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Rafiee J, Jamialahmadi K, Bazyari MJ, Aghaee-Bakhtiari SH. Drug repositioning in castration-resistant prostate cancer using systems biology and computational drug design techniques. Comput Biol Chem 2025; 115:108329. [PMID: 39731827 DOI: 10.1016/j.compbiolchem.2024.108329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 05/07/2024] [Accepted: 12/24/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND AND OBJECTIVE Castration-resistant prostate cancer (CRPC) is caused by resistance to androgen deprivation treatment and leads to the death of patients and there is almost no chance of survival. Therefore, finding a cure to overcome CRPC is challenging and important, but discovering a new drug is very time-consuming and expensive. To overcome these problems, we used Drug repositioning (drug repurposing) strategy in this study. METHODS Gene expression data of CRPC and primary prostate samples were extracted from the GEO database to identify DEGs. Pathway enrichment was performed to find the role of DEGs in signaling pathways. To identify hub proteins, the PPI network was reconstructed and analyzed. drug candidates were identified and to select the most effective drug, molecular docking analysis, and molecular dynamics simulation were performed. Then MTT and qRT-PCR tests were performed to check the effectiveness of the selected drug. RESULTS A total of 152 upregulated DEGs and 343 downregulated DEGs were identified, and after PPI network analysis, IKBKB, SNAP23, MYC, and NOTCH1 genes were introduced as hubs. drug candidates for IKBKB were identified and by examining the results of docking screening and molecular dynamics, sulfasalazine was selected as the most effective drug. Laboratory analyses proved the effectiveness of this drug and a decrease in the expression of all target genes was observed. CONCLUSION In this study, IKBKB key protein were identified in CRPC, and sulfasalazine was selected as a suitable candidate for drug repositioning and its effectiveness was confirmed through tests.
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Affiliation(s)
- Javad Rafiee
- Bioinformatics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Javad Bazyari
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Hamid Aghaee-Bakhtiari
- Bioinformatics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Liu H, Du Y, Wang Z, Fang X, Sun H, Gao F, Shang T, Shi B. Isobutyrate exerts a protective effect against liver injury in a DSS-induced colitis by inhibiting inflammation and oxidative stress. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2025; 105:2486-2496. [PMID: 39540441 DOI: 10.1002/jsfa.14021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/21/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Short-chain fatty acids have been reported to have anti-inflammatory and antioxidant functions; whether isobutyrate, a short-chain fatty acid, is protective against liver injury in a dextran sodium sulfate (DSS)-induced colitis and its molecular mechanism is unknown. In this study, DSS was used to induce a liver injury from a colitis model in piglets, which was expected to prevent and alleviate DSS-induced liver injury by feeding sodium isobutyrate in advance. RESULTS The results showed that sodium isobutyrate could restore DSS-induced histopathological changes in the liver, inhibit the activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-B signaling pathway, and then reduce the DSS-induced release of pro-inflammatory cytokines tumor necrosis factor-α, interleukin 1β, and interleukin 6, reducing inflammatory response. Moreover, we found that sodium isobutyrate could play an antioxidant and apoptosis-reducing role by maintaining reduced mitochondrial function. CONCLUSION In conclusion, sodium isobutyrate has a preventive and protective effect on liver injury in a DSS-induced colitis. There is a potential application prospect for it in treating ulcerative-colitis-induced liver injuries. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Haiyang Liu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Yongqing Du
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Zhengyi Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Xiuyu Fang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Haowen Sun
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Feng Gao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Tingting Shang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Baoming Shi
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
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Parvez A, Rahman MA, Rahman MM, Shimki AI, Ahmmed S, Supti FA, Hasan MH, Bristi MSA, Ansari SA, Islam MT. Broad-Spectrum Therapeutic Potentials of the Multifaceted Triterpene Lupeol and Its Derivatives. Chem Biodivers 2025:e202402286. [PMID: 39982855 DOI: 10.1002/cbdv.202402286] [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: 09/14/2024] [Revised: 02/05/2025] [Accepted: 02/21/2025] [Indexed: 02/23/2025]
Abstract
Lupeol (LUP), a naturally occurring pentacyclic triterpene, is found in various fruits, vegetables, and medicinal plants and is evident to possess diverse pharmacological activities. This study aimed to consolidate its findings based on updated database reports. Findings suggest that LUP and some of its derivatives have promising biological roles, including anticancer effects. Notably, LUP induces apoptosis and cell cycle arrest in cancer cells while sparing normal cells, highlighting its selective cytotoxicity. By modifying pathways such as NF-κB and phosphatidyl inositol 3-kinase (PI3K)/Akt, LUP demonstrates anticancer activity, reducing LDL oxidation by 34.4% and causing cancer cells to undergo apoptosis while leaving healthy cells unaffected. Moreover, it has strong antioxidant and anti-inflammatory properties; thus, it may act against conditions like arthritis, asthma, and cardiovascular diseases. It has broad-spectrum antimicrobial activities and can be used as an alternative to conventional antibiotics. LUP and its nanoformulations (PEGylated liposomes) improved biopharmaceutical profiles in test systems. It also showed neuroprotective effects, particularly against Alzheimer's and Parkinson's diseases. Taken together, LUP has multi-target therapeutic approaches against various diseases and pathological conditions, advocating for its inclusion in future clinical trials.
