of chemotherapeutic agents are effectively managed by its antioxidant, anti-apoptotic, anti-inflammatory, and anti-immunomodulatory properties. Clinical trials suggest that oral silymarin may be a promising adjuvant with cancer treatments, particularly against hepatotoxicity (n = 10), nephrotoxicity (n = 3), diarrhea (n = 1), and mucositis (n = 3), whereas its topical formulation can be particularly effective against radiodermatitis (n = 2) and hand-foot syndrome (HFS) (n = 1). CONCLUSION Further studies are required to determine the optimal dose, duration, and the best formulation of silymarin to prevent and/or manage chemotherapy and radiotherapy-induced complications.
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Affiliation(s)
- Mahsa Ghodousi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hedyieh Karbasforooshan
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Arabi
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Technology Institute, Nanotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sepideh Elyasi
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Wang Y, Yuan AJ, Wu YJ, Wu LM, Zhang L. Silymarin in cancer therapy: Mechanisms of action, protective roles in chemotherapy-induced toxicity, and nanoformulations. J Funct Foods 2023. [DOI: 10.1016/j.jff.2022.105384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Singh Tuli H, Kumar A, Ramniwas S, Coudhary R, Aggarwal D, Kumar M, Sharma U, Chaturvedi Parashar N, Haque S, Sak K. Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling. Molecules 2022; 27:7653. [PMID: 36364478 PMCID: PMC9654319 DOI: 10.3390/molecules27217653] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Despite the immense therapeutic advances in the field of health sciences, cancer is still to be found among the global leading causes of morbidity and mortality. Ethnomedicinally, natural bioactive compounds isolated from various plant sources have been used for the treatment of several cancer types and have gained notable attention. Ferulic acid, a natural compound derived from various seeds, nuts, leaves, and fruits, exhibits a variety of pharmacological effects in cancer, including its proapoptotic, cell-cycle-arresting, anti-metastatic, and anti-inflammatory activities. This review study presents a thorough overview of the molecular targets and cellular signaling pathways modulated by ferulic acid in diverse malignancies, showing high potential for this phenolic acid to be developed as a candidate agent for novel anticancer therapeutics. In addition, current investigations to develop promising synergistic formulations are also discussed.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, India
| | - Ajay Kumar
- Punjab Biotechnology Incubator (PBTI), Phase VIII, Mohali 160071, India
| | - Seema Ramniwas
- University Centre for Research and Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali 140413, India
| | - Renuka Coudhary
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, India
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, India
| | - Manoj Kumar
- Department of Chemistry, Maharishi Markandeshwar University, Sadopur-Ambala 134007, India
| | - Ujjawal Sharma
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda 151001, India
| | - Nidarshana Chaturvedi Parashar
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia
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Anticancer natural products targeting immune checkpoint protein network. Semin Cancer Biol 2022; 86:1008-1032. [PMID: 34838956 DOI: 10.1016/j.semcancer.2021.11.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/13/2021] [Accepted: 11/23/2021] [Indexed: 01/27/2023]
Abstract
Normal cells express surface proteins that bind to immune checkpoint proteins on immune cells to turn them off, whereby the immune system does not attack normal healthy cells. Cancer cells can also utilize this same protective mechanism by expressing surface proteins that can interact with checkpoint proteins on immune cells to overcome the immune surveillance. Immunotherapy is making the best use of the body's own immune system to reinforce anti-tumor responses. The most generally used immunotherapy is the control of immune checkpoints including the cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), programmed cell deathreceptor 1 (PD-1), or programmed cell death ligand-1 (PD-L1). In spite of the clinical effectiveness of immune checkpoint inhibitors, the overall response rate still remains low. Therefore, there have been considerable efforts in searching for alternative immune checkpoint proteins that may work as new therapeutic targets for treatment of cancer. Recent studies have identified several additional novel immune checkpoint targets, including lymphocyte activation gene-3, T cell immunoglobulin and mucin-domain containing-3, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain, V-domain Ig suppressor of T cell activation, B7 homolog 3 protein, B and T cell lymphocyte attenuator, and inducible T cell COStimulator. Natural compounds, especially those present in medicinal or dietary plants, have been investigated for their anti-tumor effects in various in vitro and in vivo models. Some phytochemicals exert anti-tumor activities based on immunoregulatioby blocking interaction between proteins involved in immune checkpoint signal transduction or regulating their expression/activity. Recently, synergistic anti-cancer effects of diverse phytochemicals with anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibody drugs have been continuously reported. Considering an increasing attention to noteworthy therapeutic effects of immune checkpoint inhibitors in the cancer therapy, this review focuses on regulatory effects of selected phytochemicals on immune checkpoint protein network and their combinational effectiveness with immune checkpoint inhibitors targeting tumor cells.
