1
|
Tian M, Zhao L, Lan Y, Li C, Ling Y, Zhou B. Design, synthesis and biological evaluation of novel urolithin derivatives targeting liver cancer cells. J Enzyme Inhib Med Chem 2025; 40:2490707. [PMID: 40375621 PMCID: PMC12086910 DOI: 10.1080/14756366.2025.2490707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/08/2025] [Accepted: 04/02/2025] [Indexed: 05/18/2025] Open
Abstract
We designed and synthesised 22 new urolithin derivatives (UDs) based on methyl-urolithin A (mUA) to identify anti-cancer drugs with high efficacy and low toxicity and evaluated their anti-cancer activities in vitro. Cytotoxicity tests were performed on three cell lines (DU145, T24, and HepG2) and a human normal cell line (HK-2). The half-inhibitory concentration (IC50) of derivative UD-4c to hepatoma HepG2 cells (IC50 = 4.66 ± 0.12 μM) was significantly lower than that of sorafenib (IC50 =7.76 ± 0.12 μM), and exhibited less toxicity to HK-2 cells. Preliminary studies on the mechanism revealed that the derivative UD-4c could significantly inhibit the HepG2 cell growth and colony formation, block the HepG2 cell cycle in the G2/M phase, and induce apoptosis of HepG2 cells dose-dependently. The derivative UD-4c can be used as a potential lead compound to further develop new drugs for hepatocellular carcinoma treatment based on the evaluation of anti-cancer activity.
Collapse
Affiliation(s)
- Mi Tian
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lirong Zhao
- Department of Pharmacy, General Hospital of The Yangtze River Shipping, Wuhan, China
| | - Yu Lan
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chen Li
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yipeng Ling
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Benhong Zhou
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
2
|
Navin AK, Rejani CT, Chandrasekaran B, Tyagi A. Urolithins: Emerging natural compound targeting castration-resistant prostate cancer (CRPC). Biomed Pharmacother 2025; 187:118058. [PMID: 40253830 DOI: 10.1016/j.biopha.2025.118058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 04/03/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025] Open
Abstract
Castration-resistant prostate cancer (CRPC) presents a significant challenge due to its resistance to conventional androgen deprivation therapies. Urolithins, bioactive metabolites derived from ellagitannins, have recently emerged as promising therapeutic agents for CRPC. Urolithins not only inhibit androgen receptor (AR) signaling, a crucial factor in the progression of CRPC, but also play a key role in regulating oxidative stress by their antioxidant properties, thereby inhibiting increased reactive oxygen species, a common feature of the aggressive nature of CRPC. Research has shown that urolithins induce apoptosis and diminish pro-survival signaling, leading to tumor inhibition. This review delves into the intricate mechanisms through which urolithins exert their therapeutic effects, focusing on both AR-dependent and AR-independent pathways. It also explores the exciting potential of combining urolithins with androgen ablation therapy, opening new avenues for CRPC treatment.
Collapse
Affiliation(s)
- Ajit Kumar Navin
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX 77845, USA
| | | | - Balaji Chandrasekaran
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX 77845, USA
| | - Ashish Tyagi
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX 77845, USA.
| |
Collapse
|
3
|
Xu H, Lv D, Guan Y. Appeal of Urolithins from Synthesis to Biological Activities. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:11477-11494. [PMID: 40300072 DOI: 10.1021/acs.jafc.5c00634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/01/2025]
Abstract
Urolithins (Uros), a series of natural polyphenols derived from ellagic acid through gut bacteria metabolism, have gathered significant attention due to their diverse bioactivities such as maintaining mitochondrial health and anti-inflammatory and antioxidative effects. However, the ability to metabolize Uros varies among individuals. This Review provides a comprehensive insight into the synthesis, encapsulation and bioactivities of Uros, focusing on their biotransformation in vivo. We highlight the critical role of gut microbiota in the biotransformation of urolithins, including primary bacterial species such as Gordonibacter urolithinfaciens, Enterocloster bolteae and Enterococcus faecium. Furthermore, the therapeutic potential of Uros in alleviating neurodegenerative diseases, cancer, and Duchenne muscular dystrophy is discussed. Finally, several encapsulation strategies for enhancing the solubility and bioavailability of Uros are summarized. Future research direction includes identifying key genes involved in Uros biotransformation, elucidating the bioactive mechanisms of Uros, and improving their bioavailability. In conclusion, we synthesized biosynthetic pathways and bioactive properties of Uros for better utilization in health management.
Collapse
Affiliation(s)
- Huanyu Xu
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China
| | - Danyu Lv
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China
| | - Yongguang Guan
- Department of Food Science, Foshan University, Foshan 528000, China
| |
Collapse
|
4
|
Li X, Zhang X, Yin C, Lu C, Shen Y. Design and Synthesis of O-Dialkylaminoalkyl Substituted Urolithin Derivatives: DNA Topoisomerase IIα Inhibition With Promising Antiproliferative Activity. Arch Pharm (Weinheim) 2025; 358:e70009. [PMID: 40401699 DOI: 10.1002/ardp.70009] [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: 12/16/2024] [Revised: 04/08/2025] [Accepted: 04/25/2025] [Indexed: 05/23/2025]
Abstract
Based on the pharmacophore structural characteristics of topoisomerase II (TopoII) inhibitors: (i) planar polyaromatic skeleton; (ii) the cation core; (iii) a groove-binding side chain moiety, 16 urolithin derivatives with O-dialkylaminoalkyl substitutions were designed and synthesized. Most of the synthesized compounds showed improved TopoIIα inhibitory and antiproliferative activities. 20 with the best TopoIIα inhibitory activity also exhibited excellent antiproliferative activity with IC50 values of 0.91 ± 0.01, 1.93 ± 0.04, and 2.84 ± 0.34 μM against the MDA-MB-231, HeLa, and A549 cell lines, being about 12.55, 3.95, and 2.17 times more active than VP-16 (IC50 11.42 ± 0.82, 7.63 ± 0.46, and 6.15 ± 0.43 μM, respectively). Meanwhile, 20 exhibited weak toxicity to normal cells. In addition, 20 exerted anti-migration and anti-invasion activity against MDA-MB-231 cells. Our results supported that 20 might act as TopoIIα inhibitor with the potential to become a new type of antitumor drug lead.
Collapse
Affiliation(s)
- Xintong Li
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xiaochun Zhang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Chan Yin
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Chunhua Lu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yuemao Shen
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| |
Collapse
|
5
|
Zhou F, Feng X, Xu Z, Yan F, Song G, Tang L. Design, synthesis and biological activity of 8-hydroxy modified urolithin A derivatives as phosphodiesterase type II (PDE2) inhibitors. Bioorg Med Chem 2025; 121:118127. [PMID: 40015121 DOI: 10.1016/j.bmc.2025.118127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 02/17/2025] [Accepted: 02/18/2025] [Indexed: 03/01/2025]
Abstract
Urolithin A (UA) is a naturally occurring polyphenolic compound.Due to its remarkable efficacy in safeguarding the central nervous system, UA has emerged as a promising candidate for drug development targeting neurodegenerative diseases such as Alzheimer's. However, the source of UA is limited and the activity of UA to inhibit PDE2 needs to be further improved. Therefore, this study will be optimized on the basis of UA to seek PDE2 inhibitors with better activity. In this study, we designed a series of UA derivatives based on 4HTX as the target protein and UA as the lead compound, utilizing the binding crystal structures of 4HTX and BAY60-7550 as references. After thorough screening, we successfully identified the 8-hydroxyl group as the precise site of modification. Utilizing 2-bromo-5-hydroxybenzoic acid as our primary raw material, we synthesized a series of the 8-hydroxyl modified UA. Subsequently, we evaluated the inhibitory activity of these synthesized UA derivatives using a phosphodiesterase assay kit. Ultimately, we screened a total of 34 derivatives; among them, compounds 1f, 1q, 2d, and 2j exhibited significant inhibitory activity against PDE2 with half-maximal inhibitory concentrations of 3.05 μM, 0.67 μM, 0.57 μM, and 4.96 μM, respectively.
Collapse
Affiliation(s)
- Feng Zhou
- School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou 213164, China.
| | - Xiaoqing Feng
- School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou 213164, China.
| | - Zhongqiu Xu
- School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou 213164, China.
| | - Fen Yan
- School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou 213164, China.
| | - Guoqiang Song
- School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou 213164, China.
| | - Long Tang
- School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou 213164, China.
| |
Collapse
|
6
|
Liu C, Zhao D, Yu G, Du H, Xu L, Cao Y, Cui M, Wang W, Wang D, Liu J, Meng F, Hu F, Li W, Du J, Li C. Alleviation of Microglia Mediating Hippocampal Neuron Impairments and Depression-Related Behaviors by Urolithin B via the SIRT1-FOXO1 Pathway. CNS Neurosci Ther 2025; 31:e70379. [PMID: 40237232 PMCID: PMC12000931 DOI: 10.1111/cns.70379] [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: 10/09/2024] [Revised: 03/17/2025] [Accepted: 03/30/2025] [Indexed: 04/18/2025] Open
Abstract
AIMS Conventional antidepressants exhibit limited efficacy and delayed onset. This study aimed to elucidate the antidepressant effects of urolithin B (UB) and its regulatory role in microglia-mediated hippocampal neuronal dysfunction. METHODS The mouse model of depression was established using both chronic unpredicted stress (CUS) and lipopolysaccharide (LPS) injection. The therapeutic efficacy of UB was assessed through behavioral paradigms. The microglia activation, cellular cytotoxicity and apoptosis levels, and underlying molecular mechanisms were delineated utilizing proteomics analysis, immunofluorescence staining, real-time PCR and Western blotting. RESULTS UB efficiently alleviated depression-related behaviors, accompanied by suppressed microglia activation, neuroinflammation, changes of classic activation (M1)/alternative activation (M2) polarization and recovered sirtuin-1 (SIRT1) and forkhead box protein O1 (FOXO1) expression in the hippocampus. Additionally, UB reduced the cytotoxicity and apoptosis of HT22 cells and depression-related phenotypes treated by the cellular supernatant from LPS-incubated BV2 cells, which was mediated by the SIRT1-FOXO1 pathway. The proteomics analysis of the cellular supernatant content revealed abundant secreting proteins among the LPS/UB application. CONCLUSION This study confirmed that microglial SIRT1 mediates UB's antidepressant effects, positioning UB as a promising therapeutic candidate for depression by targeting neuroinflammatory pathways.
Collapse
Affiliation(s)
- Cuilan Liu
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Di Zhao
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Guoxing Yu
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
| | - HengWei Du
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
| | - Lihong Xu
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Yifan Cao
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Minghu Cui
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Wentao Wang
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Dan Wang
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Jing Liu
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Fantao Meng
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Fengai Hu
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| | - Wei Li
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
| | - Jing Du
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
| | - Chen Li
- Department of Rehabilitation MedicineBinzhou Medical University HospitalBinzhouShandongChina
- Medical Research CenterBinzhou Medical University HospitalBinzhouShandongChina
- Department of PsychologyBinzhou Medical University HospitalBinzhouShandongChina
| |
Collapse
|
7
|
Leng P, Wang Y, Xie M. Ellagic Acid and Gut Microbiota: Interactions, and Implications for Health. Food Sci Nutr 2025; 13:e70133. [PMID: 40196228 PMCID: PMC11972986 DOI: 10.1002/fsn3.70133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 03/17/2025] [Accepted: 03/21/2025] [Indexed: 04/09/2025] Open
Abstract
Ellagic acid (EA), a widely distributed natural polyphenolic acid existing in many kinds of plant-based foods, undergoes complex physical and chemical transformations during digestion and biotransformation. Particularly, EA is metabolized by gut microbiota and transformed into urolithins in the colon. These metabolites exhibit enhanced bioavailability and bioactivity. This review explores the intricate interactions between EA and gut microbiota, emphasizing their implications for human health. We discuss the role of gut microbiota in EA metabolism, resulting in distinct metabolic phenotypes associated with varying urolithin production profiles. EA and its gut-derived metabolites, urolithins, have been reported to have the potential to modulate the microbial community composition and function of gut microbiota, promoting beneficial bacteria while reducing harmful ones. Furthermore, EA and urolithins exhibit a spectrum of beneficial biological activities, including antioxidant, anti-inflammatory, and anticancer properties, along with enhancements to intestinal barrier function and modulatory effects on metabolic and cardiovascular systems, through molecular mechanisms such as activating Nrf2 and inhibiting NF-κB pathways. The review highlights and compares the potential of EA and its gut microbial metabolites in the prevention and treatment of various diseases. However, further studies are required to elucidate the underlying mechanisms of the interactions between EA and gut microbiota and their health benefits. Continued investigation into EA and its metabolites is essential for advancing our understanding of their role in promoting human health and developing novel therapeutic applications.
Collapse
Affiliation(s)
- Pinze Leng
- School of MedicineJiangsu UniversityZhenjiangChina
| | - Ye Wang
- Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and EngineeringNanjing University of Finance and EconomicsNanjingChina
| | - Minhao Xie
- Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and EngineeringNanjing University of Finance and EconomicsNanjingChina
- Jiangsu Province Engineering Research Center of Edible Fungus Preservation and Intensive ProcessingNanjingChina
| |
Collapse
|
8
|
Jiménez-Salcedo M, Manzano JI, Yuste S, Iñiguez M, Pérez-Matute P, Motilva MJ. Exploring biomarkers of regular wine consumption in human urine: Targeted and untargeted metabolomics approaches. Food Chem 2025; 469:142128. [PMID: 39729665 DOI: 10.1016/j.foodchem.2024.142128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 11/07/2024] [Accepted: 11/16/2024] [Indexed: 12/29/2024]
Abstract
The epidemiological assessment of wine consumption usually has been obtained using self-reporting questionnaires. In this study, two metabolomic approaches, targeted and untargeted, were applied to 24-h urine samples from a cohort of La Rioja (Spain) (aged 52-78), comparing moderate and daily wine consumers (20 males and 13 females) without diet intervention, versus non-consumers (8 males and 35 females). Results showed that the non-targeted metabolomics approach has allowed for the annotation of sixteen compounds in 24-h urine samples from regular wine-consumers that were not detected in the urine of non-wine consumers. Additionally, the targeted metabolomics approach showed a wide range of phenol metabolites, mainly hepatic phase-II conjugates, whose concentration was significantly higher in the urine of wine consumers. As a novelty, this study focuses on discovering the main urinary biomarkers of regular wine consumption involving free-living volunteers, without dietary intervention or restrictions that might alter their regular behaviors and lifestyles.
