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Jomova K, Alomar SY, Valko R, Liska J, Nepovimova E, Kuca K, Valko M. Flavonoids and their role in oxidative stress, inflammation, and human diseases. Chem Biol Interact 2025; 413:111489. [PMID: 40147618 DOI: 10.1016/j.cbi.2025.111489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 02/23/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Richard Valko
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Jan Liska
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University, 811 08, Bratislava, Slovakia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic; Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic
| | - Kamil Kuca
- Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, 5005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia.
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Lucarini E, Schettino A, Marigliano N, Ciampi C, Smimmo M, Romano F, Paolillo A, Izzo L, Begum J, Mansour AA, Iaccarino N, Randazzo A, Greco KV, Scarpa R, Caso F, Iqbal AJ, Bucci M, Ghelardini C, Mannelli LDC, Saviano A, Maione F. Exploring the dual role of Mangifera indica L. in regulating immune response and pain persistence in inflammatory bowel disease. Pharmacol Res 2025:107773. [PMID: 40389041 DOI: 10.1016/j.phrs.2025.107773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/07/2025] [Accepted: 05/08/2025] [Indexed: 05/21/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is characterized by chronic intestinal inflammation and immune dysregulation, driven mainly by Th1 and Th17 cells and sustained by pro-inflammatory cyto-chemokines. This inflammatory milieu is associated with visceral pain, a key symptom affecting patient quality of life. Addressing both gut inflammation/immunity and visceral pain is crucial for improving IBD therapy. This study assessed the therapeutic potential of Mangifera indica L. extract (MIE), a mangiferin-rich formulation, in a DNBS-induced colitis model in rats. MIE treatment administered either simultaneously or post-DNBS induction, significantly reduced pathogenic Th1 and Th17 cell infiltration, along with pro-inflammatory cytokines (IL-1β, TNF-α) and chemokines (CXCL1, CXCL2), though histopathology showed no significant improvements in tissue healing. Additionally, MIE restored microbiota-derived short-chain fatty acids (acetate and butyrate) in colon and faecal samples. Importantly, MIE alleviated post-inflammatory visceral hypersensitivity, reducing the abdominal withdrawal reflex (AWR) to colorectal distension (CRD), after either acute or repeated treatment. These findings suggest that MIE, in the context of nutraceuticals and functional foods, shows promise as a dual-action therapeutic strategy for complementary and/or adjuvant therapy in IBD.
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Affiliation(s)
- Elena Lucarini
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Section of Pharmacology and Toxicology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Anna Schettino
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Noemi Marigliano
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Clara Ciampi
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Section of Pharmacology and Toxicology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Martina Smimmo
- Department of Pharmacy, University of Naples Federico II, School of Medicine and Surgery, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Francesca Romano
- Department of Pharmacy, University of Naples Federico II, School of Medicine and Surgery, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Antonio Paolillo
- Department of Pharmacy, University of Naples Federico II, School of Medicine and Surgery, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Luana Izzo
- Department of Pharmacy, University of Naples Federico II, School of Medicine and Surgery, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Jenefa Begum
- Department of Cardiovascular Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK
| | - Adel Abo Mansour
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 62521, Saudi Arabia
| | - Nunzia Iaccarino
- Department of Pharmacy, University of Naples Federico II, School of Medicine and Surgery, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Antonio Randazzo
- Department of Pharmacy, University of Naples Federico II, School of Medicine and Surgery, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Karin Vicente Greco
- University College London (UCL), Division of Surgery and Interventional Science, Royal Free Hospital Campus, UK; Department of Engineering of Materials and of Bioprocesses, School of Chemical Engineering, University of Campinas (UNICAMP), Av. Albert Einstein 500, CEP 13083-852 Campinas, SP, Brazil
| | - Raffaele Scarpa
- Rheumatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Francesco Caso
- Rheumatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Asif Jilani Iqbal
- Department of Cardiovascular Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK
| | - Mariarosaria Bucci
- Department of Pharmacy, University of Naples Federico II, School of Medicine and Surgery, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Carla Ghelardini
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Section of Pharmacology and Toxicology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Lorenzo Di Cesare Mannelli
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Section of Pharmacology and Toxicology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Anella Saviano
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy.
| | - Francesco Maione
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy; Nutraceuticals and Functional Foods Task Force, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy.
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Lei L, Chen CY, Wang YF, Guo ZY, Zhang Y. Mangiferin: A natural neuroprotective polyphenol with anti-inflammatory and anti-oxidant properties for depression. Prog Neuropsychopharmacol Biol Psychiatry 2025; 139:111401. [PMID: 40379124 DOI: 10.1016/j.pnpbp.2025.111401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 04/16/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
Depression is a severe global health problem accompanied by persistent low mood that harms the physical and mental health of people and places a substantial economic burden on society. Mangiferin (MGF), a natural polyphenol in the traditional Chinese herb Anemarrhena asphodeloides Bge., can improve neuronal damage, memory, and cognitive deficits, implicating the therapeutic potential of MGF for depression. MGF has a unique C-glycosyl and phenolic structure that endows it with multiple biological properties, e.g., anti-oxidant, anti-inflammatory, and anti-mitochondrial dysfunction. However, the pharmacological role of MGF in depression remains unclear. Therefore, this review describes the neuroprotective effects and the antidepressant mechanisms of MGF in preclinical depression studies. MGF ameliorates cognitive deficits in depression and neurodegenerative diseases animal models by reducing amyloid-beta deposition, ameliorating cholinergic dysfunction, and increasing neurotrophic factors. Also, MGF regulates molecular mechanisms in depressed animals mainly through anti-inflammation (by inhibiting NLRP3 inflammasome activation, mitogen-activated protein kinase phosphorylation and its downstream nuclear factor-кB signaling pathway, and indoleamine 2,3-dioxygenase activity), anti-oxidant (by increasing levels of anti-oxidant enzymes and inhibiting lipid peroxidation). Notably, the potential mechanisms of MGF in treating depression by modulating neurotransmission (e.g., glutamate, dopamine, norepinephrine, and serotonin) need to be further explored. It is hoped to explore further the potential molecular mechanisms of MGF's biological activity in depression and provide directions for further clinical applications.
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Affiliation(s)
- Lan Lei
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Cong-Ya Chen
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yu-Fei Wang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhen-Yu Guo
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China.
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Lin J, Zuo L, Yang B, Yang R, Zhang S, Zhang Z, Tian Y. Identification of the M2 Macrophage-associated Gene THBS2 as a Predictive Marker for Inflammatory Cancer Transformation. Inflamm Bowel Dis 2025; 31:963-974. [PMID: 39045635 DOI: 10.1093/ibd/izae129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Indexed: 07/25/2024]
Abstract
Ulcerative colitis (UC)-induced colitis-associated colorectal cancer (CAC) has a worse prognosis than sporadic colorectal cancer. And with the incidence of ulcerative colitis on the rise, it is critical to identify new therapeutic targets in time to stop the progression of inflammation to cancer. Through immunohistochemistry (IHC) and Gene Expression Omnibus (GEO) database analysis, we acquired the gene M2DEG, which is differentially expressed in M2 macrophages. The impact of M2DEG on the immune environment and clinical variables was confirmed through various data sets and actual tissue samples. Our findings indicate that patients with UC exhibiting reduced M2 macrophage infiltration tend to have more widespread disease, elevated endoscopic Mayo scores, and a higher probability of developing CAC. Through examining the string of M2DEG between UC and CAC, THBS2 emerged as a key marker. Elevated levels of THBS2 were notably linked to reduced overall survival (OS) and progression-free survival (RFS), and this heightened THBS2 expression played a crucial role in the spread of tumors, as verified by immunohistochemical studies. To sum up, patients with UC exhibiting reduced M2 macrophage infiltration have a higher propensity for CAC development, making THBS2 a crucial focus for converting UC into CAC. Furthermore, identifying antibody analogues targeting THBS2 could potentially lower the likelihood of CAC transformation in patients with UC.
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Affiliation(s)
- Jianxiu Lin
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Lugen Zuo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui, 233004, China
| | - Bolin Yang
- Department of Inflammatory Bowel Disease (IBD) Center/Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine and Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Ran Yang
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine and Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China
| | - Shuai Zhang
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Zhaoyang Zhang
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Yun Tian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine and Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China
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Xu P, Qian Y, Xu G, Chu J, He B. Fructosyl-mangiferin ameliorates dextran sulfate sodium-induced colitis in mice via the STAT3/M1/Th17 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156475. [PMID: 39933469 DOI: 10.1016/j.phymed.2025.156475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/27/2025] [Accepted: 02/04/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Inflammatory bowel disease (IBD), a chronic inflammatory condition categorized into ulcerative colitis (UC) and Crohn's disease (CD), affects a growing global patient population. Despite the prevalence, clinically there is a scarcity of effective therapeutic agents. PURPOSE This study investigated the therapeutic effects of fructosyl mangiferin (FM) on UC and elucidated its underlying mechanisms through in vivo and in vitro experiments. METHODS In vivo, a UC model of C57BL/6J mice was established via dextran sulfate sodium (DSS) induction, and the therapeutic effects were assessed through intragastric administration. In vitro, the murine macrophage cell line RAW264.7 was stimulated with lipopolysaccharide (LPS) to establish an M1 polarization model and introduced to explore the role of FM in immune cells. Molecular docking was further employed to investigate the specific molecular mechanisms of FM. RESULTS In vivo experimental findings indicate that FM, like mangiferin (M), preserves mucin secretion and the expression of occludin protein, and both significantly impede the progression of fibrosis associated with colitis. Additionally, FM effectively suppresses M1 macrophage polarization and exerts a pronounced inhibitory effect on the adaptive immune response, outperforming M in mitigating UC. In vitro results corroborate FM's inhibitory action on M1 polarization. Molecular docking studies identified FM as a potential signal transducer and activator of transcription 3 (STAT3) inhibitor, aligning with western blot analyses from both in vivo and in vitro experiments. CONCLUSION In conclusion, following fructosylation, FM exhibits remarkable anti-inflammatory and colonic protective effects. FM's ability to control the progression of UC offers a novel strategy for its potential treatment, warranting further investigation into its clinical application.
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Affiliation(s)
- Penghong Xu
- School of Pharmaceutical Sciences, Nanjing Tech University, 30 Puzhunan Road, Jiangbei New Area, Nanjing 211800, China
| | - Yuping Qian
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhunan Road, Jiangbei New Area, Nanjing 211800, China
| | - Guo Xu
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhunan Road, Jiangbei New Area, Nanjing 211800, China
| | - Jianlin Chu
- School of Pharmaceutical Sciences, Nanjing Tech University, 30 Puzhunan Road, Jiangbei New Area, Nanjing 211800, China.
| | - Bingfang He
- School of Pharmaceutical Sciences, Nanjing Tech University, 30 Puzhunan Road, Jiangbei New Area, Nanjing 211800, China; College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhunan Road, Jiangbei New Area, Nanjing 211800, China.
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Duarte LG, Laurindo LF, Bishayee A, Casarcia N, Detregiachi CRP, Otoboni AMM, de Alvares Goulart R, Catharin VMCS, Baldi E, Catharin VCS, Guiguer EL, Sanches Silva A, Barbalho SM, Bishayee A. Mango (Mangifera indica L.) By-products in Food Processing and Health Promotion. Nutr Rev 2025:nuae214. [PMID: 39903188 DOI: 10.1093/nutrit/nuae214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025] Open
Abstract
The edible and nonedible parts of the mango (Mangifera indica L.) contain vitamins, phytocompounds, fiber, and fatty acids. This review highlights the uses of mango by-products in the food industry and their effects on human health. The literature offers many new possibilities for the usage of mango secondary products in the food industry, such as the production of functional foods and bakery products, in addition to the potential for extraction of antioxidants and enzymes. Furthermore, due to their antioxidant and anti-inflammatory properties, the consumption of various mango by-products, in the form of peel and leaf (powder or extract), can improve glycemia, plasma lipid levels, satiety, and endothelial function, suggesting that these compounds can prevent or improve various risk factors for cardiovascular complications and metabolic syndrome. Clinical trials show that the discarded parts of mango fruits and leaves can be used to treat diabetes mellitus, obesity, and cardiovascular disorders. Moreover, mango by-products can be utilized to improve the functional characteristics of foods, may be incorporated as fat replacers, and have the potential to leverage agribusiness and reduce environmental damage resulting from the disposal of discarded materials, in addition to reducing waste and the complex chain of environmental damage. Mango by-products also have the potential to produce nutraceutical food items. The use of new technologies can bring to light the production of numerous products made from by-products, contributing to the development of industrial functional foods. In addition, products for the pharmaceutical and cosmetics industries may also be developed. Nutraceutical and pharmaceutical products could have lower prices and could, therefore, be used by low-income populations. The utilization of mango by-products meets the current trend and growing market for better and healthier products. However, more clinical trials are necessary to evaluate the effectiveness of mango by-products on human health, and new technologies can improve industrial applications.