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Affiliation(s)
- Anwar Parvez
- Department of Pharmacy, Daffodil International University, Dhaka, Bangladesh
| | | | - Md Mahfuzur Rahman
- Department of Pharmacy, Daffodil International University, Dhaka, Bangladesh
| | | | - Shakil Ahmmed
- Department of Biochemistry and Molecular Biology, Gopalganj Science and Technology University, Gopalgonj, Bangladesh
| | - Fatema Akter Supti
- Department of Pharmacy, Daffodil International University, Dhaka, Bangladesh
| | - Md Hasibul Hasan
- Department of Food Engineering, Gopalganj Science and Technology University, Gopalganj, Bangladesh
| | - Mst Sonia Akter Bristi
- Department of Chemistry, Kabi Nazrul Govt. College, University of Dhaka, Dhaka, Bangladesh
| | - Siddique Akber Ansari
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Muhammad Torequl Islam
- Department of Pharmacy, Gopalganj Science and Technology University, Gopalganj, Bangladesh
- Pharmacy Discipline, Khulna University, Khulna, Bangladesh
- Bioinformatics and Drug Innovation Laboratory, BioLuster Research Center Ltd., Gopalganj, Dhaka, Bangladesh
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Morgan EL, Saleh AD, Cornelius S, Carlson SG, Toni T, Cheng H, Jeon J, Viswanathan R, Yang X, Silvin C, Clavijo PE, Sowers AL, Mitchell JB, Ormanoglu P, Lal Nag M, Martin SE, Chen Z, Van Waes C. Functional RNAi Screening Identifies G2/M and Kinetochore Components as Modulators of TNFα/NF-κB Prosurvival Signaling in Head and Neck Squamous Cell Carcinoma. CANCER RESEARCH COMMUNICATIONS 2024; 4:2903-2918. [PMID: 39392349 PMCID: PMC11541648 DOI: 10.1158/2767-9764.crc-24-0274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/14/2024] [Accepted: 10/09/2024] [Indexed: 10/12/2024]
Abstract
SIGNIFICANCE Here, RNAi library screening reveals that multiple G2/M and kinetochore components, including TTK/monopolar spindle 1, modulate TNFα-induced NF-κB activation, cell survival, and genotoxicity, underscoring their potential importance as therapeutic targets in HNSCC.
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Affiliation(s)
- Ethan L. Morgan
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
- School of Life Sciences, University of Sussex, Brighton, United Kingdom
| | - Anthony D. Saleh
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Shaleeka Cornelius
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Sophie G. Carlson
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Tiffany Toni
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Hui Cheng
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Jun Jeon
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Ramya Viswanathan
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Xinping Yang
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Christopher Silvin
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Paul E. Clavijo
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Anastasia L. Sowers
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - James B. Mitchell
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Pinar Ormanoglu
- RNAi Screening Facility, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
| | - Madhu Lal Nag
- RNAi Screening Facility, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
| | - Scott E. Martin
- RNAi Screening Facility, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
| | - Zhong Chen
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Carter Van Waes
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
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Yu X, Pu H, Voss M. Overview of anti-inflammatory diets and their promising effects on non-communicable diseases. Br J Nutr 2024; 132:898-918. [PMID: 39411832 PMCID: PMC11576095 DOI: 10.1017/s0007114524001405] [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: 02/14/2024] [Revised: 06/26/2024] [Accepted: 08/03/2024] [Indexed: 11/20/2024]
Abstract
An anti-inflammatory diet is characterised by incorporating foods with potential anti-inflammatory properties, including fruits, vegetables, whole grains, nuts, legumes, spices, herbs and plant-based protein. Concurrently, pro-inflammatory red and processed meat, refined carbohydrates and saturated fats are limited. This article explores the effects of an anti-inflammatory diet on non-communicable diseases (NCD), concentrating on the underlying mechanisms that connect systemic chronic inflammation, dietary choices and disease outcomes. Chronic inflammation is a pivotal contributor to the initiation and progression of NCD. This review provides an overview of the intricate pathways through which chronic inflammation influences the pathogenesis of conditions including obesity, type II diabetes mellitus, CVD, autoinflammatory diseases, cancer and cognitive disorders. Through a comprehensive synthesis of existing research, we aim to identify some bioactive compounds present in foods deemed anti-inflammatory, explore their capacity to modulate inflammatory pathways and, consequently, to prevent or manage NCD. The findings demonstrated herein contribute to an understanding of the interplay between nutrition, inflammation and chronic diseases, paving a way for future dietary recommendations and research regarding preventive or therapeutic strategies.