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Mechanistic Insights into the Pharmacological Significance of Silymarin. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27165327. [PMID: 36014565 PMCID: PMC9414257 DOI: 10.3390/molecules27165327] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 12/29/2022]
Abstract
Medicinal plants are considered the reservoir of diverse therapeutic agents and have been traditionally employed worldwide to heal various ailments for several decades. Silymarin is a plant-derived mixture of polyphenolic flavonoids originating from the fruits and akenes of Silybum marianum and contains three flavonolignans, silibinins (silybins), silychristin and silydianin, along with taxifolin. Silybins are the major constituents in silymarin with almost 70–80% abundance and are accountable for most of the observed therapeutic activity. Silymarin has also been acknowledged from the ancient period and is utilized in European and Asian systems of traditional medicine for treating various liver disorders. The contemporary literature reveals that silymarin is employed significantly as a neuroprotective, hepatoprotective, cardioprotective, antioxidant, anti-cancer, anti-diabetic, anti-viral, anti-hypertensive, immunomodulator, anti-inflammatory, photoprotective and detoxification agent by targeting various cellular and molecular pathways, including MAPK, mTOR, β-catenin and Akt, different receptors and growth factors, as well as inhibiting numerous enzymes and the gene expression of several apoptotic proteins and inflammatory cytokines. Therefore, the current review aims to recapitulate and update the existing knowledge regarding the pharmacological potential of silymarin as evidenced by vast cellular, animal, and clinical studies, with a particular emphasis on its mechanisms of action.
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Firouzi J, Sotoodehnejadnematalahi F, Shokouhifar A, Rahimi M, Sodeifi N, Sahranavardfar P, Azimi M, Janzamin E, Safa M, Ebrahimi M. Silibinin exhibits anti-tumor effects in a breast cancer stem cell model by targeting stemness and induction of differentiation and apoptosis. BIOIMPACTS : BI 2022; 12:415-429. [PMID: 36381630 PMCID: PMC9596878 DOI: 10.34172/bi.2022.23336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 08/27/2021] [Accepted: 09/18/2021] [Indexed: 06/16/2023]
Abstract
Introduction: Malignant breast cancer (BC) frequently contains a rare population of cells called cancer stem cells which underlie tumor relapse and metastasis, and targeting these cells may improve treatment options and outcomes for patients with BC. The aim of the present study was to determine the effect of silibinin on the self-renewal capacity, tumorgenicity, and metastatic potential of mammospheres. Methods: The effect of silibinin on viability and proliferation of MCF-7, MDA-MB-231 mammospheres, and MDA-MB-468 cell aggregation was determined after 72-120 hours of treatment. Colony and sphere formation ability, and the expression of stemness, differentiation, and epithelial-mesenchymal-transition (EMT)-associated genes were assessed by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) in mammospheres treated with an IC50 dose of silibinin. Additionally, the antitumor capacity of silibinin was assessed in vivo, in mice. Results: The results of the present study showed that silibinin decreased the viability of all mammospheres derived from MCF-7, MDA-MB-231, and MDA-MB-468 cell aggregation in a dose-dependent manner. Colony and sphere-forming ability, as well as the expression of genes associated with EMT were reduced in mammospheres treated with silibinin. Additionally, the expression of genes associated with stemness and metastasis was also decreased and the expression of genes associated with differentiation were increased. Intra-tumoral injection of 2 mg/kg silibinin decreased tumor volumes in mice by 2.8 fold. Conclusion: The present study demonstrated that silibinin may have exerted its anti-tumor effects in BC by targeting the BC stem cells, reducing the tumorgenicity and metastasis. Therefore, silibinin may be a potential adjuvant for treatment of BC.
