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Zhang Q, Zhou Q, Li H. Action and mechanisms of neferine in inflammatory diseases (Review). Mol Med Rep 2025; 32:174. [PMID: 40242976 PMCID: PMC12046375 DOI: 10.3892/mmr.2025.13539] [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: 09/28/2024] [Accepted: 02/17/2025] [Indexed: 04/18/2025] Open
Abstract
Neferine is a bisbenzylisoquinoline alkaloid derived from the seed embryo of Nelumbo nucifera, a traditional Chinese medicine. It has been extensively studied for its therapeutic potential in various disease models. Extensive research has highlighted its diverse pharmacological activities, including antitumor, anti‑inflammatory, anti‑fibrosis, anti‑oxidative stress, anti‑platelet aggregation and anti‑arrhythmic effects. The present review, however, focuses on the anti‑inflammatory properties of neferine, emphasizing its fundamental mechanisms as demonstrated in both in vivo and in vitro studies. By critically evaluating its effect on inflammation and the underlying pathways, this review aims to provide a comprehensive understanding of the potential of neferine in the management of inflammatory diseases. Furthermore, it seeks to establish a foundational framework for the future development of neferine as a novel therapeutic agent for inflammatory conditions.
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Affiliation(s)
- Qin Zhang
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China
| | - Qiaoling Zhou
- Department of Nephropathy, Xiangya Hospital Central-South University, Changsha, Hunan 410028, P.R. China
| | - Huihui Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China
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Cao J, Zhang H, Ni Y, Ning X. Neferine reduces synovial inflammation and cardiac complications in a collagen-induced arthritis mouse model via inhibiting NF-κB/NLRP3 inflammasome axis. Mol Immunol 2025; 182:117-125. [PMID: 40262197 DOI: 10.1016/j.molimm.2025.04.001] [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: 12/02/2024] [Revised: 02/21/2025] [Accepted: 04/03/2025] [Indexed: 04/24/2025]
Abstract
For the treatment of rheumatoid arthritis (RA), there are limited options for drugs with fewer side effects. Neferine possesses anti-inflammatory, anti-fibrotic, and cardioprotective properties, but its effectiveness in the treatment of RA remains unclear. Our study aimed to explore the impact of neferine administration on ankle joint inflammation and cardiac complications of collagen-induced arthritis (CIA) mice. The CIA model was introduced in male DBA/1 mice via subcutaneous injection of Type II collagen (CII) into the tail. We found that neferine alleviated ankle joint inflammation, cartilage erosion, and bone destruction, as well as reduced the levels of IL-6, TNF-α, IL-1β, and IL-18 in the serum of CIA mice. Furthermore, neferine reduced the expression of synovial damage markers (RANKL, MMP-3, and MMP-13) in the ankle joints of CIA mice. Mechanistically, neferine lowered the levels of NF-κB pathway-related molecules such as p-IκBα, p-p65, and nuclear p65 in the synovial tissue of CIA mice. Simultaneously, neferine reversed the upregulation of NLRP3, ASC, and cleaved-caspase-1 levels in the synovial tissue of CIA mice. Additionally, our results showed that neferine reduced the contents of myocardial injury markers (cTnI, CK-MB, and LDH), alleviated myocardial fibrosis, decreased expression of α-SMA and Collagen I, as well as mitigated the activation of fibrosis-related TGF-β/Smad signaling. In summary, our study demonstrates that neferine attenuates chondral and synovial inflammation in a CIA mouse model by inhibiting the activation of the NF-κB/NLRP3 inflammasome, and neferine has a protective effect on the hearts of CIA mice.
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Affiliation(s)
- Jingjing Cao
- Department of Rheumatology and Immunology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China.
| | - Huaxing Zhang
- Division of Medical Service, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Yanhui Ni
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Xiaoran Ning
- Department of Rheumatology and Immunology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
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Singh N, Sharma P, Pal MK, Kahera R, Badoni H, Pant K, Sharma N, Bhist B. Computational drug discovery of phytochemical alkaloids targeting the NACHT/PYD domain in the NLRP3 inflammasome. Sci Rep 2025; 15:16677. [PMID: 40368915 PMCID: PMC12078577 DOI: 10.1038/s41598-024-79054-2] [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: 03/22/2024] [Accepted: 11/06/2024] [Indexed: 05/16/2025] Open
Abstract
The NLRP3 inflammasome plays a pivotal role in the innate immune system, orchestrating the activation of caspase-1 and the release of proinflammatory cytokines IL-1β and IL-18 in reaction to microbial infections and cellular damage. Despite its crucial function in defending against pathogens, the dysregulated activation of the NLRP3 inflammasome has been associated with various inflammatory disorders. In the current investigation, promising plant-derived alkaloids compounds have been discovered as targeted inhibitors against multiprotein NLRP3 using an in-silico drug development approach. The repurposing of natural compounds as anti-inflammatory agents remains a relevant approach for identifying promising early interventions to prevent and manage inflammatory diseases. In this molecular docking study targeting Chain A of the NLRP3 inflammasome protein, eight plant-derived alkaloids renowned for their anti-inflammatory properties were chosen. Docking analysis of the selected alkaloids showed the lowest/best binding energies of less than - 10 Kcal/mol against NLRP3 Chain A, based on this docking result, which is regarded as an exceptional binding score. Notably, Oxyacanthine, Magnoflorine, Corynoline, and Berbamine demonstrated the most favourable binding energies, displaying unique interactions within the binding pocket of the NACHT/PYD domain of NLRP3 Chain A among all compounds investigated. These findings highlight the potential of these alkaloids as promising therapeutic candidates specifically targeting this trans-activating NACHT/PYD domain of NLRP3 Chain A in the context of anti-inflammatory interventions. Protein-protein interactions (PPIs) play an important role in elucidating protein function and drug interactions. To identify bioactive compounds with anti-inflammatory potential, a functional protein network was constructed from publicly available PPI data. As a result, the findings of this in-silico study may cause researchers to emphasize more on alkaloids when considering natural plant products for the treatment of various illnesses that target the inflammatory intermediates. This computational approach predicted ligands that may modulate inflammatory proteins and support host immunity. However, further in vitro and in vivo studies are still needed to validate these in-silico findings before clinical use. In summary, analysing PPI networks can aid discovery of therapeutic candidates, but experimental validation remains essential.
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Affiliation(s)
- Nilay Singh
- Department of Biotechnology, Graphic Era (Deemed to be University), 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Promila Sharma
- Department of Microbiology, Graphic Era (Deemed to be University), 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India.
| | - Manoj K Pal
- Department of Microbiology, Graphic Era (Deemed to be University), 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Ragini Kahera
- Department of Biotechnology, Graphic Era (Deemed to be University), 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Himani Badoni
- School of Applied and Life Sciences, Uttaranchal University, Arcadia Grant, Prem Nagar, 248007, Chandanwari, Dehradun, Uttarakhand, India
| | - Kumud Pant
- Department of Biotechnology, Graphic Era (Deemed to be University), 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Neetu Sharma
- Department of Chemistry, Graphic Era (Deemed to be University, 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India
| | - Bhawana Bhist
- Department of Chemistry, Graphic Era (Deemed to be University, 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India
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Sun Q, Cheng Y, Huang Y, Li S, Li Y, Fu Q. Neferine inhibits PRRSV infection by disrupting p65 nuclear translocation. Microb Pathog 2025; 205:107648. [PMID: 40311944 DOI: 10.1016/j.micpath.2025.107648] [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: 04/02/2024] [Revised: 04/26/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), imposes substantial economic losses on the global swine industry due to its profound impact on pig health and production efficiency. The main clinical manifestations are reproductive disorders such as miscarriage, stillbirth or weak foetuses in sows, as well as severe respiratory diseases in pigs of all ages. Currently, due to the high genomic diversity, antigen heterogeneity, and antibody-dependent enhancement effects of PRRSV, vaccination strategies cannot effectively control PRRSV infection. It is also difficult to control these viral infectious diseases with antiviral drugs. In this study, we demonstrate that neferine (Nef), a natural compound derived from lotus seeds, inhibits NF-κB activation during PRRSV infection. Consequently, Nef effectively suppresses PRRSV gene expression and virion replication in the PRRSV-infected Marc-145 cell line. Further studies demonstrated that Nef attenuates the nuclear translocation of p65 triggered by PRRSV infection, consequently mitigating the excessive production of inflammatory cytokines in infected cells. This anti-inflammatory mechanism may contribute to its observed antiviral efficacy against PRRSV. As a result, we conclude that Nef may be an effective clinical treatment for the acute occurrence and transmission of PRRSV infections. Furthermore, PRRSV is thought to be responsible for an increase in proinflammatory cytokines.
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Affiliation(s)
- Qinqin Sun
- School of Animal Science and Technology, Foshan University, Foshan, PR China; Foshan University Veterinary Teaching Hospital, Foshan University, Foshan, PR China
| | - Yun Cheng
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Yunfei Huang
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Shun Li
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Yajuan Li
- School of Animal Science and Technology, Foshan University, Foshan, PR China
| | - Qiang Fu
- School of Animal Science and Technology, Foshan University, Foshan, PR China; Foshan University Veterinary Teaching Hospital, Foshan University, Foshan, PR China.
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Ichikawa K, Johnson HM, Curtis MA, Biswas N, Singh S, Khachatryan HN, Gater AE, Lin SX, Sperry J. Targeting glioma with heteroaromatic alkaloids: A review of potential therapeutics. Bioorg Med Chem 2025; 121:118051. [PMID: 39999647 DOI: 10.1016/j.bmc.2024.118051] [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: 09/20/2024] [Revised: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 02/27/2025]
Abstract
Glioblastoma multiforme (GBM), classified as a grade IV astrocytoma, is the most aggressive and deadly form of glioma, characterized by rapid progression, extensive genetic heterogeneity, and resistance to conventional therapies. Despite advancements in surgical techniques, radiation therapy, and the frontline chemotherapeutic agent temozolomide, the prognosis for GBM patients remains poor, with a median survival of 15 months and a 5-year survival rate of approximately 7 %. The absence of effective long-term treatments underscores the urgent, unmet clinical need for novel therapeutic strategies to improve patient outcomes. Natural products, particularly alkaloids, have garnered attention as a rich source of bioactive compounds with diverse pharmacological properties. Alkaloids, a structurally diverse group of natural products, are renowned for their chemotherapeutic properties and ability to cross the blood-brain barrier (BBB), making them promising candidates for glioma therapy. This review systematically examines all reported heteroaromatic alkaloids with documented anti-glioma activities, highlighting their mechanisms of action where available. By providing a comprehensive resource, it aims to facilitate the identification and optimisation of alkaloid-based compounds for glioma-targeted drug discovery. Additionally, this review emphasizes the importance of incorporating natural products into the drug development pipeline to address the pressing challenges associated with glioma, particularly GBM treatment.
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Affiliation(s)
- Karen Ichikawa
- School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand; Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand
| | - Hannah M Johnson
- School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
| | - Maurice A Curtis
- Centre for Brain Research, University of Auckland, Auckland, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand
| | - Nandita Biswas
- School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
| | - Snigdha Singh
- Department of Chemistry, University of Delhi, Delhi 110007, India
| | - Hasmik N Khachatryan
- Scientific Technological Centre of Organic and Pharmaceutical Chemistry, National Academy of Science of Armenia, Yerevan 0014, Armenia
| | - Anastasia E Gater
- School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
| | - Simon X Lin
- School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
| | - Jonathan Sperry
- School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand.
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Meng FD, Jia SM, Ma YB, Du YH, Liu WJ, Yang Y, Yuan L, Nan Y. Identification of key hub genes associated with anti-gastric cancer effects of lotus plumule based on machine learning algorithms. World J Gastrointest Oncol 2025; 17:103048. [PMID: 40235894 PMCID: PMC11995348 DOI: 10.4251/wjgo.v17.i4.103048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/11/2024] [Accepted: 01/16/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Lotus plumule and its active components have demonstrated inhibitory effects on gastric cancer (GC). However, the molecular mechanism of lotus plumule against GC remains unclear and requires further investigation. AIM To identify the key hub genes associated with the anti-GC effects of lotus plumule. METHODS This study investigated the potential targets of traditional Chinese medicine for inhibiting GC using weighted gene co-expression network analysis and bioinformatics. Initially, the active components and targets of the lotus plumule and the differentially expressed genes associated with GC were identified. Subsequently, a protein-protein interaction network was constructed to elucidate the interactions between drug targets and disease-related genes, facilitating the identification of hub genes within the network. The clinical significance of these hub genes was evaluated, and their upstream transcription factors and downstream targets were identified. The binding ability of a hub gene with its downstream targets was verified using molecular docking technology. Finally, molecular docking was performed to evaluate the binding affinity between the active ingredients of lotus plumule and the hub gene. RESULTS This study identified 26 genes closely associated with GC. Machine learning analysis and external validation narrowed the list to four genes: Aldo-keto reductase family 1 member B10, fructose-bisphosphatase 1, protein arginine methyltransferase 1, and carbonic anhydrase 9. These genes indicated a strong correlation with anti-GC activity. CONCLUSION Lotus plumule exhibits anti-GC effects. This study identified four hub genes with potential as novel targets for diagnosing and treating GC, providing innovative perspectives for its clinical management.