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Affiliation(s)
- Xiaoping Yu
- School of Medicine and Nursing, Chengdu University, Chengdu610106, People’s Republic of China
| | - Haomou Pu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu611137, People’s Republic of China
| | - Margaret Voss
- Department of Nutrition and Food Studies, Falk College, Syracuse University, Syracuse, NY13244, USA
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Wang H, Xu Q, Heng H, Zhao W, Ni H, Chen K, Wai Chan BK, Tang Y, Xie M, Peng M, Chi Chan EW, Yang G, Chen S. High mortality of Acinetobacter baumannii infection is attributed to macrophage-mediated induction of cytokine storm but preventable by naproxen. EBioMedicine 2024; 108:105340. [PMID: 39303669 PMCID: PMC11437915 DOI: 10.1016/j.ebiom.2024.105340] [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: 12/15/2023] [Revised: 08/25/2024] [Accepted: 08/30/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND The continuous emergence of multidrug-resistant (MDR) Acinetobacter baumannii (Ab) strains poses further challenges in its control and clinical management. It is necessary to decipher the mechanisms underlying the high mortality of Ab infections to explore unconventional strategies for controlling outbreaks of drug-resistant infections. METHODS The immune responses of Ab sepsis infection were investigated using flow cytometry, RNA-seq, qRT-PCR, and ELISA and scRNA-seq. The detailed pathways mediating Ab immune responses were also depicted and a specific therapy was developed based on the understanding of the mechanisms underlying Ab-induced cytokine storms. FINDINGS The results highlighted the critical role of alveolar and interstitial macrophages as targets of Ab during the infection process. These cells were found to undergo polarization towards the M1 phenotype, triggering a cytokine storm that eventually caused the death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-κB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen (NPXS) was shown to confer full protection of mice from lethal infections. INTERPRETATION The findings in this work depict the major mechanisms underlying the high mortality rate of Ab infections and highlight the clinical potential application of anti-inflammatory drugs or immunosuppressants in reducing the mortality of such infections, including those caused by MDR strains. FUNDING Funding sources are described in the acknowledgments section.
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Affiliation(s)
- Han Wang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China; State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Qi Xu
- State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Heng Heng
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China; State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Wenxing Zhao
- State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Hongyuhang Ni
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China; State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Kaichao Chen
- State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Bill Kwan Wai Chan
- State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Yang Tang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China; State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Miaomiao Xie
- State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Mingxiu Peng
- Shenzhen Key Lab for Food Biological Safety Control, The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, 518057, China
| | - Edward Wai Chi Chan
- State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Guan Yang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
| | - Sheng Chen
- State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China; Shenzhen Key Lab for Food Biological Safety Control, The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, 518057, China.