Collapse
Affiliation(s)
- Marta Jiménez-Salcedo
- University of La Rioja, C/Madre de Dios 53, Logroño E-26006, La Rioja, Spain; Instituto de Ciencias de la Vid y del Vino-ICVV (Consejo Superior de Investigaciones Científicas-CSIC, Universidad de La Rioja, Gobierno de La Rioja), Finca La Grajera, Ctra. de Burgos Km. 6 (LO-20, salida 13), Logroño E-26007, La Rioja, Spain
| | - José Ignacio Manzano
- Instituto de Ciencias de la Vid y del Vino-ICVV (Consejo Superior de Investigaciones Científicas-CSIC, Universidad de La Rioja, Gobierno de La Rioja), Finca La Grajera, Ctra. de Burgos Km. 6 (LO-20, salida 13), Logroño E-26007, La Rioja, Spain
| | - Silvia Yuste
- Instituto de Ciencias de la Vid y del Vino-ICVV (Consejo Superior de Investigaciones Científicas-CSIC, Universidad de La Rioja, Gobierno de La Rioja), Finca La Grajera, Ctra. de Burgos Km. 6 (LO-20, salida 13), Logroño E-26007, La Rioja, Spain; Antioxidants Research Group, Food Technology Department, Agrotecnio-Recerca Center, University of Lleida, Av/Alcalde Rovira Roure, 191, 25198 Lleida, Spain
| | - María Iñiguez
- Infectious Diseases, Microbiota and Metabolism Unit, Center for Biomedical Research of La Rioja (CIBIR), CSIC Associated Unit, E-26006 Logroño, La Rioja, Spain
| | - Patricia Pérez-Matute
- University of La Rioja, C/Madre de Dios 53, Logroño E-26006, La Rioja, Spain; Infectious Diseases, Microbiota and Metabolism Unit, Center for Biomedical Research of La Rioja (CIBIR), CSIC Associated Unit, E-26006 Logroño, La Rioja, Spain
| | - Maria-Jose Motilva
- Instituto de Ciencias de la Vid y del Vino-ICVV (Consejo Superior de Investigaciones Científicas-CSIC, Universidad de La Rioja, Gobierno de La Rioja), Finca La Grajera, Ctra. de Burgos Km. 6 (LO-20, salida 13), Logroño E-26007, La Rioja, Spain.
| |
Collapse
|
9
|
Jin Z, Zhang Y, Hu H, Li Q, Zhang L, Zhao K, Liu W, Li L, Gao C. Closed-loop theranostic microgels for immune microenvironment modulation and microbiota remodeling in ulcerative colitis. Biomaterials 2025; 314:122834. [PMID: 39288617 DOI: 10.1016/j.biomaterials.2024.122834] [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: 08/26/2024] [Accepted: 09/10/2024] [Indexed: 09/19/2024]
Abstract
Inflammatory bowel disease (IBD) is characterized by the upregulation of reactive oxygen species (ROS) and dysfunction of gut immune system, and microbiota. The conventional treatments mainly focus on symptom control with medication by overuse of drugs. There is an urgent need to develop a closed-loop strategy that combines in situ monitoring and precise treatment. Herein, we innovatively designed the 'cluster munition structure' theranostic microgels to realize the monitoring and therapy for ulcerative colitis (a subtype of IBD). The superoxide anion specific probe (tetraphenylethylene-coelenterazine, TPC) and ROS-responsive nanogels consisting of postbiotics urolithin A (UA) were loaded into alginate and ion-crosslinked to obtain the theranostic microgels. The theranostic microgels could be delivered to the inflammatory site, where the environment-triggered breakup of the microgels and release of the nanogels were achieved in sequence. The TPC-UA group had optimal results in reducing inflammation, repairing colonic epithelial tissue, and remodeling microbiota, leading to inflammation amelioration and recovery of tight junction between the colonic epithelium, and maintenance of gut microbiota. During the recovery process, the local chemiluminescence intensity, which is proportional to the degree of inflammation, was gradually inhibited. The cluster munition of theranostic microgels displayed promising outcomes in monitoring inflammation and precise therapy, and demonstrated the potential for inflammatory disease management.
Collapse
Affiliation(s)
- Zeyuan Jin
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China.
| | - Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Haijun Hu
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China
| | - Qian Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Liwen Zhang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China
| | - Kefei Zhao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China
| | - Wenxing Liu
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China; Center for Healthcare Materials, Shaoxing Institute, Zhejiang University, Shaoxing, 312099, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Changyou Gao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310058, China; Center for Healthcare Materials, Shaoxing Institute, Zhejiang University, Shaoxing, 312099, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, 310058, China.
| |
Collapse
|
10
|
Wilhelmsen A, Karagounis LG, Bennett AJ, D'Amico D, Fouassier AM, Jones SW, Tsintzas K. The polyphenol metabolite urolithin A suppresses myostatin expression and augments glucose uptake in human skeletal muscle cells. Nutr Metab (Lond) 2025; 22:12. [PMID: 39962542 PMCID: PMC11834323 DOI: 10.1186/s12986-025-00909-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/06/2025] [Indexed: 02/20/2025] Open
Abstract
PURPOSE Polyphenolic plant extracts have demonstrated anti-inflammatory and anti-catabolic effects in vitro, however their meaningful translation into humans remains elusive. Urolithin A (UA), a gut-derived metabolite of ellagitannins, has shown promise for improving muscle function and metabolic health in rodent models. This study aimed to explore the impact of UA on insulin and anabolic sensitivity in human skeletal muscle cells. METHODS Primary human myogenic cultures were derived from skeletal muscle biopsies of eight healthy adults. After differentiation, myotubes were treated with 0.002, 1 and 50 µM UA or vehicle for 24 h. Cell viability was assessed using a resazurin assay. Basal and insulin-stimulated glucose uptake was measured using tritiated deoxy-D-glucose, whilst amino acid-stimulated protein synthesis was estimated using the surface sensing of translation (SuNSET) technique. Expression of myostatin and glucose transporters was quantified via real-time PCR. RESULTS UA treatment at ≤ 50 µM did not compromise cell viability. Treatment with 50 µM UA enhanced both basal- and insulin-stimulated glucose uptake by 21% (P < 0.05) and 24% (P < 0.01), respectively, compared to vehicle and was accompanied by a 1.8-fold upregulation of GLUT4 expression (P < 0.01). 50 µM UA reduced myostatin (MSTN) expression by 14% (P < 0.01) but did not alter amino acid-stimulated global cell protein synthesis. CONCLUSION This study provides evidence of UA's metabolic benefits in primary human myotubes, notably improving basal- and insulin-stimulated glucose uptake and supressing MSTN expression. These findings suggest UA could be an effective nutraceutical for mitigating insulin resistance and warrants further investigation.
Collapse
Affiliation(s)
- Andrew Wilhelmsen
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Leonidas G Karagounis
- Mary MacKillop Institute for Health Research (MMIHR), Australian Catholic University, Melbourne, Australia
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Andrew J Bennett
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - Davide D'Amico
- Amazentis SA, EPFL Innovation Park, Bâtiment C, Lausanne, 1015, Switzerland
| | | | - Simon W Jones
- Department of Inflammation and Ageing, MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
- National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC), Birmingham, UK
| | - Kostas Tsintzas
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
| |
Collapse
|
11
|
Wang X, Ma C, Mi K, Cao X, Tan Y, Yuan H, Ren J, Liang X. Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1. Chem Biol Interact 2025; 406:111363. [PMID: 39725191 DOI: 10.1016/j.cbi.2024.111363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/02/2024] [Accepted: 12/23/2024] [Indexed: 12/28/2024]
Abstract
Doxorubicin (Dox) is a widely used antineoplastics although its clinical usage is greatly limited by its cardiotoxicity. Several studies have depicted an essential role for dampened mitophagy and mitochondrial injury in Dox cardiotoxicity. However, preventative measure to alleviate Dox-evoked cardiotoxicity via targeting mitophagy and mitochondrial integrity remains elusive. Urolithin A (UA) is a newly identified mitophagy inducer with antioxidant and anti-apoptotic properties although its effect on Dox-induced cardiotoxicity is unknown. This study was designed to explore the effect of UA on Dox cardiotoxicity and mechanisms involved. Our results indicated that UA alleviated Dox-induced cardiac dysfunction exhibited by echocardiographic parameters and histological analyses, and partially relieved Dox-induced apoptosis in vitro and in vivo, and mitochondrial dysfunction including ΔΨm dissipation and ROS production in vitro. The ability of UA to facilitate restoration of mitophagy in mice and H9C2s underscored its advantageous effects, manifested as upregulation of mitophagy-related proteins, including p62, LC3, PINK1 and Parkin, as well as the co-location between LC3 and mitochondria. Incubation with 3 -MA nearly reversed the UA-evoked rise of mitophagy-related proteins, and inhibition of apoptosis. Given that knockdown of Ambra1 almost abolished UA-induced protective effect, the enhanced expression of Ambra1 owing to UA increased PINK1 levels by inhibiting its degradation via LONP1. Collectively, our results suggest that the cardioprotective properties of UA depend on the stimulation of PINK1-dependent mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. This highlights UA's potential as a valuable treatment option and its importance in cardioprotective strategies against Dox-induced cardiotoxicity.
Collapse
Affiliation(s)
- Xiaoyan Wang
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China
| | - Chao Ma
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China
| | - Keying Mi
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China
| | - Xinran Cao
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China
| | - Yinghua Tan
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China
| | - Haitao Yuan
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China.
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
| | - Xinyue Liang
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China.
| |
Collapse
|
12
|
Jakimiuk K, Kruk A, Lemieszek MK, Strawa JW, Granica S, Wiater A, Tomczyk M. Ex vivo biotransformation of lady's mantle extracts via the human gut microbiota: the formation of phenolic metabolites and their impact on human normal and colon cancer cell lines. Front Pharmacol 2025; 16:1504787. [PMID: 39911846 PMCID: PMC11794788 DOI: 10.3389/fphar.2025.1504787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
Introduction For centuries, various species from the genus Alchemilla have been utilized in traditional medicine worldwide. Among them, Alchemilla vulgaris L. (Rosaceae) stands out as a promising herbal drug candidate due to its phytochemicals displaying anti-inflammatory and antioxidant properties. Methods In our study, we investigated the interaction between the human gut microbiota and lady's mantle herb extract (AV) following the biotransformation of the extract's constituents and their impact on colorectal cancer cells (HT-29) and normal CCD 841 CoN epithelial cells. The A. vulgaris herb metabolites were obtained by incubating the extract (AV) with human fecal slurries from three healthy donors (D1, D2, and D3). Results After incubating the AV extract with the human gut microbiota (AVD1-AVD3 samples), thirty-three metabolites were detected and characterized by LC-MS. Among them, one was identified as urolithin C. The AV and AVD1-AVD3 extracts and their metabolites exhibit various levels of antiproliferative and cytotoxic activities against cancer cells. Their biological effect might be linked to the changes and direct activity of bioavailable metabolites. Samples from AVD1, AVD2, and AVD3 increase the lactate dehydrogenase (LDH) released from damaged colon cancer cells in a dose-dependent manner. At 250 μg/mL, AVD1, AVD2, and AVD3 elevated the LDH level by 12.6%, 25.3%, and 30.0%, respectively. The biotransformed samples also showed significantly higher antiproliferative activity than the AV extract. The most active sample from donor 3 (AVD3) reached IC50 = 471 μg/mL. Discussion The differences in anticancer effect might be linked to the changes and direct activity of bioavailable metabolites. The non-transformed AV extract affected neither normal nor cancer colon cells, indicating the beneficial effect of the biotransformation procedure on the anticancer properties of the evaluated extracts. The above results clearly indicate that microbial metabolism is a crucial factor that is potent in altering the biological activity of lady's mantle extract.
Collapse
Affiliation(s)
- Katarzyna Jakimiuk
- Department of Pharmacognosy, Faculty of Pharmacy with the Division of Laboratory Medicine, Medical University of Białystok, Białystok, Poland
| | - Aleksandra Kruk
- Microbiota Lab, Department of Pharmaceutical Biology, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | | | - Jakub W. Strawa
- Department of Pharmacognosy, Faculty of Pharmacy with the Division of Laboratory Medicine, Medical University of Białystok, Białystok, Poland
| | - Sebastian Granica
- Department of Pharmaceutical Biology, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | - Adrian Wiater
- Department of Industrial and Environmental Microbiology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland
| | - Michał Tomczyk
- Department of Pharmacognosy, Faculty of Pharmacy with the Division of Laboratory Medicine, Medical University of Białystok, Białystok, Poland
| |
Collapse
|
13
|
Mandal T, Shukla D, Pattanayak S, Barman R, Ashraf R, Dixit AK, Kumar S, Kumar D, Srivastava AK. Ellagic Acid Induces DNA Damage and Apoptosis in Cancer Stem-like Cells and Overcomes Cisplatin Resistance. ACS OMEGA 2024; 9:48988-49000. [PMID: 39713677 PMCID: PMC11656259 DOI: 10.1021/acsomega.3c08819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/28/2023] [Accepted: 01/03/2024] [Indexed: 12/24/2024]
Abstract
Cancer stem cells (CSCs) are responsible for chemoresistance and tumor relapse in many solid malignancies, including lung and ovarian cancer. Ellagic acid (EA), a natural polyphenol, exhibits anticancer effects on various human malignancies. However, its impact and mechanism of action on cancer stem-like cells (CSLCs) are only partially understood. In this study, we evaluated the therapeutic potential and underlying molecular mechanism of EA isolated from tropical mango against CSLCs. Herein, we observed that EA treatment reduces the stem-like phenotypes in cancer cells, thereby lowering the cell survival and self-renewal potential of ovarian and lung CSLCs. Additionally, EA treatment limits the populations of lung and ovarian CSLCs characterized by CD133+ and CD44+CD117+, respectively. A mechanistic investigation showed that EA treatment induces ROS generation by altering mitochondrial dynamics, causing changes in the levels of Drp1 and Mfn2, which lead to an increased level of accumulation of DNA damage and eventually trigger apoptosis in CSLCs. Moreover, pretreatment with EA sensitizes CSLCs to cisplatin treatment by enhancing DNA damage accumulation and impairing the DNA repair ability of the CSLCs. Furthermore, EA pretreatment significantly reduces cisplatin-induced mutation frequency and improves drug retention in CSLCs, potentially suppressing the development of acquired drug resistance. Taken together, our results demonstrate an unreported finding that EA inhibits CSLCs by targeting mitochondrial function and triggering apoptosis. Thus, EA can be used either alone or in combination with other chemotherepeutic drugs for the management of cancer.