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Affiliation(s)
- Javad Firouzi
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | | | - Alireza Shokouhifar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Mahsa Rahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Niloufar Sodeifi
- Department of Pathology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran 16635-148, Iran
| | - Parisa Sahranavardfar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Masoumeh Azimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Ehsan Janzamin
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
| | - Majid Safa
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148
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Kirdeeva Y, Fedorova O, Daks A, Barlev N, Shuvalov O. How Should the Worldwide Knowledge of Traditional Cancer Healing Be Integrated with Herbs and Mushrooms into Modern Molecular Pharmacology? Pharmaceuticals (Basel) 2022; 15:868. [PMID: 35890166 PMCID: PMC9320176 DOI: 10.3390/ph15070868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 12/04/2022] Open
Abstract
Traditional herbal medicine (THM) is a "core" from which modern medicine has evolved over time. Besides this, one third of people worldwide have no access to modern medicine and rely only on traditional medicine. To date, drugs of plant origin, or their derivates (paclitaxel, vinblastine, vincristine, vinorelbine, etoposide, camptothecin, topotecan, irinotecan, and omacetaxine), are very important in the therapy of malignancies and they are included in most chemotherapeutic regimes. To date, 391,000 plant and 14,000 mushroom species exist. Their medical and biochemical capabilities have not been studied in detail. In this review, we systematized the information about plants and mushrooms, as well as their active compounds with antitumor properties. Plants and mushrooms are divided based on the regions where they are used in ethnomedicine to treat malignancies. The majority of their active compounds with antineoplastic properties and mechanisms of action are described. Furthermore, on the basis of the available information, we divided them into two priority groups for research and for their potential of use in antitumor therapy. As there are many prerequisites and some examples how THM helps and strengthens modern medicine, finally, we discuss the positive points of THM and the management required to transform and integrate THM into the modern medicine practice.
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Affiliation(s)
- Yulia Kirdeeva
- Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (Y.K.); (O.F.); (A.D.)
| | - Olga Fedorova
- Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (Y.K.); (O.F.); (A.D.)
| | - Alexandra Daks
- Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (Y.K.); (O.F.); (A.D.)
| | - Nikolai Barlev
- Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (Y.K.); (O.F.); (A.D.)
- Orekhovich Institute of Biomedical Chemistry, 119435 Moscow, Russia
| | - Oleg Shuvalov
- Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (Y.K.); (O.F.); (A.D.)
- Orekhovich Institute of Biomedical Chemistry, 119435 Moscow, Russia
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Shriram RG, Moin A, Alotaibi HF, Khafagy ES, Al Saqr A, Abu Lila AS, Charyulu RN. Phytosomes as a Plausible Nano-Delivery System for Enhanced Oral Bioavailability and Improved Hepatoprotective Activity of Silymarin. Pharmaceuticals (Basel) 2022; 15:ph15070790. [PMID: 35890088 PMCID: PMC9318442 DOI: 10.3390/ph15070790] [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: 06/07/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/01/2023] Open
Abstract
Silymarin, a phyto-constituent derived from the plant Silybum marianum, has been widely acknowledged for its hepatoprotective activities. Nevertheless, its clinical utility is adversely hampered by its poor water-solubility and its limited oral bioavailability. The aim of this study was to investigate the efficacy of phospholipid-based phytosomes for enhancing the oral bioavailability of silymarin. The phytosomes were prepared using the solvent evaporation technique and were optimized using a full factorial design. The optimized silymarin phytosomal formulation was then characterized for particle size, surface morphology, aqueous solubility, and in vitro drug release. Furthermore, in vivo antioxidant activity, hepatoprotective activity and oral bioavailability of the optimized formula were investigated in a rat model. The prepared silymarin phytosomes were discrete particles with a porous, nearly smooth surface and were 218.4 ± 2.54 nm in diameter. In addition, the optimized silymarin phytosomal formulation showed a significant improvement in aqueous solubility (~360 µg/mL) compared to pure silymarin and manifested a higher rate and extent of silymarin release from the optimized formula in dissolution studies. The in vivo assessment studies revealed that the optimized silymarin phytosomal formulation efficiently exerted a hepatoprotective effect in a CCl4-induced hepatotoxicity rat model via restoring the normal levels of antioxidant enzymes and ameliorating cellular abnormalities caused by CCl4-intoxication. Most notably, as compared to pure silymarin, the optimized silymarin phytosomal formulation significantly improved silymarin oral bioavailability, as indicated by a 6-fold increase in the systemic bioavailability. Collectively, phytosomes might represent a plausible phospholipid-based nanocarrier for improving the oral bioavailability of phyto-constituents with poor aqueous solubility.