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Affiliation(s)
- Fan-Di Meng
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Shu-Min Jia
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yu-Bin Ma
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yu-Hua Du
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Wen-Jing Liu
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Yang
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ling Yuan
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Nan
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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Huang S, Nan Y, Chen G, Ning N, Du Y, Duan S, Li W, Yuan L. In vitro experiments and network pharmacology-based investigation of the molecular mechanism of neferine in the treatment of gastric cancer. PLoS One 2025; 20:e0318838. [PMID: 40138292 PMCID: PMC11940423 DOI: 10.1371/journal.pone.0318838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 01/22/2025] [Indexed: 03/29/2025] Open
Abstract
Background Gastric cancer is the world's leading tumor disease in terms of morbidity and mortality and is currently treated clinically with a comprehensive approach based on surgery. Studies have demonstrated the antitumor effects of neferine, but the anti-cancer mechanism for gastric cancer is not yet clear. Methods The Pubchem and Swiss TargetPrediction databases were searched to retrieve the targets of action of neferine. Meanwhile, relevant gene expression data were downloaded by means of the Gene Expression Omnibus(GEO) database to screen for differential genes and build a drug-disease network. The selected genes were analysed by bioinformatics analysis. Finally, gastric cancer treatment potential of neferine was determined through molecular docking. The molecular mechanism of neferine in the treatment of gastric cancer was verified by CCK8 assay, monoclonal assay, apoptotic and cycle assay, qRT-PCR and Western Blot. Results The results of network pharmacological analyses illustrate that the core genes are closely related to apoptosis, cell cycle, and cell proliferation. Through molecular docking, it was confirmed that neferine were closely related to key proteins. The results of in vitro experiments indicated that neferine could significantly inhibit the viability of gastric cancer cells, induce apoptosis of gastric cancer cells, and block the cell cycle of gastric cancer cells in the G0/G1 phase. Conclusion In summary, neferine inhibited the proliferation of gastric cancer cells through the CDK4/CDK6/CyclinD1 complex. This study provides a theoretical basis for the treatment of gastric cancer with neferine and an idea for the development of neferine for gastric cancer.
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Affiliation(s)
- Shicong Huang
- Pharmacy College of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yi Nan
- Key Laboratory of Ningxia Ethnomedicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Guoqing Chen
- Pharmacy College of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Na Ning
- Pharmacy College of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yuhua Du
- Pharmacy College of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Shuai Duan
- Pharmacy College of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Weiqiang Li
- Department of Chinese Medical Gastrointestinal, The Affiliated TCM Hospital of Ningxia Medical University, Wuzhong, China
| | - Ling Yuan
- Pharmacy College of Ningxia Medical University, Yinchuan, Ningxia, China
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Liu H, Wang S, Qiu K, Zheng C, Tan H. Preparation, structural characterization, and biological activities of lotus polysaccharides: A review. Int J Biol Macromol 2024; 279:135191. [PMID: 39216588 DOI: 10.1016/j.ijbiomac.2024.135191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 08/19/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
Lotus (Nelumbo nucifera), belonging to the family of Nelumbonaceae, is a beautiful aquatic perennial plant. It has been used as an ancient horticulture plant and famous agricultural crop for thousands of years. Modern phytochemical and pharmacological experiments have proved that polysaccharide is one of the most pivotal bioactive constituents of lotus. Hence, the systematic review covering the fundamental research advances and developing prospects of N. nucifera polysaccharides (NNPs) is an urgent demand to provide theoretical basis for their further research and application. The present review summarizes current emerging research progresses on the polysaccharides isolated from lotus, and it focuses on advanced extraction and purification methods, unique structural features, engaging biological activities, potential molecular mechanisms, as well as the relationship of structure and activity of NNPs. This review sheds light on the potential values of NNPs in affording functionally bioactive agents in food industry or therapeutically effective medicines for health care. In addition, this review will provide valuable insights for further commercial product development and promising industrial application of NNPs in both of the fundamental research communities and food or pharmaceutical industries in future.
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Affiliation(s)
- Hongxin Liu
- Engineering Research Center of Health Food Design & Nutrition Regulation, School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Sasa Wang
- Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi University for Nationalities, Nanning, China
| | - Kaidi Qiu
- State Key Laboratory of Plant Diversity and Specialty Crops, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chao Zheng
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Haibo Tan
- State Key Laboratory of Plant Diversity and Specialty Crops, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Sun X, Gu Y, Liu X, Korla PK, Hao J. Neferine Pretreatment Attenuates Isoproterenol-Induced Cardiac Injury Through Modulation of Oxidative Stress, Inflammation, and Apoptosis in Rats. Appl Biochem Biotechnol 2024; 196:7404-7428. [PMID: 38526658 DOI: 10.1007/s12010-024-04917-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/04/2024] [Indexed: 03/27/2024]
Abstract
Heart attacks, also known as myocardial infarctions (MIs), are one of the main reasons people die from cardiovascular diseases (CVDs) worldwide. Neferine, an alkaloid derived from Nelumbo nucifera seeds, has garnered interest due to its purported medicinal effects. In the current research, we induced MI in rats using the β-adrenergic agonist isoproterenol to investigate whether neferine can improve cardiac dysfunction. The rats were separated into four groups: control, isoproterenol (ISO), and two treatment groups received neferine at doses of 10 or 20 mg/kg once daily for 28 days. On days 27 and 28, the groups undergoing treatment were administered with an ISO injection. Results showed that pretreatment with neferine strongly protected against changes in lipid profiles and cardiac functional markers in ISO-administered rats. Neferine attenuated histopathologic changes, collagen deposition, and myocardial fibrosis in rats administered ISO. Neferine pretreatment significantly inhibited the oxidative stress, inflammatory, and apoptotic markers in the heart of ISO-injected rats. This was achieved through Nrf2/Keap1/ARE signaling stimulation, TLR4/NF-κB/MAPK-mediated signaling inhibition, and activation of the intrinsic apoptotic pathway. Using CB-Dock-2, researchers determined that neferine has a high binding affinity with protein receptors that are pivotal in several biological processes. In conclusion, the study provides strong evidence that pretreatment with neferine protects rats from ISO-induced heart damage.
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Affiliation(s)
- Xiaoqian Sun
- Cardiovascular Medicine Department, Xi'an Gaoxin Hospital, Xi'an, 710000, China
| | - Yongwen Gu
- Cardiovascular Medicine Department, Suzhou Yongding Hospital, Suzhou, 215200, China
| | - Xinghua Liu
- Cardiovascular Medicine Department, Putuo Center Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Praveen Kumar Korla
- Department of Clinical Science, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA
| | - Junjun Hao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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Zhou YX, Wang WP, Ke J, Ou HP, Chen LY, Hou AG, Li P, Ma YS, Bin Jin W. Nuciferine analogs block voltage-gated sodium, calcium and potassium channels to regulate the action potential and treat arrhythmia. Biomed Pharmacother 2024; 179:117422. [PMID: 39276399 DOI: 10.1016/j.biopha.2024.117422] [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: 07/10/2024] [Revised: 08/30/2024] [Accepted: 09/04/2024] [Indexed: 09/17/2024] Open
Abstract
Dysfunction of the Nav1.5, Cav1.2, and Kv channels could interfere with the AP and result in arrhythmias and even heart failure. We herein present a novel library of nuciferine analogs that target ion channels for the treatment of arrhythmias. Patch clamp measurements of ventricular myocytes revealed that 6a dramatically blocked both the INa and ICa without altering the currentvoltage relationship (including the activation potential and peak potential), accelerated the inactivation of Nav and Cav channels and delayed the resurrection of these channels after inactivation. Additionally, 6a significantly decreased the APA and RMP without affecting the APD30 or APD50. The IC50 values of 6a against Nav1.5 and Cav1.2 were 4.98 μM and 4.62 μM, respectively. Furthermore, 6a (10 μM) blocked IKs, IK1, and Ito with values of 17.01 %±2.54 %, 9.09 %±2.78 %, and 11.15 %±3.52 %, respectively. Surprisingly, 6a weakly inhibited hERG channels, suggesting a low risk of proarrhythmia. The cytotoxicity evaluation of 6a with the H9c2 cell line indicated that this compound was noncytotoxic. In vivo studies suggested that these novel nuciferine analogs could shorten the time of arrhythmia continuum induced by BaCl2 and normalize the HR, QRS, QT and QTc interval and the R wave amplitude. Moreover, 6a dose-dependently affected aconitine-induced arrhythmias and notably improved the cumulative dosage of aconitine required to evoke VP, VT, VF and CA in rats with aconitine-induced arrhythmia. In conclusion, nuciferine analogs could be promising ion channel blockers that could be further developed into antiarrhythmic agents.
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Affiliation(s)
- Ying Xun Zhou
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Wen Ping Wang
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Jin Ke
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Hui Ping Ou
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Lin Yun Chen
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - An Guo Hou
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Peng Li
- School of Food and Drug, Shenzhen Polytechnic University, Shenzhen, Guangdong, China; State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
| | - Yun Shu Ma
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China.
| | - Wen Bin Jin
- Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China; State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
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Xiong Y, Zhong J, Chen W, Li X, Liu H, Li Y, Xiong W, Li H. Neferine alleviates acute kidney injury by regulating the PPAR-α/NF-κB pathway. Clin Exp Nephrol 2024; 28:969-987. [PMID: 38658442 DOI: 10.1007/s10157-024-02504-8] [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: 07/15/2023] [Accepted: 04/07/2024] [Indexed: 04/26/2024]
Abstract
Acute kidney injury (AKI) is a cluster of clinical syndromes with diverse etiologies that ultimately result in a swift decline in kidney function. Regrettably, AKI lacks effective therapeutic agents at present. Neferine, a bioactive alkaloid derived from Lotus Plumule, has been reported to alleviate AKI triggered by cisplatin, ischemia/reperfusion (I/R), and sepsis by inhibiting inflammatory pathways. However, the precise molecular mechanisms underpinning its renoprotective effects remain elusive. Peroxisome proliferator-activated receptor alpha (PPAR-α), a regulator of lipid metabolism with anti-inflammatory properties, was investigated in this study to examine its role in neferine's renoprotective effects in cellular and mouse models of AKI. We found that neferine pretreatment in both I/R- or lipopolysaccharide (LPS)-induced AKI models inhibited the activation of the NF-κB inflammatory pathway and reversed PPAR-α deficiency. In NRK-52E cells exposed to hypoxia/reoxygenation (H/R) or LPS, overexpression of PPAR-α resulted in inhibition of the NF-κB pathway and TNF-α production, while PPAR-α silencing via siRNA transfection negated neferine's anti-inflammatory effects. Furthermore, pretreatment with neferine not only reduced lipid accumulation but also reversed the downregulation of FAO-related enzymes induced by LPS. Our findings suggest that neferine's renoprotective effects against AKI are partially mediated through the reversal of renal PPAR-α deficiency and subsequent inhibition of the inflammatory NF-κB pathway. Therefore, regulating renal PPAR-α expression by neferine could represent a promising therapeutic strategy for AKI.
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Affiliation(s)
- Yanying Xiong
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Jin Zhong
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Wenhang Chen
- Department of Nephropathy, Xiangya Hospital Central-South University, Changsha, Hunan, China
| | - Xuan Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Hong Liu
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Ying Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Weijian Xiong
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Huihui Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China.
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Meneses-Sagrero SE, Rascón-Valenzuela LA, Arellano-García ME, Toledano-Magaña Y, García-Ramos JC. Natural compounds combined with imatinib as promising antileukemic therapy: An updated review. Fitoterapia 2024; 178:106185. [PMID: 39142530 DOI: 10.1016/j.fitote.2024.106185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/02/2024] [Accepted: 08/10/2024] [Indexed: 08/16/2024]
Abstract
Natural products (NP) have been an alternative therapy for several diseases for centuries, and they also serve as an essential source of bioactive molecules, enhancing our drug discovery capacity. Among these NP, some phytochemicals have shown multiple biological effects, including anticancer activity, with higher effectiveness and less toxicity than actual treatments, suggesting their possible use on resilient human malignancies such as leukemia. Imatinib mesylate (Im) is a selective tyrosine kinase inhibitor widely used as an anticancer drug, the gold standard to attend chronic myeloid leukemia (CML). Nevertheless, resistance to this drug in patients with CML renders it insufficient to eliminate cells with Philadelphia chromosome (BCR/ABL+). Moreover, recent studies show that imatinib can induce genotoxic and chromosomic damage in some in vitro and in vivo models. These facts urge finding new therapeutic alternatives to increase the effectiveness of antileukemic treatment. Recent research has shown that the combined effects of phytochemicals with imatinib can improve the cytotoxicity or resensitized the resistant cells to this drug in diverse leukemia cell lines. Independent mechanisms of action among phytochemicals and imatinib include BCR/ABL regulation, downregulation of transcription factors, inhibition of anti-apoptotic and activation of pro-apoptotic proteins, apoptosis induction dependent- and independent of ROS-overproduction, membrane functions disruption, induction of cell cycle arrest, and cell death. This review summarizes and discusses the synergic effect of some phytochemicals combined with imatinib on leukemia cells and the mechanism of action proposed for these combinations, looking to contribute to developing new effective alternatives for leukemia treatment.