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Fang W, Song X, Li H, Meng F, Lv T, Huang J, Ji X, Lv J, Cai Z, Wang Z. Wnt/β-catenin signaling inhibits oxidative stress-induced ferroptosis to improve interstitial cystitis/bladder pain syndrome by reducing NF-κB. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119766. [PMID: 38823528 DOI: 10.1016/j.bbamcr.2024.119766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 04/29/2024] [Accepted: 05/23/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND Interstitial cystitis/bladder pain syndrome (IC/BPS) is a bladder syndrome of unknown etiology. Reactive oxygen species (ROS) plays a major role in ferroptosis and bladder dysfunction of IC/BPS, while the role of ferroptosis in IC/BPS progression is still unclear. This study aims to investigate the role and mechanism of ROS-induced ferroptosis in IC/BPS using cell and rat model. METHODS We collected IC/BPS patient bladder tissue samples and established a LPS-induced IC/BPS rat model (LRM). The level of oxidative stress and ferroptosis in IC/BPS patients and LRM rats was analyzed. Function and regulatory mechanism of ferroptosis in IC/BPS were explored by in vitro and in vivo experiments. RESULTS The patients with IC/BPS showed mast cells and inflammatory cells infiltration in bladder epithelial tissues. Expression of NRF2 was up-regulated, and GPX4 was decreased in IC/BPS patients compared with normal tissues. IC model cells underwent oxidative stress, which induced ferroptosis. These above results were validated in LRM rat models, and inhibition of ferroptosis ameliorated bladder dysfunction in LRM rats. Wnt/β-catenin signaling was deactivated in IC/BPS patients and animals, and activation of Wnt/β-catenin signaling reduced cellular free radical production, thereby inhibited ferroptosis in IC model cells. Mechanistically, the Wnt/β-catenin signaling pathway inhibited oxidative stress-induced ferroptosis by down-regulating NF-κB, thus contributing to recover IC/BPS both in vitro and in vivo. CONCLUSIONS We demonstrate for the first time that oxidative stress-induced ferroptosis plays an important role in the pathology of IC/BPS. Mechanistically, the Wnt/β-catenin signaling suppressed oxidative stress-induced ferroptosis by down-regulating NF-κB to improve bladder injury in IC/BPS.
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Affiliation(s)
- Weilin Fang
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
| | - Xin Song
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
| | - Hailong Li
- Institute of Molecular Enzymology, Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Fanguo Meng
- Redox Medical Center for Public Health, Soochow University, Suzhou, Jiangsu 215123, China
| | - Tingting Lv
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
| | - Jin Huang
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
| | - Xiang Ji
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
| | - Jianwei Lv
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China.
| | - Zhikang Cai
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
| | - Zhong Wang
- Department of Urology and Andrology, Shanghai Pudong New Area Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
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Kołodziejska R, Tafelska-Kaczmarek A, Pawluk M, Sergot K, Pisarska L, Woźniak A, Pawluk H. Ashwagandha-Induced Programmed Cell Death in the Treatment of Breast Cancer. Curr Issues Mol Biol 2024; 46:7668-7685. [PMID: 39057095 PMCID: PMC11275341 DOI: 10.3390/cimb46070454] [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: 06/21/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The aim of this review is to provide experimental evidence for the programmed-death activity of Ashwagandha (Withania somnifera) in the anti-cancer therapy of breast cancer. The literature search was conducted using online electronic databases (Google Scholar, PubMed, Scopus). Collection schedule data for the review article covered the years 2004-2024. Ashwagandha active substances, especially Withaferin A (WA), are the most promising anti-cancer compounds. WS exerts its effect on breast cancer cells by inducing programmed cell death, especially apoptosis, at the molecular level. Ashwagandha has been found to possess a potential for treating breast cancer, especially estrogen receptor/progesterone receptor (ER/PR)-positive and triple-negative breast cancer.
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Affiliation(s)
- Renata Kołodziejska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Agnieszka Tafelska-Kaczmarek
- Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland;
| | - Mateusz Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Krzysztof Sergot
- Laboratory of Laser Molecular Spectroscopy, Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Wroblewskiego 15, 93-590 Lodz, Poland;
| | - Lucyna Pisarska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Hanna Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
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Gauss C, Stone LD, Ghafouri M, Quan D, Johnson J, Fribley AM, Amm HM. Overcoming Resistance to Standard-of-Care Therapies for Head and Neck Squamous Cell Carcinomas. Cells 2024; 13:1018. [PMID: 38920648 PMCID: PMC11201455 DOI: 10.3390/cells13121018] [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: 05/29/2024] [Accepted: 06/05/2024] [Indexed: 06/27/2024] Open
Abstract
Although there have been some advances during in recent decades, the treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging. Resistance is a major issue for various treatments that are used, including both the conventional standards of care (radiotherapy and platinum-based chemotherapy) and the newer EGFR and checkpoint inhibitors. In fact, all the non-surgical treatments currently used for HNSCC are associated with intrinsic and/or acquired resistance. Herein, we explore the cellular mechanisms of resistance reported in HNSCC, including those related to epigenetic factors, DNA repair defects, and several signaling pathways. This article discusses these mechanisms and possible approaches that can be used to target different pathways to sensitize HNSCC to the existing treatments, obtain better responses to new agents, and ultimately improve the patient outcomes.