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Affiliation(s)
- Ravi Gundadka Shriram
- Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore 575018, Karnataka, India;
| | - Afrasim Moin
- Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia;
| | - Hadil Faris Alotaibi
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdul Rahman University, Riyadh 11671, Saudi Arabia;
| | - El-Sayed Khafagy
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (E.-S.K.); (A.A.S.)
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed Al Saqr
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (E.-S.K.); (A.A.S.)
| | - Amr Selim Abu Lila
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
- Correspondence: (A.S.A.L.); (R.N.C.)
| | - Rompicherla Narayana Charyulu
- Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore 575018, Karnataka, India;
- Correspondence: (A.S.A.L.); (R.N.C.)
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Yaghoubian I, Antar M, Ghassemi S, Modarres-Sanavy SAM, Smith DL. The Effects of Hydro-Priming and Colonization with Piriformospora indica and Azotobacter chroococcum on Physio-Biochemical Traits, Flavonolignans and Fatty Acids Composition of Milk Thistle ( Silybum marianum) under Saline Conditions. PLANTS (BASEL, SWITZERLAND) 2022; 11:1281. [PMID: 35631705 PMCID: PMC9142994 DOI: 10.3390/plants11101281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 06/15/2023]
Abstract
Salinity is an important challenge around the world, effecting all physiological and biochemical processes of plants. It seems that seed priming can diminish the negative impacts of salinity. To study the effects of hydro-priming and inoculation with Piriformospora indica (Pi) and Azotobacter chroococcum (Az) on physio-biochemical traits, flavonolignans and fatty acids composition of milk thistle under saline conditions, a greenhouse experiment was carried out. Our results indicated that under salinity, seed priming, especially Pi, improved physio-biochemical properties in milk thistle. Under 120 mM NaCl, inoculation with Pi increased membrane stability index (MSI) and relative water content (RWC) (by 21.86 and 33.43%, respectively). However, peroxidase (POX) (5.57- and 5.68-fold in roots and leaves, respectively), superoxide dismutase (SOD) (4.74- and 4.44-fold in roots and leaves, respectively), catalase (CAT) (6.90- and 8.50-fold in roots and leaves, respectively) and ascorbate peroxidase (APX) (5.61- and 5.68-fold in roots and leaves, respectively) activities increased with increasing salinity. Contrary to salinity, hydro-priming with Az and Pi positively altered all these traits. The highest content of the osmolytes, adenosine triphosphate (ATP) content and rubisco activity were recorded in Pi treatments under 120 mM NaCl. Stearic acid (20.24%), oleic acid (21.06%) and palmitic acid (10.48%) increased, but oil content (3.81%), linolenic and linoleic acid content (22.21 and 15.07%, respectively) decreased under saline conditions. Inoculations of Pi positively altered all these traits. The present study indicated that seed priming with Pi under 120 mM NaCl resulted in maximum silychristin, taxidolin, silydianin, isosilybin, silybin and silymarin of milk thistle seeds.
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Affiliation(s)
- Iraj Yaghoubian
- Department of Agronomy, Tarbiat Modares University, Tehran P.O Box 14115-336, Iran; (I.Y.); (S.A.M.M.-S.)