Collapse
Affiliation(s)
- Tanima Mandal
- Cancer
Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal 700032, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Devendra Shukla
- Cancer
Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal 700032, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Subhamoy Pattanayak
- Organic
and Medicinal Chemistry Division, CSIR-Indian
Institute of Chemical Biology, Kolkata, West Bengal 700032, India
| | - Raju Barman
- Organic
and Medicinal Chemistry Division, CSIR-Indian
Institute of Chemical Biology, Kolkata, West Bengal 700032, India
| | - Rahail Ashraf
- Division
of Biology, Indian Institute of Science
Education & Research Tirupati, Tirupati, Andhra Pradesh 517507, India
| | - Amit Kumar Dixit
- CCRAS-Central
Ayurveda Research Institute, Kolkata, West Bengal 700091, India
| | - Sanjay Kumar
- Division
of Biology, Indian Institute of Science
Education & Research Tirupati, Tirupati, Andhra Pradesh 517507, India
| | - Deepak Kumar
- Organic
and Medicinal Chemistry Division, CSIR-Indian
Institute of Chemical Biology, Kolkata, West Bengal 700032, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amit Kumar Srivastava
- Cancer
Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal 700032, India
- Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| |
Collapse
|
14
|
Manoni M, Gschwend F, Amelchanka S, Terranova M, Pinotti L, Widmer F, Silacci P, Tretola M. Gallic and Ellagic Acids Differentially Affect Microbial Community Structures and Methane Emission When Using a Rumen Simulation Technique. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:27163-27176. [PMID: 39588639 PMCID: PMC11638960 DOI: 10.1021/acs.jafc.4c06214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
Dietary tannins can affect rumen microbiota and enteric fermentation to mitigate methane emissions, although such effects have not yet been fully elucidated. We tested two subunits of hydrolyzable tannins named gallic acid (GA) and ellagic acid (EA), alone (75 mg/g DM each) or combined (150 mg/g DM in total), using the Rusitec system. EA and EA+GA treatments decreased methane production, volatile fatty acids, nutrient degradation, relative abundance of Butyrivibrio fibrisolvens, Fibrobacter succinogenes, Ruminococcus flavefaciens but increased Selenomonas ruminantium. EA and EA+GA increased urolithins A and B. Also, EA and EA+GA reduced bacterial richness, with limited effects on archaeal richness. For bacteria, Megasphaera elsdenii was more abundant after EA and EA+GA, while Methanomethylophilaceae dominated archaea in all treatments. EA was more effective than GA in altering rumen microbiota and fermentation but GA did not reduce VFA and nutrient degradation. Thus, dietary supplementation of EA-plant extracts for ruminants may be considered to mitigate enteric methane, although a suitable dosage must be ensured to minimize the negative effects on fermentation.
Collapse
Affiliation(s)
- Michele Manoni
- Department
of Veterinary Medicine and Animal Science, University of Milan, Via dell’Università 6, Lodi 26900 Italy
| | | | | | | | - Luciano Pinotti
- Department
of Veterinary Medicine and Animal Science, University of Milan, Via dell’Università 6, Lodi 26900 Italy
- CRC
Innovation For Well-Being And Environment (I-WE), University of Milan, Milan, 20134 Italy
| | - Franco Widmer
- Molecular
Ecology, Agroscope, Zurich 8046, Switzerland
| | - Paolo Silacci
- Paolo
Silacci − Animal Biology, Agroscope, Posieux 1725, Switzerland
| | - Marco Tretola
- Swine Research
Group, Agroscope, Posieux 1725, Switzerland
| |
Collapse
|
15
|
Li M, Cui H, Deng H, Deng Y, Yin S, Li T, Yuan T. Urolithin A promotes the degradation of TMSB10 to deformation F-actin in non-small-cell lung cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156109. [PMID: 39368341 DOI: 10.1016/j.phymed.2024.156109] [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: 02/16/2024] [Revised: 09/14/2024] [Accepted: 09/28/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Lung cancer is one of the most frequently diagnosed cancers and non-small-cell lung cancer (NSCLC) poses major diagnoses. Urolithin A (UA) is a natural compound produced by the gut microbiota through the metabolism of polyphenol ellagitannins (ETs) and ellagic acid (EA), which has been found to inhibit epithelial-mesenchymal transition (EMT) in lung cancer cell lines. However, the mechanism of UA function in NSCLC remains elusive. PROPOSE This study aimed to investigate the potential effectiveness of UA in NSCLC therapeutic and uncovering its underlying mechanisms. METHODS Effects of UA treatment, TMSB10 gene knockdown or overexpression on NSCLC cell phenotype were evaluated by availability, transwell assays. The downstream factors and pathways of UA were investigated by proteomics. TMSB10 expression in NSCLC tissues was detected by bioinformatics analysis as well as immunohistochemistry. Confocal imaging, GST pull-down and western blotting investigated the mechanism of UA induced TMSB10 degradation. RESULTS In the present study, we demonstrated that UA shows an inhibitory role in NSCLC cell proliferation, migration, and invasion. This inhibition is attributed to the accelerated degradation of TMSB10, a biomarker among various cancers, via the autophagy-lysosome pathway. Additionally, knocked down of TMSB10 showed a similar phenotype with UA treatment. The reduction of TMSB10 protein level following decreased ATP level inhibits the F-actin formation for cell migration, thereby disrupting the equilibrium between G-actin-TMSB10 and G-actin-ATP interactions in A549 cells. CONCLUSION Our results reveal that UA is potential for NSCLC therapeutics through reducing the protein level of TMSB10 to deformation the F-actin.
Collapse
Affiliation(s)
- Miaomiao Li
- School of Health, Jiangxi Normal University, Jiangxi Province Key Laboratory of Natural and Biomimetic Drugs Research, Nanchang, 330022, China; College of Life Science, Jiangxi Normal University, Nanchang, 330022, China
| | - Hao Cui
- College of Life Science, Jiangxi Normal University, Nanchang, 330022, China
| | - Huan Deng
- Rehabiliation Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China; Tumor Immunology Institute, Nanchang University, 330006, Nanchang, Jiangxi, China; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, 330031, Nanchang, Jiangxi, China
| | - Yanjuan Deng
- Rehabiliation Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China; Tumor Immunology Institute, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Sheng Yin
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China
| | - Tianzhi Li
- School of Health, Jiangxi Normal University, Jiangxi Province Key Laboratory of Natural and Biomimetic Drugs Research, Nanchang, 330022, China.
| | - Tao Yuan
- School of Health, Jiangxi Normal University, Jiangxi Province Key Laboratory of Natural and Biomimetic Drugs Research, Nanchang, 330022, China; College of Life Science, Jiangxi Normal University, Nanchang, 330022, China.
| |
Collapse
|
16
|
Zhang Y, Wang H, Sang Y, Liu M, Wang Q, Yang H, Li X. Gut microbiota in health and disease: advances and future prospects. MedComm (Beijing) 2024; 5:e70012. [PMID: 39568773 PMCID: PMC11577303 DOI: 10.1002/mco2.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/02/2024] [Accepted: 10/10/2024] [Indexed: 11/22/2024] Open
Abstract
The gut microbiota plays a critical role in maintaining human health, influencing a wide range of physiological processes, including immune regulation, metabolism, and neurological function. Recent studies have shown that imbalances in gut microbiota composition can contribute to the onset and progression of various diseases, such as metabolic disorders (e.g., obesity and diabetes) and neurodegenerative conditions (e.g., Alzheimer's and Parkinson's). These conditions are often accompanied by chronic inflammation and dysregulated immune responses, which are closely linked to specific forms of cell death, including pyroptosis and ferroptosis. Pathogenic bacteria in the gut can trigger these cell death pathways through toxin release, while probiotics have been found to mitigate these effects by modulating immune responses. Despite these insights, the precise mechanisms through which the gut microbiota influences these diseases remain insufficiently understood. This review consolidates recent findings on the impact of gut microbiota in these immune-mediated and inflammation-associated conditions. It also identifies gaps in current research and explores the potential of advanced technologies, such as organ-on-chip models and the microbiome-gut-organ axis, for deepening our understanding. Emerging tools, including single-bacterium omics and spatial metabolomics, are discussed for their promise in elucidating the microbiota's role in disease development.
Collapse
Affiliation(s)
- Yusheng Zhang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases Experimental Research Center China Academy of Chinese Medical Sciences Beijing China
| | - Hong Wang
- School of Traditional Chinese Medicine Southern Medical University Guangzhou China
| | - Yiwei Sang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases Experimental Research Center China Academy of Chinese Medical Sciences Beijing China
| | - Mei Liu
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases Experimental Research Center China Academy of Chinese Medical Sciences Beijing China
| | - Qing Wang
- School of Life Sciences Beijing University of Chinese Medicine Beijing China
| | - Hongjun Yang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs China Academy of Chinese Medical Sciences Beijing China
| | - Xianyu Li
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases Experimental Research Center China Academy of Chinese Medical Sciences Beijing China
| |
Collapse
|
17
|
Wang Y, Cao X, Ma J, Liu S, Jin X, Liu B. Unveiling the Longevity Potential of Natural Phytochemicals: A Comprehensive Review of Active Ingredients in Dietary Plants and Herbs. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:24908-24927. [PMID: 39480905 PMCID: PMC11565747 DOI: 10.1021/acs.jafc.4c07756] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/25/2024] [Accepted: 10/25/2024] [Indexed: 11/02/2024]
Abstract
Ancient humans used dietary plants and herbs to treat disease and to pursue eternal life. Today, phytochemicals in dietary plants and herbs have been shown to be the active ingredients, some of which have antiaging and longevity-promoting effects. Here, we summarize 210 antiaging phytochemicals in dietary plants and herbs, systematically classify them into 8 groups. We found that all groups of phytochemicals can be categorized into six areas that regulate organism longevity: ROS levels, nutrient sensing network, mitochondria, autophagy, gut microbiota, and lipid metabolism. We review the role of these processes in aging and the molecular mechanism of the health benefits through phytochemical-mediated regulation. Among these, how phytochemicals promote longevity through the gut microbiota and lipid metabolism is rarely highlighted in the field. Our understanding of the mechanisms of phytochemicals based on the above six aspects may provide a theoretical basis for the further development of antiaging drugs and new insights into the promotion of human longevity.
Collapse
Affiliation(s)
- Yu Wang
- State
Key Laboratory of Subtropical Silviculture, School of Forestry and
Biotechnology, Zhejiang A&F University, Hangzhou 311300, China
| | - Xiuling Cao
- State
Key Laboratory of Subtropical Silviculture, School of Forestry and
Biotechnology, Zhejiang A&F University, Hangzhou 311300, China
| | - Jin Ma
- State
Key Laboratory of Subtropical Silviculture, School of Forestry and
Biotechnology, Zhejiang A&F University, Hangzhou 311300, China
| | - Shenkui Liu
- State
Key Laboratory of Subtropical Silviculture, School of Forestry and
Biotechnology, Zhejiang A&F University, Hangzhou 311300, China
| | - Xuejiao Jin
- State
Key Laboratory of Subtropical Silviculture, School of Forestry and
Biotechnology, Zhejiang A&F University, Hangzhou 311300, China
| | - Beidong Liu
- State
Key Laboratory of Subtropical Silviculture, School of Forestry and
Biotechnology, Zhejiang A&F University, Hangzhou 311300, China
- Department
of Chemistry and Molecular Biology, University
of Gothenburg, Gothenburg 41390, Sweden
| |
Collapse
|
18
|
Shafi H, Lora AJ, Donow HM, Aggarwal S, Fu P, Wang T, Mansour HM. Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance. ACS Pharmacol Transl Sci 2024; 7:3540-3558. [PMID: 39539257 PMCID: PMC11555509 DOI: 10.1021/acsptsci.4c00436] [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: 07/21/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 11/16/2024]
Abstract
Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro, cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.
Collapse
Affiliation(s)
- Hasham Shafi
- Florida
International University Center for Translational Science, Port St. Lucie, Florida 34987, United States
| | - Andrea J. Lora
- Florida
International University Center for Translational Science, Port St. Lucie, Florida 34987, United States
| | - Haley M. Donow
- Florida
International University Center for Translational Science, Port St. Lucie, Florida 34987, United States
| | - Saurabh Aggarwal
- Dept.
of Cellular and Molecular Medicine, FIU
Herbert Wertheim College of Medicine, Miami, Florida 33199, United States
| | - Panfeng Fu
- Florida
International University Center for Translational Science, Port St. Lucie, Florida 34987, United States
- Dept.
of Environmental Health Sciences, FIU Robert
Stempel College of Public Health & Social Work, Miami, Florida 33199, United States
| | - Ting Wang
- Florida
International University Center for Translational Science, Port St. Lucie, Florida 34987, United States
- Dept.
of Cellular and Molecular Medicine, FIU
Herbert Wertheim College of Medicine, Miami, Florida 33199, United States
- Dept.
of Environmental Health Sciences, FIU Robert
Stempel College of Public Health & Social Work, Miami, Florida 33199, United States
| | - Heidi M. Mansour
- Florida
International University Center for Translational Science, Port St. Lucie, Florida 34987, United States
- Dept.
of Cellular and Molecular Medicine, FIU
Herbert Wertheim College of Medicine, Miami, Florida 33199, United States
- Dept.
of Environmental Health Sciences, FIU Robert
Stempel College of Public Health & Social Work, Miami, Florida 33199, United States
- Dept.
of Biomedical Engineering, FIU College of
Engineering & Computing, Miami, Florida 33199, United States
| |
Collapse
|
19
|
Xu MY, Xu JJ, Kang LJ, Liu ZH, Su MM, Zhao WQ, Wang ZH, Sun L, Xiao JB, Evans PC, Tian XY, Wang L, Huang Y, Liang XM, Weng JP, Xu SW. Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice. Acta Pharmacol Sin 2024; 45:2277-2289. [PMID: 38886550 PMCID: PMC11489441 DOI: 10.1038/s41401-024-01317-5] [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: 10/30/2023] [Accepted: 05/16/2024] [Indexed: 06/20/2024]
Abstract
Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 μM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.