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Affiliation(s)
| | - Luisa Alondra Rascón-Valenzuela
- Departamento de Ciencias Químico Biológicas, Universidad de Sonora, Blvd. Luis Encinas y Rosales S/N, Col. Centro, Hermosillo, Sonora, Mexico
| | - María Evarista Arellano-García
- Facultad de Ciencias, Universidad Autónoma de Baja California, Ctra. Transpeninsular No. 3917, Col. Playitas, Ensenada, Baja California, Mexico
| | - Yanis Toledano-Magaña
- Instituto Tecnológico de Ensenada, Tecnológico Nacional de México, Blvd. Tecnológico #150, Ex Ejido Chapultepec, Ensenada, Baja California, Mexico; Centro de Bachillerato Tecnológico Industrial y de Servicios No. 41. Dirección General de Educación Tecnológica Industrial y de Servicios, Carr. Transpeninsular km 115, Ex-Ejido Chapultepec, Ensenada, Baja California, Mexico.
| | - Juan Carlos García-Ramos
- Instituto Tecnológico de Ensenada, Tecnológico Nacional de México, Blvd. Tecnológico #150, Ex Ejido Chapultepec, Ensenada, Baja California, Mexico; Centro de Bachillerato Tecnológico Industrial y de Servicios No. 41. Dirección General de Educación Tecnológica Industrial y de Servicios, Carr. Transpeninsular km 115, Ex-Ejido Chapultepec, Ensenada, Baja California, Mexico.
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13
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Alkanad M, Hani U, V AH, Ghazwani M, Haider N, Osmani RAM, M D P, Hamsalakshmi, Bhat R. Bitter yet beneficial: The dual role of dietary alkaloids in managing diabetes and enhancing cognitive function. Biofactors 2024; 50:634-673. [PMID: 38169069 DOI: 10.1002/biof.2034] [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: 06/24/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
With the rising prevalence of diabetes and its association with cognitive impairment, interest in the use of dietary alkaloids and other natural products has grown significantly. Understanding how these compounds manage diabetic cognitive dysfunction (DCD) is crucial. This comprehensive review explores the etiology of DCD and the effects of alkaloids in foods and dietary supplements that have been investigated as DCD therapies. Data on how dietary alkaloids like berberine, trigonelline, caffeine, capsaicin, 1-deoxynojirimycin, nuciferine, neferine, aegeline, tetramethylpyrazine, piperine, and others regulate cognition in diabetic disorders were collected from PubMed, Research Gate, Web of Science, Science Direct, and other relevant databases. Dietary alkaloids could improve memory in behavioral models and modulate the mechanisms underlying the cognitive benefits of these compounds, including their effects on glucose metabolism, gut microbiota, vasculopathy, neuroinflammation, and oxidative stress. Evidence suggests that dietary alkaloids hold promise for improving cognition in diabetic patients and could open exciting avenues for future research in diabetes management.
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Affiliation(s)
- Maged Alkanad
- Department of Pharmacognosy, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, India
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Annegowda H V
- Department of Pharmacognosy, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, India
| | - Mohammed Ghazwani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Nazima Haider
- Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Riyaz Ali M Osmani
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
| | - Pandareesh M D
- Center for Research and Innovations, Adichunchanagiri University, BGSIT, Mandya, India
| | - Hamsalakshmi
- Department of Pharmacognosy, Cauvery College of Pharmacy, Cauvery Group of Institutions, Mysuru, India
| | - Rajeev Bhat
- ERA-Chair in Food By-Products Valorisation Technologies (VALORTECH), Estonian University of Life Sciences, Tartu, Estonia
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14
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Zheng ZJ, Zhu LZ, Qiu H, Zheng WYX, You PT, Chen SH, Hu CL, Huang JR, Zhou YJ. Neferine inhibits BMECs pyroptosis and maintains blood-brain barrier integrity in ischemic stroke by triggering a cascade reaction of PGC-1α. Sci Rep 2024; 14:14438. [PMID: 38910141 PMCID: PMC11194274 DOI: 10.1038/s41598-024-64815-w] [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: 01/15/2024] [Accepted: 06/13/2024] [Indexed: 06/25/2024] Open
Abstract
Blood-brain barrier disruption is a critical pathological event in the progression of ischemic stroke (IS). Most studies regarding the therapeutic potential of neferine (Nef) on IS have focused on neuroprotective effect. However, whether Nef attenuates BBB disruption during IS is unclear. We here used mice underwent transient middle cerebral artery occlusion (tMCAO) in vivo and bEnd.3 cells exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro to simulate cerebral ischemia. We showed that Nef reduced neurobehavioral dysfunction and protected brain microvascular endothelial cells and BBB integrity. Molecular docking, short interfering (Si) RNA and plasmid transfection results showed us that PGC-1α was the most binding affinity of biological activity protein for Nef. And verification experiments were showed that Nef upregulated PGC-1α expression to reduce mitochondrial oxidative stress and promote TJ proteins expression, further improves the integrity of BBB in mice. Intriguingly, our study showed that neferine is a natural PGC-1α activator and illustrated the mechanism of specific binding site. Furthermore, we have demonstrated Nef reduced mitochondria oxidative damage and ameliorates endothelial inflammation by inhibiting pyroptosis to improve BBB permeability through triggering a cascade reaction of PGC-1α via regulation of PGC-1α/NLRP3/GSDMD signaling pathway to maintain the integrity of BBB in ischemia/reperfusion injury.
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Affiliation(s)
- Zi-Jian Zheng
- Department of Pharmacy, Gongan Hospital of Traditional Chinese Medicine, Jingzhou, 434300, China
- Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Li-Zhi Zhu
- Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518055, China
| | - Han Qiu
- Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 West Sungang Rd, Shenzhen, 518020, China
| | - Wu-Yin-Xiao Zheng
- Department of Pharmacy, Gongan Hospital of Traditional Chinese Medicine, Jingzhou, 434300, China
- Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Peng-Tao You
- Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Shu-He Chen
- Department of Pharmacy, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
- Hubei Shizhen Laboratory, Wuhan, 430061, China
| | - Chun-Ling Hu
- Hubei University of Chinese Medicine, Wuhan, 430061, China
| | - Jun-Rong Huang
- Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518055, China
| | - Ya-Jun Zhou
- Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 West Sungang Rd, Shenzhen, 518020, China.
- Department of Pharmacy, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China.
- Hubei Shizhen Laboratory, Wuhan, 430061, China.
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15
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Jiang XX, Zhang R, Wang HS. Neferine mitigates angiotensin II-induced atrial fibrillation and fibrosis via upregulation of Nrf2/HO-1 and inhibition of TGF-β/p-Smad2/3 pathways. Aging (Albany NY) 2024; 16:8630-8644. [PMID: 38775722 PMCID: PMC11164477 DOI: 10.18632/aging.205829] [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: 01/08/2024] [Accepted: 04/10/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND Atrial fibrillation (AF) is often associated with atrial fibrosis and oxidative stress. Neferine, a bisbenzylisoquinoline alkaloid, has been reported to exert an antiarrhythmic effect. However, its impact on Angiotensin II (Ang II) infusion-induced AF and the underlying mechanism remains unclear. This study aimed to investigate whether neferine alleviates Ang II-induced AF and explore the underlying mechanisms. METHODS Mice subjected to Ang II infusion to induce AF were concurrently treated with neferine or saline. AF incidence, myocardial cell size, fibrosis, and oxidative stress were then examined. RESULTS Neferine treatment inhibited Ang II-induced AF, atrial size augmentation, and atrial fibrosis. Additionally, we observed that Ang II increased reactive oxygen species (ROS) generation, induced mitochondrial membrane potential depolarization, and reduced glutathione (GSH) and superoxide dismutase (SOD) levels, which were reversed to some extent by neferine. Mechanistically, neferine activated the Nrf2/HO-1 signaling pathway and inhibited TGF-β/p-Smad2/3 in Ang II-infused atria. Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, reduced the anti-oxidative effect of neferine to some extent and subsequently abolished the beneficial effect of neferine on Ang II-induced AF. CONCLUSIONS These findings provide hitherto undocumented evidence that the protective role of neferine in Ang II-induced AF is dependent on HO-1.
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Affiliation(s)
- Xiao-Xiao Jiang
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Ri Zhang
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Hui-Shan Wang
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Command, Shenyang 110016, Liaoning, China
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16
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Chen J, Gao Y, Liu N, Hai D, Wei W, Liu Y, Lan X, Jin X, Yu J, Ma L. Mechanism of NLRP3 Inflammasome in Epilepsy and Related Therapeutic Agents. Neuroscience 2024; 546:157-177. [PMID: 38574797 DOI: 10.1016/j.neuroscience.2024.03.029] [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: 12/31/2023] [Revised: 03/05/2024] [Accepted: 03/27/2024] [Indexed: 04/06/2024]
Abstract
Epilepsy is one of the most widespread and complex diseases in the central nervous system (CNS), affecting approximately 65 million people globally, an important factor resulting in neurological disability-adjusted life year (DALY) and progressive cognitive dysfunction. Medication is the most essential treatment. The currently used drugs have shown drug resistance in some patients and only control symptoms; the development of novel and more efficacious pharmacotherapy is imminent. Increasing evidence suggests neuroinflammation is involved in the occurrence and development of epilepsy, and high expression of NLRP3 inflammasome has been observed in the temporal lobe epilepsy (TLE) brain tissue of patients and animal models. The inflammasome is a crucial cause of neuroinflammation by activating IL-1β and IL-18. Many preclinical studies have confirmed that regulating NLRP3 inflammasome pathway can prevent the development of epilepsy, reduce the severity of epilepsy, and play a neuroprotective role. Therefore, regulating NLRP3 inflammasome could be a potential target for epilepsy treatment. In summary, this review describes the priming and activation of inflammasome and its biological function in the progression of epilepsy. In addition, we reviewes the current pharmacological researches for epilepsy based on the regulation of NLRP3 inflammasome, aiming to provide a basis and reference for developing novel antiepileptic drugs.
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Affiliation(s)
- Juan Chen
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Yuan Gao
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Ning Liu
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Dongmei Hai
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Wei Wei
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Yue Liu
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Xiaobing Lan
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Xueqin Jin
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China.
| | - Jianqiang Yu
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China.
| | - Lin Ma
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China.
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Liang J, Bao D, Ye Z, Cao B, Lu Z, Chen J. Neferine alleviates ovariectomy-induced osteoporosis by enhancing osteogenic differentiation of bone marrow mesenchymal stem cells via regulation of the p38MAPK pathway. Connect Tissue Res 2024; 65:253-264. [PMID: 38753365 DOI: 10.1080/03008207.2024.2351097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 04/29/2024] [Indexed: 05/31/2024]
Abstract
OBJECTIVE Osteoporosis, a skeletal ailment marked by bone metabolism imbalance and disruption of bone microarchitecture, Neferine, a bisbenzylisoquinoline alkaloid with diverse pharmacological activities, has received limited attention in the context of osteoporosis treatment. METHODS We employed a bilateral ovariectomy (OVX) rat model to induce osteoporosis and subsequently administered Neferine treatment for four weeks following successful model establishment. Throughout the modeling and treatment phases, we closely monitored rat body weights. We assessed alterations in bone tissue microstructure through micro-CT, HE staining, and safranin O-fast green staining. Levels of bone formation and resorption markers in serum were evaluated using ELISA assay. Western blot analysis was employed to determine the expression levels of p38MAPK, p-p38MAPK, and bone formation-related genes in bone tissue. We isolated and cultured OVX rat BMSCs (OVX-BMSCs) and induced osteogenic differentiation while simultaneously introducing Neferine and the p38MAPK inhibitor SB203580 for intervention. RESULTS Neferine treatment effectively curbed the rapid weight gain in OVX rats, ameliorated bone loss, and decreased serum levels of TRAP, CTX-I, PINP, and BALP. Most notably, Neferine promoted the expression of bone formation-related factors in bone tissue of OVX rats, while concurrently activating the p38MAPK signaling pathway. In in vitro experiments, Neferine facilitated the expression of bone formation-related factors in OVX-BMSCs, increased the osteogenic differentiation potential of OVX-BMSCs, and activated the p38MAPK signaling pathway. Nevertheless, SB203580 partially reversed Neferine's promotive effect. CONCLUSION Neferine can boost the osteoblastic differentiation of BMSCs and alleviate OVX-induced osteoporosis in rats by activating the p38MAPK signaling pathway.
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Affiliation(s)
- Jianwei Liang
- Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China
| | - Dandan Bao
- Department of Pharmacy, Taizhou First People's Hospital, Taizhou, China
| | - Zhan Ye
- Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China
| | - Binhao Cao
- Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China
| | - Zhenyu Lu
- Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China
| | - Jianjun Chen
- Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China
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18
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Yang K, Zeng L, He Q, Wang S, Xu H, Ge J. Advancements in research on the immune-inflammatory mechanisms mediated by NLRP3 inflammasome in ischemic stroke and the regulatory role of natural plant products. Front Pharmacol 2024; 15:1250918. [PMID: 38601463 PMCID: PMC11004298 DOI: 10.3389/fphar.2024.1250918] [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: 06/30/2023] [Accepted: 01/11/2024] [Indexed: 04/12/2024] Open
Abstract
Ischemic stroke (IS) is a major cause of mortality and disability among adults. Recanalization of blood vessels to facilitate timely reperfusion is the primary clinical approach; however, reperfusion itself may trigger cerebral ischemia-reperfusion injury. Emerging evidence strongly implicates the NLRP3 inflammasome as a potential therapeutic target, playing a key role in cerebral ischemia and reperfusion injury. The aberrant expression and function of NLRP3 inflammasome-mediated inflammation in cerebral ischemia have garnered considerable attention as a recent research focus. Accordingly, this review provides a comprehensive summary of the signaling pathways, pathological mechanisms, and intricate interactions involving NLRP3 inflammasomes in cerebral ischemia-reperfusion injury. Moreover, notable progress has been made in investigating the impact of natural plant products (e.g., Proanthocyanidins, methylliensinine, salidroside, α-asarone, acacia, curcumin, morin, ginsenoside Rd, paeoniflorin, breviscapine, sulforaphane, etc.) on regulating cerebral ischemia and reperfusion by modulating the NLRP3 inflammasome and mitigating the release of inflammatory cytokines. These findings aim to present novel insights that could contribute to the prevention and treatment of cerebral ischemia and reperfusion injury.