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Affiliation(s)
- Chester Gauss
- Carman and Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48202, USA; (C.G.); (M.G.)
| | - Logan D. Stone
- Oral & Maxillofacial Surgery, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Mehrnoosh Ghafouri
- Carman and Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48202, USA; (C.G.); (M.G.)
| | - Daniel Quan
- Department of Otolaryngology Head and Neck Surgery, School of Medicine, Wayne State University, Detroit, MI 48202, USA; (D.Q.)
| | - Jared Johnson
- Department of Otolaryngology Head and Neck Surgery, School of Medicine, Wayne State University, Detroit, MI 48202, USA; (D.Q.)
| | - Andrew M. Fribley
- Carman and Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48202, USA; (C.G.); (M.G.)
- Department of Otolaryngology Head and Neck Surgery, School of Medicine, Wayne State University, Detroit, MI 48202, USA; (D.Q.)
- Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA
| | - Hope M. Amm
- Oral & Maxillofacial Surgery, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
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Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, Zeng C, Zhou T, Zhang J. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9:53. [PMID: 38433280 PMCID: PMC10910037 DOI: 10.1038/s41392-024-01757-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 03/05/2024] Open
Abstract
NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
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Affiliation(s)
- Qing Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yizi Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, PR China
| | - Xiaomin Ye
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Xin Shen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingxi Lin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Zeng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Zhou
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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11
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Li Y, Zhao B, Peng J, Tang H, Wang S, Peng S, Ye F, Wang J, Ouyang K, Li J, Cai M, Chen Y. Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers. Drug Resist Updat 2024; 73:101042. [PMID: 38219532 DOI: 10.1016/j.drup.2023.101042] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/16/2024]
Abstract
Drug resistance in cancer remains a major challenge in oncology, impeding the effectiveness of various treatment modalities. The nuclear factor-kappa B (NF-κB) signaling pathway has emerged as a critical player in the development of drug resistance in cancer cells. This comprehensive review explores the intricate relationship between NF-κB and drug resistance in cancer. We delve into the molecular mechanisms through which NF-κB activation contributes to resistance against chemotherapeutic agents, targeted therapies, and immunotherapies. Additionally, we discuss potential strategies to overcome this resistance by targeting NF-κB signaling, such as small molecule inhibitors and combination therapies. Understanding the multifaceted interactions between NF-κB and drug resistance is crucial for the development of more effective cancer treatment strategies. By dissecting the complex signaling network of NF-κB, we hope to shed light on novel therapeutic approaches that can enhance treatment outcomes, ultimately improving the prognosis for cancer patients. This review aims to provide a comprehensive overview of the current state of knowledge on NF-κB and its role in drug resistance, offering insights that may guide future research and therapeutic interventions in the fight against cancer.
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Affiliation(s)
- Yuanfang Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer，Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Baiwei Zhao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer，Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Juzheng Peng
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer，Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Sicheng Wang
- School of Medicine, Sun Yat-sen University, China
| | - Sicheng Peng
- School of Medicine, Sun Yat-sen University, China
| | - Feng Ye
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer，Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Junye Wang
- School of Medicine, Sun Yat-sen University, China
| | - Kai Ouyang
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Jianjun Li
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Manbo Cai
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Yongming Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer，Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
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12
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Chen B, Jin W. A comprehensive review of stroke-related signaling pathways and treatment in western medicine and traditional Chinese medicine. Front Neurosci 2023; 17:1200061. [PMID: 37351420 PMCID: PMC10282194 DOI: 10.3389/fnins.2023.1200061] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/19/2023] [Indexed: 06/24/2023] Open
Abstract
This review provides insight into the complex network of signaling pathways and mechanisms involved in stroke pathophysiology. It summarizes the historical progress of stroke-related signaling pathways, identifying potential interactions between them and emphasizing that stroke is a complex network disease. Of particular interest are the Hippo signaling pathway and ferroptosis signaling pathway, which remain understudied areas of research, and are therefore a focus of the review. The involvement of multiple signaling pathways, including Sonic Hedgehog (SHH), nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), hypoxia-inducible factor-1α (HIF-1α), PI3K/AKT, JAK/STAT, and AMPK in pathophysiological mechanisms such as oxidative stress and apoptosis, highlights the complexity of stroke. The review also delves into the details of traditional Chinese medicine (TCM) therapies such as Rehmanniae and Astragalus, providing an analysis of the recent status of western medicine in the treatment of stroke and the advantages and disadvantages of TCM and western medicine in stroke treatment. The review proposes that since stroke is a network disease, TCM has the potential and advantages of a multi-target and multi-pathway mechanism of action in the treatment of stroke. Therefore, it is suggested that future research should explore more treasures of TCM and develop new therapies from the perspective of stroke as a network disease.