Collapse
Affiliation(s)
- Meng-Yun Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China
| | - Jing-Jing Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Li-Jing Kang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Zheng-Hong Liu
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China
| | - Mei-Ming Su
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China
| | - Wen-Qi Zhao
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China
| | - Zhi-Hua Wang
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China
| | - Lu Sun
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China
| | - Jian-Bo Xiao
- Universidade de Vigo, Department of Analytical and Food Chemistry, Faculty of Sciences, Ourense, 32004, Spain
| | - Paul C Evans
- Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Xiao-Yu Tian
- School of Biomedical Sciences, Heart and Vascular Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Xin-Miao Liang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116000, China.
| | - Jian-Ping Weng
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China.
| | - Suo-Wen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230000, China.
| |
Collapse
|
20
|
Espín JC, Jarrín‐Orozco MP, Osuna‐Galisteo L, Ávila‐Gálvez MÁ, Romo‐Vaquero M, Selma MV. Perspective on the Coevolutionary Role of Host and Gut Microbiota in Polyphenol Health Effects: Metabotypes and Precision Health. Mol Nutr Food Res 2024; 68:e2400526. [PMID: 39538982 PMCID: PMC11605795 DOI: 10.1002/mnfr.202400526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/25/2024] [Indexed: 11/16/2024]
Abstract
"Personalized nutrition" aims to establish nutritional strategies to improve health outcomes for non-responders. However, it is utopian since most people share similar nutritional requirements. "Precision health," encompassing lifestyles, may be more fitting. Dietary (poly)phenols are "healthy" but non-nutritional molecules (thus, we can live without them). The gut microbiota influences (poly)phenol effects, producing metabolites with different activity than their precursors. Furthermore, producing distinctive metabolites, like urolithins, lunularin, and equol, leads to the term "polyphenol-related gut microbiota metabotypes," grouping individuals based on a genuine microbial metabolism of ellagic acid, resveratrol, and isoflavones, respectively. Additionally, (poly)phenols exert prebiotic-like effects through their antimicrobial activities, typically reducing microbial diversity and modulating microbiota functionality by impacting its composition and transcriptomics. Since the gut microbiota perceives (poly)phenols as a threat, (poly)phenol effects are mostly a consequence of microbiota adaptation through differential (poly)phenol metabolism (e.g., distinctive reductions, dehydroxylations, etc.). This viewpoint is less prosaic than considering (poly)phenols as essential nutritional players in human health, yet underscores their health significance in a coevolutionary partnership with the gut microbiota. In the perspective on the gut microbiota and (poly)phenols interplay, microbiota metabotypes could arbiter health effects. An innovative aspect is also emphasized: modulating the interacting microbial networks without altering the composition.
Collapse
Affiliation(s)
- Juan Carlos Espín
- Laboratory of Food & Health; Research Group on Quality, Safety and Bioactivity of Plant FoodsCEBAS‐CSIC30100 Campus de EspinardoMurciaSpain
| | - María Paula Jarrín‐Orozco
- Laboratory of Food & Health; Research Group on Quality, Safety and Bioactivity of Plant FoodsCEBAS‐CSIC30100 Campus de EspinardoMurciaSpain
| | - Leire Osuna‐Galisteo
- Laboratory of Food & Health; Research Group on Quality, Safety and Bioactivity of Plant FoodsCEBAS‐CSIC30100 Campus de EspinardoMurciaSpain
| | - María Ángeles Ávila‐Gálvez
- Laboratory of Food & Health; Research Group on Quality, Safety and Bioactivity of Plant FoodsCEBAS‐CSIC30100 Campus de EspinardoMurciaSpain
| | - María Romo‐Vaquero
- Laboratory of Food & Health; Research Group on Quality, Safety and Bioactivity of Plant FoodsCEBAS‐CSIC30100 Campus de EspinardoMurciaSpain
| | - María Victoria Selma
- Laboratory of Food & Health; Research Group on Quality, Safety and Bioactivity of Plant FoodsCEBAS‐CSIC30100 Campus de EspinardoMurciaSpain
| |
Collapse
|
21
|
Yang H, Wu B, Yang Q, Tan T, Shang D, Chen J, Cao C, Xu C. Urolithin C suppresses colorectal cancer progression via the AKT/mTOR pathway. J Nat Med 2024; 78:887-900. [PMID: 38849679 PMCID: PMC11364574 DOI: 10.1007/s11418-024-01821-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 04/29/2024] [Indexed: 06/09/2024]
Abstract
Urolithin families are gut-microbial metabolites of ellagic acid (EA). Although urolithin A (UA) and urolithin B (UB) were reported to have antiproliferative activities in cancer cells, the role and related mechanisms of urolithin C (UC) in colorectal cancer (CRC) have not yet been clarified. In this study, we assess the antitumor activities of UC in vitro and in vivo and further explore the underlying mechanisms in CRC cell lines. We found that UC inhibited the proliferation and migration of CRC cells, induced apoptosis, and arrested the cell cycle at the G2/M phase in vitro, and UC inhibited tumor growth in a subcutaneous transplantation tumor model in vivo. Mechanically, UC blocked the activation of the AKT/mTOR signaling pathway by decreasing the expression of Y-box binding protein 1(YBX1). The AKT agonist SC79 could reverse the suppression of cell proliferation in UC-treated CRC cells. In conclusion, our research revealed that UC could prevent the progression of CRC by blocking AKT/mTOR signaling, suggesting that it may have potential therapeutic values.
Collapse
Affiliation(s)
- Haochi Yang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Binghuo Wu
- Department of Oncology and Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Department of Laboratory Medicine, Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610047, China
- Yu-Yue Pathology Scientific Research Centre, Chongqing, 400039, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Qi Yang
- Biotherapy Centre, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Tian Tan
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Dan Shang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610047, China
| | - Jie Chen
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610047, China
| | - Chenhui Cao
- Sichuan Cancer Hospital and Institute, Sichuan Cancer Centre, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610042, China.
| | - Chuan Xu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
- Department of Oncology and Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- Department of Laboratory Medicine, Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610047, China.
- Yu-Yue Pathology Scientific Research Centre, Chongqing, 400039, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
| |
Collapse
|
22
|
Broome SC, Whitfield J, Karagounis LG, Hawley JA. Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing. Sports Med 2024; 54:2291-2309. [PMID: 39060742 PMCID: PMC11393155 DOI: 10.1007/s40279-024-02072-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 07/28/2024]
Abstract
The age-related loss of skeletal muscle mass and physical function leads to a loss of independence and an increased reliance on health-care. Mitochondria are crucial in the aetiology of sarcopenia and have been identified as key targets for interventions that can attenuate declines in physical capacity. Exercise training is a primary intervention that reduces many of the deleterious effects of ageing in skeletal muscle quality and function. However, habitual levels of physical activity decline with age, making it necessary to implement adjunct treatments to maintain skeletal muscle mitochondrial health and physical function. This review provides an overview of the effects of ageing and exercise training on human skeletal muscle mitochondria and considers several supplements that have plausible mechanistic underpinning to improve physical function in ageing through their interactions with mitochondria. Several supplements, including MitoQ, urolithin A, omega-3 polyunsaturated fatty acids (n3-PUFAs), and a combination of glycine and N-acetylcysteine (GlyNAC) can improve physical function in older individuals through a variety of inter-dependent mechanisms including increases in mitochondrial biogenesis and energetics, decreases in mitochondrial reactive oxygen species emission and oxidative damage, and improvements in mitochondrial quality control. While there is evidence that some nicotinamide adenine dinucleotide precursors can improve physical function in older individuals, such an outcome seems unrelated to and independent of changes in skeletal muscle mitochondrial function. Future research should investigate the safety and efficacy of compounds that can improve skeletal muscle health in preclinical models through mechanisms involving mitochondria, such as mitochondrial-derived peptides and mitochondrial uncouplers, with a view to extending the human health-span.
Collapse
Affiliation(s)
- Sophie C Broome
- Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, 3000, Australia.
| | - Jamie Whitfield
- Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, 3000, Australia
| | - Leonidas G Karagounis
- Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, 3000, Australia
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - John A Hawley
- Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, 3000, Australia
| |
Collapse
|
23
|
Prabakaran NN, Prasad S, Krishnan K, Venkatabalasubramanian S. Geraniin: A dietary ellagitannin as a modulator of signalling pathways in cancer progression. Fitoterapia 2024; 177:106107. [PMID: 38950635 DOI: 10.1016/j.fitote.2024.106107] [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: 04/12/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/03/2024]
Abstract
Cancer remains a global health challenge, necessitating the exploration of novel therapeutic agents. Current treatment options are unable to overwhelm and cure the cancer burden. Hence, identifying new bioactive molecular entities with potent anticancer activity is the need of the hour. Ellagitannin Geraniin (GN) is one such evidence-based novel bioactive molecular entity (BME) available from different natural sources that can effectively combat cancer. This narrative review attempts to investigate the potential of BME-GN from 2005 to 2023 as an efficient molecular anti-cancer therapeutic against diverse cancers. We provide information on GN's pharmacological advantages, metabolite profile, and capacity to modulate multiple molecular targets involved in the hallmarks of cancer. Using the search terms "Geraniin," "Gallic acid," "Ellagitannin," "pharmacological properties," "health," "antioxidant," "apoptosis," "disease management," "anti-proliferative," "in vitro," "anti-inflammatory," "anti-angiogenic," "in vivo," and "clinical trials," We searched the scientific literature using Scopus, Web of Science, Google Scholar, and PubMed. We removed publications that included overlap or equivalent content and used the most recent review on each issue as our primary reference. From an initial pool of 430 articles, 52 studies met the search criteria. These studies collectively provide substantial in vitro, in vivo, and clinical evidence of GN's potential to combat diverse cancers. Mechanistic insights revealed its involvement in fostering apoptosis, anti-inflammatory, and modulation of key signalling pathways implicated in the hallmarks of cancer. GN's pleiotropic pharmacological and molecular therapeutic properties strongly suggest its potential as a promising anticancer agent.
Collapse
Affiliation(s)
- Naresh Narayanan Prabakaran
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai 603203, Tamil Nadu, India
| | - Suvaasni Prasad
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai 603203, Tamil Nadu, India
| | - Kiruthigaa Krishnan
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai 603203, Tamil Nadu, India
| | | |
Collapse
|
24
|
Laurindo LF, Rodrigues VD, Minniti G, de Carvalho ACA, Zutin TLM, DeLiberto LK, Bishayee A, Barbalho SM. Pomegranate (Punica granatum L.) phytochemicals target the components of metabolic syndrome. J Nutr Biochem 2024; 131:109670. [PMID: 38768871 DOI: 10.1016/j.jnutbio.2024.109670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 04/08/2024] [Accepted: 05/14/2024] [Indexed: 05/22/2024]
Abstract
Pomegranate (Punica granatum L.) is a multipurpose dietary and medicinal plant known for its ability to promote various health benefits. Metabolic syndrome (MetS) is a complex metabolic disorder driving health and socioeconomic challenges worldwide. It may be characterized by insulin resistance, abdominal obesity, hypertension, and dyslipidemia. This study aims to conduct a review of pomegranate's effects on MetS parameters using a mechanistic approach relying on pre-clinical studies. The peel, juice, roots, bark, seeds, flowers, and leaves of the fruit present several bioactive compounds that are related mainly to anti-inflammatory and antioxidant activities as well as cardioprotective, antidiabetic, and antiobesity effects. The use of the juice extract can work as a potent inhibitor of angiotensin-converting enzyme activities, consequently regulating blood pressure. The major bioactive compounds found within the fruit are phenolic compounds (hydrolysable tannins and flavonoids) and fatty acids. Alkaloids, punicalagin, ellagitannins, ellagic acid, anthocyanins, tannins, flavonoids, luteolin, and punicic acid are also present. The antihyperglycemia, antihyperlipidemia, and weight loss promoting effects are likely related to the anti-inflammatory and antioxidant effects. When considering clinical application, pomegranate extracts are found to be frequently well-tolerated, further supporting its efficacy as a treatment modality. We suggest that pomegranate fruit, extract, or processed products can be used to counteract MetS-related risk factors. This review represents an important step towards exploring potential avenues for further research in this area.
Collapse
Affiliation(s)
- Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), São Paulo, São Paulo, Brazil; Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), São Paulo, São Paulo, Brazil
| | - Victória Dogani Rodrigues
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), São Paulo, São Paulo, Brazil
| | - Giulia Minniti
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), São Paulo, São Paulo, Brazil
| | - Antonelly Cassio Alves de Carvalho
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, Universidade de Marília (UNIMAR), São Paulo, São Paulo, Brazil
| | - Tereza Laís Menegucci Zutin
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), São Paulo, São Paulo, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, Universidade de Marília (UNIMAR), São Paulo, São Paulo, Brazil
| | - Lindsay K DeLiberto
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL USA
| | - Anupam Bishayee
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL USA.
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), São Paulo, São Paulo, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, Universidade de Marília (UNIMAR), São Paulo, São Paulo, Brazil; Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), São Paulo, São Paulo, Brazil.
| |
Collapse
|
25
|
Adiamo OQ, Bobasa EM, Phan ADT, Akter S, Seididamyeh M, Dayananda B, Gaisawat MB, Kubow S, Sivakumar D, Sultanbawa Y. In-vitro colonic fermentation of Kakadu plum (Terminalia ferdinandiana) fruit powder: Microbial biotransformation of phenolic compounds and cytotoxicity. Food Chem 2024; 448:139057. [PMID: 38555694 DOI: 10.1016/j.foodchem.2024.139057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/26/2024] [Accepted: 03/15/2024] [Indexed: 04/02/2024]
Abstract
Kakadu plum (Terminalia ferdinandiana) (KP) is an indigenous fruit used as a functional ingredient in powdered form. Three KP doses (1, 2.5 and 5 g) were digested in a dynamic in vitro gut digestion model over 48 h. Faecal water digests from the colonic reactors were assessed for total soluble polyphenols (TSP), ferric reducing antioxidant power (FRAP), phenolic metabolites and short-chain fatty acids (SCFAs). Effects of digests on cell viability were tested against Caco-2 intestinal and HepG2 hepatic cells. All doses of KP fermentation produced castalagin, corilagin, chebulagic acid, chebulinic acid, and gallic acid. TSP and FRAP significantly increased in 5 g KP digests at 0 and 48 h of fermentation. SCFA concentrations significantly increased after 48 h. Cytotoxic effects of 2.5 and 5 g KP digests diminished significantly after 12 h. Overall, colonic fermentation increased antioxidant activity and polyphenolic metabolites of 5 g KP powder for 48 h.