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Affiliation(s)
- Kailin Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Academy of Chinese Medicine, Changsha, Hunan, China
| | - Liuting Zeng
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi He
- Department of Critical Care Medicine, People’s Hospital of Ningxiang City, Ningxiang, China
| | - Shanshan Wang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Hao Xu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Jinwen Ge
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Academy of Chinese Medicine, Changsha, Hunan, China
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19
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Yarmohammadi F, Hesari M, Shackebaei D. The Role of mTOR in Doxorubicin-Altered Cardiac Metabolism: A Promising Therapeutic Target of Natural Compounds. Cardiovasc Toxicol 2024; 24:146-157. [PMID: 38108960 DOI: 10.1007/s12012-023-09820-7] [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: 09/22/2023] [Accepted: 12/09/2023] [Indexed: 12/19/2023]
Abstract
Doxorubicin (DOX) is commonly used for the treatment of various types of cancer, however can cause serious side effects, including cardiotoxicity. The mechanisms involved in DOX-induced cardiac damage are complex and not yet fully understood. One mechanism is the disruption of cardiac metabolism, which can impair cardiac function. The mammalian target of rapamycin (mTOR) is a key regulator of cardiac energy metabolism, and dysregulation of mTOR signaling has been implicated in DOX-induced cardiac dysfunction. Natural compounds (NCs) have been shown to improve cardiac function in vivo and in vitro models of DOX-induced cardiotoxicity. This review article explores the protective effects of NCs against DOX-induced cardiac injury, with a focus on their regulation of mTOR signaling pathways. Generally, the modulation of mTOR signaling by NCs represents a promising strategy for decreasing the cardiotoxic effects of DOX.
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Affiliation(s)
- Fatemeh Yarmohammadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mahvash Hesari
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Dareuosh Shackebaei
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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20
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Wang Q, Guo L, Zeng Z, Huang Y, Tang H, Hu H, Yuan X, Deng J, Qin G, Wang X, Zhang Y. Neferine Attenuates HDM-Induced Allergic Inflammation by Inhibiting the Activation of Dendritic Cell. Inflammation 2023; 46:2433-2448. [PMID: 37702907 DOI: 10.1007/s10753-023-01891-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/05/2023] [Accepted: 08/15/2023] [Indexed: 09/14/2023]
Abstract
House dust mite (HDM) acts as an environmental antigen that might cause chronic allergic diseases. Neferine (NEF) shows anti-inflammation therapeutic effects. This study is to explore the protection role of NEF against HDM-induced allergic inflammation. HDM-induced allergic asthmatic C57BL/6J mice models were established. Differential histological staining was used to analyze lung tissue pathological scores. Flow cytometry was used to analyze subtypes and biomarker expression of immune cells. RT-PCR and ELISA were used to test cytokines-related gene and/or protein expression levels. Western blot was performed to investigate the signaling pathway that mediates allergic inflammation from mice lung tissue and bone marrow-derived dendritic cells (BMDCs). H&E and PAS staining results indicate NEF significantly attenuated inflammatory index and the percentage of goblet cells in the lung tissue induced by HDM. The HDM-elevated TH2 and TH17 cells were significantly decreased by NEF; inflammatory cytokines Il-4, Il-13 and Il-17 were dramatically downregulated in the NEF plus HDM group compared with HDM alone. CD40+ and CD86+ DCs, eosinophils and mast cells, and ILC2 cells were decreased by NEF which was elevated under HDM stimulation. In vivo and ex vivo investigations indicated NEF can attenuate the activated NF-κB signaling induced by HDM is involved in allergic inflammatory immune response and regulates cytokines-related gene expression. HDM-activated DCs promoted differentiation of TH2 and TH17 cells but were attenuated by NEF. This study suggests NEF interrupts the overexpression of some cytokines released by DCs, TH2, and TH17 cells; NEF attenuates HDM-induced allergic inflammation via inhibiting NF-κB signaling of DCs.
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Affiliation(s)
- Qiao Wang
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Linlin Guo
- Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, USA.
| | - Ziling Zeng
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yueru Huang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Hongmei Tang
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Hang Hu
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xiefang Yuan
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jun Deng
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Gang Qin
- Department of Otolaryngology Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xing Wang
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Yun Zhang
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
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Dasari S, Pathak N, Thomas A, Bitla S, Kumar R, Munirathinam G. Neferine Targets the Oncogenic Characteristics of Androgen-Dependent Prostate Cancer Cells via Inducing Reactive Oxygen Species. Int J Mol Sci 2023; 24:14242. [PMID: 37762540 PMCID: PMC10532349 DOI: 10.3390/ijms241814242] [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: 08/22/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Castration resistance poses a significant challenge in the management of advanced prostate cancer (PCa), with androgen deprivation therapy (ADT) or chemotherapy being the primary treatment options. However, these approaches often lead to significant side effects and the development of therapeutic resistance. Therefore, it is crucial to explore novel treatment options that can efficiently target PCa, improve patient survival, and enhance their quality of life. Neferine (Nef), a bioactive compound derived from plants, has emerged as a promising candidate for cancer treatment due to its ability to induce apoptosis, autophagy, and cell cycle arrest. In this study, we investigated the potential anticancer effects of Nef in androgen receptor (AR)-positive LNCaP and VCaP cells, representative models of androgen-dependent PCa. Our findings demonstrate that Nef effectively inhibits cell growth, proliferation, and the tumorigenic potential of androgen-dependent PCa cells. Furthermore, Nef treatment resulted in the excessive production of reactive oxygen species (ROS), leading to the activation of key markers of autophagy and apoptosis. These results suggest that Nef has the potential to target the oncogenic characteristics of androgen-dependent PCa cells by exploiting the potency of ROS and inducing autophagy and apoptosis in AR-positive PCa cells. These findings shed light on the therapeutic potential of Nef as a novel treatment option with reduced side effects for androgen-dependent prostate cancer. Further investigations are warranted to assess its efficacy and safety in preclinical and clinical settings.
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Affiliation(s)
- Subramanyam Dasari
- School of Medicine, Indiana University Bloomington, Bloomington, IN 47405, USA;
| | - Nishtha Pathak
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL 61108, USA; (N.P.); (A.T.); (S.B.)
| | - Amy Thomas
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL 61108, USA; (N.P.); (A.T.); (S.B.)
| | - Shreeja Bitla
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL 61108, USA; (N.P.); (A.T.); (S.B.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173234, Himachal Pradesh, India;
| | - Gnanasekar Munirathinam
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL 61108, USA; (N.P.); (A.T.); (S.B.)
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22
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Yang J, Zhang Q, Huang G, Cong J, Wang T, Zhai X, Zhang J, Qi G, Zhou L, Jin J. Combined effects of vitamin D and neferine on the progression and metastasis of colorectal cancer. J Cancer Res Clin Oncol 2023; 149:6203-6210. [PMID: 36697773 PMCID: PMC10356635 DOI: 10.1007/s00432-022-04552-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 12/21/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE To investigate the synergistic effect of vitamin D and neferine on the growth and metastasis of colorectal cancer (CRC). METHODS The synergistic effect of biologically active form of vitamin D, VD3 and neferine on the treatment of CRC was investigated by bliss analysis. Colony formation and wound healing ability, migration and invasion ability, and epithelial mesenchymal transition of HCT-116 cells, as a response to the combination treatment with VD3 and neferine were evaluated. RESULTS VD3 and neferine showed a synergistic effect on CRC cell growth at a relatively low dose. The wound healing and colony formation capacity, cell migration and invasion abilities were all decreased by combination use of VD3 and neferine, compared to the VD3 or neferine treated single group. Furthermore, VD3 and neferine significantly decreased the expressions of N-cadherin, vimentin, snail, and slug in HCT-116 cells. CONCLUSION These data suggest that neferine enhances the anticancer capability of VD3 and reduces the dose dependency of VD3. The combination of vitamin D with neferine appears to be a potential therapeutic strategy for CRC.
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Affiliation(s)
- Jinfeng Yang
- School of Pharmacy, Guilin Medical University, Guilin, 541199 China
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Department of Immunology, Guilin Medical University, Guilin, 541199 China
| | - Qinyu Zhang
- School of Pharmacy, Guilin Medical University, Guilin, 541199 China
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
| | - Guanlin Huang
- School of Pharmacy, Guilin Medical University, Guilin, 541199 China
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
| | - Jiacheng Cong
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Department of Immunology, Guilin Medical University, Guilin, 541199 China
| | - Ting Wang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199 China
| | - Xiaoya Zhai
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199 China
| | - Juzheng Zhang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199 China
| | - Guangying Qi
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199 China
| | - Lihua Zhou
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
| | - Jiamin Jin
- School of Pharmacy, Guilin Medical University, Guilin, 541199 China
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199 China
- Guangxi Health Commission Key Laboratory of Tumor Immunology and Receptor-Targeted Drug Basic Research, Guilin Medical University, Guilin, 541199 China
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Wu F, Wu Z, Ye Z, Niu G, Ma Z, Zhang P. PLGA/BGP/Nef porous composite restrains osteoclasts by inhibiting the NF-κB pathway, enhances IGF-1-mediated osteogenic differentiation and promotes bone regeneration. J Biol Eng 2023; 17:45. [PMID: 37461106 DOI: 10.1186/s13036-023-00354-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/15/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Novel bone substitutes are urgently needed in experimental research and clinical orthopaedic applications. There are many traditional Chinese medicines that have effects on bone repair. However, application of natural medicines in traditional Chinese medicine to bone tissue engineering and its mechanism were rarely reported. RESULTS In this study, the osteogenic ability of bioactive glass particles (BGPs) and the osteogenic and osteoclastic ability of neferine (Nef) were fused into PLGA-based bone tissue engineering materials for bone regeneration. BGPs were prepared by spray drying and calcination. Particles and Nef were then mixed with PLGA solution to prepare porous composites by the phase conversion method. Here we showed that Nef inhibited proliferation and enhanced ALP activity of MC3T3-E1 cells in a dose- and time-dependent manner. And the composites containing Nef could also inhibit RANKL-induced osteoclast formation (p < 0.05). Mechanistically, the PLGA/BGP/Nef composite downregulated the expression of NFATC1 by inhibiting the NF-κB pathway to restrain osteoclasts. In the other hands, PLGA/BGP/Nef composite was first demonstrated to effectively activate the IGF-1R/PI3K/AKT/mTOR pathway to enhance IGF-1-mediated osteogenic differentiation. The results of animal experiments show that the material can effectively promote the formation and maturation of new bone in the skull defect site. CONCLUSIONS The PLGA/BGP/Nef porous composite can restrain osteoclasts by inhibiting the NF-κB pathway, enhance IGF-1-mediated osteogenic differentiation and promotes bone regeneration, and has the potential for clinical application.
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Affiliation(s)
- Feng Wu
- Foshan Hospital of Traditional Chinese Medicine/Foshan Hospital of TCM, Foshan, China.
| | - Zhenxu Wu
- Key Laboratory of Polymer Ecomaterials, Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
| | - Zhijun Ye
- Foshan Hospital of Traditional Chinese Medicine/Foshan Hospital of TCM, Foshan, China
| | - Guoqing Niu
- Foshan Hospital of Traditional Chinese Medicine/Foshan Hospital of TCM, Foshan, China
| | - Zhiliang Ma
- Foshan Hospital of Traditional Chinese Medicine/Foshan Hospital of TCM, Foshan, China
| | - Peibiao Zhang
- Key Laboratory of Polymer Ecomaterials, Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
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Liu CM, Shao Z, Chen X, Chen H, Su M, Zhang Z, Wu Z, Zhang P, An L, Jiang Y, Ouyang AJ. Neferine attenuates development of testosterone-induced benign prostatic hyperplasia in mice by regulating androgen and TGF-β/Smad signaling pathways. Saudi Pharm J 2023; 31:1219-1228. [PMID: 37293563 PMCID: PMC10244910 DOI: 10.1016/j.jsps.2023.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/06/2023] [Indexed: 06/10/2023] Open
Abstract
Benign prostatic hyperplasia (BPH) is a common urinary disease among the elderly, characterized by abnormal prostatic cell proliferation. Neferine is a dibenzyl isoquinoline alkaloid extracted from Nelumbo nucifera and has antioxidant, anti-inflammatory and anti-prostate cancer effects. The beneficial therapeutic effects and mechanism of action of neferine in BPH remain unclear. A mouse model of BPH was generated by subcutaneous injection of 7.5 mg/kg testosterone propionate (TP) and 2 or 5 mg/kg neferine was given orally for 14 or 28 days. Pathological and morphological characteristics were evaluated. Prostate weight, prostate index (prostate/body weight ratio), expression of type Ⅱ 5α-reductase, androgen receptor (AR) and prostate specific antigen were all decreased in prostate tissue of BPH mice after administration of neferine. Neferine also downregulated the expression of pro-caspase-3, uncleaved PARP, TGF-β1, TGF-β receptor Ⅱ (TGFBR2), p-Smad2/3, N-cadherin and vimentin. Expression of E-cadherin, cleaved PARP and cleaved caspase-3 was increased by neferine treatment. 1-100 μM neferine with 1 μM testosterone or 10 nM TGF-β1 were added to the culture medium of the normal human prostate stroma cell line, WPMY-1, for 24 h or 48 h. Neferine inhibited cell growth and production of reactive oxygen species (ROS) in testosterone-treated WPMY-1 cells and regulated the expression of androgen signaling pathway proteins and those related to epithelial-mesenchymal transition (EMT). Moreover, TGF-β1, TGFBR2 and p-Smad2/3, N-cadherin and vimentin expression were increased but E-cadherin was decreased after 24 h TGF-β1 treatment in WPMY-1 cells. Neferine reversed the effects of TGF-β1 treatment in WPMY-1 cells. Neferine appeared to suppress prostate growth by regulating the EMT, AR and TGF-β/Smad signaling pathways in the prostate and is suggested as a potential agent for BPH treatment.