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Affiliation(s)
- Lidiane Gonsalves Duarte
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marilia, São Paulo 17500-000, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília, São Paulo 17519-030, Brazil
| | | | - Nicolette Casarcia
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, United States
| | - Claudia Rucco P Detregiachi
- Department of Biochemistry and Pharmacology, Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Marília, Sao Paulo 17012-150, Brazil
| | - Alda Maria M Otoboni
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marilia, São Paulo 17500-000, Brazil
| | - Ricardo de Alvares Goulart
- Department of Biochemistry and Pharmacology, Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Marília, Sao Paulo 17012-150, Brazil
| | - Virgínia Maria Cavallari Strozze Catharin
- Department of Biochemistry and Pharmacology, Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Marília, Sao Paulo 17012-150, Brazil
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Marília, São Paulo 17012-150, Brazil
| | - Edgar Baldi
- Department of Biochemistry and Pharmacology, Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Marília, Sao Paulo 17012-150, Brazil
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Marília, São Paulo 17012-150, Brazil
| | - Vitor Cavallari Strozze Catharin
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Marília, São Paulo 17012-150, Brazil
| | - Elen Landgraf Guiguer
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marilia, São Paulo 17500-000, Brazil
- Department of Biochemistry and Pharmacology, Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Marília, Sao Paulo 17012-150, Brazil
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Marília, São Paulo 17012-150, Brazil
| | - Ana Sanches Silva
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Study in Animal Science (CECA), University of Oporto, 4501-401 Oporto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1300-477 Lisbon, Portugal
| | - Sandra Maria Barbalho
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marilia, São Paulo 17500-000, Brazil
- Department of Biochemistry and Pharmacology, Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Marília, Sao Paulo 17012-150, Brazil
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Marília, São Paulo 17012-150, Brazil
- Medical School of Marília, Research Coordinator, Hospital Beneficente UNIMAR, Marilia, São Paulo, Brazil
| | - Anupam Bishayee
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, United States
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Kim H, Kim E, Ma L, Kim C, Park K, Liu Z, Huang K, Kim DJ, Ryoo ZY, Yi JK, Sung Y, Jang S, Kim MO. Gossypetin Alleviates DSS-induced Colitis by Regulating COX2 and ROS-JNK Signaling. Curr Pharm Biotechnol 2025; 26:769-777. [PMID: 39601169 DOI: 10.2174/0113892010331882240901095733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/10/2024] [Accepted: 07/22/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Inflammatory Bowel Disease (IBD) represents a chronic and recurrent inflammatory condition affecting the gastrointestinal tract, with a rising global incidence. Current treatment approaches include surgery and drugs. However, surgeries are invasive procedures, while drug treatments often present with various side effects. Gossypetin, a flavonoid found abundantly in plants such as hibiscus, exhibits anti-oxidant and anti-cancer properties. However, its potential impact on IBD remains unexplored. OBJECTIVE This study aimed to investigate the therapeutic potential of gossypetin on colitis. METHODS We employed the DSS-induced colitis model to evaluate the therapeutic potential of gossypetin on colitis. The efficacy of gossypetin was assessed within this model using the Disease Activity Index (DAI) score and histological analysis. Additionally, we utilized qRT-PCR to measure the levels of inflammatory cytokines and Superoxide Dismutase (SOD). Immunohistochemistry confirmed the expression of tight junction markers, COX-2, and phosphorylated JNK protein, normally associated with disease progression. Furthermore, Western blot analysis was conducted to examine the SOD levels and anti-apoptotic effects of gossypetin. RESULTS In DSS-induced colitis mice, gossypetin treatment ameliorated weight loss and reduced colon length caused by DSS treatment. Additionally, gossypetin-treated groups exhibited DAI scores and reduced histological damage. Moreover, gossypetin treatment increased tight junction expression, decreased inflammatory responses, reduced ROS levels, attenuated JNK signaling, and decreased apoptosis. CONCLUSION Gossypetin shows therapeutic potential for mitigating the symptoms and progression of colitis by targeting ROS-JNK signaling involved in inflammation and tissue damage. This highlights the potential of natural compounds such as gossypetin for targeted therapies with reduced side effects and improved efficacy.
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Affiliation(s)
- Hyeonjin Kim
- Department of Animal Science and Biotechnology, Research Institute for Innovative Animal Science, Kyungpook National University, Sangju-si, Gyeongsang buk-do, Republic of Korea, Daegu, South Korea
| | - Eungyung Kim
- Department of Animal Science and Biotechnology, Research Institute for Innovative Animal Science, Kyungpook National University, Sangju-si, Gyeongsang buk-do, Republic of Korea, Daegu, South Korea
| | - Lei Ma
- Department of Animal Science and Biotechnology, Research Institute for Innovative Animal Science, Kyungpook National University, Sangju-si, Gyeongsang buk-do, Republic of Korea, Daegu, South Korea
| | - ChaeYeon Kim
- Department of Animal Science and Biotechnology, Research Institute for Innovative Animal Science, Kyungpook National University, Sangju-si, Gyeongsang buk-do, Republic of Korea
| | - Kanghyun Park
- Department of Animal Science and Biotechnology, Research Institute for Innovative Animal Science, Kyungpook National University, Sangju-si, Gyeongsang buk-do, Republic of Korea, Daegu, South Korea
| | - Zhibin Liu
- Department of Dental Hygiene, Kyungpook National University, Sangju, Republic of Korea, Daegu, South Korea
| | - Ke Huang
- Department of Dental Hygiene, Kyungpook National University, Sangju, Republic of Korea, Daegu, South Korea
| | - Dong Joon Kim
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Zae Young Ryoo
- School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea, Daegu, South Korea
| | - Jun Koo Yi
- School of Animal Life Convergence Science, Hankyong National University, Anseong, South Korea
| | - Yonghun Sung
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea, Daegu, South Korea
| | - Soyoung Jang
- School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea, Daegu, South Korea
| | - Myoung Ok Kim
- Department of Animal Science and Biotechnology, Research Institute for Innovative Animal Science, Kyungpook National University, Sangju-si, Gyeongsang buk-do, Republic of Korea, Daegu, South Korea
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Zhang C, Li L, Lin J, Luo J, Liu L, Peng X. Barley polysaccharides inhibit colorectal cancer by two relatively independent pathways. Int J Biol Macromol 2024; 277:133820. [PMID: 39002916 DOI: 10.1016/j.ijbiomac.2024.133820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 07/07/2024] [Accepted: 07/09/2024] [Indexed: 07/15/2024]
Abstract
Colorectal cancer is one of the most common types of cancer worldwide that can lead to serious injury and death. Although polysaccharides are widely recognized as having antitumor activity, there has been little research on the role of barley polysaccharides (BP)1 in colorectal cancer. The results of our research suggest that BP (300 mg/kg) had a significant inhibitory effect on colorectal cancer, and this effect was achieved through two pathways. First, BP can directly promote the secretion of protective metabolites like 5-(4-Hydroxyphenyl)-5-phenylimidazolidine-2,4-dione and 2,3-Bis(4-hydroxyphenyl)propionitrile thereby inhibiting the cancer pathways such as ERK, PI3K, WNT, JAK-STAT, Calcium, and Cell cycle cancer pathways to alleviate inflammation. Second, BP also can enrich beneficial intestinal bacteria such as Colidextribacter, Bilophila, and UCG-003 improve the intestinal barrier, promote the production of beneficial metabolites such as 5,8-Epoxy-5,8-dihydro-3-hydroxy-8'-apo-b,y-carotenal and L-Glutamic acid, and thus inhibit cancer pathways such as ERK, PI3K, Nuclear receptor, Cell cycle, Apoptosis and TGF-β. In conclusion, our findings suggest for the first time that BP can alleviate colorectal cancer by two relatively independent pathways: direct action and indirect action via the gut microbiota on both colon tumor cells and microbiota.
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Affiliation(s)
- Cheng Zhang
- Department of Food Science and Engineering, Jinan University, Guangzhou 510630, China
| | - Li Li
- Department of Food Science and Engineering, Jinan University, Guangzhou 510630, China
| | - Jiali Lin
- Department of Food Science and Engineering, Jinan University, Guangzhou 510630, China
| | - Jianming Luo
- Department of Food Science and Engineering, Jinan University, Guangzhou 510630, China
| | - Liu Liu
- Department of Food Science and Engineering, Jinan University, Guangzhou 510630, China
| | - Xichun Peng
- Department of Food Science and Engineering, Jinan University, Guangzhou 510630, China.
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9
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Baghel M, Baghel I, Kumari P, Bharkatiya M, Joshi G, Sakure K, Badwaik H. Nano-delivery Systems and Therapeutic Applications of Phytodrug Mangiferin. Appl Biochem Biotechnol 2024; 196:7429-7463. [PMID: 38526662 DOI: 10.1007/s12010-024-04906-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/04/2024] [Indexed: 03/27/2024]
Abstract
In order to cure a range of ailments, scientists have investigated a number of bioactive antioxidant compounds produced from natural sources. Mangiferin, a C-glycosyl xanthone-structured yellow polyphenol, is abundant in mangoes and other dietary sources. In-depth examinations found that it is effective in the treatment of a variety of disorders due to its antiviral, anti-inflammatory, antiproliferative, antigenotoxic, antiatherogenic, radioprotective, nephroprotective, antihyperlipidemic, and antidiabetic properties. However, it is recognised that mangiferin's poor bioavailability, volatility, and limited solubility restrict its therapeutic usefulness. Over time, effective solutions to these problems have arisen in the shape of effective delivery methods. The current articles present a summary of the several researches that have updated Mangiferin's biopharmaceutical characteristics. Additionally, strategies for enhancing the bioavailability, stability, and solubility of this phytodrug have been discussed. This review provides detailed information on the development of innovative Mangiferin delivery methods such as nanoparticles, liposomes, micelles, niosomes, microspheres, metal nanoparticles, and complexation, as well as its therapeutic applications in a variety of sectors. This article provides effective guidance for researchers who desire to work on the formulation and development of an effective delivery method for improved magniferin therapeutic effectiveness.
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Affiliation(s)
- Madhuri Baghel
- Apollo College of Pharmacy, Anjora, Durg, 491001, Chhattisgarh, India
| | - Ishita Baghel
- Foothill High School, 4375, Foothill Road, Pleasanton, CA, 94588, USA
| | | | - Meenakshi Bharkatiya
- Bhupal Nobles' Institute of Pharmaceutical Sciences, Bhupal Nobles' University, Udaipur, 313001, India
| | - Garvita Joshi
- Mahakal Institute of Pharmaceutical Studies, Ujjain, India
| | - Kalyani Sakure
- Rungta College of Pharmaceutical Sciences and Research, Bhilai, 490023, CG, India
| | - Hemant Badwaik
- Shri Shankaracharya Institute of Pharmaceutical Sciences and Research, Junwani, Bhilai, 490020, Chhattisgarh, India.
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10
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Lu C, Deng S, Liu Y, Yang S, Qin D, Zhang L, Wang RR, Zhang Y. Inhibition of macrophage MAPK/NF-κB pathway and Th2 axis by mangiferin ameliorates MC903-induced atopic dermatitis. Int Immunopharmacol 2024; 133:112038. [PMID: 38621336 DOI: 10.1016/j.intimp.2024.112038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/05/2024] [Accepted: 04/05/2024] [Indexed: 04/17/2024]
Abstract
Available online Atopic dermatitis (AD) is a chronic, persistent inflammatory skin disease characterized by eczema-like lesions and itching. Although topical steroids have been reported for treating AD, they are associated with adverse effects. Thus, safer medications are needed for those who cannot tolerate these agents for long periods. Mangiferin (MAN) is a flavonoid widely found in many herbs, with significant anti-inflammatory and immunomodulatory activities. However, the potential modulatory effects and mechanisms of MAN in treating Th2 inflammation in AD are unknown. In the present study, we reported that MAN could reduce inflammatory cell infiltration and scratching at the lesion site by decreasing MC903-induced levels of Th2-type cytokines, Histamine, thymic stromal lymphopoietin, Leukotriene B4, and immunoglobulin E. The mechanism may be related to reductions in MAPK and NF-κB-associated protein phosphorylation by macrophages. The results suggested that MAN may be a promising therapeutic agent for AD.
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Affiliation(s)
- Cheng Lu
- School of Chinese Materia Medica,Yunnan University of Chinese Medicine, Kunming 650500, China
| | - ShiJun Deng
- School of Chinese Materia Medica,Yunnan University of Chinese Medicine, Kunming 650500, China
| | - YanJiao Liu
- School of Chinese Materia Medica,Yunnan University of Chinese Medicine, Kunming 650500, China
| | - ShengJin Yang
- School of Chinese Materia Medica,Yunnan University of Chinese Medicine, Kunming 650500, China
| | - DingMei Qin
- School of Chinese Materia Medica,Yunnan University of Chinese Medicine, Kunming 650500, China
| | - LiJuan Zhang
- School of Basic Medical, Yunnan University of Chinese Medicine, Kunming, China
| | - Rui-Rui Wang
- School of Chinese Materia Medica,Yunnan University of Chinese Medicine, Kunming 650500, China.
| | - Yi Zhang
- School of Chinese Materia Medica,Yunnan University of Chinese Medicine, Kunming 650500, China.