Collapse
Affiliation(s)
- Oladipupo Q Adiamo
- ARC Industrial Transformation Training Centre for Uniquely Australian Foods, Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland (UQ), Indooroopilly, QLD 4068, Australia
| | - Eshetu M Bobasa
- ARC Industrial Transformation Training Centre for Uniquely Australian Foods, Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland (UQ), Indooroopilly, QLD 4068, Australia
| | - Anh Dao Thi Phan
- ARC Industrial Transformation Training Centre for Uniquely Australian Foods, Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland (UQ), Indooroopilly, QLD 4068, Australia
| | - Saleha Akter
- ARC Industrial Transformation Training Centre for Uniquely Australian Foods, Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland (UQ), Indooroopilly, QLD 4068, Australia
| | - Maral Seididamyeh
- ARC Industrial Transformation Training Centre for Uniquely Australian Foods, Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland (UQ), Indooroopilly, QLD 4068, Australia
| | - Buddhi Dayananda
- School of Agriculture and Food Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | | | - Stan Kubow
- School of Human Nutrition, McGill University, Montréal, QC, Canada
| | - Dharini Sivakumar
- ARC Industrial Transformation Training Centre for Uniquely Australian Foods, Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland (UQ), Indooroopilly, QLD 4068, Australia; Phytochemical Food Network, Department of Crop Sciences, Tshwane University of Technology, Pretoria 001, South Africa
| | - Yasmina Sultanbawa
- ARC Industrial Transformation Training Centre for Uniquely Australian Foods, Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland (UQ), Indooroopilly, QLD 4068, Australia.
| |
Collapse
|
26
|
Jato J, Orman E, Boakye YD, Belga FN, Ndjonka D, Oppong Bekoe E, Liebau E, Spiegler V, Hensel A, Agyare C. Influence of fecal fermentation on the anthelmintic activity of proanthocyanidins and ellagitannins against human intestinal nematodes and Caenorhabditis elegans. Front Pharmacol 2024; 15:1390500. [PMID: 39104390 PMCID: PMC11298482 DOI: 10.3389/fphar.2024.1390500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 06/25/2024] [Indexed: 08/07/2024] Open
Abstract
Some tannin-rich plants such as Combretum mucronatum and Phyllanthus urinaria are widely used in Africa for the control of parasitic nematodes in both humans and livestock. Tannins have been recognized as an alternative source of anthelmintic therapies, and hence, recent studies have focused on both the hydrolyzable and condensed tannins. These groups of compounds, however, have poor oral bioavailability and are metabolized by gut microbiota into lower molecular weight compounds. The role of these metabolites in the anthelmintic activities of tannins has not been explored yet. This study investigated the effects of fecal metabolism on the anthelmintic potential of procyanidin C1 (PC1) and geraniin and the tannin-enriched extracts of C. mucronatum (CML) and P. urinaria (PUH), which contain these compounds, respectively. Metabolites were formed by anaerobic fermentation of the test compounds and extracts in a fresh human fecal suspension for 0 h, 4 h, and 24 h. Lyophilized samples were tested in vitro against hookworm larvae and whipworm (Trichuris trichiura) larvae obtained from naturally infected human populations in Pru West District, Bono East Region, Ghana, and against the wildtype strain of Caenorhabditis elegans (L4). Both extracts and compounds in the undegraded state exhibited concentration-dependent inhibition of the three nematodes. Their activity, however, significantly decreased upon fecal metabolism. Without fermentation, the proanthocyanidin-rich CML extract was lethal against hookworm L3 (LC50 = 343.5 μg/mL, 95% confidence interval (CI) = 267.5-445.4), T. trichiura L1 (LC50 = 230.1 μg/mL, CI = 198.9-271.2), and C. elegans (LC50 = 1468.1 μg/mL, CI = 990.3-1946.5). PUH, from which the ellagitannin geraniin was isolated, exhibited anthelmintic effects in the unfermented form with LC50 of 300.8 μg/mL (CI = 245.1-374.8) against hookworm L3 and LC50 of 331.6 μg/mL (CI = 290.3-382.5) against T. trichiura L1, but it showed no significant activity against C. elegans L4 larvae at the tested concentrations. Similarly, both compounds, procyanidin C1 and geraniin, lost their activity when metabolized in fecal matter. The activity of geraniin at a concentration of 170 μg/mL against C. elegans significantly declined from 30.4% ± 1.8% to 14.5% ± 1.5% when metabolized for 4 h, whereas that of PC1 decreased from 32.4% ± 2.3% to 8.9% ± 0.9% with similar treatment. There was no significant difference between the anthelmintic actions of metabolites from the structurally different tannin groups. The outcome of this study revealed that the intact bulky structure of tannins (hydrolyzable or condensed) may be required for their anthelmintic action. The fermented products from the gut may not directly contribute toward the inhibition of the larvae of soil-transmitted helminths.
Collapse
Affiliation(s)
- Jonathan Jato
- Department of Pharmacognosy, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana
- Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Münster, Germany
- Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Emmanuel Orman
- Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Münster, Germany
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana
| | - Yaw Duah Boakye
- Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - François Ngnodandi Belga
- Department of Biological Sciences, Faculty of Sciences, University of Ngaoundéré, Ngaoundéré, Cameroon
| | - Dieudonné Ndjonka
- Department of Biological Sciences, Faculty of Sciences, University of Ngaoundéré, Ngaoundéré, Cameroon
| | - Emelia Oppong Bekoe
- Department of Pharmacognosy and Herbal Medicine, School of Pharmacy, College of Health Science, University of Ghana, Accra, Ghana
| | - Eva Liebau
- Institute of Integrative Cell Biology and Physiology, University of Münster, Münster, Germany
| | - Verena Spiegler
- Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Münster, Germany
| | - Andreas Hensel
- Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Münster, Germany
| | - Christian Agyare
- Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| |
Collapse
|
27
|
王 洪, 谢 海, 徐 乌, 李 明. [Urolithin A alleviates respiratory syncytial virus-induced lung infection in neonatal mice by activating miR-136-mediated Sirt1 signaling]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2024; 44:1370-1381. [PMID: 39051083 PMCID: PMC11270657 DOI: 10.12122/j.issn.1673-4254.2024.07.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Indexed: 07/27/2024]
Abstract
OBJECTIVE To observe the therapeutic effects of urolithin A (UA) on respiratory syncytial virus (RSV)-induced lung infection in neonatal mice and explore the underlying mechanisms. METHODS Babl/c mice (5-7 days old) were subjected to nasal instillation of RSV and received intraperitoneal injection of saline or 2.5, 5 and 10 mg/kg UA 2 h after the infection and then once daily for 2 weeks. Bronchoalveolar lavage fluid (BALF) was then collected for detection of inflammatory cells and mediators, and lung pathology was evaluated with HE staining. RSV-infected BEAS-2B cells were treated with 2.5, 5 or 10 µmol/ L UA. Inflammatory factors, cell viability, apoptosis and autophagy were analyzed using ELISA, CCK-8 assay, TUNEL staining, flow cytometry, Western blotting and immunofluorescence staining. The cellular expressions of miR-136 and Sirt1 mRNAs were detected using qRT-PCR. A dual-luciferase reporter system was used to verify the binding between miR-136 and Sirt1. RESULTS In neonatal Babl/c mice, RSV infection caused obvious lung pathologies, promoted pulmonary cell apoptosis and LC3-Ⅱ/Ⅰ, Beclin-1 and miR-136 expressions, and increased the total cell number, inflammatory cells and factors in the BALF and decreased p62 and Sirt1 expressions. All these changes were alleviated dose-dependently by UA. In BEAS-2B cells, RSV infection significantly increased cell apoptosis, LC3B-positive cells and miR-136 expression and reduced Sirt1 expression (P<0.01), which were dose-dependently attenuated by UA. Dual-luciferase reporter assay confirmed the binding between miR-136 and Sirt1. In RSV-infected BEAS-2B cells with UA treatment, overexpression of miR-136 and Ex527 treatment both significantly increased the inflammatory factors and cell apoptosis but decreased LC3B expression, and these changes were further enhanced by their combined treatment. CONCLUSION UA ameliorates RSV-induced lung infection in neonatal mice by activating miR-136-mediated Sirt1 signaling pathway.
Collapse
|
28
|
Yasuda T, Takagi T, Asaeda K, Hashimoto H, Kajiwara M, Azuma Y, Kitae H, Hirai Y, Mizushima K, Doi T, Inoue K, Dohi O, Yoshida N, Uchiyama K, Ishikawa T, Konishi H, Ukawa Y, Kohara A, Kudoh M, Inoue R, Naito Y, Itoh Y. Urolithin A-mediated augmentation of intestinal barrier function through elevated secretory mucin synthesis. Sci Rep 2024; 14:15706. [PMID: 38977770 PMCID: PMC11231190 DOI: 10.1038/s41598-024-65791-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/24/2024] [Indexed: 07/10/2024] Open
Abstract
Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.
Collapse
Affiliation(s)
- Takeshi Yasuda
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
- Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
| | - Kohei Asaeda
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Hikaru Hashimoto
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Mariko Kajiwara
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yuka Azuma
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Hiroaki Kitae
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yasuko Hirai
- Department of Human Immunology and Nutrition Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Katsura Mizushima
- Department of Human Immunology and Nutrition Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Toshifumi Doi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Ken Inoue
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Osamu Dohi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Naohisa Yoshida
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Hideyuki Konishi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yuichi Ukawa
- Daicel Corporation, Healthcare SBU, Tokyo, 108-8230, Japan
| | - Akiko Kohara
- Daicel Corporation, Healthcare SBU, Tokyo, 108-8230, Japan
| | - Masatake Kudoh
- Daicel Corporation, Healthcare SBU, Niigata, 944-8550, Japan
| | - Ryo Inoue
- Laboratory of Animal Science, Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University, Hirakata, 572-8508, Japan
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
- Department of Human Immunology and Nutrition Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| |
Collapse
|
29
|
Hu Y, Zhang L, Wen QH, Cheng XP, Zhou LQ, Chen MS, Ke DW, Tu ZC. Prebiotic saccharides polymerization improves the encapsulation efficiency, stability, bioaccessibility and gut microbiota modulation of urolithin A liposomes. Int J Biol Macromol 2024; 273:133045. [PMID: 38942666 DOI: 10.1016/j.ijbiomac.2024.133045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 05/30/2024] [Accepted: 06/07/2024] [Indexed: 06/30/2024]
Abstract
This work was to investigate the effect of four prebiotic saccharides gum arabic (GA), fructooligosaccharide (FOS), konjac glucomannan (KGM), and inulin (INU) incorporation on the encapsulation efficiency (EE), physicochemical stability, and in vitro digestion of urolithin A-loaded liposomes (UroA-LPs). The regulation of liposomes on gut microbiota was also investigated by in vitro colonic fermentation. Results indicated that liposomes coated with GA showed the best EE, bioaccessibility, storage and thermal stability, the bioaccessibility was 1.67 times of that of UroA-LPs. The UroA-LPs coated with FOS showed the best freeze-thaw stability and transformation. Meanwhile, saccharides addition remarkably improved the relative abundance of Bacteroidota, reduced the abundances of Proteobacteria and Actinobacteria. The UroA-LPs coated with FOS, INU, and GA exhibited the highest beneficial bacteria abundance of Parabacteroides, Monoglobus, and Phascolarctobacterium, respectively. FOS could also decrease the abundance of harmful bacteria Collinsella and Enterococcus, and increase the levels of acetic acid, butyric acid and iso-butyric acid. Consequently, prebiotic saccharides can improve the EE, physicochemical stability, gut microbiota regulation of UroA-LPs, and promote the bioaccessibility of UroA, but the efficiency varied based on saccharides types, which can lay a foundation for the application of UroA in foods industry and for the enhancement of its bio-activities.
Collapse
Affiliation(s)
- Yue Hu
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Lu Zhang
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.
| | - Qing-Hui Wen
- School of Health, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Xin-Peng Cheng
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Li-Qiang Zhou
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, Jiangxi 330047, China
| | - Ming-Shun Chen
- School of Health, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Dai-Wei Ke
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Zong-Cai Tu
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, Jiangxi 330047, China.
| |
Collapse
|
30
|
Bahiraii S, Braunböck-Müller B, Heiss EH. Increased Glycolytic Activity Is Part of Impeded M1(LPS) Macrophage Polarization in the Presence of Urolithin A. PLANTA MEDICA 2024; 90:546-553. [PMID: 38843794 PMCID: PMC11156499 DOI: 10.1055/a-2240-7462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/09/2023] [Indexed: 06/10/2024]
Abstract
Urolithin A is a gut metabolite of ellagitannins and reported to confer health benefits, e.g., by increased clearance of damaged mitochondria by macroautophagy or curbed inflammation. One targeted cell type are macrophages, which are plastic and able to adopt pro- or anti-inflammatory polarization states, usually assigned as M1 and M2 macrophages, respectively. This flexibility is tightly coupled to characteristic shifts in metabolism, such as increased glycolysis in M1 macrophages, and protein expression upon appropriate stimulation. This study aimed at investigating whether the anti-inflammatory properties of U: rolithin A may be driven by metabolic alterations in cultivated murine M1(lipopolysaccharide) macrophages. Expression and extracellular flux analyses showed that urolithin A led to reduced il1β, il6, and nos2 expression and boosted glycolytic activity in M1(lipopolysaccharide) macrophages. The pro-glycolytic feature of UROLITHIN A: occurred in order to causally contribute to its anti-inflammatory potential, based on experiments in cells with impeded glycolysis. Mdivi, an inhibitor of mitochondrial fission, blunted increased glycolytic activity and reduced M1 marker expression in M1(lipopolysaccharide/UROLITHIN A: ), indicating that segregation of mitochondria was a prerequisite for both actions of UROLITHIN A: . Overall, we uncovered a so far unappreciated metabolic facet within the anti-inflammatory activity of UROLITHIN A: and call for caution about the simplified notion of increased aerobic glycolysis as an inevitably proinflammatory feature in macrophages upon exposure to natural products.