- Department of Plant Science, McGill University, Montreal, QC H9X3V9, Canada;
| | - Mohammed Antar
- Department of Plant Science, McGill University, Montreal, QC H9X3V9, Canada;
| | - Saeid Ghassemi
- Department of Ecophysiology, University of Tabriz, Tabriz 5166616471, Iran;
| | | | - Donald L. Smith
- Department of Plant Science, McGill University, Montreal, QC H9X3V9, Canada;
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Melim C, Magalhães M, Santos AC, Campos EJ, Cabral C. Nanoparticles as phytochemical carriers for cancer treatment: News of the last decade. Expert Opin Drug Deliv 2022; 19:179-197. [PMID: 35166619 DOI: 10.1080/17425247.2022.2041599] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The development and application of novel therapeutic medicines for the treatment of cancer are of vital importance to improve the disease's outcome and survival rate. One noteworthy treatment approach is the use of biologically active compounds present in natural products. Even though these phytocompounds present anti-inflammatory, antioxidant, and anticancer properties, their use is limited essentially due to poor systemic delivery, low bioavailability, and water solubility concerns. To make full use of the anticancer potential of natural products, these limitations need to be technologically addressed. In this sense, nanotechnology emerges as a promising drug delivery system strategy. AREAS COVERED In this review, the benefits and potential of nanodelivery systems for natural products encapsulation as promising therapeutic approaches for cancer, which were developed during the last decade, are highlighted. EXPERT OPINION The nanotechnology area has been under extensive research in the medical field given its capacity for improving the therapeutic potential of drugs by increasing their bioavailability and allowing a targeted delivery to the tumor site. Thereby, the nanoencapsulation of phytocompounds can have a direct impact on the recognized therapeutic activity of natural products towards cancer.
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Affiliation(s)
- Catarina Melim
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Clinic Academic Center of Coimbra (CACC), Faculty of Medicine, 3000-548 Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal
| | - Mariana Magalhães
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Clinic Academic Center of Coimbra (CACC), Faculty of Medicine, 3000-548 Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal.,PhD Programme in Experimental Biology and Biomedicine, Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão, 3030-789 Coimbra, Portugal
| | - Ana Cláudia Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.,REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Elisa Julião Campos
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Clinic Academic Center of Coimbra (CACC), Faculty of Medicine, 3000-548 Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal.,Association for Innovation and Biomedical Research on Light and Image (AIBILI), 3000-548 Coimbra, Portugal
| | - Célia Cabral
- University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Clinic Academic Center of Coimbra (CACC), Faculty of Medicine, 3000-548 Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal.,Centre for Functional Ecology, Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal
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Jia C, Zhang Z, Wang J, Nie Z. Silymarin protects the rats against paraquat-induced acute kidney injury via Nrf2. Hum Exp Toxicol 2022; 41:9603271221074334. [PMID: 35128959 DOI: 10.1177/09603271221074334] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Paraquat (PQ) poisoning induces severe acute kidney injury and causes extremely high rate of death. In this study, we aimed to investigate the protective effects of silymarin on PQ-induced acute kidney injury and explore the underlying mechanisms. METHODS A rat model was established through intraperitoneal injection of PQ. Rats were administrated with saline or silymarin for 3 days. Then, survival rate, physiological parameters, and renal injury score were evaluated. The apoptosis and oxidative stress in kidney tissues were determined through hematoxylin and eosin staining, quantitative reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assays. RESULTS Silymarin administration could significantly increase the survival rate of PQ-poisoned rats. It was found that silymarin treatment improved renal function, decreased injury score in kidney tissues, and inhibited the apoptosis and oxidative stress in PQ-induced acute kidney injury through the activating the signaling pathway of Nrf2 and promoting its nuclear translocation. CONCLUSION Silymarin exhibited a protective effect against PQ-induced kidney injury, suggesting that treatment with this flavonoid could be a potential therapeutic agent for the treatment of acute kidney injury.
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Affiliation(s)
- C Jia
- Department of Emergency, 585241Xingtai People's Hospital of Hebei Province, Xingtai, China
| | - Z Zhang
- Department of Emergency, 585241Xingtai People's Hospital of Hebei Province, Xingtai, China
| | - J Wang
- Department of Emergency, 585241Xingtai People's Hospital of Hebei Province, Xingtai, China
| | - Z Nie
- Department of Emergency, 585241Xingtai People's Hospital of Hebei Province, Xingtai, China
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Sekar P, Ravitchandirane R, Khanam S, Muniraj N, Cassinadane AV. Novel molecules as the emerging trends in cancer treatment: an update. Med Oncol 2022; 39:20. [PMID: 34982273 DOI: 10.1007/s12032-021-01615-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/19/2021] [Indexed: 12/15/2022]
Abstract
As per World Health Organization cancer remains as a leading killer disease causing nearly 10 million deaths in 2020. Since the burden of cancer increases worldwide, warranting an urgent search for anti-cancer compounds from natural sources. Secondary metabolites from plants, marine organisms exhibit a novel chemical and structural diversity holding a great promise as therapeutics in cancer treatment. These natural metabolites target only the cancer cells and the normal healthy cells are left unharmed. In the emerging trends of cancer treatment, the natural bioactive compounds have long become a part of cancer chemotherapy. In this review, we have tried to compile about eight bioactive compounds from plant origin viz. combretastatin, ginsenoside, lycopene, quercetin, resveratrol, silymarin, sulforaphane and withaferin A, four marine-derived compounds viz. bryostatins, dolastatins, eribulin, plitidepsin and three microorganisms viz. Clostridium, Mycobacterium bovis and Streptococcus pyogenes with their well-established anticancer potential, mechanism of action and clinical establishments are presented.