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11
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Dharmapuri G, Kotha AK, Kalangi SK, Reddanna P. Mangiferin, A Naturally Occurring Glucosylxanthone, Induces Apoptosis in Caco-2 Cells In Vitro and Exerts Protective Effects on Acetic Acid-Induced Ulcerative Colitis in Mice through the Regulation of NLRP3. ACS Pharmacol Transl Sci 2024; 7:1270-1277. [PMID: 38751614 PMCID: PMC11091985 DOI: 10.1021/acsptsci.3c00323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 04/03/2024] [Accepted: 04/09/2024] [Indexed: 05/18/2024]
Abstract
Inflammatory bowel diseases (IBD), an inflammatory disease, include Crohn's disease and ulcerative colitis. Dysregulated autoimmune response to gut dysbiosis is mainly involved in the pathogenesis of IBD and is triggered by various inciting environmental factors. With its rising prevalence in every continent, IBD has evolved into a global disease, which is on the rise, affecting people of all ages. There is a growing incidence of IBD in the elderly population, as evidenced by epidemiological data. IBD is characterized by an inflammatory process that requires a lifelong treatment. The main challenge in IBD management is the adverse side effects associated with almost all of the currently available drugs. Hence, there is a search for drugs with more efficacy and fewer side effects. Natural products with great structural diversity and ease of modification chemically are being explored, as they were shown to control IBD by safely suppressing pro-inflammatory pathways. The present study aims at understanding the role of mangiferin, a COX-2 inhibitor isolated from tubers of Pueraria tuberosa in the treatment of IBD and colon cancer, in vitro on the Caco-2 human colon cancer cell line and in vivo in the acetic acid-induced IBD mouse model. In the acetic acid-induced colitis model, it prevented the decrease in length of the colon, mucosal erosion, and cellular infiltration in a dose-dependent manner. The expression levels of various pro-inflammatory markers like COX-2, IL1β, TNF-α, INF-γ, IL-6, NLRP3, and caspase-1 were downregulated in an acetic acid-induced mouse model on treatment with mangiferin in a dose dependent manner. Mangiferin also showed anticancer effects on Caco-2 cells by increasing the expression of Fas ligand, Fas receptor, FADD, caspase-8, and caspase-3 proteins, whereas Bid and Bcl-2 proteins showed decreased expression. These data suggest that mangiferin, an inhibitor of COX, induces apoptosis in colon cancer cells in vitro and protects mice from acetic acid-induced colitis in vivo.
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Affiliation(s)
- Gangappa Dharmapuri
- Department
of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
| | - Anil Kumar Kotha
- Department
of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
| | - Suresh K. Kalangi
- Department
of Microbiology, Faculty of Allied Health Sciences, SGT University, Gurugram 122505,India
| | - Pallu Reddanna
- Department
of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
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12
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Saviano A, Schettino A, Iaccarino N, Mansour AA, Begum J, Marigliano N, Raucci F, Romano F, Riccardi G, Mitidieri E, d'Emmanuele di Villa Bianca R, Bello I, Panza E, Smimmo M, Vellecco V, Rimmer P, Cheesbrough J, Zhi Z, Iqbal TH, Pieretti S, D'Amore VM, Marinelli L, La Pietra V, Sorrentino R, Costa L, Caso F, Scarpa R, Cirino G, Randazzo A, Bucci M, McGettrick HM, Iqbal AJ, Maione F. A reverse translational approach reveals the protective roles of Mangifera indica in inflammatory bowel disease. J Autoimmun 2024; 144:103181. [PMID: 38522129 DOI: 10.1016/j.jaut.2024.103181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 02/05/2024] [Accepted: 02/10/2024] [Indexed: 03/26/2024]
Abstract
Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from Mangifera indica L. extract (MIE, commonly known as mango) mitigate intestinal inflammation and splenic Th17/Treg ratio. In this study, we aimed to dissect the immunomodulatory and anti-inflammatory properties of MIE using a reverse translational approach, by initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Of clinical relevance, MIE modulates TNF-α and IL-17 levels in LPS spiked sera from IBD patients as an ex vivo model of intestinal barrier breakdown. Preclinically, therapeutic administration of MIE significantly reduced colitis severity, pathogenic T-cell intestinal infiltrate and intestinal pro-inflammatory mediators (IL-6, IL-17A, TNF-α, IL-2, IL-22). Moreover, MIE reversed colitis-induced gut permeability and restored tight junction functionality and intestinal metabolites. Mechanistic insights revealed MIE had direct effects on blood vascular endothelial cells, blocking TNF-α/IFN-γ-induced up-regulation of COX-2 and the DP2 receptors. Collectively, we demonstrate the therapeutic potential of MIE to reverse the immunological perturbance during the onset of colitis and dampen the systemic inflammatory response, paving the way for its clinical use as nutraceutical and/or functional food.
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Affiliation(s)
- Anella Saviano
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Anna Schettino
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Nunzia Iaccarino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Adel Abo Mansour
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Jenefa Begum
- Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Noemi Marigliano
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Federica Raucci
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Francesca Romano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Gelsomina Riccardi
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Emma Mitidieri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | | | - Ivana Bello
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Elisabetta Panza
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Martina Smimmo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Valentina Vellecco
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Peter Rimmer
- Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK; Department of Gastroenterology, Queen Elizabeth Hospital Birmingham NHS Foundation Trust, Birmingham, UK
| | - Jonathan Cheesbrough
- Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK; Department of Gastroenterology, Birmingham Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Zhaogong Zhi
- Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Tariq H Iqbal
- Department of Gastroenterology, Queen Elizabeth Hospital Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Microbiology and Infection (IMI), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2WB, UK
| | - Stefano Pieretti
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Vincenzo Maria D'Amore
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Luciana Marinelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Valeria La Pietra
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Raffaella Sorrentino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Luisa Costa
- Rheumatology Research Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Francesco Caso
- Rheumatology Research Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Raffaele Scarpa
- Rheumatology Research Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, via S. Pansini 5, 80131, Naples, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Antonio Randazzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Mariarosaria Bucci
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy
| | - Helen Michelle McGettrick
- Institute of Inflammation and Ageing (IIA), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2WB, UK
| | - Asif Jilani Iqbal
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy; Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
| | - Francesco Maione
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy.
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13
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Zivković J, Kumar KA, Rushendran R, Ilango K, Fahmy NM, El-Nashar HAS, El-Shazly M, Ezzat SM, Melgar-Lalanne G, Romero-Montero A, Peña-Corona SI, Leyva-Gomez G, Sharifi-Rad J, Calina D. Pharmacological properties of mangiferin: bioavailability, mechanisms of action and clinical perspectives. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:763-781. [PMID: 37658210 DOI: 10.1007/s00210-023-02682-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 08/20/2023] [Indexed: 09/03/2023]
Abstract
This review aims to provide an in-depth analysis of the pharmacological properties of mangiferin, focusing primarily on its bioavailability and mechanisms of action, and its potential therapeutic applications, especially in the context of chronic diseases. We conducted a comprehensive examination of in vitro and in vivo studies, as well as clinical trials involving mangiferin or plant extracts containing mangiferin. The primary source of mangiferin is Mangifera indica, but it's also found in other plant species from the families Anacardiaceae, Gentianaceae, and Iridaceae. Mangiferin has exhibited a myriad of therapeutic properties, presenting itself as a promising candidate for treating various chronic conditions including neurodegenerative disorders, cardiovascular diseases, renal and pulmonary diseases, diabetes, and obesity. Despite the promising results showcased in many in vitro studies and certain animal studies, the application of mangiferin has been limited due to its poor solubility, absorption, and overall bioavailability. Mangiferin offers significant therapeutic potential in treating a spectrum of chronic diseases, as evidenced by both in vitro and clinical trials. However, the challenges concerning its bioavailability necessitate further research, particularly in optimizing its delivery and absorption, to harness its full medicinal potential. This review serves as a comprehensive update on the health-promoting and therapeutic activities of mangiferin.
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Affiliation(s)
- Jelena Zivković
- Institute for Medicinal Plants Research "Dr. Josif Pančić", Tadeuša Košćuška 1, Belgrade, Serbia.
| | - Kammala Ananth Kumar
- Department of Obstetrics and Gynecology, Division of Basic Sciences and Translational Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Rapuru Rushendran
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology (SRMIST), Kattankulatur, 603203, Tamil Nadu, India
| | - Kaliappan Ilango
- School of Pharmacy, Hindustan Institute Technology and Science, Padur, Chennai, 603 103, India
| | - Nouran M Fahmy
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
- Center of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
| | - Heba A S El-Nashar
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
- Center of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
| | - Mohamed El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
- Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt
| | - Shahira M Ezzat
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt
- Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Guiomar Melgar-Lalanne
- Instituto de Ciencias Básicas, Universidad Veracruzana, Avda. Castelazo Ayala S/N, 91190, Xalapa, Veracruz, Mexico
| | - Alejandra Romero-Montero
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico
| | - Sheila I Peña-Corona
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico
| | - Gerardo Leyva-Gomez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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14
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Vezza T, Molina-Tijeras JA, Rodríguez-Nogales A, Garrido-Mesa J, Cádiz-Gurrea MDLL, Segura-Carretero A, González-Tejero MR, Rodríguez-Cabezas ME, Gálvez J, Algieri F. The Antioxidant Properties of Salvia verbenaca Extract Contribute to Its Intestinal Antiinflammatory Effects in Experimental Colitis in Rats. Antioxidants (Basel) 2023; 12:2071. [PMID: 38136191 PMCID: PMC10741154 DOI: 10.3390/antiox12122071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/25/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammation with unpredictable symptom fluctuations. While there is no effective cure for IBD, various treatments aim to manage symptoms and improve the quality of life for affected individuals. In recent years, there has been growing interest in the potential benefits of certain natural plants and herbs in the management of IBD. In this regard, this study aimed to evaluate the immunomodulatory and anti-inflammatory effects of a well-characterized extract of Salvia verbenaca (S. verbenaca) in an experimental model of colitis in rats. Interestingly, the daily administration of S. verbenaca (10 and 25 mg/kg) effectively alleviated colitis symptoms, as evidenced by reduced weight/length ratio and colonic damage. Moreover, it reduced oxidative stress markers (MPO and GSH), decreased pro-inflammatory cytokine expression (Il-6, Il-12a, Il-1β, Il-23, Icam-1, Mcp-1, Cinc-1), and preserved the integrity of the intestinal barrier (Villin, Muc-2, Muc-3). These effects suggest S. verbenaca extract could represent a potential complementary candidate to treat gastrointestinal disorders. Its beneficial actions can be related to its antioxidant properties as well as the downregulation of the immune response, which can result in the improvement in the intestine epithelial barrier.
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Affiliation(s)
- Teresa Vezza
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (T.V.); (J.A.M.-T.); (J.G.-M.); (J.G.); (F.A.)
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), 18012 Granada, Spain
- Servicio de Digestivo, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | - Jose Alberto Molina-Tijeras
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (T.V.); (J.A.M.-T.); (J.G.-M.); (J.G.); (F.A.)
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), 18012 Granada, Spain
| | - Alba Rodríguez-Nogales
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (T.V.); (J.A.M.-T.); (J.G.-M.); (J.G.); (F.A.)
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), 18012 Granada, Spain
| | - Jose Garrido-Mesa
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (T.V.); (J.A.M.-T.); (J.G.-M.); (J.G.); (F.A.)
| | - María de la Luz Cádiz-Gurrea
- Department of Analytical Chemistry, Faculty of Science, University of Granada, 18071 Granada, Spain; (M.d.l.L.C.-G.); (A.S.-C.)
| | - Antonio Segura-Carretero
- Department of Analytical Chemistry, Faculty of Science, University of Granada, 18071 Granada, Spain; (M.d.l.L.C.-G.); (A.S.-C.)
| | | | - María Elena Rodríguez-Cabezas
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (T.V.); (J.A.M.-T.); (J.G.-M.); (J.G.); (F.A.)
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), 18012 Granada, Spain
| | - Julio Gálvez
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (T.V.); (J.A.M.-T.); (J.G.-M.); (J.G.); (F.A.)
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), 18012 Granada, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Francesca Algieri
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; (T.V.); (J.A.M.-T.); (J.G.-M.); (J.G.); (F.A.)
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), 18012 Granada, Spain
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15
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Zhu MZ, Yang MF, Song Y, Xu HM, Xu J, Yue NN, Zhang Y, Tian CM, Shi RY, Liang YJ, Yao J, Wang LS, Nie YQ, Li DF. Exploring the efficacy of herbal medicinal products as oral therapy for inflammatory bowel disease. Biomed Pharmacother 2023; 165:115266. [PMID: 37541177 DOI: 10.1016/j.biopha.2023.115266] [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: 03/27/2023] [Revised: 07/30/2023] [Accepted: 07/31/2023] [Indexed: 08/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) encompasses a collection of idiopathic diseases characterized by chronic inflammation in the gastrointestinal (GI) tract. Patients diagnosed with IBD often experience necessitate long-term pharmacological interventions. Among the multitude of administration routes available for treating IBD, oral administration has gained significant popularity owing to its convenience and widespread utilization. In recent years, there has been extensive evaluation of the efficacy of orally administered herbal medicinal products and their extracts as a means of treating IBD. Consequently, substantial evidence has emerged, supporting their effectiveness in IBD treatment. This review aimed to provide a comprehensive summary of recent studies evaluating the effects of herbal medicinal products in the treatment of IBD. We delved into the regulatory role of these products in modulating immunity and maintaining the integrity of the intestinal epithelial barrier. Additionally, we examined their impact on antioxidant activity, anti-inflammatory properties, and the modulation of intestinal flora. By exploring these aspects, we aimed to emphasize the significant advantages associated with the use of oral herbal medicinal products in the treatment of IBD. Of particular note, this review introduced the concept of herbal plant-derived exosome-like nanoparticles (PDENs) as the active ingredient in herbal medicinal products for the treatment of IBD. The inclusion of PDENs offers distinct advantages, including enhanced tissue penetration and improved physical and chemical stability. These unique attributes not only demonstrate the potential of PDENs but also pave the way for the modernization of herbal medicinal products in IBD treatment.
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Affiliation(s)
- Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, Guangdong, China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People's Hospital, Shenzhen 518020, Guangdong, China
| | - Yang Song
- Department of Gastroenterology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China; Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, Guangdong, China
| | - Jing Xu
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, Guangdong, China
| | - Ning-Ning Yue
- Department of Gastroenterology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University), Shenzhen 518020, Guangdong, China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou 516000, Guangdong, China
| | - Cheng-Mei Tian
- Department of Emergency, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Rui-Yue Shi
- Department of Gastroenterology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China; Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen 518020, Guangdong, China.