Collapse
Affiliation(s)
- Sheyda Bahiraii
- Department of Pharmaceutical Sciences/Pharmacognosy, University of Vienna, Vienna, Austria
- Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences, University of Vienna, Vienna, Austria
| | | | - Elke H. Heiss
- Department of Pharmaceutical Sciences/Pharmacognosy, University of Vienna, Vienna, Austria
| |
Collapse
|
31
|
Cao G, Zuo J, Wu B, Wu Y. Polyphenol supplementation boosts aerobic endurance in athletes: systematic review. Front Physiol 2024; 15:1369174. [PMID: 38651044 PMCID: PMC11033476 DOI: 10.3389/fphys.2024.1369174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
In recent years, an increasing trend has been observed in the consumption of specific polyphenols, such as flavonoids and phenolic acids, derived from green tea, berries, and other similar sources. These compounds are believed to alleviate oxidative stress and inflammation resulting from exercise, potentially enhancing athletic performance. This systematic review critically examines the role of polyphenol supplementation in improving aerobic endurance among athletes and individuals with regular exercise habits. The review involved a thorough search of major literature databases, including PubMed, Web of Science, SCOPUS, SPORTDiscus, and Embase, covering re-search up to the year 2023. Out of 491 initially identified articles, 11 met the strict inclusion criteria for this review. These studies specifically focused on the incorporation of polyphenols or polyphenol-containing complexes in their experimental design, assessing their impact on aerobic endurance. The methodology adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the risk of bias was evaluated using the Cochrane bias risk assessment tool. While this review suggests that polyphenol supplementation might enhance certain aspects of aerobic endurance and promote fat oxidation, it is important to interpret these findings with caution, considering the limited number of studies available. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023453321.
Collapse
Affiliation(s)
- Gexin Cao
- Department of Exercise Physiology, School of Sports Science, Beijing Sports University, Beijing, China
- Laboratory of Sports Stress and Adaptation of General Administration of Sport, Beijing Sports University, Beijing, China
| | - Jing Zuo
- Laboratory of Sports Stress and Adaptation of General Administration of Sport, Beijing Sports University, Beijing, China
- Department of Anatomy Laboratory, School of Sports Science, Beijing Sports University, Beijing, China
| | - Baile Wu
- Department of Exercise Physiology, School of Sports Science, Beijing Sports University, Beijing, China
- Laboratory of Sports Stress and Adaptation of General Administration of Sport, Beijing Sports University, Beijing, China
| | - Ying Wu
- Department of Exercise Physiology, School of Sports Science, Beijing Sports University, Beijing, China
- Laboratory of Sports Stress and Adaptation of General Administration of Sport, Beijing Sports University, Beijing, China
| |
Collapse
|
32
|
Matić J, Akladios F, Battisti UM, Håversen L, Nain-Perez A, Füchtbauer AF, Kim W, Monjas L, Rivero AR, Borén J, Mardinoglu A, Uhlen M, Grøtli M. Sulfone-based human liver pyruvate kinase inhibitors - Design, synthesis and in vitro bioactivity. Eur J Med Chem 2024; 269:116306. [PMID: 38471358 DOI: 10.1016/j.ejmech.2024.116306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 02/02/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have been investigating potential targets for NAFLD drug development. One promising candidate is the liver isoform of pyruvate kinase (PKL). In recent studies, Urolithin C, an allosteric inhibitor of PKL, has emerged as a potential lead compound for therapeutic intervention. Building upon this knowledge, our team has conducted a comprehensive structure-activity relationship of Urolithin C. In this work, we have employed a scaffold-hopping approach, modifying the urolithin structure by replacing the urolithin carbonyl with a sulfone moiety. Our structure-activity relationship analysis has identified the sulfone group as particularly favourable for potent PKL inhibition. Additionally, we have found that the presence of catechol moieties on the two aromatic rings further improves the inhibitory activity. The most promising inhibitor from this new series displayed nanomolar inhibition, boasting an IC50 value of 0.07 μM. This level of potency rivals that of urolithin D and significantly surpasses the effectiveness of urolithin C by an order of magnitude. To better understand the molecular interactions underlying this inhibition, we obtained the crystal structure of one of the inhibitors complexed with PKL. This structural insight served as a valuable reference point, aiding us in the design of inhibitors.
Collapse
Affiliation(s)
- Josipa Matić
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Fady Akladios
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Umberto Maria Battisti
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Liliana Håversen
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden
| | - Amalyn Nain-Perez
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Anders Foller Füchtbauer
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Woonghee Kim
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Leticia Monjas
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Alexandra Rodriguez Rivero
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK
| | - Mathias Uhlen
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Morten Grøtli
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden.
| |
Collapse
|
33
|
El-Wetidy MS, Rady MI, Rady I, Helal H. Urolithin A affects cellular migration and modulates matrix metalloproteinase expression in colorectal cancer cells. Cell Biochem Funct 2024; 42:e4019. [PMID: 38622949 DOI: 10.1002/cbf.4019] [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: 01/24/2024] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/17/2024]
Abstract
Colorectal cancer (CRC) is the world's second most common gastrointestinal malignancy. Preventing tumor cell proliferation and dissemination is critical for patient survival. Polyphenols have a variety of health advantages and can help prevent cancer. The current study examined different cellular activities of the gut-microbiota metabolite urolithin A (UA) on several colon cancer cell lines. The results revealed that UA suppressed cell growth in a dose- and time-dependent manner. In the current investigation, UA substantially affected cell migration in the wound-healing experiment and greatly decreased the number of colonies generated in each CRC cell culture. UA decreased cellular migration in CRC cells 48 h after treatment, which was significant (p < .001) compared to the migration rate in untreated cells. When compared to untreated cells, UA slowed the process of colony formation by reducing the number of colonies or altering their morphological shape. The western blot analysis investigation revealed that UA inhibits cellular metastasis by lowering the expression levels of matrix metalloproteinases 1 and 2 (MMP1 and MMP2) by more than 43% and 41% (p < .001) in HT29, 28% and 149% (p < .001) in SW480, and 90% and 74% (p < .001) in SW620, respectively, at a 100 µM dosage of UA compared to the control. Surprisingly, at a 100 µM dosage of UA, the expression levels of the tissue inhibitor of metalloproteinases 1 (TIMP1) were elevated in HT29, SW480, and SW620 cells treated with 100 µM of UA by more than 89%, 57%, and 29%, respectively. Our findings imply that UA has anticancer properties and might be used therapeutically to treat CRC. The findings provided the first indication of the influence of UA on cellular migration and metastasis in colon cancer cells. All of these data showed that UA might be used as an adjuvant therapy in the treatment of various forms of CRC.
Collapse
Affiliation(s)
- Mohammad S El-Wetidy
- Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
- College of Medicine Research Center, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mohamad I Rady
- Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Islam Rady
- Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
- Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hamed Helal
- Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
| |
Collapse
|
34
|
Isla KKY, Tanae MM, de Lima-Landman MTR, de Magalhães PM, Lapa AJ, Souccar C. Vasorelaxant effects of ellagitannins isolated from Cuphea carthagenensis. PLANTA MEDICA 2024; 90:276-285. [PMID: 38272038 DOI: 10.1055/a-2240-7372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
Cuphea carthagenensis (Jacq.) J. F. Macbr. is a popular plant in Brazilian folk medicine owing to its hypotensive and central nervous system depressant effects. This study aimed to validate the hypotensive effect of the plant's aqueous extract (AE) in rats and examine the vascular actions of three hydrolyzable tannins, oenothein B, woodfordin C, and eucalbanin B, isolated from AE. Systolic blood pressure in unanesthetized rats was determined using the non-invasive tail-cuff method. Oral treatment of normotensive rats with 0.5 and 1.0 g/kg/day AE induced a dose-related hypotensive effect after 1 week. In rat aortic rings pre-contracted with noradrenaline, all ellagitannins (20 - 180 µM) induced a concentration-related vasorelaxation. This effect was blocked by either removing the endothelium or pre-incubating with NG-nitro-l-arginine methyl ester (10 µM), an inhibitor of nitric oxide (NO) synthase. In KCl-depolarized rat portal vein preparations, the investigated compounds did not affect significantly the maximal contractile responses and pD2 values of the concentration-response curves to CaCl2. Our results demonstrated the hypotensive effect of C. carthagenensis AE in unanesthetized rats. All isolated ellagitannins induced vasorelaxation in vitro via activating NO synthesis/NO release from endothelial cells, without altering the Ca2+ influx in vascular smooth muscle preparations. Considering the low oral bioavailability of ellagitannins, the determined in vitro actions of these compounds are unlikely to account for the hypotensive effect of AE in vivo. It remains to be determined the role of the bioactive ellagitannin-derived metabolites in the hypotensive effect observed after oral treatment of unanesthetized rats with the plant extract.
Collapse
Affiliation(s)
- Kaori Katiuska Yamaguchi Isla
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Mirtes Midori Tanae
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | - Pedro Melillo de Magalhães
- Multidisciplinary Center for Chemical, Biological and Agricultural Research, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil
| | - Antônio José Lapa
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Caden Souccar
- Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| |
Collapse
|
35
|
Hao Z, Ding X, Wang J. Effects of gut bacteria and their metabolites on gut health of animals. ADVANCES IN APPLIED MICROBIOLOGY 2024; 127:223-252. [PMID: 38763528 DOI: 10.1016/bs.aambs.2024.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
The intestine tract is a vital site for the body to acquire nutrients, serving as the largest immune organ. Intestinal health is crucial for maintaining a normal physiological state. Abundant microorganisms reside in the intestine, colonized in a symbiotic manner. These microorganisms can generate various metabolites that influence host physiological activities. Microbial metabolites serve as signaling molecules or metabolic substrates in the intestine, and some intestinal microorganisms act as probiotics and promote intestinal health. Researches on host, probiotics, microbial metabolites and their interactions are ongoing. This study reviews the effects of gut bacteria and their metabolites on intestinal health to provide useful references for animal husbandry.
Collapse
Affiliation(s)
- Zhuang Hao
- College of Animal Science and Technology, Nanjing Agricultural University, National Center for International Research on Animal Gut Nutrition, Nanjing, Jiangsu, P.R. China
| | - Xuedong Ding
- College of Animal Science and Technology, Nanjing Agricultural University, National Center for International Research on Animal Gut Nutrition, Nanjing, Jiangsu, P.R. China
| | - Jing Wang
- College of Animal Science and Technology, Nanjing Agricultural University, National Center for International Research on Animal Gut Nutrition, Nanjing, Jiangsu, P.R. China.
| |
Collapse
|
36
|
Aljabouri I, Rostami M, Mirzavi F, Kakhki MK, Alalikhan A, Gheybi E, Hakimi A, Soukhtanloo M. Urolithin B protects PC12 cells against glutamate-induced toxicity. Mol Biol Rep 2024; 51:360. [PMID: 38402341 DOI: 10.1007/s11033-024-09236-8] [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: 11/11/2023] [Accepted: 01/09/2024] [Indexed: 02/26/2024]
Abstract
BACKGROUND The involvement of malfunctioning glutamate systems in various central nervous system (CNS) disorders is widely acknowledged. Urolithin B, known for its neuroprotective and antioxidant properties, has shown potential as a therapeutic agent for these disorders. However, little is known about its protective effects against glutamate-induced toxicity in PC12 cells. Therefore, in this study, for the first time we aimed to investigate the ability of Urolithin B to reduce the cytotoxic effects of glutamate on PC12 cells. METHODS Different non-toxic concentrations of urolithin B were applied to PC12 cells for 24 h before exposure to glutamate (10 mM). The cells were then analyzed for cell viability, intracellular reactive oxygen species (ROS), cell cycle arrest, apoptosis, and the expression of Bax and Bcl-2 genes. RESULTS The results of MTT assay showed that glutamate at a concentration of 10 mM and urolithin B at a concentration of 114 μM can reduce PC12 cell viability by 50%. However, urolithin B at non-toxic concentrations of 4 and 8 μM significantly reduced glutamate-induced cytotoxicity (p < 0.01). Interestingly, treatment with glutamate significantly enhanced the intracellular ROS levels and apoptosis rate in PC12 cells, while pre-treatment with non-toxic concentrations of urolithin B significantly reduced these cytotoxic effects. The results also showed that pre-treatment with urolithin B can decrease the Bax (p < 0.05) and increase the Bcl-2 (p < 0.01) gene expression, which was dysregulated by glutamate. CONCLUSIONS Taken together, urolithin B may play a protective role through reducing oxidative stress and apoptosis against glutamate-induced toxicity in PC12 cells, which merits further investigations.
Collapse
Affiliation(s)
- Israa Aljabouri
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farshad Mirzavi
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Mahla Kazemian Kakhki
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Alalikhan
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elaheh Gheybi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Hakimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Soukhtanloo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
37
|
Ghosh S, Erickson D, Chua MJ, Collins J, Jala VR. The microbial metabolite urolithin A reduces Clostridioides difficile toxin expression and toxin-induced epithelial damage. mSystems 2024; 9:e0125523. [PMID: 38193707 PMCID: PMC10878087 DOI: 10.1128/msystems.01255-23] [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: 11/27/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
Clostridioides difficile is a Gram-positive, anaerobic, spore-forming bacterium responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activity, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection.IMPORTANCETherapy for Clostridioides difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation. However, these treatments have several drawbacks, including the loss of colonization resistance, the promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.