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Affiliation(s)
- Priyanka Sekar
- Sri Venkateshwaraa Medical College Hospital and Research Centre, Pondicherry, 605102, India
| | | | - Sofia Khanam
- Calcutta Institute of Pharmaceutical Technology and Allied Health Sciences, Howrah, WB, 711316, India
| | - Nethaji Muniraj
- Centre for Cancer Immunology Research, Children's National Hospital, Children's National Research Institute, 111 Michigan Ave NW, Washington, D.C, 20010, USA.
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Yassin NYS, AbouZid SF, El-Kalaawy AM, Ali TM, Almehmadi MM, Ahmed OM. Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. Biomed Pharmacother 2022; 145:112409. [PMID: 34781148 DOI: 10.1016/j.biopha.2021.112409] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has been identified as one of the most deadly malignancies with limited therapeutic efficacy worldwide. However, understanding the molecular mechanisms of crosstalk between signaling pathways in HCC and predicting cancer cell responses to targeted therapeutic interventions remain to be challenge. Thus, in this study, we aimed to evaluate the anticancerous efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally-induced HCC in rats. In vitro investigations were also performed and the anticancer effects against HCC cell lines (HepG2 and Huh7) were confirmed. Wistar rats were given diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4) and were orally treated with STE (200 mg/kg body weight (bw)), Sm (150 mg/kg bw), and Sb (5 mg/kg bw) every other day from the 1st or 16th week to the 25th week of DEN/AAF/CCl4 injection. Treatment with STE, Sm, and Sb inhibited the growth of cancerous lesions in DEN/AAF/CCl4-treated rats. This inhibition was associated with inhibition of Ki-67 expression and repression of HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. STE, Sm, and Sb improved liver function biomarkers and tumor markers (AFP, CEA, and CA19.9) and increased total protein and albumin levels in serum. STE, Sm, and Sb treatment was also noted to reduce the hepatic production of lipid peroxides, increase hepatic glutathione content, and induce the activities of hepatic antioxidant enzymes in DEN/AAF/CCl4-treated rats. These results indicate that STE, Sm, and Sb exert anti-HCC effects through multiple pathways, including suppression of Ki-67 expression and HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR pathways and enhancement of antioxidant defense mechanisms.
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Affiliation(s)
- Nour Y S Yassin
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Sameh F AbouZid
- Department of Pharmacognosy, Faculty of Pharmacy, Heliopolis University for Sustainable Development, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Asmaa M El-Kalaawy
- Department of Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Tarek M Ali
- Department of Physiology, College of Medicine, Taif University, P. O. Box 11099, Taif 21944, Saudi Arabia
| | - Mazen M Almehmadi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P. O. Box 11099, Taif 21944, Saudi Arabia
| | - Osama M Ahmed
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt.