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China; Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China.
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China; Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China.
| | - Yu-Qiang Nie
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, Guangdong, China.
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China; Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China.
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Niu Y, Zhang J, Shi D, Zang W, Niu J. Glycosides as Potential Medicinal Components for Ulcerative Colitis: A Review. Molecules 2023; 28:5210. [PMID: 37446872 DOI: 10.3390/molecules28135210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/21/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic, non-specific disease of unknown etiology. The disease develops mainly in the rectum or colon, and the main clinical symptoms include abdominal pain, diarrhea, and purulent bloody stools, with a wide variation in severity. The specific causative factors and pathogenesis of the disease are not yet clear, but most scholars believe that the disease is caused by the interaction of genetic, environmental, infectious, immune, and intestinal flora factors. As for the treatment of UC, medications are commonly used in clinical practice, mainly including aminosalicylates, glucocorticoids, and immunosuppressive drugs. However, due to the many complications associated with conventional drug therapy and the tendency for UC to recur, there is an urgent need to discover new, safer, and more effective drugs. Natural compounds with biodiversity and chemical structure diversity from medicinal plants are the most reliable source for the development of new drug precursors. Evidence suggests that glycosides may reduce the development and progression of UC by modulating anti-inflammatory responses, inhibiting oxidative stress, suppressing abnormal immune responses, and regulating signal transduction. In this manuscript, we provide a review of the epidemiology of UC and the available drugs for disease prevention and treatment. In addition, we demonstrate the protective or therapeutic role of glycosides in UC and describe the possible mechanisms of action to provide a theoretical basis for preclinical studies in drug development.
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Affiliation(s)
- Yating Niu
- School of Basic Medical Science, Ningxia Medical University, Yinchuan 750004, China
| | - Jun Zhang
- Shandong Academy of Chinese Medicine, Jinan 250014, China
| | - Dianhua Shi
- Shandong Academy of Chinese Medicine, Jinan 250014, China
| | - Weibiao Zang
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Jianguo Niu
- School of Basic Medical Science, Ningxia Medical University, Yinchuan 750004, China
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Raj V, Venkataraman B, Ojha SK, Almarzooqi S, Subramanian VS, Al-Ramadi BK, Adrian TE, Subramanya SB. Cis-Nerolidol Inhibits MAP Kinase and NF-κB Signaling Pathways and Prevents Epithelial Tight Junction Dysfunction in Colon Inflammation: In Vivo and In Vitro Studies. Molecules 2023; 28:molecules28072982. [PMID: 37049744 PMCID: PMC10096091 DOI: 10.3390/molecules28072982] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/23/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Inflammation of the GI tract leads to compromised epithelial barrier integrity, which increases intestine permeability. A compromised intestinal barrier is a critical event that leads to microbe entry and promotes inflammatory responses. Inflammatory bowel diseases that comprise Crohn’s disease (CD) and ulcerative colitis (UC) show an increase in intestinal permeability. Nerolidol (NED), a naturally occurring sesquiterpene alcohol, has potent anti-inflammatory properties in preclinical models of colon inflammation. In this study, we investigated the effect of NED on MAPKs, NF-κB signaling pathways, and intestine epithelial tight junction physiology using in vivo and in vitro models. The effect of NED on proinflammatory cytokine release and MAPK and NF-κB signaling pathways were evaluated using lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages. Subsequently, the role of NED on MAPKs, NF-κB signaling, and the intestine tight junction integrity were assessed using DSS-induced colitis and LPS-stimulated Caco-2 cell culture models. Our result indicates that NED pre-treatment significantly inhibited proinflammatory cytokine release, expression of proteins involved in MAP kinase, and NF-κB signaling pathways in LPS-stimulated RAW macrophages and DSS-induced colitis. Furthermore, NED treatment significantly decreased FITC-dextran permeability in DSS-induced colitis. NED treatment enhanced tight junction protein expression (claudin-1, 3, 7, and occludin). Time-dependent increases in transepithelial electrical resistance (TEER) measurements reflect the formation of healthy tight junctions in the Caco-2 monolayer. LPS-stimulated Caco-2 showed a significant decrease in TEER. However, NED pre-treatment significantly prevented the fall in TEER measurements, indicating its protective role. In conclusion, NED significantly decreased MAPK and NF-κB signaling pathways and decreased tight junction permeability by enhancing epithelial tight junction protein expression.
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Affiliation(s)
- Vishnu Raj
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
| | - Balaji Venkataraman
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
| | - Shreesh K. Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
| | - Saeeda Almarzooqi
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
| | | | - Basel K. Al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. BOX 15551, United Arab Emirates
| | - Thomas E. Adrian
- Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai P.O. Box 505055, United Arab Emirates
| | - Sandeep B. Subramanya
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
- Correspondence:
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Zhang M, Li X, Zhang Q, Yang J, Liu G. Roles of macrophages on ulcerative colitis and colitis-associated colorectal cancer. Front Immunol 2023; 14:1103617. [PMID: 37006260 PMCID: PMC10062481 DOI: 10.3389/fimmu.2023.1103617] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Colitis-associated colorectal cancer is the most serious complication of ulcerative colitis. Long-term chronic inflammation increases the incidence of CAC in UC patients. Compared with sporadic colorectal cancer, CAC means multiple lesions, worse pathological type and worse prognosis. Macrophage is a kind of innate immune cell, which play an important role both in inflammatory response and tumor immunity. Macrophages are polarized into two phenotypes under different conditions: M1 and M2. In UC, enhanced macrophage infiltration produces a large number of inflammatory cytokines, which promote tumorigenesis of UC. M1 polarization has an anti-tumor effect after CAC formation, whereas M2 polarization promotes tumor growth. M2 polarization plays a tumor-promoting role. Some drugs have been shown to that prevent and treat CAC effectively by targeting macrophages.
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Tao Y, Tian X, Luo J, Zhu H, Chu Y, Pei L. Mangiferin inhibits chronic stress-induced tumor growth in colorectal liver metastases via WAVE2 signaling pathway. Heliyon 2023; 9:e13753. [PMID: 36873506 PMCID: PMC9981907 DOI: 10.1016/j.heliyon.2023.e13753] [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: 10/15/2022] [Revised: 02/07/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
Background Evidence indicates that chronic stress promotes progression of colorectal liver metastases (CLM). Mangiferin is the active chemical constituent of the rhizomes of Anemarrhena asphodeloides Bunge. Mangiferin (MGF) exerts anti-inflammatory, anti-proliferative, anti-angiogenic, anti-fibrotic and antioxidant effects in a variety of cancers. Its mechanism in chronic stress and tumor growth is still poorly understood. Methods To investigate the effects of MGF on the CLM and tumor-associated depression, activated hepatic stellate cells (a-HSCs), HT-29 CRC cells, were used in chronic unpredictable mild stress (CUMS) of tumor-bearing models. Potential antidepressant activity was determined by FST, TST, SIT and serum cytokine (IL-6, IL-18 and TNF-α) examination. Downstream signaling molecules were detected by Western blot, immunohistochemistry and fluorescence microscopy. Results CUMS induced depression behavior and depression-related cytokines and promoted tumor growth in CLM. MGF-treated mice significantly improved chronic stress behaviors by reducing depression-related cytokines. In addition, MGF treatment inhibits WAVE2 signaling pathway, leading to TGF-β1 induced HSC inhibition, thereby reducing depressive behavior and tumor growth in CLM. Conclusion MGF can alleviate CUMS induced tumor growth and the treatment of CLM patients with MGF may be beneficial.
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Affiliation(s)
- Yiming Tao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Xuefei Tian
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Jia Luo
- Department of Surgery, Hunan Cancer Hospital, Affiliated Tumor Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Hongyi Zhu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, 410011, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, 410011, China
| | - Yi Chu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, 410011, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, 410011, China
| | - Lei Pei
- Department of General Surgery, The Second Xiangya Hospital, Central South University, 410011, China
- Corresponding author. Department of General Surgery, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, 410011, Changsha, China.
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20
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Wang X, Su L, Tan J, Ding T, Yue Y. Albiflorin alleviates DSS-induced ulcerative colitis in mice by reducing inflammation and oxidative stress. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:48-56. [PMID: 36594064 PMCID: PMC9790056 DOI: 10.22038/ijbms.2022.66678.14624] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/26/2022] [Indexed: 01/04/2023]
Abstract
Objectives To clarify therapeutic potential of albiflorin and its intrinsic mechanisms against dextran sulfate sodium (DSS)-induced Ulcerative colitis (UC) mice. Materials and Methods Sixty male C57BL/6 mice were randomly divided into five groups: negative control, positive, albiflorin low-dose group, albiflorin high-dose group and treatment control (Salicylazosulfapyridine "SASP", 100 mg/kg) group. Acute colitis was induced in all groups except NC by administration of 3% DSS for 7 days. Albiflorin and SASP were administered via the intragastric route twice a day for 7 days. The changes of colon tissue were assessed by disease activity index (DAI), HE staining, and ELISA. Adrenodoxin expressions of UC colon tissues were evaluated by immunohistochemistry. Western blotting was performed to investigate related protein of the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Results It has been found that the albiflorin shares similar influences as the SASP in ameliorating the DSS-induced UC. The reduced DAI and alleviated colon tissue damage were observed in albiflorin intervened groups. Moreover, albiflorin significantly inhibited myeloperoxidase activities and attenuated immuno-inflammatory response and elevated Foxp3 mRNA in colon tissue. Furthermore, investigations revealed that albiflorin could inhibit adrenodoxin isoform and activate activated phosphorylated NF-κB p65 and IκBα, which consequently suppressed phosphorylated p38 MAPK, extracellular regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK). Conclusion These findings showed that albiflorin could alleviate DSS-induced murine colitis by activating inhibiting NF-κB and MAPK signaling pathways. It might be a potential therapeutic reagent for UC treatment.
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Affiliation(s)
- Xiaohui Wang
- Department of General Surgery, Bayinguoleng Mongolian Autonomous Prefecture People’s Hospital, Korla, 841000, Xinjiang, China,These authors contributed eqully to this work
| | - Lianlin Su
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China,These authors contributed eqully to this work
| | - Jinhua Tan
- Department of General Surgery, Bayinguoleng Mongolian Autonomous Prefecture People’s Hospital, Korla, 841000, Xinjiang, China
| | - Tianwen Ding
- Department of General Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215009, Jiangsu, China
| | - Yinzi Yue
- Department of General Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215009, Jiangsu, China,Corresponding author: Yinzi Yue. Department of General Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215009, Jiangsu, China.
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Mangiferin Ameliorates Obesity-Associated Inflammation and Autophagy in High-Fat-Diet-Fed Mice: In Silico and In Vivo Approaches. Int J Mol Sci 2022; 23:ijms232315329. [PMID: 36499655 PMCID: PMC9735994 DOI: 10.3390/ijms232315329] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/07/2022] Open
Abstract
Obesity-induced insulin resistance is the fundamental cause of metabolic syndrome. Accordingly, we evaluated the effect of mangiferin (MGF) on obesity and glucose metabolism focusing on inflammatory response and autophagy. First, an in silico study was conducted to analyze the mechanism of MGF in insulin resistance. Second, an in vivo experiment was conducted by administering MGF to C57BL/6 mice with high-fat-diet (HFD)-induced metabolic disorders. The in silico analysis revealed that MGF showed a high binding affinity with macrophage-related inflammatory cytokines and autophagy proteins. In the in vivo study, mice were divided into three groups: normal chow, HFD, and HFD + MGF 150 mg/kg. MGF administration to obese mice significantly improved the body weight, insulin-sensitive organs weights, glucose and lipid metabolism, fat accumulation in the liver, and adipocyte size compared to HFD alone. MGF significantly reduced the macrophages in adipose tissue and Kupffer cells, inhibited the gene expression ratio of tumor necrosis factor-α and F4/80 in adipose tissue, reduced the necrosis factor kappa B gene, and elevated autophagy-related gene 7 and fibroblast growth factor 21 gene expressions in the liver. Thus, MGF exerted a therapeutic effect on metabolic diseases by improving glucose and lipid metabolism through inhibition of the macrophage-mediated inflammatory responses and activation of autophagy.
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22
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Liu MX, Li T, Wang WG, Guo J, Wang RR, He HP, Li SQ, Li YP. Regulatory effect of isovitexin on MAPK/NF- κB signal in mice with acute ulcerative colitis. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2022:1-18. [PMID: 36394271 DOI: 10.1080/10286020.2022.2142121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 06/16/2023]
Abstract
The aim of this study was to investigate the anti-inflammatory effects and mechanism of isovitexin on ulcerative colitis mice and RAW264.7 cells. The results showed that isovitexin had strong antioxidant and anti-inflammatory effects, and could restore intestinal barrier integrity (p < 0.01). In addition, isovitexin inhibited the expression of MyD88, TLR4 and NF-κB p65 proteins. At the same time, isovitexin can inhibit the activation of MAPK/NF-κB signaling pathway in RAW264.7 cells. In conclusion, isovitexin has a protective effect on UC mice, and its improvement mechanism of UC might be related to MAPK/NF-κB signaling pathway.