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Affiliation(s)
- Chi-Ming Liu
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - ZiChen Shao
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
- College of Chemistry and Bio-engineering, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - XuZhou Chen
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - HanWu Chen
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - MengQiao Su
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
- College of Chemistry and Bio-engineering, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - ZiWen Zhang
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - ZhengPing Wu
- School of Aesthetic Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - Peng Zhang
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - LiJie An
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
- College of Chemistry and Bio-engineering, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - YinJie Jiang
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China
| | - Ai-Jun Ouyang
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang 330006, Jiangxi Province, China
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Wang MY, Zhang SS, An MF, Xia YF, Fan MS, Sun ZR, Zhang LJ, Zhao YL, Sheng J, Wang XJ. Neferine ameliorates nonalcoholic steatohepatitis through regulating AMPK pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154798. [PMID: 37031639 DOI: 10.1016/j.phymed.2023.154798] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD), peculiarly nonalcoholic steatohepatitis (NASH), has become the main cause of liver transplantation and liver-related death. However, the US Food and Drug Administration has not approved a specific medication for treating NASH. Neferine (NEF), a natural bisbenzylisoquinoline alkaloid separated from the traditional Chinese medicine Nelumbinis plumula, has a variety of pharmacological properties, especially on metabolic diseases. Nevertheless, the anti-NASH effect and mechanisms of NEF remain unclear. PURPOSE This study aimed to investigate the amelioration of NEF on NASH and the potential mechanisms. STUDY DESIGN HepG2 cells, hepatic stellate cells (HSCs) and high-fat diet (HFD)+carbon tetrachloride (CCl4) induced C57BL/6 mice were used to observe the effect of NEF against NASH and investigate the engaged mechanism. METHODS HSCs and HepG2 cells stimulated by oleic acid (OA) were treated with NEF. C57BL/6 mice were fed with HFD+CCl4 to induce NASH mouse model and treated with or without NEF (5 mg/kg or 10 mg/kg, once daily, i.p) for 4 weeks. RESULTS NEF significantly attenuated the accumulation of lipid droplets, intracellular triglyceride (TG) levels and hepatocytes apoptosis in OA-exposed HepG2 cells. NEF not only enhanced the AMPK and ACC phosphorylation in OA-stimulated HepG2 cells, but also reduced inflammatory response and fibrosis in lipopolysaccharide (LPS)-stimulated HepG2 and in LX-2, respectively. In HFD+CCl4-induced NASH mice, pathological staining confirmed NEF treatment mitigated hepatic lipid deposition, inflammatory cell infiltration as well as hepatic fibrosis. Furthermore, the liver weight, serum and hepatic TG and total cholesterol (TC) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were decreased compared with the model group. HFD+CCl4 also induced the upregulation of specific proteins and genes associated to inflammation (ILs, TNF-α, NLRP3, ASC, CCL2 and CXCL10) and hepatic fibrosis (collagens, α-SMA, TGF-β and TIPM1), which were also suppressed by NEF treatment. CONCLUSION Our results demonstrated that NEF played a protective role in hepatic steatosis via the regulation of AMPK pathways, which may serve as an attractive candidate for a potential novel strategy on prevention and treatment of NASH.
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Affiliation(s)
- Ming-Yue Wang
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650224, P. R. China
| | - Shao-Shi Zhang
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650224, P. R. China
| | - Meng-Fei An
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Science, Yunnan Agricultural University, Kunming 650224, P. R. China
| | - Yue-Fei Xia
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650224, P. R. China
| | - Mao-Si Fan
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650224, P. R. China
| | - Ze-Rui Sun
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650224, P. R. China
| | - Li-Juan Zhang
- School of Basic Medicine, Yunnan University of Chinese Medicine Chinese, Kunming 650500, P. R. China
| | - Yun-Li Zhao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Provincial Center for Research & Development of Natural Products; School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China.
| | - Jun Sheng
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Science, Yunnan Agricultural University, Kunming 650224, P. R. China; State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming 650224, P. R. China.
| | - Xuan-Jun Wang
- Key Laboratory of Pu-erh Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650224, P. R. China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650224, P. R. China; Yunnan Research Institute of Plateau Characteristic Agricultural and Industry, Yunnan Agricultural University, Kunming 650224, P. R. China.
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Hao C, Yang W, Dong G, Yu Y, Liu Y, Zhang J, Zhu Y, Wei X, Chen S. Visualization and identification of benzylisoquinoline alkaloids in various nelumbo nucifera tissues. Heliyon 2023; 9:e16138. [PMID: 37251486 PMCID: PMC10220311 DOI: 10.1016/j.heliyon.2023.e16138] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 05/31/2023] Open
Abstract
Benzylisoquinoline alkaloids in lotus (Nelumbo nucifera) seed plumules and leaves exhibit significant tissue specificity for their pharmacological effects and potential nutritional properties. Herein, 46 benzylisoquinoline alkaloids were identified via UPLC-QTOF-HRMS, of which 9 were annotated as glycosylated monobenzylisoquinoline alkaloids concentrated in the seed plumules. The spatial distribution of targeted benzylisoquinoline alkaloids in leaves, seed plumules, and milky sap was determined via MALDI-MSI. Furthermore, 37 Nelumbo cultivars were investigated using targeted metabolomics to provide insights into functional tea development. While aporphine alkaloids comprised the main compounds present in lotus leaves, bisbenzylisoquinoline alkaloids were the main compounds in lotus plumules, where glycosylation primarily occurs. These findings can help understand the distribution of benzylisoquinoline alkaloids in lotus tissue and the directional breeding of varieties enriched with specific chemical functional groups for nutritional and pharmacological applications.
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Affiliation(s)
- Chenyang Hao
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
| | - Wei Yang
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
| | | | - Yuetong Yu
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
| | - Yan Liu
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
| | - Jun Zhang
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
| | - Yongping Zhu
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
| | - Xiaolu Wei
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
| | - Sha Chen
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimennei, Beijing 100700, China
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Moldovan OL, Sandulea A, Lungu IA, Gâz ȘA, Rusu A. Identification of Some Glutamic Acid Derivatives with Biological Potential by Computational Methods. Molecules 2023; 28:molecules28104123. [PMID: 37241864 DOI: 10.3390/molecules28104123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/07/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Glutamic acid is a non-essential amino acid involved in multiple metabolic pathways. Of high importance is its relationship with glutamine, an essential fuel for cancer cell development. Compounds that can modify glutamine or glutamic acid behaviour in cancer cells have resulted in attractive anticancer therapeutic alternatives. Based on this idea, we theoretically formulated 123 glutamic acid derivatives using Biovia Draw. Suitable candidates for our research were selected among them. For this, online platforms and programs were used to describe specific properties and their behaviour in the human organism. Nine compounds proved to have suitable or easy to optimise properties. The selected compounds showed cytotoxicity against breast adenocarcinoma, lung cancer cell lines, colon carcinoma, and T cells from acute leukaemia. Compound 2Ba5 exhibited the lowest toxicity, and derivative 4Db6 exhibited the most intense bioactivity. Molecular docking studies were also performed. The binding site of the 4Db6 compound in the glutamine synthetase structure was determined, with the D subunit and cluster 1 being the most promising. In conclusion, glutamic acid is an amino acid that can be manipulated very easily. Therefore, molecules derived from its structure have great potential to become innovative drugs, and further research on these will be conducted.
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Affiliation(s)
- Octavia-Laura Moldovan
- Medicine and Pharmacy Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Alexandra Sandulea
- Pharmaceutical and Therapeutic Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Ioana-Andreea Lungu
- Medicine and Pharmacy Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Șerban Andrei Gâz
- Organic Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Aura Rusu
- Pharmaceutical and Therapeutic Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
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He J, Fang J, Wang Y, Ge C, Liu S, Jiang Y. Discovery of Small-Molecule Antagonists of Orexin 1/2 Receptors from Traditional Chinese Medicinal Plants with a Hypnotic Effect. Pharmaceuticals (Basel) 2023; 16:ph16040542. [PMID: 37111298 PMCID: PMC10146837 DOI: 10.3390/ph16040542] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/25/2023] [Accepted: 03/31/2023] [Indexed: 04/29/2023] Open
Abstract
Insomnia is an important public health problem. The currently available treatments for insomnia can cause some adverse effects. Orexin receptors 1 (OX1R) and 2 (OX2R) are burgeoning targets for insomnia treatment. It is an effective approach to screening OX1R and OX2R antagonists from traditional Chinese medicine, which contains abundant and diverse chemical components. This study established an in-home ligand library of small-molecule compounds from medicinal plants with a definite hypnotic effect, as described in the Chinese Pharmacopoeia. Molecular docking was applied to virtually screen potential orexin receptor antagonists using molecular operating environment software, and surface plasmon resonance (SPR) technology was used to detect the binding affinity between potential active compounds and orexin receptors. Finally, the results of virtual screening and SPR analysis were verified through in vitro assays. We successfully screened one potential lead compound (neferine) as an orexin receptor antagonist from the in-home ligand library, which contained more than 1000 compounds. The screened compound was validated as a potential agent for insomnia treatment through comprehensive biological assays. This research enabled the discovery of a potential small-molecule antagonist of orexin receptors for the treatment of insomnia, providing a novel screening approach for the detection of potential candidate compounds for corresponding targets.
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Affiliation(s)
- Jia He
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jing Fang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yuxin Wang
- College of Pharmacy, Dali University, Dali 671000, China
| | - Chengyu Ge
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Shao Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yueping Jiang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
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Gielecińska A, Kciuk M, Mujwar S, Celik I, Kołat D, Kałuzińska-Kołat Ż, Kontek R. Substances of Natural Origin in Medicine: Plants vs. Cancer. Cells 2023; 12:986. [PMID: 37048059 PMCID: PMC10092955 DOI: 10.3390/cells12070986] [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] [Received: 02/02/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 04/14/2023] Open
Abstract
Continuous monitoring of the population's health is the main method of learning about disease prevalence. National and international data draw attention to the persistently high rates of cancer incidence. This necessitates the intensification of efforts aimed at developing new, more effective chemotherapeutic and chemopreventive drugs. Plants represent an invaluable source of natural substances with versatile medicinal properties. Multidirectional activities exhibited by natural substances and their ability to modulate key signaling pathways, mainly related to cancer cell death, make these substances an important research direction. This review summarizes the information regarding plant-derived chemotherapeutic drugs, including their mechanisms of action, with a special focus on selected anti-cancer drugs (paclitaxel, irinotecan) approved in clinical practice. It also presents promising plant-based drug candidates currently being tested in clinical and preclinical trials (betulinic acid, resveratrol, and roburic acid).
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Affiliation(s)
- Adrianna Gielecińska
- Doctoral School of Exact and Natural Sciences, University of Lodz, 90-237 Lodz, Poland
- Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland
| | - Mateusz Kciuk
- Doctoral School of Exact and Natural Sciences, University of Lodz, 90-237 Lodz, Poland
- Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland
| | - Somdutt Mujwar
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
| | - Ismail Celik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey
| | - Damian Kołat
- Department of Experimental Surgery, Faculty of Medicine, Medical University of Lodz, Narutowicza 60, 90-136 Lodz, Poland
| | - Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Faculty of Medicine, Medical University of Lodz, Narutowicza 60, 90-136 Lodz, Poland
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland
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Hu P, Wan P, Xu A, Yan B, Liu C, Xu Q, Wei Z, Xu J, Liu S, Yang G, Pan Y. Neferine, a novel ROCK1-targeting inhibitor, blocks EMT process and induces apoptosis in non-small cell lung cancer. J Cancer Res Clin Oncol 2023; 149:553-566. [PMID: 35984492 DOI: 10.1007/s00432-022-04280-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 08/10/2022] [Indexed: 11/28/2022]
Abstract
The compounds derived from Traditional Chinese Medicines have shown various pharmacological activities with unique advantages, especially in the aspect of antitumor. Neferine (Nef), a natural compound, extracted from green seed embryos of Lotus (Nelumbo nucifera Gaertn.) also exerts antitumor effects on cancers. In this study, the effects and mechanisms of Nef on epithelial-to-mesenchymal transition (EMT) process in non-small cell lung cancer (NSCLC) were evaluated. The results showed that Nef had the antitumor effects in vivo and in vitro. Nef significantly suppressed cell viability and induced apoptosis in NSCLC cells, with elevated reactive oxygen species and reduced BCL2/BAX ratio. Nef was also demonstrated to inhibit the invasion, metastasis and EMT process of NSCLC cells, and attenuate EMT-related changes of E-cadherin, N-cadherin and Vimentin at both transcriptional and translational levels. Moreover, we concluded that the inhibitory effects of Nef on EMT was achieved by targeting Rho-associated protein kinase 1, a protein mediating the process of EMT in various cancers. These results showed that Nef had a significant antitumor effect on NSCLC cells by inducing apoptosis and blocking EMT, providing the therapeutical prospect on NSCLC treatment.