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Zahra N, Wahid A, Hafeez MB, Alyemeni MN, Shah T, Ahmad P. Plant growth promoters mediated quality and yield attributes of milk thistle (Silybum marianum L.) ecotypes under salinity stress. Sci Rep 2021; 11:23200. [PMID: 34853350 PMCID: PMC8636566 DOI: 10.1038/s41598-021-02435-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 10/18/2021] [Indexed: 11/08/2022] Open
Abstract
Silybum marianum (L.) Gaertn (Astraceae) is a well-reputed medicinal plant mostly utilized for silymarin (Sily) content and oil production, however, the information about Sily contents in achene part is still fragmented under different climatic conditions. In this study four milk thistle ecotypes from Faisalabad (FSD), Gujranwala (GUJ), Quetta (QTA), and Kallar kahar (KK) having an altered achene color were analyzed under salt stress. Application of plant growth promoters (PGPs) is one of the solution for ameliorating the effect of salinity and increasing the quantity and quality traits of milk thistle, so ascorbic acid (AsA), thiourea (TU), and moringa leaf extract (MLE) were soil supplied after developing salinity stress (120 mM with irrigation) at germination stage. Predetermined levels were selected for PGPs such as AsA (500 µM), MLE (3%), and TU (250 µM). Results revealed that all yield related attributes were significantly decreased, while secondary metabolites, pericarp epidermis, pericarp parenchyma, and pericarp seed integument increased under salinity stress. Data suggested that PGPs treatment was helpful to alleviate the deleterious effects of salinity stress and enhance the milk thistle quality and quantity parameters. The ecotypic variations with altered achene color patterns represent an advantage for QTA ecotypes for higher Sily extraction under salt stressed conditions.
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Affiliation(s)
- Noreen Zahra
- Department of Botany, University of Agriculture, Faisalabad, 38040, Pakistan
| | - Abdul Wahid
- Department of Botany, University of Agriculture, Faisalabad, 38040, Pakistan.
| | - Muhammad Bilal Hafeez
- Department of Agronomy, University of Agriculture, Faisalabad, 38040, Pakistan
- College of Agronomy, Northwest A&F University, Yangling, 712100, China
| | - Mohammed Nasser Alyemeni
- Botany and Microbiology Department, College of Science, King Saud University, P.O. Box 2460, Riyadh, 11451, Saudi Arabia
| | - Tariq Shah
- Department of Agroecology, Universite de Bourgogne, 21000, Dijon, France
| | - Parvaiz Ahmad
- Botany and Microbiology Department, College of Science, King Saud University, P.O. Box 2460, Riyadh, 11451, Saudi Arabia.
- Department of Botany, GDC, Pulwama, Srinagar, India.
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Takke A, Shende P. Monodispersed magnetographene quantum dot nanocomposites for delivery of silibinin. Colloids Surf A Physicochem Eng Asp 2021. [DOI: 10.1016/j.colsurfa.2021.127349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Zivarpour P, Hallajzadeh J, Asemi Z, Sadoughi F, Sharifi M. Chitosan as possible inhibitory agents and delivery systems in leukemia. Cancer Cell Int 2021; 21:544. [PMID: 34663339 PMCID: PMC8524827 DOI: 10.1186/s12935-021-02243-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 10/03/2021] [Indexed: 12/29/2022] Open
Abstract
Leukemia is a lethal cancer in which white blood cells undergo proliferation and immature white blood cells are seen in the bloodstream. Without diagnosis and management in early stages, this type of cancer can be fatal. Changes in protooncogenic genes and microRNA genes are the most important factors involved in development of leukemia. At present, leukemia risk factors are not accurately identified, but some studies have pointed out factors that predispose to leukemia. Studies show that in the absence of genetic risk factors, leukemia can be prevented by reducing the exposure to risk factors of leukemia, including smoking, exposure to benzene compounds and high-dose radioactive or ionizing radiation. One of the most important treatments for leukemia is chemotherapy which has devastating side effects. Chemotherapy and medications used during treatment do not have a specific effect and destroy healthy cells besides leukemia cells. Despite the suppressing effect of chemotherapy against leukemia, patients undergoing chemotherapy have poor quality of life. So today, researchers are focusing on finding more safe and effective natural compounds and treatments for cancer, especially leukemia. Chitosan is a valuable natural compound that is biocompatible and non-toxic to healthy cells. Anticancer, antibacterial, antifungal and antioxidant effects are examples of chitosan biopolymer properties. The US Food and Drug Administration has approved the use of this compound in medical treatments and the pharmaceutical industry. In this article, we take a look at the latest advances in the use of chitosan in the treatment and improvement of leukemia.
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Affiliation(s)
- Parinaz Zivarpour
- Department of Biological Sciences, Faculty of Basic Sciences, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Jamal Hallajzadeh
- Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehran Sharifi
- Department of Internal Medicine, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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