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Affiliation(s)
- Ming-Xiu Liu
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Ting Li
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Wei-Guang Wang
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650500, China
| | - Jing Guo
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Rui-Rui Wang
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Hong-Ping He
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Shu-Quan Li
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Yan-Ping Li
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
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23
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Fiorindi C, Russo E, Balocchini L, Amedei A, Giudici F. Inflammatory Bowel Disease and Customized Nutritional Intervention Focusing on Gut Microbiome Balance. Nutrients 2022; 14:4117. [PMID: 36235770 PMCID: PMC9572914 DOI: 10.3390/nu14194117] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/24/2022] [Accepted: 09/30/2022] [Indexed: 11/05/2022] Open
Abstract
Inflammatory bowel disease (IBD) represents a chronic relapsing-remitting condition affecting the gastrointestinal system. The specific triggering IBD elements remain unknown: genetic variability, environmental factors, and alterations in the host immune system seem to be involved. An unbalanced diet and subsequent gut dysbiosis are risk factors, too. This review focuses on the description of the impact of pro- and anti-inflammatory food components on IBD, the role of different selected regimes (such as Crohn's Disease Exclusion Diet, Immunoglobulin Exclusion Diet, Specific Carbohydrate Diet, LOFFLEX Diet, Low FODMAPs Diet, Mediterranean Diet) in the IBD management, and their effects on the gut microbiota (GM) composition and balance. The purpose is to investigate the potential positive action on IBD inflammation, which is associated with the exclusion or addition of certain foods or nutrients, to more consciously customize the nutritional intervention, taking also into account GM fluctuations during both disease flare-up and remission.
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Affiliation(s)
- Camilla Fiorindi
- Department of Health Science, AOUC Careggi, 50134 Florence, Italy
| | - Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Francesco Giudici
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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24
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Hassanein EHM, Mohamed WR, Ahmed OS, Abdel-Daim MM, Sayed AM. The role of inflammation in cadmium nephrotoxicity: NF-κB comes into view. Life Sci 2022; 308:120971. [PMID: 36130617 DOI: 10.1016/j.lfs.2022.120971] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/06/2022] [Accepted: 09/13/2022] [Indexed: 11/29/2022]
Abstract
Kidney diseases are major health problem and understanding the underlined mechanisms that lead to kidney diseases are critical research points with a marked potential impact on health. Cadmium (Cd) is a heavy metal that occurs naturally and can be found in contaminated food. Kidneys are the most susceptible organ to heavy metal intoxication as it is the main route of waste excretion. The harmful effects of Cd were previously well proved. Cd induces inflammatory responses, oxidative injury, mitochondrial dysfunction and disturbs Ca2+ homeostasis. The nuclear factor-kappa B (NF-κB) is a cellular transcription factor that regulates inflammation and controls the expression of many inflammatory cytokines. Therefore, great therapeutic benefits can be attained from NF-κB inhibition. In this review we focused on certain compounds including cytochalasin D, mangiferin, N-acetylcysteine, pyrrolidine dithiocarbamate, roflumilast, rosmarinic acid, sildenafil, sinapic acid, telmisartan and wogonin and certain plants as Astragalus Polysaccharide, Ginkgo Biloba and Thymus serrulatus that potently inhibit NF-κB and effectively counteracted Cd-associated renal intoxication. In conclusion, the proposed NF-κB involvement in Cd-renal intoxication clarified the underlined inflammation associated with Cd-nephropathy and the beneficial effects of NF-κB inhibitors that make them the potential to substantially optimize treatment protocols for Cd-renal intoxication.
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Affiliation(s)
- Emad H M Hassanein
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Osama S Ahmed
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Mohamed M Abdel-Daim
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia; Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, 41522 Ismailia, Egypt
| | - Ahmed M Sayed
- Biochemistry Laboratory, Chemistry Department, Faculty of Science, Assiut University, Egypt.
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25
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Tiwari PC, Chaudhary MJ, Pal R, Nath R. Effects of mangiferin and its combination with nNOS inhibitor 7‐nitro‐indazole (7‐NI) in 6‐hydroxydopamine (6‐OHDA) lesioned Parkinson's disease rats. Fundam Clin Pharmacol 2022; 36:944-955. [DOI: 10.1111/fcp.12817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 05/21/2022] [Accepted: 07/07/2022] [Indexed: 10/17/2022]
Affiliation(s)
- Prafulla Chandra Tiwari
- Department of Pharmacology and Therapeutics King George's Medical University Lucknow Uttar Pradesh India
| | - Manju J. Chaudhary
- Department of Physiology Government Medical College Kannauj Uttar Pradesh India
| | - Rishi Pal
- Department of Pharmacology and Therapeutics King George's Medical University Lucknow Uttar Pradesh India
| | - Rajendra Nath
- Department of Pharmacology and Therapeutics King George's Medical University Lucknow Uttar Pradesh India
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Mazumder S, Bindu S, De R, Debsharma S, Pramanik S, Bandyopadhyay U. Emerging role of mitochondrial DAMPs, aberrant mitochondrial dynamics and anomalous mitophagy in gut mucosal pathogenesis. Life Sci 2022; 305:120753. [PMID: 35787999 DOI: 10.1016/j.lfs.2022.120753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 12/22/2022]
Abstract
Gastroduodenal inflammation and ulcerative injuries are increasing due to expanding socio-economic stress, unhealthy food habits-lifestyle, smoking, alcoholism and usage of medicines like non-steroidal anti-inflammatory drugs. In fact, gastrointestinal (GI) complications, associated with the prevailing COVID-19 pandemic, further, poses a challenge to global healthcare towards safeguarding the GI tract. Emerging evidences have discretely identified mitochondrial dysfunctions as common etiological denominators in diseases. However, it is worth realizing that mitochondrial dysfunctions are not just consequences of diseases. Rather, damaged mitochondria severely aggravate the pathogenesis thereby qualifying as perpetrable factors worth of prophylactic and therapeutic targeting. Oxidative and nitrosative stress due to endogenous and exogenous stimuli triggers mitochondrial injury causing production of mitochondrial damage associated molecular patterns (mtDAMPs), which, in a feed-forward loop, inflicts inflammatory tissue damage. Mitochondrial structural dynamics and mitophagy are crucial quality control parameters determining the extent of mitopathology and disease outcomes. Interestingly, apart from endogenous factors, mitochondria also crosstalk and in turn get detrimentally affected by gut pathobionts colonized during luminal dysbiosis. Although mitopathology is documented in various pre-clinical/clinical studies, a comprehensive account appreciating the mitochondrial basis of GI mucosal pathologies is largely lacking. Here we critically discuss the molecular events impinging on mitochondria along with the interplay of mitochondria-derived factors in fueling mucosal pathogenesis. We specifically emphasize on the potential role of aberrant mitochondrial dynamics, anomalous mitophagy, mitochondrial lipoxidation and ferroptosis as emerging regulators of GI mucosal pathogenesis. We finally discuss about the prospect of mitochondrial targeting for next-generation drug discovery against GI disorders.
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Affiliation(s)
- Somnath Mazumder
- Department of Zoology, Raja Peary Mohan College, 1 Acharya Dhruba Pal Road, Uttarpara, West Bengal 712258, India
| | - Samik Bindu
- Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal 736101, India
| | - Rudranil De
- Amity Institute of Biotechnology, Amity University, Kolkata, Plot No: 36, 37 & 38, Major Arterial Road, Action Area II, Kadampukur Village, Newtown, Kolkata, West Bengal 700135, India
| | - Subhashis Debsharma
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, West Bengal 700032, India
| | - Saikat Pramanik
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, West Bengal 700032, India
| | - Uday Bandyopadhyay
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, West Bengal 700032, India; Division of Molecular Medicine, Bose Institute, EN 80, Sector V, Bidhan Nagar, Kolkata, West Bengal 700091, India.
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Wu J, Wu Y, Chen Y, Liu M, Yu H, Zhang Y, Wang T. Desmethylbellidifolin Attenuates Dextran Sulfate Sodium-Induced Colitis: Impact on Intestinal Barrier, Intestinal Inflammation and Gut Microbiota. PLANTA MEDICA 2022; 88:559-569. [PMID: 34098585 DOI: 10.1055/a-1506-3476] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Ulcerative colitis has been recognized as a chronic inflammatory disease predominantly disturbing the colon and rectum. Clinically, the aminosalicylates, steroids, immunosuppressants, and biological drugs are generally used for the treatment of ulcerative colitis at different stages of disease progression. However, the therapeutic efficacy of these drugs does not satisfy the patients due to the frequent drug resistance. Herein, we reported the anti-ulcerative colitis activity of desmethylbellidifolin, a xanthone isolated from Gentianella acuta, in dextran sulfate sodium-induced colitis in mice. C57BL/6 mice were treated with 2% dextran sulfate sodium in drinking water to induce acute colitis. Desmethylbellidifolin or balsalazide sodium was orally administrated once a day. Biological samples were collected for immunohistological analysis, intestinal barrier function evaluation, cytokine measurement, and gut microbiota analysis. The results revealed that desmethylbellidifolin alleviated colon shortening and body weight loss in dextran sulfate sodium-induced mice. The disease activity index was also lowered by desmethylbellidifolin after 9 days of treatment. Furthermore, desmethylbellidifolin remarkably ameliorated colonic inflammation through suppressing the expression of interleukin-6 and tumor necrosis factor-α. The intestinal epithelial barrier was strengthened by desmethylbellidifolin through increasing levels of occludin, ZO-1, and claudins. In addition, desmethylbellidifolin modulated the gut dysbiosis induced by dextran sulfate sodium. These findings suggested that desmethylbellidifolin effectively improved experimental ulcerative colitis, at least partly, through maintaining intestinal barrier integrity, inhibiting proinflammatory cytokines, and modulating dysregulated gut microbiota.
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Affiliation(s)
- Jiaqi Wu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuzheng Wu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yue Chen
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mengyang Liu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yi Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tao Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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28
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Tiwari PC, Chaudhary MJ, Pal R, Kartik S, Nath R. Pharmacological, Biochemical and Immunological Studies on Protective Effect of Mangiferin in 6-Hydroxydopamine (6-OHDA)-Induced Parkinson's Disease in Rats. Ann Neurosci 2022; 28:137-149. [PMID: 35341236 PMCID: PMC8948331 DOI: 10.1177/09727531211051976] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 09/25/2021] [Indexed: 01/24/2023] Open
Abstract
Background: Parkinson’s disease is a neurodegenerative disorder and is marked by
inflammation and death of neurons in the striatum region of the midbrain. It
has been reported that expression of NF-κB increases during Parkinson’s
disease, which promotes oxidative stress, stimulates release of
proinflammatory cytokines, and induces expression of nitric oxide.
Therefore, in this study, we have used mangiferin a specific NF-κB
inhibitor. Mangiferin is a polyphenolic compound traditionally used for its
antioxidant and anti-inflammatory properties. Methods: The study utilized male Wistar rats weighing 200–250 g (56 rats;
n = 8/group). On day “0,” stereotaxic surgery of rats
was done to induce 6-hydroxydopamine lesioning in rats. Coordinates for
substantia nigra were anteroposterior-2 mm, mediolateral-5 mm and
dorsoventral-8.2 mm. After 14 days, those rats which show at least 210
contralateral rotations after administration of apomorphine (0.5 mg/kg S.C.)
were selected for the study and were given treatment for 28 days. On day 28
of treatment, rats were subjected to behavioral studies to evaluate the
effect of mangiferin and their brains were taken out after euthanasia to
perform biochemical, molecular and immunological studies. Results: Treatment with mangiferin significantly improves the key parameters of
locomotor activity and oxidative stress and reduces the parameters of
inflammatory stress. Also, the activity of caspases was reduced. Significant
decrease in activity of both cyclooxygenase 1 and 2 was also observed.
Maximum improvement in all parameters was observed in rats treated with
grouping of mangiferin 45 µg/kg and levodopa 10 mg/kg. Treatment with
levodopa alone has no significant effect on biochemical and molecular
parameters though it significantly improves behavioral parameters. Conclusion: Current treatment of Parkinson’s disease does not target progression of
Parkinson’s disease. Results of this study suggest that mangiferin has
protective effect in hemi-Parkinsonian rats. Therefore, the combination
therapy of mangiferin and levodopa can be helpful in management of
Parkinson’s disease.
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Affiliation(s)
- Prafulla Chandra Tiwari
- Department of Pharmacology & Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Manju J Chaudhary
- Department of Physiology, Government Medical College, Kannauj, Uttar Pradesh, India
| | - Rishi Pal
- Department of Pharmacology & Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Shipra Kartik
- Department of Pharmacology & Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Rajendra Nath
- Department of Pharmacology & Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
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Wang M, Zhang Z, Huo Q, Wang M, Sun Y, Liu H, Chang J, He B, Liang Y. Targeted Polymeric Nanoparticles Based on Mangiferin for Enhanced Protection of Pancreatic β-Cells and Type 1 Diabetes Mellitus Efficacy. ACS APPLIED MATERIALS & INTERFACES 2022; 14:11092-11103. [PMID: 35199981 DOI: 10.1021/acsami.1c22964] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Mangiferin (MGF) is found in many natural plants, such as Rhizoma Anemarrhenae, and has anti-diabetes effects. However, its clinical applications and development are limited by poor solubility and low-concentration enrichment in pancreatic islets. In this paper, targeted polymeric nanoparticles were constructed for MGF delivery with the desired drug loading content (6.86 ± 0.60%), excellent blood circulation, and missile-like delivery to the pancreas. Briefly, Glucagon-like peptide 1 (GLP-1) as an active targeting agent to the pancreas was immobilized on the block copolymer polyethyleneglycol-polycaprolactone (PEG-PCL) to obtain final GLP-1-PEG-PCL amphiphiles. Spherical MGF-loaded polymeric nanoparticles were acquired from the self-assembly of the targeted GDPP nanoparticles and MGF with a homogeneous size of 158.9 ± 1.7 nm and a negative potential for a good steady state in circulation. In this drug vehicle, GLP-1 acts as the missile vanguard via the GLP-1 receptor on the surface of the pancreas for improving the accumulation and efficiency of MGF in the pancreas, the hypoglycemic effect of MGF, and the restorative effect on pancreatic islets, which were investigated. As compared to free MGF, MGF/GDPP nanoparticles appeared to be more concentrated in the pancreas, with better blood glucose and glucose tolerance, enhanced insulin levels, increased β-cell proliferation, reduced β-cell apoptosis, and islet repair in vivo. This targeted drug delivery system provided a novel strategy and hope for enhancing MGF delivery and anti-diabetes efficacy.