Collapse
Affiliation(s)
- Sweta Ghosh
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
- UofL-Brown Cancer Center, Louisville, Kentucky, USA
| | - Daniel Erickson
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
| | - Michelle J. Chua
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
| | - James Collins
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
- Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA
- Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, Kentucky, USA
| | - Venkatakrishna Rao Jala
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
- UofL-Brown Cancer Center, Louisville, Kentucky, USA
- Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville, Louisville, Kentucky, USA
- Center for Integrative Environmental Health Sciences, University of Louisville, Louisville, Kentucky, USA
| |
Collapse
|
38
|
Kim HS, Kim JS, Suh MK, Eom MK, Do HE, Lee JH, Park SH, Kang SW, Lee DH, Yoon H, Lee JH, Lee JS. Gordonibacter faecis sp. nov., producing urolithin C from ellagic acid, isolated from feces of healthy Korean subjects. Arch Microbiol 2024; 206:108. [PMID: 38368591 DOI: 10.1007/s00203-024-03844-5] [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: 11/22/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 02/19/2024]
Abstract
A Gram-stain-positive, anaerobic, motile, and short rod-shaped bacterium, designated KGMB12511T, was isolated from the feces of healthy Koreansubjects. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain KGMB12511T was closely related to Gordonibacter pamelaeae 7-10-1-bT (95.2%). The draft genome of KGMB12511T comprised 33 contigs and 2,744 protein-coding genes. The DNA G + C content was 59.9% based on whole-genome sequences. The major cellular fatty acids (>10%) of strain KGMB12511T were C18:1 cis9, C18:1 cis9 DMA (dimethylacetal), and C16:0 DMA. The predominant polar lipids included a diphosphatydilglycerol, four glycolipids, and an unidentified phospholipid. The major respiratory quinones were menaquinone 6 (MK-6) and monomethylmenaquinone 6 (MMK-6). Furthermore, HPLC analysis demonstrated the ability of strain KGMB12511T to convert ellagic acid into urolithin. Based on a comprehensive analysis of phenotypic, chemotaxonomic, and phylogenetic data, strain KGMB12511T represents a novel species in the genus Gordonibacter. The type strain is KGMB12511T (= KCTC 25343T = NBRC 116190T).
Collapse
Affiliation(s)
- Han Sol Kim
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
- Department of Lifestyle Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan-si, Jeollabuk-do, 54596, Republic of Korea
| | - Ji-Sun Kim
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Min Kuk Suh
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
- Department of Lifestyle Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan-si, Jeollabuk-do, 54596, Republic of Korea
| | - Mi Kyung Eom
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Hyo Eun Do
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
- Department of Oriental Medicine Resources, Jeonbuk National University, 79 Gobong-ro, Iksan-si, Jeollabuk-do, 54596, Republic of Korea
| | - Ju Huck Lee
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Seung-Hwan Park
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Se Won Kang
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea
| | - Dong Ho Lee
- Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-Gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Hyuk Yoon
- Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-Gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Je Hee Lee
- CJ Bioscience, Inc., 14 Sejong-Daero, Jung-Gu, Seoul, 04527, Republic of Korea
| | - Jung-Sook Lee
- Korean Collection for Type Cultures, (KCTC), Korea Research Institute of Bioscience and Biotechnology, (KRIBB), 181 Ipsin-Gil, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea.
- University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
| |
Collapse
|
39
|
Pavlova JA, Guseva EA, Dontsova OA, Sergiev PV. Natural Activators of Autophagy. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:1-26. [PMID: 38467543 DOI: 10.1134/s0006297924010012] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/25/2023] [Accepted: 11/29/2023] [Indexed: 03/13/2024]
Abstract
Autophagy is the process by which cell contents, such as aggregated proteins, dysfunctional organelles, and cell structures are sequestered by autophagosome and delivered to lysosomes for degradation. As a process that allows the cell to get rid of non-functional components that tend to accumulate with age, autophagy has been associated with many human diseases. In this regard, the search for autophagy activators and the study of their mechanism of action is an important task for treatment of many diseases, as well as for increasing healthy life expectancy. Plants are rich sources of autophagy activators, containing large amounts of polyphenolic compounds in their composition, which can be autophagy activators in their original form, or can be metabolized by the intestinal microbiota to active compounds. This review is devoted to the plant-based autophagy activators with emphasis on the sources of their production, mechanism of action, and application in various diseases. The review also describes companies commercializing natural autophagy activators.
Collapse
Affiliation(s)
- Julia A Pavlova
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia.
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
- Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Ekaterina A Guseva
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
- Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Olga A Dontsova
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
- Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia
| | - Petr V Sergiev
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143025, Russia.
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
- Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia
- Institute of Functional Genomics, Lomonosov Moscow State University, Moscow, 119991, Russia
| |
Collapse
|
40
|
Zhang H, Li C, Han L, Xiao Y, Bian J, Liu C, Gong L, Liu Z, Wang M. MUP1 mediates urolithin A alleviation of chronic alcohol-related liver disease via gut-microbiota-liver axis. Gut Microbes 2024; 16:2367342. [PMID: 38889450 PMCID: PMC11188796 DOI: 10.1080/19490976.2024.2367342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 06/07/2024] [Indexed: 06/20/2024] Open
Abstract
Alcohol-related liver disease (ALD) is recognized as a global health crisis, contributing to approximately 20% of liver cancer-associated fatalities. Dysbiosis of the gut microbiome is associated with the development of ALD, with the gut microbial metabolite urolithin A (UA) exhibiting a potential for alleviating liver symptoms. However, the protective efficacy of UA against ALD and its underlying mechanism mediated by microbiota remain elusive. In this study, we provide evidence demonstrating that UA effectively ameliorates alcohol-induced metabolic disorders and hepatic endoplasmic reticulum (ER) stress through a specific gut-microbiota-liver axis mediated by major urinary protein 1 (MUP1). Moreover, UA exhibited the potential to restore alcohol-induced dysbiosis of the intestinal microbiota by enriching the abundance of Bacteroides sartorii (B. sartorii), Parabacteroides distasonis (P. distasonis), and Akkermansia muciniphila (A. muciniphila), along with their derived metabolite propionic acid. Partial attenuation of the hepatoprotective effects exerted by UA was observed upon depletion of gut microbiota using antibiotics. Subsequently, a fecal microbiota transplantation (FMT) experiment was conducted to evaluate the microbiota-dependent effects of UA in ALD. FMT derived from mice treated with UA exhibited comparable efficacy to direct UA treatment, as it effectively attenuated ER stress through modulation of MUP1. It was noteworthy that strong associations were observed among the hepatic MUP1, gut microbiome, and metabolome profiles affected by UA. Intriguingly, oral administration of UA-enriched B. sartorii, P. distasonis, and A. muciniphila can enhance propionic acid production to effectively suppress ER stress via MUP1, mimicking UA treatment. Collectively, these findings elucidate the causal mechanism that UA alleviated ALD through the gut-microbiota-liver axis. This unique mechanism sheds light on developing novel microbiome-targeted therapeutic strategies against ALD.
Collapse
Affiliation(s)
- Hongbo Zhang
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Chaoyue Li
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Lin Han
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Yao Xiao
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Ji Bian
- Kolling Institute, Sydney Medical School, Royal North Shore Hospital, University of Sydney, Sydney, Australia
| | - Chao Liu
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan, P.R. China
| | - Lan Gong
- UNSW Microbiome Research Centre, St George and Sutherland Clinical Campus, University of New South Wales, Sydney, Australia
| | - Zhigang Liu
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| | - Min Wang
- College of Food Science and Engineering, Northwest A&F University, Yang ling, Shaanxi, China
| |
Collapse
|
41
|
Xiong R, Li B, Yu H, Fan T, Yu H, Yang Y, Wang JZ, Pi G, Yang X. Urolithin A Inhibits Anterior Basolateral Amygdala to Ventral Hippocampal CA1 Circuit to Ameliorate Amyloid-β-Impaired Social Ability. J Alzheimers Dis 2024; 99:1303-1316. [PMID: 38759018 DOI: 10.3233/jad-240298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2024]
Abstract
BACKGROUND Anxiety and social withdrawal are highly prevalent among patients with Alzheimer's disease (AD). However, the neural circuit mechanisms underlying these symptoms remain elusive, and there is a need for effective prevention strategies. OBJECTIVE This study aims to elucidate the neural circuitry mechanisms underlying social anxiety in AD. METHODS We utilized 5xFAD mice and conducted a series of experiments including optogenetic manipulation, Tandem Mass Tag-labeled proteome analysis, behavioral assessments, and immunofluorescence staining. RESULTS In 5xFAD mice, we observed significant amyloid-β (Aβ) accumulation in the anterior part of basolateral amygdala (aBLA). Behaviorally, 6-month-old 5xFAD mice displayed excessive social avoidance during social interaction. Concurrently, the pathway from aBLA to ventral hippocampal CA1 (vCA1) was significantly activated and exhibited a disorganized firing patterns during social interaction. By optogenetically inhibiting the aBLA-vCA1 pathway, we effectively improved the social ability of 5xFAD mice. In the presence of Aβ accumulation, we identified distinct changes in the protein network within the aBLA. Following one month of administration of Urolithin A (UA), we observed significant restoration of the abnormal protein network within the aBLA. UA treatment also attenuated the disorganized firings of the aBLA-vCA1 pathway, leading to an improvement in social ability. CONCLUSIONS The aBLA-vCA1 circuit is a vulnerable pathway in response to Aβ accumulation during the progression of AD and plays a crucial role in Aβ-induced social anxiety. Targeting the aBLA-vCA1 circuit and UA administration are both effective strategies for improving the Aβ-impaired social ability.
Collapse
Affiliation(s)
- Rui Xiong
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binrui Li
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haitao Yu
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- Department of Fundamental Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Tianceng Fan
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiling Yu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Yang
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Zhi Wang
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guilin Pi
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xifei Yang
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| |
Collapse
|
42
|
Hu Y, Zhang L, Wei LF, Lu FY, Wang LH, Ding Q, Chen MS, Tu ZC. Liposomes encapsulation by pH driven improves the stability, bioaccessibility and bioavailability of urolithin A: A comparative study. Int J Biol Macromol 2023; 253:127554. [PMID: 37865359 DOI: 10.1016/j.ijbiomac.2023.127554] [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: 08/09/2023] [Revised: 10/03/2023] [Accepted: 10/18/2023] [Indexed: 10/23/2023]
Abstract
Urolithin A (UroA) is gut metabolites of ellagitannins possessing a vast range of biological activities, but its poor water solubility and low bioavailability hinder its potential applications. This study utilized the pH dependent dissolution characteristics of UroA and employed a simple pH-driven method to load UroA into liposomes. The characterization and stability of obtained liposomes under different conditions were evaluated, and their oral bioavailability was tested by pharmacokinetics, and compared with UroA liposomes prepared using traditional thin film dispersion (TFM-ULs). Results indicated that liposomes could effectively encapsulate UroA. The UroA liposomes prepared by the pH-driven method (PDM-ULs) showed lower particle size, polydispersity index, zeta potential, and higher encapsulation efficiency than TFM-ULs. Interestingly, better thermal stability, storage stability, in vitro digestion stability, and higher bioaccessibility were also found on PDM-ULs. Moreover, pharmacokinetic experiments in rats demonstrated that PDM-ULs could significantly improve the bioavailability of UroA, with an absorption efficiency 1.91 times that of TFM-ULs. Therefore, our findings suggest that liposomes prepared by pH-driven methods have great potential in improving the stability and bioavailability of UroA.
Collapse
Affiliation(s)
- Yue Hu
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Lu Zhang
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; Jiangxi Deshang Pharmaceutical Co., Ltd., Yichun, Jiangxi 330006, China.
| | - Lin-Feng Wei
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Fei-Yan Lu
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Le-Huai Wang
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Qiao Ding
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Ming-Shun Chen
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; School of Health, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Zong-Cai Tu
- National R&D Center of Freshwater Fish Processing, College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi 330022, China; State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, Jiangxi 330047, China.
| |
Collapse
|
43
|
Bianconi E, Gidari A, Souma M, Sabbatini S, Grifagni D, Bigiotti C, Schiaroli E, Comez L, Paciaroni A, Cantini F, Francisci D, Macchiarulo A. The hope and hype of ellagic acid and urolithins as ligands of SARS-CoV-2 Nsp5 and inhibitors of viral replication. J Enzyme Inhib Med Chem 2023; 38:2251721. [PMID: 37638806 PMCID: PMC10464554 DOI: 10.1080/14756366.2023.2251721] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 08/29/2023] Open
Abstract
Non-structural protein 5 (Nsp5) is a cysteine protease that plays a key role in SARS-CoV-2 replication, suppressing host protein synthesis and promoting immune evasion. The investigation of natural products as a potential strategy for Nsp5 inhibition is gaining attention as a means of developing antiviral agents. In this work, we have investigated the physicochemical properties and structure-activity relationships of ellagic acid and its gut metabolites, urolithins A-D, as ligands of Nsp5. Results allow us to identify urolithin D as promising ligand of Nsp5, with a dissociation constant in the nanomolar range of potency. Although urolithin D is able to bind to the catalytic cleft of Nsp5, the appraisal of its viral replication inhibition against SARS-CoV-2 in Vero E6 assay highlights a lack of activity. While these results are discussed in the framework of the available literature reporting conflicting data on polyphenol antiviral activity, they provide new clues for natural products as potential viral protease inhibitors.
Collapse
Affiliation(s)
- Elisa Bianconi
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Anna Gidari
- Department of Medicine and Surgery, Clinic of Infectious Diseases, University of Perugia, Perugia, Italy
| | - Maria Souma
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Samuele Sabbatini
- Medical Microbiology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Deborah Grifagni
- Centre for Magnetic Resonance, University of Florence, Sesto Fiorentino, Italy
- Department of Chemistry, University of Florence, Sesto Fiorentino, Italy
| | - Carlo Bigiotti
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Elisabetta Schiaroli
- Department of Medicine and Surgery, Clinic of Infectious Diseases, University of Perugia, Perugia, Italy
| | - Lucia Comez
- Istituto Officina dei Materiali-IOM, National Research Council-CNR, Perugia, Italy
| | | | - Francesca Cantini
- Centre for Magnetic Resonance, University of Florence, Sesto Fiorentino, Italy
- Department of Chemistry, University of Florence, Sesto Fiorentino, Italy
| | - Daniela Francisci
- Department of Medicine and Surgery, Clinic of Infectious Diseases, University of Perugia, Perugia, Italy
| | - Antonio Macchiarulo
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| |
Collapse
|
44
|
Rogowska-van der Molen MA, Berasategui-Lopez A, Coolen S, Jansen RS, Welte CU. Microbial degradation of plant toxins. Environ Microbiol 2023; 25:2988-3010. [PMID: 37718389 DOI: 10.1111/1462-2920.16507] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/05/2023] [Indexed: 09/19/2023]
Abstract
Plants produce a variety of secondary metabolites in response to biotic and abiotic stresses. Although they have many functions, a subclass of toxic secondary metabolites mainly serve plants as deterring agents against herbivores, insects, or pathogens. Microorganisms present in divergent ecological niches, such as soil, water, or insect and rumen gut systems have been found capable of detoxifying these metabolites. As a result of detoxification, microbes gain growth nutrients and benefit their herbivory host via detoxifying symbiosis. Here, we review current knowledge on microbial degradation of toxic alkaloids, glucosinolates, terpenes, and polyphenols with an emphasis on the genes and enzymes involved in breakdown pathways. We highlight that the insect-associated microbes might find application in biotechnology and become targets for an alternative microbial pest control strategy.