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Affiliation(s)
- Po Hu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Peng Wan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Anna Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Binghui Yan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Chunmei Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Qixuan Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhenhuan Wei
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jingyi Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Siqi Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Guangming Yang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Yang Pan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Li H, Ge H, Song X, Tan X, Xiong Q, Gong Y, Zhang L, He Y, Zhang W, Zhu P, Lin W, Xiao X. Neferine mitigates cisplatin-induced acute kidney injury in mice by regulating autophagy and apoptosis. Clin Exp Nephrol 2023; 27:122-131. [PMID: 36326941 DOI: 10.1007/s10157-022-02292-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE The nephrotoxicity caused by cisplatin severely limits the application and affects related platinum-based therapeutics. Neferine is a dibenzylisoquinoline alkaloid extracted from a Chinese medicinal herb (Nelumbo nucifera Gaertn), which can decrease cisplatin-induced apoptosis of NRK-52E cells by activating autophagy in vitro in our previous study. In this article, we aimed to further investigate the protective effect of neferine, against to the cispltain-induced kidney damage in mice. METHODS Six groups were designed in our study. Renal index, mice serum creatinine and blood urea nitrogen levels were detected after the mice were killed. HE staining was used to observe the pathological changes of each group. The apoptosis of mouse kidney tissue was detected by TUNEL. Immunofluorescence and Western blot were used to detect the expression of cleaved-caspase3 and LC3. The transmission electron microscope was used to reveal the changes of apoptosis and autophagy of renal tubular epithelial cells in different groups. RESULTS In our findings, the pathological changes of acute kidney injury were easily observed in cisplatin-treated mice while those in the neferine-pretreated groups were significantly alleviated. The apoptosis induced by cisplatin in mice increased evidently compared with the control group, which was decreased in the mice with neferine pretreatment. What' more, we found that autophagy increased obviously in mice pretreated by neferine contrast to the cisplatin-treated mice. CONCLUSION In our study, neferine can effectively alleviate cisplatin-induced renal injury in mice, as well act as an autophagy-regulator in kidney protection.
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Affiliation(s)
- Hui Li
- Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, 410008, Hunan, China
| | - Huipeng Ge
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.,National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiaoyun Song
- Department of Science and Education, The First Hospital of Changsha, Changsha, 410008, Hunan, China
| | - Xin Tan
- Department of Pediatrics, The First Hospital of Changsha, Changsha, 410008, Hunan, China
| | - Qi Xiong
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Yizi Gong
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Linlin Zhang
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Yikai He
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Weiwei Zhang
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Peng Zhu
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Wei Lin
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. .,National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Xiangcheng Xiao
- Department of Nephrology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China. .,National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Sharma A, Sharma L, Nandy SK, Payal N, Yadav S, Vargas-De-La-Cruz C, Anwer MK, Khan H, Behl T, Bungau SG. Molecular Aspects and Therapeutic Implications of Herbal Compounds Targeting Different Types of Cancer. Molecules 2023; 28:750. [PMID: 36677808 PMCID: PMC9867434 DOI: 10.3390/molecules28020750] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/05/2023] [Accepted: 01/08/2023] [Indexed: 01/15/2023] Open
Abstract
Due to genetic changes in DNA (deoxyribonucleic acid) sequences, cancer continues to be the second most prevalent cause of death. The traditional target-directed approach, which is confronted with the importance of target function in healthy cells, is one of the most significant challenges in anticancer research. Another problem with cancer cells is that they experience various mutations, changes in gene duplication, and chromosomal abnormalities, all of which have a direct influence on the potency of anticancer drugs at different developmental stages. All of these factors combine to make cancer medication development difficult, with low clinical licensure success rates when compared to other therapy categories. The current review focuses on the pathophysiology and molecular aspects of common cancer types. Currently, the available chemotherapeutic drugs, also known as combination chemotherapy, are associated with numerous adverse effects, resulting in the search for herbal-based alternatives that attenuate resistance due to cancer therapy and exert chemo-protective actions. To provide new insights, this review updated the list of key compounds that may enhance the efficacy of cancer treatment.
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Affiliation(s)
- Aditi Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan 173229, Himachal Pradesh, India
| | - Lalit Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan 173229, Himachal Pradesh, India
| | - Shouvik Kumar Nandy
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan 173229, Himachal Pradesh, India
| | - Nazrana Payal
- School of Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan 173229, Himachal Pradesh, India
| | - Shivam Yadav
- Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Chhatrapati Shahu ji Maharaj University, Kanpur 208024, Uttar Pradesh, India
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Faculty of Pharmacy and Biochemistry, Bromatology and Toxicology, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Md. Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Tapan Behl
- School of Health Science and Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410028 Oradea, Romania
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Ju J, Liu Y, Liang H, Yang B. The role of pyroptosis in endothelial dysfunction induced by diseases. Front Immunol 2023. [DOI: 10.3389/fimmu.2023.1093985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Most organs in the body rely on blood flow, and vesicular damage is the leading cause of injury in multiple organs. The endothelium, as the barriers of vessels, play a critical role in ensuring vascular homeostasis and angiogenesis. The rapid development of risk factors in endothelial injuries has been seen in the past decade, such as smoking, infectious, and diabetes mellites. Pyroptotic endothelium is an inflammatory mode of governed endothelial cell death that depend on the metabolic disorder and severe infectious such as atherosclerosis, and sepsis-related acute lung injury, respectively. Pyroptotic endothelial cells need GSDMD cleaved into N- and C-terminal by caspase1, and the cytokines are released by a pore constructed by the N-terminal of GSDMD in the membrane of ECs, finally resulting in severe inflammation and pyroptotic cell death. This review will focus on the patho-physiological and pharmacological pathways of pyroptotic endothelial metabolism in diseases. Overall, this review indicates that pyroptosis is a significant risk factor in diseases and a potential drug target in related diseases.
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Ju J, Liu Y, Liang H, Yang B. The role of pyroptosis in endothelial dysfunction induced by diseases. Front Immunol 2023; 13:1093985. [PMID: 36776394 PMCID: PMC9910335 DOI: 10.3389/fimmu.2022.1093985] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/19/2022] [Indexed: 01/27/2023] Open
Abstract
Most organs in the body rely on blood flow, and vesicular damage is the leading cause of injury in multiple organs. The endothelium, as the barriers of vessels, play a critical role in ensuring vascular homeostasis and angiogenesis. The rapid development of risk factors in endothelial injuries has been seen in the past decade, such as smoking, infectious, and diabetes mellites. Pyroptotic endothelium is an inflammatory mode of governed endothelial cell death that depend on the metabolic disorder and severe infectious such as atherosclerosis, and sepsis-related acute lung injury, respectively. Pyroptotic endothelial cells need GSDMD cleaved into N- and C-terminal by caspase1, and the cytokines are released by a pore constructed by the N-terminal of GSDMD in the membrane of ECs, finally resulting in severe inflammation and pyroptotic cell death. This review will focus on the patho-physiological and pharmacological pathways of pyroptotic endothelial metabolism in diseases. Overall, this review indicates that pyroptosis is a significant risk factor in diseases and a potential drug target in related diseases.
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Affiliation(s)
- Jin Ju
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
| | - Yanyan Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, China
| | - Haihai Liang
- Key Laboratory of Cardiovascular Research, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Ministry of Education, Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China,Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang, China
| | - Baofeng Yang
- Key Laboratory of Cardiovascular Research, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Ministry of Education, Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China,Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang, China,*Correspondence: Baofeng Yang,
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Effects of neferine on retinal tissue in experimental diabetic rat model. Int Ophthalmol 2023; 43:249-260. [PMID: 35852698 DOI: 10.1007/s10792-022-02424-0] [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: 01/14/2022] [Accepted: 07/04/2022] [Indexed: 02/07/2023]
Abstract
PURPOSE To investigate vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) immunoreactivities, as well as apoptosis and oxidative stress levels in Streptozotocin (STZ)-induced diabetic rats, and determine how neferine affected these parameters. METHODS Thirty-five male Sprague Dawley rats were divided into five groups of seven. Fasting blood glucose was measured 72 h after diabetes mellitus (DM) induction in 21 rats using 60 mg/kg STZ dissolved in 0.4 ml (0.1 M) sodium-citrate buffer (pH:4.5), with values > 250 mg/dl considered diabetic. Group 1 received no treatment. Group 3 (healthy rats) received daily intraperitoneal (IP) 4 mg/kg neferine. Following DM induction: Group 2 (sham) received daily IP 0.25 ml/kg 0.9% normal saline; Group 4 received single IP 0.01 mL (2.5 mg/kg) bevacizumab, followed by daily IP 0.25 mL/kg 0.9% normal saline; and Group 5 received daily IP 4 mg/kg neferine. Total antioxidant capacity (TAC) and total oxidative stress (TOS) levels in serum and ocular tissue homogenates were evaluated using ELISA. TUNEL method was used for determining apoptosis and immuno-histochemical staining for PCNA and VEGF immunoreactivities. RESULTS Group 5 had significantly higher TAC and lower TOS in serum and ocular tissue homogenates than Group 4 (p < 0.05). Despite significantly lower VEGF levels and apoptosis (p < 0.05), there was no significant change in PCNA immunoreactivity in Group 5 (p > 0.05). CONCLUSIONS DM was associated with lower TAC, higher TOS and apoptotic cells, as well as VEGF and PCNA immunoreactivities in the retina. Neferine altered parameters other than PCNA in the opposite direction, demonstrating reductive effects on DM.
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36
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Fan Y, Zhang Y, Shi K, Cheng S, Pei D, Shu X. Identification of a group of bisbenzylisoquinoline (BBIQ) compounds as ferroptosis inhibitors. Cell Death Dis 2022; 13:1000. [PMID: 36435804 PMCID: PMC9701226 DOI: 10.1038/s41419-022-05447-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/28/2022]
Abstract
Ferroptosis induced by detrimental accumulation of lipid peroxides has been recently linked to a variety of pathological conditions ranging from acute tissue injuries to chronic degenerative diseases and suppression of ferroptosis by small chemical inhibitors is beneficial to the prevention and treatment of these diseases. However, in vivo applicable small chemical ferroptosis inhibitors are limited currently. In this study, we screened an alkaloid natural compound library for compounds that can inhibit RSL3-induced ferroptosis in HT1080 cells and identified a group of bisbenzylisoquinoline (BBIQ) compounds as novel ferroptosis-specific inhibitors. These BBIQ compounds are structurally different from known ferroptosis inhibitors and they do not appear to regulate iron homeostasis or lipid ROS generation pathways, while they are able to scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH) in cell-free reactions and prevent accumulation of lipid peroxides in living cells. These BBIQ compounds demonstrate good in vivo activities as they effectively protect mice from folic acid-induced renal tubular ferroptosis and acute kidney injury. Several BBIQ compounds are approved drugs in Japan and China for traditional uses and cepharanthine is currently in clinical trials against SARS-CoV-2, our discovery of BBIQs as in vivo applicable ferroptosis inhibitors will expand their usage to prevent ferroptotic tissue damages under various pathological conditions.
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Affiliation(s)
- Yipu Fan
- grid.428926.30000 0004 1798 2725CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China ,grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Yihan Zhang
- grid.508040.90000 0004 9415 435XGuangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, 510005 China
| | - Kunyu Shi
- grid.508040.90000 0004 9415 435XGuangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, 510005 China
| | - Shan Cheng
- grid.494629.40000 0004 8008 9315School of Life Science, Westlake University, Hangzhou, 310030 China
| | - Duanqing Pei
- grid.428926.30000 0004 1798 2725CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China
| | - Xiaodong Shu
- grid.428926.30000 0004 1798 2725CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China ,grid.508040.90000 0004 9415 435XGuangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, 510005 China ,grid.410737.60000 0000 8653 1072Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 511436 China
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He Y, Tao Y, Qiu L, Xu W, Huang X, Wei H, Tao X. Lotus ( Nelumbo nucifera Gaertn.) Leaf-Fermentation Supernatant Inhibits Adipogenesis in 3T3-L1 Preadipocytes and Suppresses Obesity in High-Fat Diet-Induced Obese Rats. Nutrients 2022; 14:4348. [PMID: 36297031 PMCID: PMC9610561 DOI: 10.3390/nu14204348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/01/2022] [Accepted: 10/12/2022] [Indexed: 11/29/2022] Open
Abstract
The lotus (Nelumbo nucifera Gaertn.) leaf is a typical homologous ingredient of medicine and food with lipid-lowering and weight-loss effects. In the present study, lotus leaves were fermented by two probiotics, Enterococcus faecium WEFA23 and Enterococcus hirae WEHI01, and the anti-adipogenic effect of Enterococcus fermented lotus leaf supernatant (FLLS) was evaluated in 3T3-L1 preadipocytes with the aim of exploring whether its anti-obesity ability will be enhanced after fermentation with Enterococcus and to dig out the potential corresponding mechanism. The FLLS fermented by E. hirae WEHI01 (FLLS-WEHI01) was selected and further investigated for its ability to inhibit obesity in vivo in high-fat diet (HFD)-induced obese rats (male, 110 ± 5 g, 4 weeks old) due to its superior inhibitory effect on adipogenesis and lipid accumulation (inhibition rate of up to 56.17%) in 3T3-L1 cells (p = 0.008 for WEHI01-L, p < 0.001 for WEHI01-H). We found that the oral administration of both the low and high doses of FLLS-WEHI01 could achieve some effects, namely decreasing body weight (p < 0.001), epididymal fat mass, adipocyte cell size, LDL-C levels (p = 0.89, 0.02, respectively), liver TC levels (p < 0.001, p = 0.01, respectively), and TG levels (p = 0.2137, p = 0.0464, respectively), fasting blood glucose (p = 0.1585, p = 0.0009), and improved insulin resistance (p = 0.33, 0.01, respectively) in rats of the model group. Moreover, the administration of both high and low doses of FLLS-WEHI01 decreased the transcription levels of adipogenic transcription factors and corresponding genes such as Pparγ (p < 0.001), Cebpα (p < 0.001), Acc (p < 0.001), and Fas (p < 0.001) by at least three times. These results indicate that FLLS-WEHI01 can potentially be developed as an healthy, anti-obesity foodstuff.