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Affiliation(s)
- Mengdi Wang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
| | - Zhuoran Zhang
- Department of Dentistry, Qingdao Special Service Sanatorium of PLA Navy, Qingdao 266021, China
| | - Qingqing Huo
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
| | - Maolong Wang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
| | - Hongling Liu
- Department of Pharmacy, Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Jing Chang
- College of Marine Life Science, Ocean University of China, Qingdao 266003, China
| | - Bin He
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Yan Liang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
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30
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Wang M, Liang Y, Chen K, Wang M, Long X, Liu H, Sun Y, He B. The management of diabetes mellitus by mangiferin: advances and prospects. NANOSCALE 2022; 14:2119-2135. [PMID: 35088781 DOI: 10.1039/d1nr06690k] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Diabetes mellitus has become one of the most challenging public health problems today. There are still various deficiencies that remain in existing therapeutic drugs. With increasing prevalence and mortality rates, more effective therapeutic agents are required for treatment clinically. As a kind of polyphenol and as a natural product, mangiferin has numerous pharmacological and excellent effects. In this review, the underlying mechanisms of mangiferin on diabetes mellitus and complications will be summarized. Moreover, mangiferin belongs to the BSC IV class and the clinical application and development of mangiferin are limited due to its poor aqueous solubility and fat solubility as well as low bioavailability. Our review also elaborated on improving the solubility of mangiferin by changing the dosage form and introduced the existing results, which hope to provide useful reference for mangiferin for further treating diabetes. In conclusion, mangiferin might be a potential adjuvant therapy for the treatment of diabetes mellitus and complications in the future.
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Affiliation(s)
- Mengdi Wang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China.
| | - Yan Liang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China.
| | - Keqi Chen
- Department of Clinical laboratory, Qingdao special servicemen recuperation centre of PLA navy, Qingdao 266021, China
| | - Maolong Wang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xuehua Long
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China.
| | - HongLing Liu
- Department of Pharmacy, Affiliated Hospital of Qingdao University, Qingdao 266000, China.
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China.
| | - Bin He
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
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31
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Verma A, Pittala S, Alhozeel B, Shteinfer-Kuzmine A, Ohana E, Gupta R, Chung JH, Shoshan-Barmatz V. The role of the mitochondrial protein VDAC1 in inflammatory bowel disease: a potential therapeutic target. Mol Ther 2022; 30:726-744. [PMID: 34217890 PMCID: PMC8821898 DOI: 10.1016/j.ymthe.2021.06.024] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 04/19/2021] [Accepted: 06/22/2021] [Indexed: 02/04/2023] Open
Abstract
Recent studies have implicated mitochondrial dysfunction as a trigger of inflammatory bowel diseases, including Crohn's disease (CD) and ulcerative colitis (UC). We have investigated the role of the mitochondria gate-keeper protein, the voltage-dependent-anion channel 1 (VDAC1), in gastrointestinal inflammation and tested the effects of the newly developed VDAC1-interacting molecules, VBIT-4 and VBIT-12, on UC induced by dextran sulfate sodium (DSS) or trinitrobenzene sulphonic acid (TNBS) in mice. VDAC1, which controls metabolism, lipids transport, apoptosis, and inflammasome activation, is overexpressed in the colon of CD and UC patients and DSS-treated mice. VBIT-12 treatment of cultured colon cells inhibited the DSS-induced VDAC1 overexpression, oligomerization, and apoptosis. In the DSS-treated mice, VBIT-12 suppressed weight loss, diarrhea, rectal bleeding, pro-inflammatory cytokine production, crypt and epithelial cell damage, and focal inflammation. VBIT-12 also inhibited the infiltration of inflammatory cells, apoptosis, mtDNA release, and activation of caspase-1 and NRLP3 inflammasome to reduce the inflammatory response. The levels of the ATP-gated P2X7-Ca2+/K+ channel and ER-IP3R-Ca2+ channel, and of the mitochondrial anti-viral protein (MAVS), mediating NLRP3 inflammasome assembly and activation, were highly increased in DSS-treated mice, but not when VBIT-12 treated. We conclude that UC may be promoted by VDAC1-overexpression and may therefore be amenable to treatment with novel VDAC1-interacting molecules. This VDAC1-based strategy exploits a completely new target for UC treatment and opens a new avenue for treating other inflammatory/autoimmune diseases.
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Affiliation(s)
- Ankit Verma
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Srinivas Pittala
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Belal Alhozeel
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Anna Shteinfer-Kuzmine
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Ehud Ohana
- The Department of Physiology, Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Rajeev Gupta
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Jay H Chung
- Laboratory of Obesity and Aging Research, Cardiovascular Branch, NHLBI, NIH, Bethesda, MD 20892, USA
| | - Varda Shoshan-Barmatz
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
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Hao L, Alkry LT, Alattar A, Faheem M, Alshaman R, Shah FA, Li S. Ibrutinib attenuated DSS-induced ulcerative colitis, oxidative stress, and the inflammatory cascade by modulating the PI3K/Akt and JNK/NF-κB pathways. Arch Med Sci 2022; 18:805-815. [PMID: 35591835 PMCID: PMC9103379 DOI: 10.5114/aoms/146792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/18/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Liangliang Hao
- Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Lina Tariq Alkry
- College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates
| | - Abdullah Alattar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Muhammad Faheem
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Reem Alshaman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Fawad Ali Shah
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China
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Zhang J, Xu X, Li N, Cao L, Sun Y, Wang J, He S, Si J, Qing D. Licoflavone B, an isoprene flavonoid derived from licorice residue, relieves dextran sodium sulfate-induced ulcerative colitis by rebuilding the gut barrier and regulating intestinal microflora. Eur J Pharmacol 2021; 916:174730. [PMID: 34968462 DOI: 10.1016/j.ejphar.2021.174730] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 11/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022]
Abstract
Ulcerative colitis (UC) is a major inflammatory disease worldwide. We previously demonstrated that licorice residue flavones (LFs) showed satisfactory efficacy in the treatment of UC. Therefore, research into the ingredients of LFs may lead to the discovery of novel anti-UC targets. In the current study, we separated licoflavone B (LB) from LFs and administered it to dextran sodium sulfate (DSS)-exposed C57BL/6 mice for 14 days. Our results demonstrated that high dose LB (120mg/kg) significantly prevented DSS-induced weight loss, disease activity index (DAI) increase, histological damage, and colonic inflammation, indicating that LB has ameliorative effects on UC. We also investigated the composition of the intestinal barrier and microflora in an attempt to explore the mechanisms of LB against UC. As a result, we found that LB preserved the integrity of the colonic barrier by inhibiting colonic cell apoptosis and protecting the expression of occludin, claudin-1, and ZO-1. Moreover, LB reshaped the microflora composition by suppressing harmful bacteria (Enterococcus et al.) and boosting beneficial microorganisms (Bacteroides et al.). Further molecular exploration implied that LB exerted anti-UC activity through blocking the MAPK pathway. Here, we explored anti-UC activity of LB for the first time and clarified its mechanisms. These results will provide valuable clues for the discovery of novel anti-UC agents.
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Affiliation(s)
- Juan Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China
| | - Xiaoqin Xu
- XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Li Cao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Yu Sun
- XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China
| | - Junchi Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Shuaibing He
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou Central Hospital, Huzhou, 313000, China
| | - Jianyong Si
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China.
| | - Degang Qing
- XinJiang Institute of Chinese Materia Medica and Ethnodrug, Urumqi, 830002, China.
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Cai SQ, Zhang Q, Zhao XH, Shi J. The In Vitro Anti-Inflammatory Activities of Galangin and Quercetin towards the LPS-Injured Rat Intestinal Epithelial (IEC-6) Cells as Affected by Heat Treatment. Molecules 2021; 26:7495. [PMID: 34946578 PMCID: PMC8703769 DOI: 10.3390/molecules26247495] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/01/2021] [Accepted: 12/09/2021] [Indexed: 01/06/2023] Open
Abstract
Flavonols possess several beneficial bioactivities in vitro and in vivo. In this study, two flavonols galangin and quercetin with or without heat treatment (100 °C for 15-30 min) were assessed for their anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated rat intestinal epithelial (IEC-6) cells and whether the heat treatment caused activity changes. The flavonol dosages of 2.5-20 μmol/L had no cytotoxicity on the cells but could enhance cell viability (especially using 5 μmol/L flavonol dosage). The flavonols could decrease the production of prostaglandin E2 and three pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and simultaneously promote the production of two anti-inflammatory cytokines IL-10 and transforming growth factor-β. The Western-blot results verified that the flavonols could suppress the LPS-induced expression of TLR4 and phosphorylated IκBα and p65, while the molecular docking results also illustrated that the flavonols could bind with TLR4 and NF-κB to yield energy decreases of -(21.9-28.6) kJ/mol. Furthermore, an inhibitor BAY 11-7082 blocked the NF-κB signaling pathway by inhibiting the expression of phosphorylated IκBα/p65 and thus mediated the production of IL-6/IL-10 as the flavonols did, which confirmed the assessed anti-inflammatory effect of the flavonols. Consistently, galangin had higher anti-inflammatory activity than quercetin, while the heated flavonols (especially those with longer heat time) were less active than the unheated counterparts to exert these target anti-inflammatory effects. It is highlighted that the flavonols could antagonize the LPS-caused IEC-6 cells inflammation via suppressing TLR4/NF-κB activation, but heat treatment of the flavonols led to reduced anti-inflammatory efficacy.
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Affiliation(s)
- Shi-Qing Cai
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China;
- School of Biology and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China;
| | - Qiang Zhang
- School of Biology and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China;
- Research Centre of Food Nutrition and Human Healthcare, Guangdong University of Petrochemical Technology, Maoming 525000, China
| | - Xin-Huai Zhao
- School of Biology and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China;
- Research Centre of Food Nutrition and Human Healthcare, Guangdong University of Petrochemical Technology, Maoming 525000, China
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong University of Petrochemical Technology, Maoming 525000, China
| | - Jia Shi
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China;
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35
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Fu W, Fu H, Ye W, Han Y, Liu X, Zhu S, Li H, Tang R, Wang Q. Peripheral blood neutrophil-to-lymphocyte ratio in inflammatory bowel disease and disease activity: A meta-analysis. Int Immunopharmacol 2021; 101:108235. [PMID: 34678692 DOI: 10.1016/j.intimp.2021.108235] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVE The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a valuable predictor of clinical disease activity in inflammatory bowel disease (IBD). Therefore, we conducted a meta-analysis to evaluate the clinical significance of peripheral blood NLR in IBD patients. METHODS A comprehensive literature search was conducted by searching PubMed, Embase, Web of Science, Cochrane Library, and Chinese databases from inception to May 10, 2021. We used the standard mean difference (SMD) with a 95% confidence interval (CI) to estimate the pooled effect and subgroup analysis to investigate heterogeneity. RESULTS Sixteen studies including 2185 IBD patients and 993 healthy controls (HCs) were enrolled in this study. The peripheral blood NLR values were significantly higher in 1,092 IBD patients than in 933 HCs (SMD = 1.54, 95% CI = 1.05-2.02, P < 0.001) and in 1,269 patients with active IBD than in 1,056 patients with remissive IBD (SMD = 1.55, 95% CI = 1.06-2.05, P < 0.001). Subgroup analysis of the major subtypes of IBD revealed significantly elevated peripheral blood NLR values in patients with active ulcerative colitis (UC) compared to HCs (SMD = 2.04), remissive UC than HCs (SMD = 0.63), and active UC than in those with remissive UC (SMD = 1.32) (P < 0.05). Both Crohn's disease (CD) patients and active CD patients had significantly elevated peripheral blood NLR values than HCs with the SMD of 0.52 and 3.53 (P < 0.001). CONCLUSIONS Peripheral blood NLR could serve as a valuable biomarker for predicting disease severity in IBD patients.
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Affiliation(s)
- Wei Fu
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Hu Fu
- Department of Laboratory Medicine, Chengdu First People's Hospital, Chengdu 610000, Sichuan, PR China
| | - Weixia Ye
- Department of Gastroenterology, Luzhou People's Hospital, Luzhou 646000, Sichuan, PR China.
| | - Yinsuo Han
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Xianqiang Liu
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Sirui Zhu
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Hongmin Li
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Rong Tang
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Qin Wang
- Sichuan Provincial Center for Gynecology and Breast Diseases (Gynecology), Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, PR China.