Collapse
Affiliation(s)
- Magda A Rogowska-van der Molen
- Department of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen, The Netherlands
| | - Aileen Berasategui-Lopez
- Department of Microbiology and Biotechnology, University of Tübingen, Tübingen, Baden-Württemberg, Germany
- Amsterdam Institute for Life and Environment, Section Ecology and Evolution, Vrije Universiteit, Amsterdam, The Netherlands
| | - Silvia Coolen
- Department of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen, The Netherlands
| | - Robert S Jansen
- Department of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen, The Netherlands
| | - Cornelia U Welte
- Department of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen, The Netherlands
| |
Collapse
|
45
|
Wu JJ, Wei Z. Advances in the study of the effects of gut microflora on microglia in Alzheimer's disease. Front Mol Neurosci 2023; 16:1295916. [PMID: 38098943 PMCID: PMC10720669 DOI: 10.3389/fnmol.2023.1295916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 10/31/2023] [Indexed: 12/17/2023] Open
Abstract
Alzheimer's disease (AD) is a central nervous system (CNS) degenerative disorder, is caused by various factors including β-amyloid toxicity, hyperphosphorylation of tau protein, oxidative stress, and others. The dysfunction of microglia has been associated with the onset and advancement of different neurodevelopmental and neurodegenerative disorders, such as AD. The gut of mammals harbors a vast and complex population of microorganisms, commonly referred to as the microbiota. There's a growing recognition that these gut microbes are intrinsically intertwined with mammalian physiology. Through the circulation of metabolites, they establish metabolic symbiosis, enhance immune function, and establish communication with different remote cells, including those in the brain. The gut microbiome plays a crucial part in influencing the development and performance of microglia, as indicated by recent preclinical studies. Dysbiosis of the intestinal flora leads to alterations in the microglia transcriptome that regulate the interconversion of microglia subtypes. This conversation explores recent research that clarifies how gut bacteria, their byproducts, and harmful elements affect the activation and characteristics of microglia. This understanding opens doors to innovative microbial-based therapeutic strategies for early identification and treatment goals in AD.
Collapse
Affiliation(s)
- Jin-Jing Wu
- School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zhe Wei
- School of Medicine, Lishui University, Lishui, Zhejiang, China
- Institute of Breast Oncology, Lishui University Medical College, Lishui, Zhejiang, China
| |
Collapse
|
46
|
Kolesarova A, Baldovska S, Kohut L, Vasicek J, Ivanisova E, Arvay J, Duracka M, Roychoudhury S. Modulatory effect of pomegranate peel extract on key regulators of ovarian cellular processes in vitro. Front Endocrinol (Lausanne) 2023; 14:1277155. [PMID: 38027211 PMCID: PMC10663288 DOI: 10.3389/fendo.2023.1277155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
In this study, response of ovarian cells (human granulosa cell line HGL5, and human adenocarcinoma cell line OVCAR-3) to short-term pomegranate peel extract (PPE) treatment (for 24 hours in cell culture) was evaluated in vitro. Quantitative and qualitative screening of polyphenols revealed punicalagins α and β as major polyphenolic components. Total phenolic content (TPC) was 93.76 mg GAE/g d.w. with a high antioxidant activity of 95.30 mg TEAC/g d.w. In OVCAR-3, PPE treatment inhibited the metabolic activity, and increased cyclin-dependent kinase 1 (CDKN1A, p21) level at the highest dose, but not in HGL5. Flow cytometry analysis could not detect any significant difference between proportions of live, dead, and apoptotic cells in both cell lines. Reactive oxygen species (ROS) revealed an antioxidant effect on HGL5, and a prooxidant effect by stimulating ROS generation in OVCAR-3 cells at the higher doses of PPE. However, in contrast to HGL5, PPE treatment decreased release of growth factors - TGF-β2 and EGF at the highest dose, as well as their receptors TGFBR2 and EGFR in OVCAR-3 cells. PPE also influenced steroidogenesis in granulosa cells HGL5 by stimulating 17β-estradiol secretion at higher doses. In conclusion, the present study highlighted the bioactive compounds in pomegranate peels and the possible mechanisms of action of PPE, shedding light on its promising role in ovarian cancer (chemo)prevention and/or management.
Collapse
Affiliation(s)
- Adriana Kolesarova
- Institute of Applied Biology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Nitra, Slovakia
- AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Nitra, Slovakia
| | - Simona Baldovska
- Institute of Applied Biology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Nitra, Slovakia
| | - Ladislav Kohut
- Institute of Applied Biology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Nitra, Slovakia
| | - Jaromir Vasicek
- Institute of Farm Animal Genetics and Reproduction, NPPC - Research Institute for Animal Production Nitra, Lužianky, Slovakia
- Institute of Biotechnology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Nitra, Slovakia
| | - Eva Ivanisova
- Institute of Food Sciences, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Nitra, Slovakia
| | - Julius Arvay
- Institute of Food Sciences, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, Nitra, Slovakia
| | - Michal Duracka
- AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Nitra, Slovakia
| | | |
Collapse
|
47
|
Revankar AG, Bagewadi ZK, Shaikh IA, Mannasaheb BA, Ghoneim MM, Khan AA, Asdaq SMB. In-vitro and computational analysis of Urolithin-A for anti-inflammatory activity on Cyclooxygenase 2 (COX-2). Saudi J Biol Sci 2023; 30:103804. [PMID: 37727526 PMCID: PMC10505678 DOI: 10.1016/j.sjbs.2023.103804] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/16/2023] [Accepted: 09/01/2023] [Indexed: 09/21/2023] Open
Abstract
Cyclooxygenase 2 (COX-2) participates in the inflammation process by converting arachidonic acid into prostaglandin G2 which increases inflammation, pain and fever. COX-2 has an active site and a heme pocket and blocking these sites stops the inflammation. Urolithin A is metabolite of ellagitannin produced from humans and animals gut microbes. In the current study, Urolithin A showed good pharmacokinetic properties. Molecular docking of the complex of Urolithin A and COX-2 revealed the ligand affinity of -7.97 kcal/mol with the ligand binding sites at TYR355, PHE518, ILE517 and GLN192 with the 4-H bonds at a distance of 2.8 Å, 2.3 Å, 2.5 Å and 1.9 Å. The RMSD plot for Urolithin A and COX-2 complex was observed to be constant throughout the duration of dynamics. A total of 3 pair of hydrogen bonds was largely observed on average of 3 simulation positions for dynamics duration of 500 ns. The MMPBSA analysis showed that active site amino acids had a binding energy of -22.0368 kJ/mol indicating that throughout the simulation the protein of target was bounded by Urolithin A. In-silico results were validated by biological assays. Urolithin A strongly revealed to exhibit anti-inflammatory effect on COX-2 with an IC50 value of 44.04 µg/mL. The anti-inflammatory capability was also depicted through reduction of protein denaturation that showed 37.6 ± 0.1 % and 43.2 ± 0.07 % reduction of protein denaturation for BSA and egg albumin respectively at 500 µg/mL. The present study, suggests Urolithin A to be an effective anti-inflammatory compound for therapeutic use.
Collapse
Affiliation(s)
- Archana G. Revankar
- Department of Biotechnology, KLE Technological University, Hubballi, Karnataka 580031, India
| | - Zabin K. Bagewadi
- Department of Biotechnology, KLE Technological University, Hubballi, Karnataka 580031, India
| | - Ibrahim Ahmed Shaikh
- Department of Pharmacology, College of Pharmacy, Najran University, Najran 66462, Saudi Arabia
| | | | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia
| | - Aejaz Abdullatif Khan
- Department of General Science, Ibn Sina National College for Medical Studies, Jeddah 21418, Saudi Arabia
| | | |
Collapse
|
48
|
Hao W, Gan H, Wang L, Huang J, Chen J. Polyphenols in edible herbal medicine: targeting gut-brain interactions in depression-associated neuroinflammation. Crit Rev Food Sci Nutr 2023; 63:12207-12223. [PMID: 35838146 DOI: 10.1080/10408398.2022.2099808] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Supplementing with edible herbal medicine is an important strategy because of its role in nutrition. Many polyphenols, which are universal components in edible herbal medicines, have low bioavailability. Therefore, gut microbiota is a key determinant of polyphenol bioactivity. Polyphenols can alter the abundance of flora associated with neuroinflammation by reversing intestinal microbiota dysbiosis. Intestinal flora-mediated chemical modification of polyphenols can result in their conversion into active secondary metabolites. The current review summarizes the main edible medicines used in anti-depression and details the interactions between polyphenols and gut microbiota; in addition, it provides insights into the mechanisms underlying the possible suppression of neuroinflammation associated with depression, by polyphenols in edible herbal medicine. A better understanding of polyphenols with bioactivities that are crucial in edible herbal medicine may facilitate their use in the prevention and treatment of neuroinflammation associated with depression.
Collapse
Affiliation(s)
- Wenzhi Hao
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Hua Gan
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Lu Wang
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Junqing Huang
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Jiaxu Chen
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| |
Collapse
|
49
|
Zhao H, Song G, Zhu H, Qian H, Pan X, Song X, Xie Y, Liu C. Pharmacological Effects of Urolithin A and Its Role in Muscle Health and Performance: Current Knowledge and Prospects. Nutrients 2023; 15:4441. [PMID: 37892516 PMCID: PMC10609777 DOI: 10.3390/nu15204441] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Urolithin A (UA) is a naturally occurring compound derived from the metabolism of gut microbiota, which has attracted considerable research attention due to its pharmacological effects and potential implications in muscle health and performance. Recent studies have demonstrated that Urolithin A exhibits diverse biological activities, encompassing anti-inflammatory, antioxidant, anti-tumor, and anti-aging properties. In terms of muscle health, accumulating evidence suggests that Urolithin A may promote muscle protein synthesis and muscle growth through various pathways, offering promise in mitigating muscle atrophy. Moreover, Urolithin A exhibits the potential to enhance muscle health and performance by improving mitochondrial function and regulating autophagy. Nonetheless, further comprehensive investigations are still warranted to elucidate the underlying mechanisms of Urolithin A and to assess its feasibility and safety in human subjects, thereby advancing its potential applications in the realms of muscle health and performance.
Collapse
Affiliation(s)
- Haotian Zhao
- Department of Physical Education, Jiangnan University, Wuxi 214122, China;
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (H.Z.); (H.Q.)
| | - Ge Song
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (G.S.); (X.P.)
| | - Hongkang Zhu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (H.Z.); (H.Q.)
| | - He Qian
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (H.Z.); (H.Q.)
| | - Xinliang Pan
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (G.S.); (X.P.)
| | - Xiaoneng Song
- Department of Physical Education, Jiangnan University, Wuxi 214122, China;
| | - Yijie Xie
- Affiliated Hospital of Jiangnan University, Wuxi 214062, China
| | - Chang Liu
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (G.S.); (X.P.)
| |
Collapse
|
50
|
Jato J, Waindok P, Ngnodandi FNBF, Orman E, Agyare C, Bekoe EO, Strube C, Hensel A, Liebau E, Spiegler V. Anthelmintic Activities of Extract and Ellagitannins from Phyllanthus urinaria against Caenorhabditis elegans and Zoonotic or Animal Parasitic Nematodes. PLANTA MEDICA 2023; 89:1215-1228. [PMID: 37459860 DOI: 10.1055/a-2117-9426] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
The aerial parts of Phyllanthus urinaria are used in traditional medicine in West Africa against helminthiasis, but their anthelmintic potential has not been evaluated until now. Within the current study, a hydroacetonic extract (AWE) and fractions and isolated ellagitannins from P. urinaria were, therefore, tested in vitro against Caenorhabditis elegans and the larvae of the animal parasites Toxocara canis, Ascaris suum, Ancylostoma caninum, and Trichuris suis. Compounds 1: - 13: , mainly representing ellagitannins, were isolated using different chromatographic methods, and their structures were elucidated by HR-MS and 1H/13C-NMR. AWE exerted concentration-dependent lethal effects (LC50 of 2.6 mg/mL) against C. elegans and inhibited larval migration of all animal parasites tested (T. suis L1 IC50 24.3 µg/mL, A. suum L3 IC50 35.7 µg/mL, A. caninum L3 IC50 112.8 µg/mL, T. canis L3 IC50 1513.2 µg/mL). The anthelmintic activity of AWE was mainly related to the polar, tannin-containing fractions. Geraniin 1: , the major ellagitannin in the extract, showed the strongest anthelmintic activity in general (IC50 between 0.6 and 804 µM, depending on parasite species) and was the only compound active against A. caninum (IC50 of 35.0 µM). Furosin 9: was least active despite structural similarities to 1: . Among the parasites tested, Trichuris suis L1 larvae turned out to be most sensitive with IC50 of 0.6, 6.4, 4.0, 4.8, and 2.6 µM for geraniin 1: , repandusinic acid A 3: , punicafolin 8: , furosin 9: , and phyllanthusiin A 10: , respectively.
Collapse
Affiliation(s)
- Jonathan Jato
- University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany
- Kwame Nkrumah University of Science and Technology, Faculty of Pharmacy and Pharmaceutical Sciences, Kumasi, Ghana
- University of Health and Allied Sciences, School of Pharmacy, Ho, Ghana
- University of Münster, Institute of Integrative Cell Biology and Physiology, Münster, Germany
| | - Patrick Waindok
- University of Veterinary Medicine Hannover, Institute for Parasitology, Centre for Infection Medicine, Hannover, Germany
| | | | - Emmanuel Orman
- University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany
- University of Health and Allied Sciences, School of Pharmacy, Ho, Ghana
| | - Christian Agyare
- Kwame Nkrumah University of Science and Technology, Faculty of Pharmacy and Pharmaceutical Sciences, Kumasi, Ghana
| | - Emelia Oppong Bekoe
- University of Ghana, College of Health Science, School of Pharmacy, Accra, Ghana
| | - Christina Strube
- University of Veterinary Medicine Hannover, Institute for Parasitology, Centre for Infection Medicine, Hannover, Germany
| | - Andreas Hensel
- University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany
| | - Eva Liebau
- University of Münster, Institute of Integrative Cell Biology and Physiology, Münster, Germany
| | - Verena Spiegler
- University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany
| |
Collapse
|