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Affiliation(s)
- Yao He
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Yue Tao
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Liang Qiu
- Department of Medical Translational Center, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
| | - Wenfeng Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Xiaoli Huang
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Hua Wei
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Xueying Tao
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
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Machihara K, Kageyama S, Oki S, Makino H, Sasaki M, Iwahashi H, Namba T. Lotus germ extract rejuvenates aging fibroblasts via restoration of disrupted proteostasis by the induction of autophagy. Aging (Albany NY) 2022; 14:7662-7691. [PMID: 36170016 PMCID: PMC9596218 DOI: 10.18632/aging.204303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 09/05/2022] [Indexed: 01/18/2023]
Abstract
Cell aging attenuates cellular functions, resulting in time-dependent disruption of cellular homeostasis, which maintains the functions of proteins and organelles. Mitochondria are important organelles responsible for cellular energy production and various metabolic processes, and their dysfunction is strongly related to the progression of cellular aging. Here we demonstrate that disruption of proteostasis attenuates mitochondrial function before the induction of DNA damage signaling by proliferative and replicative cellular aging. We found that lotus (Nelumbo nucifera Gaertn.) germ extract clears abnormal proteins and agglutinates via autophagy-mediated restoration of mitochondrial function and cellular aging phenotypes. Pharmacological analyses revealed that DAPK1 expression was suppressed in aging cells, and lotus germ extract upregulated DAPK1 expression by stimulating the acetylation of histones and then induced autophagy by activating the DAPK1-Beclin1 signaling pathway. Furthermore, treatment of aging fibroblasts with lotus germ extract stimulated collagen production and increased contractile ability in three-dimensional cell culture. Thus, time-dependent accumulation of abnormal proteins and agglutinates suppressed mitochondrial function in cells in the early stage of aging, and reactivation of mitochondrial function by restoring proteostasis rejuvenated aging cells. Lotus germ extract rejuvenates aging fibroblasts via the DAPK1-Beclin1 pathway-induced autophagy to clear abnormal proteins and agglutinates.
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Affiliation(s)
- Kayo Machihara
- Research and Education Faculty, Multidisciplinary Science Cluster, Interdisciplinary Science Unit, Kochi University, Kochi 783-8505, Japan
| | - Sou Kageyama
- Department of Marine Resource Science, Faculty of Agriculture and Marine Science, Kochi University, Kochi 783-8502, Japan
| | - Shoma Oki
- Department of Marine Resource Science, Faculty of Agriculture and Marine Science, Kochi University, Kochi 783-8502, Japan
| | - Hiroki Makino
- Department of Marine Resource Science, Faculty of Agriculture and Marine Science, Kochi University, Kochi 783-8502, Japan
| | - Masamichi Sasaki
- Research Center, Maruzen Pharmaceuticals Co. Ltd., Fukuyama City, Hiroshima 729-3102, Japan
| | - Hiroyasu Iwahashi
- Research Center, Maruzen Pharmaceuticals Co. Ltd., Fukuyama City, Hiroshima 729-3102, Japan
| | - Takushi Namba
- Research and Education Faculty, Multidisciplinary Science Cluster, Interdisciplinary Science Unit, Kochi University, Kochi 783-8505, Japan.,Department of Marine Resource Science, Faculty of Agriculture and Marine Science, Kochi University, Kochi 783-8502, Japan
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Lin B, Xu P, Zheng J, Deng X, Ye Q, Huang Z, Wang N. Effects and mechanisms of natural alkaloids for prevention and treatment of osteoporosis. Front Pharmacol 2022; 13:1014173. [PMID: 36210805 PMCID: PMC9539536 DOI: 10.3389/fphar.2022.1014173] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 08/31/2022] [Indexed: 11/20/2022] Open
Abstract
Natural alkaloids are polycyclic, nitrogen-containing, and basic compounds obtained from plants. In this review, the advances in bioactive alkaloids with respect to their chemical structures, herbal sources, and effects for the prevention and treatment of osteoporosis are discussed. Anti-osteoporosis alkaloids are classified into six categories based on the chemical structure, namely, isoquinoline alkaloids, quinolizidine alkaloids, piperidine alkaloids, indole alkaloids, pyrrolizidine alkaloids and steroidal alkaloids. They promote mesenchymal stem cells differentiation, improve osteoblast proliferation, stimulate osteoblast autophagy and suppress osteoclast formation. These natural alkaloids can regulate multiple signaling pathways, including interrupting the tumor necrosis factor receptor associated factor 6- receptor activator of nuclear factor kappa B interaction, inhibiting the nuclear factor kappa B pathway in osteoclasts, activating the p38 mitogen-activated protein kinases pathway in osteoblasts, and triggering the wingless and int-1 pathway in mesenchymal stem cells. This review provides evidence and support for novel drug and clinical treatment of osteoporosis using natural alkaloids.
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Affiliation(s)
- Bingfeng Lin
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Pingcui Xu
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Juan Zheng
- Hangzhou Institute for Food and Drug Control, Hangzhou, China
| | - Xuehui Deng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qitao Ye
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhongping Huang
- College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, China
| | - Nani Wang
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
- *Correspondence: Nani Wang,
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Dong Z, Xie Q, Xu F, Shen X, Hao Y, Li J, Xu H, Peng Q, Kuang W. Neferine alleviates chronic stress-induced depression by regulating monoamine neurotransmitter secretion and gut microbiota structure. Front Pharmacol 2022; 13:974949. [PMID: 36120376 PMCID: PMC9479079 DOI: 10.3389/fphar.2022.974949] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/16/2022] [Indexed: 12/05/2022] Open
Abstract
Neferine (Nef) might possess anti-depressive properties; however, its therapeutic effects are yet to be elucidated. Therefore, in this study, we aimed to explore the anti-depressant property of Nef using a mouse model of chronic stress-induced depression. Fifteen depression-prone mice were randomly selected and divided into three groups, namely, the model, Nef, and fluoxetine (Flu) groups. We observed that in tail suspension and forced swimming tests, the Nef and Flu treatments significantly decreased the immobility time of the depressed mice, and increased their sucrose preference indices. Moreover, both Nef and Flu treatments induced significant increases in the levels of anti-depressant neurotransmitters, including dopamine (DA), serotonin (5-HT), and norepinephrine (NE), and also reduced pathological damage to the hippocampus of the depressed mice. Incidentally, Illumina MiSeq sequencing analysis demonstrated that the relative abundance of Lactobacillus in the intestinal microbiota of depressed mice was restored after Nef/Flu treatment. Moreover, colonic Lactobacillus abundance was positively correlated with the levels of DA, 5-HT, and NE in the hippocampus of the mice. In conclusion, Nef improved monoamine neurotransmitter secretion and modulated the intestinal flora structure, particularly the abundance of Lactobacillus. Hence, it showed considerable anti-depressant potential, and might be a prospective anti-depressant therapeutic agent.
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Affiliation(s)
- Zaiquan Dong
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
- Department of Psychiatry and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qinglian Xie
- Department of Outpatient, West China Hospital, Sichuan University, Chengdu, China
| | - Feiyu Xu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Xiaoling Shen
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
| | - Yanni Hao
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
| | - Jin Li
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
| | - Haizhen Xu
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
| | - Qiang Peng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- *Correspondence: Qiang Peng, ; Weihong Kuang,
| | - Weihong Kuang
- Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
- Department of Psychiatry and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Qiang Peng, ; Weihong Kuang,
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Bajalia EM, Azzouz FB, Chism DA, Giansiracusa DM, Wong CG, Plaskett KN, Bishayee A. Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms. Cancers (Basel) 2022; 14:3278. [PMID: 35805049 PMCID: PMC9265746 DOI: 10.3390/cancers14133278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/26/2022] [Accepted: 06/30/2022] [Indexed: 11/18/2022] Open
Abstract
Renal cell carcinoma (RCC) is associated with about 90% of renal malignancies, and its incidence is increasing globally. Plant-derived compounds have gained significant attention in the scientific community for their preventative and therapeutic effects on cancer. To evaluate the anticancer potential of phytocompounds for RCC, we compiled a comprehensive and systematic review of the available literature. Our work was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. The literature search was performed using scholarly databases such as PubMed, Scopus, and ScienceDirect and keywords such as renal cell carcinoma, phytochemicals, cancer, tumor, proliferation, apoptosis, prevention, treatment, in vitro, in vivo, and clinical studies. Based on in vitro results, various phytochemicals, such as phenolics, terpenoids, alkaloids, and sulfur-containing compounds, suppressed cell viability, proliferation and growth, showed cytotoxic activity, inhibited invasion and migration, and enhanced the efficacy of chemotherapeutic drugs in RCC. In various animal tumor models, phytochemicals suppressed renal tumor growth, reduced tumor size, and hindered angiogenesis and metastasis. The relevant antineoplastic mechanisms involved upregulation of caspases, reduction in cyclin activity, induction of cell cycle arrest and apoptosis via modulation of a plethora of cell signaling pathways. Clinical studies demonstrated a reduced risk for the development of kidney cancer and enhancement of the efficacy of chemotherapeutic drugs. Both preclinical and clinical studies displayed significant promise of utilizing phytochemicals for the prevention and treatment of RCC. Further research, confirming the mechanisms and regulatory pathways, along with randomized controlled trials, are needed to establish the use of phytochemicals in clinical practice.
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Affiliation(s)
| | | | | | | | | | | | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (E.M.B.); (F.B.A.); (D.A.C.); (D.M.G.); (C.G.W.); (K.N.P.)
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Zhou Y, Xiang S, Zheng H, Hou Y, Wang Y, Li CC, Wu Q, Shi J, Chen X. Neferine Suppresses Experimental Colitis-Associated Colorectal Cancer by Inhibition of NF-[Formula: see text]B p65 and STAT3. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:1387-1400. [PMID: 35726141 DOI: 10.1142/s0192415x22500598] [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: 06/15/2023]
Abstract
Colitis is an important risk factor for the development of colorectal cancer (CRC). The inhibitory effect and the underlying mechanism of neferine on colitis-associated colorectal cancer (CA-CRC) were investigated using an azoxymethane (AOM)/dextran sulfate sodium (DSS) triggered mice model. Compared with the CA-CRC model, oral treatment of neferine (2.5 and 5.0 mg/kg) significantly inhibited the DAI scores, decreased the tumor number, and reduced the tumor size. Neferine decreased inflammatory cell infiltration and epithelial hyperplasia in colon tissues. The levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text], interleukin-1beta (IL-1[Formula: see text], and interleukin 6 (IL-6) in colon tissues were decreased by neferine. Furthermore, neferine significantly decreased protein expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), p-p65, and p-STAT3 in both tumor and non-tumor tissues. In addition, neferine inhibited LPS and IL-6-induced phosphorylation of both NF-[Formula: see text]B p65 and STAT3. Molecular docking demonstrated the interactions of neferine with both NF-[Formula: see text]B p65 and STAT3. In conclusion, these results suggested that neferine inhibited CA-CRC carcinogenesis possibly by regulating NF-[Formula: see text]B and STAT3. Neferine might be a lead compound for the chemoprevention of CA-CRC.
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Affiliation(s)
- Yishan Zhou
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical University, Zunyi 563003, P. R. China
| | - Shuangli Xiang
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical University, Zunyi 563003, P. R. China
| | - Haoyi Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, P. R. China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, P. R. China
| | - Ying Hou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, P. R. China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, P. R. China
| | - Ying Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, P. R. China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, P. R. China
| | - Chuang-Chuang Li
- Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, P. R. China
| | - Qin Wu
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical University, Zunyi 563003, P. R. China
| | - Jingshan Shi
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical University, Zunyi 563003, P. R. China
| | - Xiuping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, P. R. China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, P. R. China
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao 999078, P. R. China
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Yang C, Mai Z, Liu C, Yin S, Cai Y, Xia C. Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113513. [PMID: 35684449 PMCID: PMC9181879 DOI: 10.3390/molecules27113513] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/13/2022]
Abstract
Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.
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Affiliation(s)
- Chuansheng Yang
- Department of Head-Neck and Breast Surgery, Yuebei People’s Hospital of Shantou University, Shaoguan 512027, China;
| | - Zhikai Mai
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Can Liu
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shuanghong Yin
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yantao Cai
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- Correspondence: (Y.C.); (C.X.)
| | - Chenglai Xia
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- Correspondence: (Y.C.); (C.X.)