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Yan T, Luo Y, Xia Y, Hamada K, Wang Q, Yan N, Krausz KW, Ward JM, Hao H, Wang P, Gonzalez FJ. St. John's Wort alleviates dextran sodium sulfate-induced colitis through pregnane X receptor-dependent NFκB antagonism. FASEB J 2021; 35:e21968. [PMID: 34644426 PMCID: PMC10167919 DOI: 10.1096/fj.202001098r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 09/04/2021] [Accepted: 09/17/2021] [Indexed: 12/13/2022]
Abstract
St. John's wort (SJW), from traditional herbs, activates the pregnane X receptor (PXR), a potential drug target for treating inflammatory bowel disease (IBD). However, how SJW alleviates dextran sodium sulfate (DSS)-induced experimental IBD by activating PXR is unknown. To test this, PXR-humanized, wild-type (WT) and Pxr-null mice, primary intestinal organoids cultures, and the luciferase reporter gene assays were employed. In vivo, a diet supplemented with SJW was found to activate intestinal PXR both in WT and PXR-humanized mice, but not in Pxr-null mice. SJW prevented DSS-induced IBD in PXR-humanized and WT mice, but not in Pxr-null mice. In vitro, hyperforin, a major component of SJW, activated PXR and suppressed tumor necrosis factor (TNF)α-induced nuclear factor (NF) κB translocation in primary intestinal organoids from PXR-humanized mice, but not Pxr-null mice. Luciferase reporter gene assays showed that hyperforin dose-dependently alleviated TNFα-induced NFκB transactivation by activating human PXR in Caco2 cells. Furthermore, SJW therapeutically attenuated DSS-induced IBD in PXR-humanized mice. These data indicate the therapeutic potential of SJW in alleviating DSS-induced IBD in vivo, and TNFα-induced NFκB activation in vitro, dependent on PXR activation, which may have clinical implications for using SJW as a herbal drug anti-IBD treatment.
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Affiliation(s)
- Tingting Yan
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Yuhong Luo
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Yangliu Xia
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Keisuke Hamada
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Qiong Wang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Nana Yan
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.,State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jerrold M Ward
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Ping Wang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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The Regulatory Effects of Licochalcone A on the Intestinal Epithelium and Gut Microbiota in Murine Colitis. Molecules 2021; 26:molecules26144149. [PMID: 34299424 PMCID: PMC8304238 DOI: 10.3390/molecules26144149] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 12/31/2022] Open
Abstract
The gut epithelium is a mechanical barrier that protects the host from the luminal microenvironment and interacts with the gut microflora, which influences the development and progression of ulcerative colitis (UC). Licochalcone A (LA) exerts anti-inflammatory effects against UC; however, whether it also regulates both the gut barrier and microbiota during colitis is unknown. The current study was conducted to reveal the regulatory effects of LA on the intestinal epithelium and gut microflora in C57BL/6 mice subjected to dextran sodium sulfate (DSS). Sulfasalazine (SASP) was used as the positive control. Results of clinical symptoms evaluation, hematoxylin, and eosin (H&E) staining, and enzyme-linked immunosorbent (ELISA) assays showed that LA significantly inhibited DSS-induced weight loss, disease activity index (DAI) increase, histological damage, and gut inflammation. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunohistochemical (IHC) analysis showed that LA maintained the integrity of the intestinal barrier by suppressing cell apoptosis and preserving the expression of tight junction (TJ) proteins. Notably, the optimal dose of LA for gut barrier preservation was low, while that for anti-inflammatory effects was high, indicating that LA might preserve gut barrier integrity via direct effects on the epithelial cells (ECs) and TJ proteins. Furthermore, 16S rRNA analysis suggested that the regulatory effect of LA on the gut microbiota differed distinctly according to dose. Correlation analysis indicated that a low dose of LA significantly modulated the intestinal barrier-associated bacteria as compared with a moderate or high dose of LA. Western blot (WB) analysis indicated that LA exhibited anti-UC activity partly by blocking the mitogen-activated protein kinase (MAPK) pathway. Our results further elucidate the pharmacological activity of LA against UC and will provide valuable information for future studies regarding on the regulatory effects of LA on enteric diseases.
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Shi Z, Dun B, Wei Z, Liu C, Tian J, Ren G, Yao Y. Peptides Released from Extruded Adzuki Bean Protein through Simulated Gastrointestinal Digestion Exhibit Anti-inflammatory Activity. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:7028-7036. [PMID: 34138556 DOI: 10.1021/acs.jafc.1c01712] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Increasing attention has been focused on plant-derived peptides because of their potential bioactivities. In this study, bioactive peptides were released from extruded adzuki bean protein by simulated gastrointestinal digestion. A peptide (KQS-1) sequenced as KQSESHFVDAQPEQQQR was separated and identified using ultrafiltration, pre-high-performance liquid chromatography (HPLC), and ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). KQS-1 was shown to exert significant anti-inflammatory effects in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages by reducing the production of IL-1, IL-6, TNF-α, and MCP-1 to 38.31, 6.07, 43.96, and 41.74%, respectively. The involved signaling pathways were identified by transcriptome analysis. Overall, 5236 differentially expressed genes (DEGs) were identified. Gene ontology (GO) functions demonstrated that DEGs were significantly related to the NF-κB pathway. In conclusion, KQS-1 prevented the activation and expression of NF-κB/caspase-1 by upstream and downstream factors. These findings highlight the bioactivity of adzuki bean peptides.
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Affiliation(s)
- Zhenxing Shi
- Institute of Crop Science, Chinese Academy of Agricultural Sciences (CAAS), 80 South Xueyuan Road, Haidian District, Beijing 100081, People's Republic of China
| | - Baoqing Dun
- Institute of Crop Science, Chinese Academy of Agricultural Sciences (CAAS), 80 South Xueyuan Road, Haidian District, Beijing 100081, People's Republic of China
| | - Zuchen Wei
- Institute of Crop Science, Chinese Academy of Agricultural Sciences (CAAS), 80 South Xueyuan Road, Haidian District, Beijing 100081, People's Republic of China
- Laboratory for Green Cultivation and Deep Processing of Three Gorges Reservoir Area's Medicinal Herbs, College of Life Science & Engineering, The Chongqing Engineering, Chongqing Three Gorges University, No. 666 Tianxing Road, Wanzhou District, Chongqing 404000, People's Republic of China
| | - Changyou Liu
- Institute of Cereal and Oil Crops, Hebei Academy of Agricultural and Forestry Sciences/Hebei Laboratory of Crop Genetic and Breeding, Shijiazhuang 050035, Hebei, People's Republic of China
| | - Jing Tian
- Institute of Cereal and Oil Crops, Hebei Academy of Agricultural and Forestry Sciences/Hebei Laboratory of Crop Genetic and Breeding, Shijiazhuang 050035, Hebei, People's Republic of China
| | - Guixing Ren
- Institute of Crop Science, Chinese Academy of Agricultural Sciences (CAAS), 80 South Xueyuan Road, Haidian District, Beijing 100081, People's Republic of China
| | - Yang Yao
- Institute of Crop Science, Chinese Academy of Agricultural Sciences (CAAS), 80 South Xueyuan Road, Haidian District, Beijing 100081, People's Republic of China
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Guo C, Guo D, Fang L, Sang T, Wu J, Guo C, Wang Y, Wang Y, Chen C, Chen J, Chen R, Wang X. Ganoderma lucidum polysaccharide modulates gut microbiota and immune cell function to inhibit inflammation and tumorigenesis in colon. Carbohydr Polym 2021; 267:118231. [PMID: 34119183 DOI: 10.1016/j.carbpol.2021.118231] [Citation(s) in RCA: 247] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/16/2021] [Accepted: 05/17/2021] [Indexed: 02/06/2023]
Abstract
This study investigated the effects of water-soluble polysaccharide extracted from the sporoderm-removed spores of Ganoderma lucidum (GLP) against AOM/DSS-induced inflammation, tumorigenesis, and gut microbiota modification, which has never been reported before. Our data revealed that GLP (200 and 300 mg/kg) decreased AOM/DSS-induced colitis and tumorigenesis, manifested by significantly reduced disease activity index score, and total number and size of tumors. Furthermore, GLP ameliorated AOM/DSS-induced microbiota dysbiosis, increased short-chain fatty acid production, and alleviated endotoxemia by inhibiting TLR4/MyD88/NF-κB signaling. Besides, GLP profoundly improved gut barrier function as evidenced by increased numbers of goblet cells, MUC2 secretion, and tight junction protein expressions. GLP treatment inhibited macrophage infiltration and downregulated IL-1β, iNOS, and COX-2 expressions. Additionally, GLP inhibited lipopolysaccharides (LPS)-induced inflammation markers and MAPK (JNK and ERK) activation in macrophage RAW264.7, intestinal HT-29, and NCM460 cells. In conclusion, these results indicate that GLP is a promising prebiotic for the treatment of colorectal cancer.
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Affiliation(s)
- Cuiling Guo
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Dandan Guo
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Liu Fang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Tingting Sang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Jianjun Wu
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Chengjie Guo
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Yujie Wang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Ying Wang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Chaojie Chen
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Jiajun Chen
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Rong Chen
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Xingya Wang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, PR China.
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Kim H, Castellon-Chicas MJ, Arbizu S, Talcott ST, Drury NL, Smith S, Mertens-Talcott SU. Mango ( Mangifera indica L.) Polyphenols: Anti-Inflammatory Intestinal Microbial Health Benefits, and Associated Mechanisms of Actions. Molecules 2021; 26:2732. [PMID: 34066494 PMCID: PMC8124428 DOI: 10.3390/molecules26092732] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 01/05/2023] Open
Abstract
Mango is rich in polyphenols including gallotannins and gallic acid, among others. The bioavailability of mango polyphenols, especially polymeric gallotannins, is largely dependent on the intestinal microbiota, where the generation of absorbable metabolites depends on microbial enzymes. Mango polyphenols can favorably modulate bacteria associated with the production of bioactive gallotannin metabolites including Lactobacillus plantarum, resulting in intestinal health benefits. In several studies, the prebiotic effects of mango polyphenols and dietary fiber, their potential contribution to lower intestinal inflammation and promotion of intestinal integrity have been demonstrated. Additionally, polyphenols occurring in mango have some potential to interact with intestinal and less likely with hepatic enzymes or transporter systems. This review provides an overview of interactions of mango polyphenols with the intestinal microbiome, associated health benefits and underlying mechanisms.
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Affiliation(s)
- Hyemee Kim
- Department of Food Science and Nutrition, Pusan National University, Busan 46241, Korea
| | - Maria Joselyn Castellon-Chicas
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Shirley Arbizu
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Stephen T. Talcott
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Nicholas L. Drury
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Shayna Smith
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
| | - Susanne U. Mertens-Talcott
- Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA; (M.J.C.-C.); (S.A.); (S.T.T.); (N.L.D.); (S.S.)
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Pinocembrin alleviates ulcerative colitis in mice via regulating gut microbiota, suppressing TLR4/MD2/NF-κB pathway and promoting intestinal barrier. Biosci Rep 2021; 40:225839. [PMID: 32687156 PMCID: PMC7391130 DOI: 10.1042/bsr20200986] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/24/2020] [Accepted: 07/17/2020] [Indexed: 12/11/2022] Open
Abstract
Pinocembrin, a plant-derived flavonoid, has a variety of pharmacological activities, including anti-infection, anti-cancer, anti-inflammation, cardiovascular protection, etc. However, the mechanism of pinocembrin on the anti-colitis efficacy remains elusive and needs further investigation. Here, we reported that pinocembrin eased the severity of dextran sulfate sodium (DSS)-induced colitis in mice by suppressing the abnormal activation of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signal pathway in vivo. In addition, the gut microbiota was disordered in DSS colitis mice, which was associated with a significant decrease in microbiota diversity and a great shift in bacteria profiles; however, pinocembrin treatment improved the imbalance of gut microbiota and made it similar to that in normal mice. On the other hand, in vitro, pinocembrin down-regulated the TLR4/NF-κB signaling cascades in lipopolysaccharide (LPS)-stimulated macrophages. At the upstream level, pinocembrin competitively inhibited the binding of LPS to myeloid differentiation protein 2 (MD2), thereby blocking the formation of receptor multimer TLR4/MD2·LPS. Furthermore, pinocembrin dose-dependently promoted the expression of tight junction proteins (ZO-1, Claudin-1, Occludin and JAM-A) in Caco-2 cells. In conclusion, our work presented evidence that pinocembrin attenuated DSS-induced colitis in mouse, at least in part, via regulating intestinal microbiota, inhibiting the over-activation of TLR4/MD2/NF-κB signaling pathway, and improving the barriers of intestine.
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Al-Sadi R, Engers J, Haque M, King S, Al-Omari D, Ma TY. Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation. PLoS One 2021; 16:e0249544. [PMID: 33826658 PMCID: PMC8026081 DOI: 10.1371/journal.pone.0249544] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/20/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear. AIMS The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system. RESULTS MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis. CONCLUSION Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.
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Affiliation(s)
- Rana Al-Sadi
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
- * E-mail:
| | - Jessica Engers
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Mohammad Haque
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Steven King
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Deemah Al-Omari
- Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Thomas Y. Ma
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
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Whole and polysaccharide powdered Sporisorium reilianum improves DSS-induced colitis in BALB/c mice by modulating gut microbiota. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104409] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Food and Food Groups in Inflammatory Bowel Disease (IBD): The Design of the Groningen Anti-Inflammatory Diet (GrAID). Nutrients 2021; 13:nu13041067. [PMID: 33806061 PMCID: PMC8064481 DOI: 10.3390/nu13041067] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 12/19/2022] Open
Abstract
Diet plays a pivotal role in the onset and course of inflammatory bowel disease (IBD). Patients are keen to know what to eat to reduce symptoms and flares, but dietary guidelines are lacking. To advice patients, an overview of the current evidence on food (group) level is needed. This narrative review studies the effects of food (groups) on the onset and course of IBD and if not available the effects in healthy subjects or animal and in vitro IBD models. Based on this evidence the Groningen anti-inflammatory diet (GrAID) was designed and compared on food (group) level to other existing IBD diets. Although on several foods conflicting results were found, this review provides patients a good overview. Based on this evidence, the GrAID consists of lean meat, eggs, fish, plain dairy (such as milk, yoghurt, kefir and hard cheeses), fruit, vegetables, legumes, wheat, coffee, tea and honey. Red meat, other dairy products and sugar should be limited. Canned and processed foods, alcohol and sweetened beverages should be avoided. This comprehensive review focuses on anti-inflammatory properties of foods providing IBD patients with the best evidence on which foods they should eat or avoid to reduce flares. This was used to design the GrAID.
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Mei S, Ma H, Chen X. Anticancer and anti-inflammatory properties of mangiferin: A review of its molecular mechanisms. Food Chem Toxicol 2021; 149:111997. [DOI: 10.1016/j.fct.2021.111997] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
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Liu F, Yao Y, Lu Z, Zhang Q, Liu C, Zhu C, Lin C. 5-Hydroxy-4-methoxycanthin-6-one alleviates dextran sodium sulfate-induced colitis in rats via regulation of metabolic profiling and suppression of NF-κB/p65 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 82:153438. [PMID: 33422953 DOI: 10.1016/j.phymed.2020.153438] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 11/26/2020] [Accepted: 12/04/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND 5-Hydroxy-4-methoxycanthin-6-one (PQ-A) is the main active compound in Ramulus et Folium Picrasmae, a Chinese herbal medicine commonly used in colitis treatment. PURPOSE To clarify PQ-A's role and mechanism in colitis treatment based on a non-targeted metabolomics study. METHODS Rats with ulcerative colitis (UC) established with 4% dextran sulfate sodium (DSS) were orally treated with PQ-A. Body weight, disease activity index (DAI), colon length, biochemical parameters (MDA and SOD), and histopathological score in colon tissue were measured. A UPLC-Q-TOF-MS/MS approach-based metabolomics analysis was conducted to explore the underlying mechanisms of PQ-A in colitis treatment. Inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10) concentrations in serum and their protein levels in the colon were determined. CD3 and NF-κB/p65 immunohistochemistry in the colon was semi-quantified. The related protein or mRNA in IKK-NF-κB/p65 signaling pathway was measured by Western blotting or RT-PCR, respectively. Potential molecular interactions between PQ-A and NF-κB/p65 was predicted using DS 2.5 software. RESULTS PQ-A significantly prevented body weight loss and colonic shortening in colitic rats, and reduced the DAI and histopathologic score as well. PQ-A decreased MDA levels in the UC rat serum and increased those of SOD. Metabolomics results revealed forty-nine differential metabolites as biomarkers of DSS-induced colitis, demonstrating that the path-mechanism of colitis involved the perturbation of eight metabolic pathways, including alpha-linolenic acid and linoleic acid metabolism, sphingolipid metabolism, retinol metabolism, bile acid metabolism, et al. Thirty-six biomarkers were especially reversed to normal-like levels by PQ-A via regulation of alpha-linolenic acid and linoleic acid metabolism, sphingolipid metabolism, and retinol metabolism, which effectively hinted the potential pharmacological mechanism of PQ-A related to NF-κB/p65 inflammatory signaling. Molecular docking results predicted high affinity interaction between PQ-A and NF-κB/p65, involving hydrogen-bond interactions at five amino acid residues, suggesting NF-κB/p65 as a target. PQ-A decreased TNF-α, IL-1β, and IL-6 concentrations in serum and their protein levels in colon tissue in colitic rats. CD3, MYD88, p-IκBα, NF-κB/p65, and p-NF-κB/p65 expression levels decreased, whereas those of IKKβ and IκBα increased in colitic tissue following PQ-A treatment. PQ-A strongly inhibited nuclear translocation of NF-κB/p65. CONCLUSIONS We provide an overview of PQ-A's possible mechanism of action in colitis treatment based on serum non-targeted metabolomics. PQ-A treatment can protect rats against DSS-induced colitis by suppressing the NF-κB/p65 signaling pathway.
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Affiliation(s)
- Fangle Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China; School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China
| | - Yufeng Yao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China
| | - Zenghui Lu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China
| | - Qiuyu Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China
| | - Chenchen Zhu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
| | - Chaozhan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
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Ren J, Yue B, Wang H, Zhang B, Luo X, Yu Z, Zhang J, Ren Y, Mani S, Wang Z, Dou W. Acacetin Ameliorates Experimental Colitis in Mice via Inhibiting Macrophage Inflammatory Response and Regulating the Composition of Gut Microbiota. Front Physiol 2021; 11:577237. [PMID: 33536931 PMCID: PMC7848181 DOI: 10.3389/fphys.2020.577237] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/28/2020] [Indexed: 12/20/2022] Open
Abstract
Acacetin, a natural dietary flavonoid abundantly found in acacia honey and citrus fruits, reportedly exerts several biological effects, such as anti-tumor, anti-inflammatory, and anti-oxidative effects. However, the effects of acacetin on intestinal inflammation remain unclear. We sought to investigate whether acacetin ameliorates inflammatory bowel disease (IBD) in mice with dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Our results suggest that acacetin alleviates the clinical symptoms of DSS-induced colitis, as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration, and histological injury. Further studies showed that acacetin remarkably inhibited both the macrophage inflammatory response in vitro and levels of inflammatory mediators in mice with colitis. In addition, some features of the gut microbiota were disordered in mice with DSS-induced colitis, as evidenced by a significant reduction in microbiota diversity and a marked shift in bacterial profiles. However, acacetin treatment improved this imbalance and restored gut microbiota to levels that were similar to those in normal mice. In conclusion, our work presents evidence that acacetin attenuates DSS-induced colitis in mice, at least in part, by inhibiting inflammation and regulating the intestinal microbiota.
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Affiliation(s)
- Junyu Ren
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Bei Yue
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Hao Wang
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Beibei Zhang
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Xiaoping Luo
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Zhilun Yu
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Jing Zhang
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Yijing Ren
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Sridhar Mani
- Department of Medicine and Genetics, Albert Einstein College of Medicine, The Bronx, NY, United States
| | - Zhengtao Wang
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
| | - Wei Dou
- The MOE key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, China
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Zhang Y, Zha Z, Shen W, Li D, Kang N, Chen Z, Liu Y, Xu G, Xu Q. Anemoside B4 ameliorates TNBS-induced colitis through S100A9/MAPK/NF-κB signaling pathway. Chin Med 2021; 16:11. [PMID: 33461587 PMCID: PMC7814617 DOI: 10.1186/s13020-020-00410-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/10/2020] [Accepted: 12/10/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Despite the increased morbidity of ulcerative colitis (UC) in the developing countries, available treatments remain unsatisfactory. Therefore, it is urgent to discover more effective therapeutic strategies. Pulsatilla chinensis was widely used for the treatment of inflamed intestinal diseases including UC for thousands of years in China. Anemoside B4, the most abundant triterpenoid saponin isolated from P. chinensis, exerts anti-inflammatory and antioxidant effects and may be the most active compounds, which is responsible for the therapeutic effects. However, the mechanism how anemoside B4 executes its biological functions is still elusive. METHODS Here, we used the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model to evaluate the therapeutic effect of anemoside B4. Blood samples of colitis rats were collected for hematology analysis. The inflammation-associated factors were investigated by enzyme-linked immunosorbent assay (ELISA). Cell proliferation and apoptosis was determined with EdU cell proliferation assay and TUNEL assay. The proteins regulated by anemoside B4 were identified by label-free quantitative proteomics. The significantly down-regulated proteins were verified by Western blotting analysis. mRNA expression was analyzed by quantitative real-time RT-PCR. RESULTS The results showed that anemoside B4 ameliorated TNBS-induced colitis symptoms, including tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine production, apoptosis and slowed proliferation in colon. Quantitative proteomic analyses discovered that 56 proteins were significantly altered by anemoside B4 in the TNBS-induced rats. These proteins mainly clustered in tricarboxylic acid (TCA) cycle and respiratory electron transport chain. Among the altered proteins, S100A9 is one of the most significantly down-regulated proteins and associated with NF-κB and MAPK signaling pathways in the pathogenesis of UC. Further experiments revealed that anemoside B4 suppressed the expression of S100A9 and its downstream genes including TLR4 and NF-κB in colon. In vitro, anemoside B4 could inhibit the NF-κB signaling pathway induced by recombinant S100A9 protein in human intestinal epithelial Caco-2 cells. Moreover, anemoside B4 inhibits neutrophils recruitment and activation in colon induced by TNBS. CONCLUSIONS Our results demonstrate that anemoside B4 prevents TNBS-induced colitis by inhibiting the NF-κB signaling pathway through deactivating S100A9, suggesting that anemoside B4 is a promising therapeutic candidate for colitis.
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Affiliation(s)
- Yong Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Zhengxia Zha
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Wenhua Shen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Dan Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China.,Jiangsu Key Laboratory of Neuropsychiatric Diseases and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Naixin Kang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Zhong Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Yanli Liu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Guoqiang Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China. .,Jiangsu Key Laboratory of Neuropsychiatric Diseases and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, 215123, Jiangsu, China.
| | - Qiongming Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China.
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Morozkina SN, Nhung Vu TH, Generalova YE, Snetkov PP, Uspenskaya MV. Mangiferin as New Potential Anti-Cancer Agent and Mangiferin-Integrated Polymer Systems-A Novel Research Direction. Biomolecules 2021; 11:79. [PMID: 33435313 PMCID: PMC7827323 DOI: 10.3390/biom11010079] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 12/13/2022] Open
Abstract
For a long time, the pharmaceutical industry focused on natural biologically active molecules due to their unique properties, availability and significantly less side-effects. Mangiferin is a naturally occurring C-glucosylxantone that has substantial potential for the treatment of various diseases thanks to its numerous biological activities. Many research studies have proven that mangiferin possesses antioxidant, anti-infection, anti-cancer, anti-diabetic, cardiovascular, neuroprotective properties and it also increases immunity. It is especially important that it has no toxicity. However, mangiferin is not being currently applied to clinical use because its oral bioavailability as well as its absorption in the body are too low. To improve the solubility, enhance the biological action and bioavailability, mangiferin integrated polymer systems have been developed. In this paper, we review molecular mechanisms of anti-cancer action as well as a number of designed polymer-mangiferin systems. Taking together, mangiferin is a very promising anti-cancer molecule with excellent properties and the absence of toxicity.
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Affiliation(s)
- Svetlana N. Morozkina
- Institute BioEngineering, ITMO University, Kronverkskiy Prospekt, 49A, 197101 Saint-Petersburg, Russia; (T.H.N.V.); (P.P.S.); (M.V.U.)
| | - Thi Hong Nhung Vu
- Institute BioEngineering, ITMO University, Kronverkskiy Prospekt, 49A, 197101 Saint-Petersburg, Russia; (T.H.N.V.); (P.P.S.); (M.V.U.)
| | - Yuliya E. Generalova
- Department of Analytical Chemistry, Faculty of Industrial Technology of Dosage Forms, Saint Petersburg State Chemical Pharmaceutical University, Prof. Popova Street 14A, 197022 Saint-Petersburg, Russia;
| | - Petr P. Snetkov
- Institute BioEngineering, ITMO University, Kronverkskiy Prospekt, 49A, 197101 Saint-Petersburg, Russia; (T.H.N.V.); (P.P.S.); (M.V.U.)
| | - Mayya V. Uspenskaya
- Institute BioEngineering, ITMO University, Kronverkskiy Prospekt, 49A, 197101 Saint-Petersburg, Russia; (T.H.N.V.); (P.P.S.); (M.V.U.)
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50
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Tang Z, Lai CC, Luo J, Ding YT, Chen Q, Guan ZZ. Mangiferin prevents the impairment of mitochondrial dynamics and an increase in oxidative stress caused by excessive fluoride in SH-SY5Y cells. J Biochem Mol Toxicol 2021; 35:e22705. [PMID: 33393728 DOI: 10.1002/jbt.22705] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 09/21/2020] [Accepted: 12/17/2020] [Indexed: 11/08/2022]
Abstract
Previous studies both invivo and in vitro have revealed that high levels of fluoride cause neurotoxicity. Mangiferin has been reported to possess antioxidant, antiapoptotic, and anti-inflammatory properties. The present study was designed to characterize the mechanisms by which mangiferin protects against NaF-induced neurotoxicity. Increased levels of proapoptotic Bax, Caspase-3, Caspase-9, and cleaved-caspase 3, as well as a decreased level of antiapoptotic Bcl-2 induced by fluoride in human neuroblastoma SH-SY5Y cells, these effects were prevented by pretreatment of mangiferin. In addition, mangiferin attenuated the enhancement of p-JNK, reductions of Nrf2 and HO-1, and increased level of the mitochondrial fission proteins Drp1 caused by fluoride. Moreover, oxidative stress, as reflected in the levels of reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, and 4-hydroxynonenal, was elevated by fluoride and these effects were again ameliorated by mangiferin. In conclusion, protection by mangiferin against fluoride-induced neurotoxicity involves normalizing the impaired mitochondrial apoptotic pathway and dynamics and reducing oxidative stress via inactivation of the JNK and activation of the Nrf2/HO-1 pathways.
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Affiliation(s)
- Zhi Tang
- Key Laboratory of Endemic and Ethnic Disease, Guizhou Medical University, Ministry of Education, Guiyang, China.,Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Clinical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Chen-Cen Lai
- Clinical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jun Luo
- Department of Pharmacy, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yuan-Ting Ding
- Clinical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Qian Chen
- Clinical Research Center, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Zhi-Zhong Guan
- Key Laboratory of Endemic and Ethnic Disease, Guizhou Medical University, Ministry of Education, Guiyang, China.,Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
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