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Lin TY, Hung CY, Chiu KM, Lee MY, Lu CW, Wang SJ. Neferine, an Alkaloid from Lotus Seed Embryos, Exerts Antiseizure and Neuroprotective Effects in a Kainic Acid-Induced Seizure Model in Rats. Int J Mol Sci 2022; 23:ijms23084130. [PMID: 35456948 PMCID: PMC9027762 DOI: 10.3390/ijms23084130] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/01/2022] [Accepted: 04/07/2022] [Indexed: 12/12/2022] Open
Abstract
Current anti-seizure drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective anti-seizure drugs, and medicinal plants provide an attractive source for new compounds. This study aimed to evaluate the possible anti-seizure and neuroprotective effects of neferine, an alkaloid from the lotus seed embryos of Nelumbo nucifera, in a kainic acid (KA)-induced seizure rat model and its underlying mechanisms. Rats were intraperitoneally (i.p.) administrated neferine (10 and 50 mg/kg) 30 min before KA injection (15 mg/kg, i.p.). Neferine pretreatment increased seizure latency and reduced seizure scores, prevented glutamate elevation and neuronal loss, and increased presynaptic protein synaptophysin and postsynaptic density protein 95 expression in the hippocampi of rats with KA. Neferine pretreatment also decreased glial cell activation and proinflammatory cytokine (interleukin-1β, interleukin-6, tumor necrosis factor-α) expression in the hippocampi of rats with KA. In addition, NOD-like receptor 3 (NLRP3) inflammasome, caspase-1, and interleukin-18 expression levels were decreased in the hippocampi of seizure rats pretreated with neferine. These results indicated that neferine reduced seizure severity, exerted neuroprotective effects, and ameliorated neuroinflammation in the hippocampi of KA-treated rats, possibly by inhibiting NLRP3 inflammasome activation and decreasing inflammatory cytokine secretion. Our findings highlight the potential of neferine as a therapeutic option in the treatment of epilepsy.
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Affiliation(s)
- Tzu-Yu Lin
- Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 22060, Taiwan;
- Department of Mechanical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan
| | - Chih-Yu Hung
- School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan;
| | - Kuan-Ming Chiu
- Cardiovascular Center, Division of Cardiovascular Surgery, Far-Eastern Memorial Hospital, New Taipei 22060, Taiwan; (K.-M.C.); (M.-Y.L.)
- Department of Electrical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan
| | - Ming-Yi Lee
- Cardiovascular Center, Division of Cardiovascular Surgery, Far-Eastern Memorial Hospital, New Taipei 22060, Taiwan; (K.-M.C.); (M.-Y.L.)
| | - Cheng-Wei Lu
- Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 22060, Taiwan;
- Department of Mechanical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan
- Correspondence: (C.-W.L.); (S.-J.W.)
| | - Su-Jane Wang
- School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan;
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan
- Correspondence: (C.-W.L.); (S.-J.W.)
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QSAR study, molecular docking, and ADMET prediction of vinyl sulfone-containing Nrf2 activator derivatives for treating Parkinson disease. Struct Chem 2022. [DOI: 10.1007/s11224-022-01909-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Tabnak P, Masrouri S, Mafakheri A. Natural products in suppressing glioma progression: A focus on the role of microRNAs. Phytother Res 2022; 36:1576-1599. [PMID: 35174549 DOI: 10.1002/ptr.7414] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 12/07/2021] [Accepted: 01/29/2022] [Indexed: 11/06/2022]
Abstract
Glioma is one of the most common malignancies of the central nervous system. Due to inadequate response to the current treatments available, glioma has been at the center of recent cancer studies searching for novel treatment strategies. This has prompted an intensive search using linkage studies and preliminary evidence to gain efficient insight into the mechanisms involved in the alleviation of the pathogenesis of glioma mediated by miRNAs, a group of noncoding RNAs that affect gene expression posttranscriptionally. Dysregulated expression of miRNAs can exacerbate the malignant features of tumor cells in glioma and other cancers. Natural products can exert anticancer effects on glioma cells by stimulating the expression levels of tumor suppressor miRNAs and repressing the expression levels of oncogenic miRNAs. In this review, we aimed to collect and analyze the literature addressing the roles of natural products in the treatment of glioma, with an emphasis on their involvement in the regulation of miRNAs.
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Affiliation(s)
- Peyman Tabnak
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soroush Masrouri
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asrin Mafakheri
- Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Bishayee A, Patel PA, Sharma P, Thoutireddy S, Das N. Lotus (Nelumbo nucifera Gaertn.) and Its Bioactive Phytocopounds: A Tribute to Cancer Prevention and Intervention. Cancers (Basel) 2022; 14:cancers14030529. [PMID: 35158798 PMCID: PMC8833568 DOI: 10.3390/cancers14030529] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The plant Nelumbo nucifera (Gaertn.), commonly known as lotus, sacred lotus, Indian lotus, water lily, or Chinese water lily, is an aquatic perennial crop belonging to the family of Nelumbonaceae. N. nucifera has traditionally been used as an herbal medicine and functional food in many parts of Asia. It has been found that different parts of this plant consist of various bioactive phytocompounds. Within the past few decades, N. nucifera and its phytochemicals have been subjected to intense cancer research. In this review, we critically evaluate the potential of N. nucifera phytoconstituents in cancer prevention and therapy with related mechanisms of action. Abstract Cancer is one of the major leading causes of death worldwide. Accumulating evidence suggests a strong relationship between specific dietary habits and cancer development. In recent years, a food-based approach for cancer prevention and intervention has been gaining tremendous attention. Among diverse dietary and medicinal plants, lotus (Nelumbo nucifera Gaertn., family Nymphaeaceae), also known as Indian lotus, sacred lotus or Chinese water lily, has the ability to effectively combat this disease. Various parts of N. nucifera have been utilized as a vegetable as well as an herbal medicine for more than 2000 years in the Asian continent. The rhizome and seeds of N. nucifera represent the main edible parts. Different parts of N. nucifera have been traditionally used to manage different disorders, such as fever, inflammation, insomnia, nervous disorders, epilepsy, hypertension, cardiovascular diseases, obesity, and hyperlipidemia. It is believed that numerous bioactive components, including alkaloids, polyphenols, terpenoids, steroids, and glycosides, are responsible for its various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immune-modulatory, antiviral, hepatoprotective, cardioprotective, and hypoglycemic activities. Nevertheless, there is no comprehensive review with an exclusive focus on the anticancer attributes of diverse phytochemicals from different parts of N. nucifera. In this review, we have analyzed the effects of N. nucifera extracts, fractions and pure compounds on various organ-specific cancer cells and tumor models to understand the cancer-preventive and therapeutic potential and underlying cellular and molecular mechanisms of action of this interesting medicinal and dietary plant. In addition, the bioavailability, pharmacokinetics, and possible toxicity of N. nucifera-derived phytochemicals, as well as current limitations, challenges and future research directions, are also presented.
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Affiliation(s)
- Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (P.A.P.); (P.S.); (S.T.)
- Correspondence: or
| | - Palak A. Patel
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (P.A.P.); (P.S.); (S.T.)
| | - Priya Sharma
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (P.A.P.); (P.S.); (S.T.)
| | - Shivani Thoutireddy
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (P.A.P.); (P.S.); (S.T.)
| | - Niranjan Das
- Department of Chemistry, Iswar Chandra Vidyasagar College, Belonia 799155, Tripura, India;
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Tang B, Zeng W, Song LL, Wang HM, Qu LQ, Lo HH, Yu L, Wu AG, Wong VKW, Law BYK. Extracellular Vesicle Delivery of Neferine for the Attenuation of Neurodegenerative Disease Proteins and Motor Deficit in an Alzheimer’s Disease Mouse Model. Pharmaceuticals (Basel) 2022; 15:ph15010083. [PMID: 35056140 PMCID: PMC8779383 DOI: 10.3390/ph15010083] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/30/2021] [Accepted: 01/03/2022] [Indexed: 01/08/2023] Open
Abstract
Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood–brain barrier in order to target the central nervous system (CNS). In this study, high-purity exosomes isolated by the ultra-high-speed separation method were applied as the natural compound carrier, with the loading efficiency confirmed by UHPLC-MS analysis. Through the optimization of various cargo loading methods using exosomes, this study compared the efficiency of different ways for the separation of exosomes and the exosome encapsulation of natural compounds with increasing molecular weights via extensive in vitro and in vivo efficacy studies. In a pharmacokinetic study, our data suggested that the efficiency of compound’s loading into exosomes is positively correlated to its molecular weight. However, with a molecular weight of greater than 1109 Da, the exosome-encapsulated natural compounds were not able to pass through the blood–brain barrier (BBB). In vitro cellular models confirmed that three of the selected exosome-encapsulated natural compounds—baicalin, hederagenin and neferine—could reduce the level of neurodegenerative disease mutant proteins—including huntingtin 74 (HTT74), P301L tau and A53T α-synuclein (A53T α-syn)—more effectively than the compounds alone. With the traditional pharmacological role of the herbal plant Nelumbo nucifera in mitigating anxiety, exosome-encapsulated-neferine was, for the first time, reported to improve the motor deficits of APP/PS1 (amyloid precursor protein/ presenilin1) double transgenic mice, and to reduce the level of β-amyloid (Aβ) in the brain when compared with the same concentration of neferine alone. With the current trend in advocating medicine–food homology and green healthcare, this study has provided a rationale from in vitro to in vivo for the encapsulation of natural compounds using exosomes for the targeting of BBB permeability and neurodegenerative diseases in the future.
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Affiliation(s)
- Bin Tang
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
| | - Wu Zeng
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
| | - Lin Lin Song
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
| | - Hui Miao Wang
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
| | - Li Qun Qu
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
| | - Hang Hong Lo
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
| | - Lu Yu
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (L.Y.); (A.G.W.)
| | - An Guo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (L.Y.); (A.G.W.)
| | - Vincent Kam Wai Wong
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
- Correspondence: (V.K.W.W.); (B.Y.K.L.)
| | - Betty Yuen Kwan Law
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.T.); (W.Z.); (L.L.S.); (H.M.W.); (L.Q.Q.); (H.H.L.)
- Correspondence: (V.K.W.W.); (B.Y.K.L.)
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49
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Shen L, Chu X, Zhang Z, Wu T. Structural characterization and in vitro anti-inflammatory estimation of an unusual pectin linked by rhamnogalacturonan I and xylogalacturonan from lotus plumule. Int J Biol Macromol 2022; 194:100-109. [PMID: 34863824 DOI: 10.1016/j.ijbiomac.2021.11.178] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 11/05/2022]
Abstract
A novel homogenous polysaccharide LPWF together with its three acid hydrolysis products LPWF1-3 were isolated and prepared from lotus plumule (germs of Nelumbo nucifera). LPWF was composed of rhamnose (Rha), arabinose (Ara), galactose (Gal), xylose (Xyl), and galacturonic acid (GalA) in the molar ratio of 7.3: 34.0: 7.0: 19.1: 32.6 with a molecular weight of 567.6 kDa. The structure of LPWF was elucidated by methylation and NMR analysis of LPWF1-3 and a follow-up structural assembling aided by high-resolution mass spectrometry mapping of oligosaccharides and ROSEY spectra. LPWF was characterized as an unusual pectin linked by rhamnogalacturonan I (RGI, composed of LPWF1-2) and xylogalacturonan (XGA, LPWF3). LPWF1 was an arabinan peeled from the RGI part with a 1,5-linked backbone branching on the O-2 position, while LPWF2 was the remaining part of RGI composed of Rha (36.1%), Gal (17.8%), and GalA (43.7%). LPWF3 was identified as the XGA part with a backbone of α-1,4-linked GalA and branches of mono-xylose substitutions on the O-3 of GalA. LPWF (25 μg/mL) demonstrated significant inhibitions on the expression of IL-1β, IL-6, and TNF-α in LPS-stimulated primary murine microglia cultures. LPWF1 and 2 showed selectively and significantly inhibitory activity against the expression of IL-1β.
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Affiliation(s)
- Lulu Shen
- Key Laboratory of Standardization of Chinese Medicines of Ministry of Education, The Shanghai Key Laboratory for Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Green-Valley Pharmaceutical Co., Ltd., Shanghai 201200, China
| | - Xingkun Chu
- Shanghai Green-Valley Pharmaceutical Co., Ltd., Shanghai 201200, China
| | - Zhenqing Zhang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China
| | - Tao Wu
- Key Laboratory of Standardization of Chinese Medicines of Ministry of Education, The Shanghai Key Laboratory for Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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50
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Wang Z, Li Y, Ma D, Zeng M, Wang Z, Qin F, Chen J, Christian M, He Z. Alkaloids from lotus ( Nelumbo nucifera): recent advances in biosynthesis, pharmacokinetics, bioactivity, safety, and industrial applications. Crit Rev Food Sci Nutr 2021:1-34. [PMID: 34845950 DOI: 10.1080/10408398.2021.2009436] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Different parts of lotus (Nelumbo nucifera Gaertn.) including the seeds, rhizomes, leaves, and flowers, are used for medicinal purposes with health promoting and illness preventing benefits. The presence of active chemicals such as alkaloids, phenolic acids, flavonoids, and terpenoids (particularly alkaloids) may account for this plant's pharmacological effects. In this review, we provide a comprehensive overview and summarize up-to-date research on the biosynthesis, pharmacokinetics, and bioactivity of lotus alkaloids as well as their safety. Moreover, the potential uses of lotus alkaloids in the food, pharmaceutical, and cosmetic sectors are explored. Current evidence shows that alkaloids, mainly consisting of aporphines, 1-benzylisoquinolines, and bisbenzylisoquinolines, are present in different parts of lotus. The bioavailability of these alkaloids is relatively low in vivo but can be enhanced by technological modification using nanoliposomes, liposomes, microcapsules, and emulsions. Available data highlights their therapeutic and preventive effects on obesity, diabetes, neurodegeneration, cancer, cardiovascular disease, etc. Additionally, industrial applications of lotus alkaloids include their use as food, medical, and cosmetic ingredients in tea, other beverages, and healthcare products; as lipid-lowering, anticancer, and antipsychotic drugs; and in facial masks, toothpastes, and shower gels. However, their clinical efficacy and safety remains unclear; hence, larger and longer human trials are needed to achieve their safe and effective use with minimal side effects.
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Affiliation(s)
- Zhenyu Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Yong Li
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Dandan Ma
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Maomao Zeng
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Zhaojun Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Fang Qin
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Jie Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Mark Christian
- School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK
| | - Zhiyong He
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
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