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Affiliation(s)
- Binhao Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weifeng Jin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
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13
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Wen T, Geng M, Bai E, Wang X, Miao H, Chen Z, Zhou H, Wang J, Shi J, Zhang Y, Lei M, Zhu Y. KPT-330 and Y219 exert a synergistic antitumor effect in triple-negative breast cancer through inhibiting NF-κB signaling. FEBS Open Bio 2023; 13:751-762. [PMID: 36847599 PMCID: PMC10068319 DOI: 10.1002/2211-5463.13588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 03/09/2023] [Accepted: 02/24/2023] [Indexed: 03/01/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype, which has poor prognosis due to the lack of effective targeted drugs. KPT-330, an inhibitor of the nuclear export protein CRM-1, has been widely used in clinical medicine. Y219, a novel proteasome inhibitor designed by our group, shows superior efficacy, reduced toxicity, and reduced off-target effects as compared to the proteasome inhibitor bortezomib. In this study, we investigated the synergistic effect of KPT-330 and Y219 against TNBC cells, as well as the underlying mechanisms. We report that combination treatment with KPT-330 and Y219 synergistically inhibited the viability of TNBC cells in vitro and in vivo. Further analysis revealed that the combined use of KPT-330 and Y219 induced G2-M phase arrest and apoptosis in TNBC cells, and attenuated nuclear factor kappa B (NF-κB) signaling by facilitating nuclear localization of IκB-α. Collectively, these results suggest that the combined use of KPT-330 and Y219 may be an effective therapeutic strategy for the treatment of TNBC.
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Affiliation(s)
- Tiantian Wen
- College of Life Science, Nanjing Normal University, China
| | - Mengzhu Geng
- College of Life Science, Nanjing Normal University, China
| | - Enhe Bai
- College of Life Science, Nanjing Normal University, China
| | - Xueyuan Wang
- College of Life Science, Nanjing Normal University, China
| | - Hang Miao
- College of Science, Nanjing Forestry University, China
| | - Zhimeng Chen
- College of Science, Nanjing Forestry University, China
| | - Hui Zhou
- College of Life Science, Nanjing Normal University, China
| | - Jia Wang
- Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., Nanjing, China
| | - Jingmiao Shi
- Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., Nanjing, China
| | - Yin Zhang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, China
| | - Meng Lei
- College of Science, Nanjing Forestry University, China
| | - Yongqiang Zhu
- College of Life Science, Nanjing Normal University, China
- Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., Nanjing, China
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, China
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14
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Mussa A, Afolabi HA, Syed NH, Talib M, Murtadha AH, Hajissa K, Mokhtar NF, Mohamud R, Hassan R. The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer. Biomedicines 2023; 11:biomedicines11041060. [PMID: 37189677 DOI: 10.3390/biomedicines11041060] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Breast cancer (BC) is the most common cancer type among women with a distinct clinical presentation, but the survival rate remains moderate despite advances in multimodal therapy. Consequently, a deeper understanding of the molecular etiology is required for the development of more effective treatments for BC. The relationship between inflammation and tumorigenesis is well established, and the activation of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is frequently identified in BC. Constitutive NF-κB activation is linked to cell survival, metastasis, proliferation, and hormonal, chemo-, and radiotherapy resistance. Moreover, the crosstalk between NF-κB and other transcription factors is well documented. It is reported that vitamin C plays a key role in preventing and treating a number of pathological conditions, including cancer, when administered at remarkably high doses. Indeed, vitamin C can regulate the activation of NF-κB by inhibiting specific NF-κB-dependent genes and multiple stimuli. In this review, we examine the various NF-κB impacts on BC development. We also provide some insight into how the NF-κB network may be targeted as a potential vulnerability by using natural pro-oxidant therapies such as vitamin C.
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15
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Bahreyni A, Mohamud Y, Luo H. Recent advancements in immunotherapy of melanoma using nanotechnology-based strategies. Biomed Pharmacother 2023; 159:114243. [PMID: 36641926 DOI: 10.1016/j.biopha.2023.114243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Melanoma is a malignant tumor that accounts for the deadliest form of skin cancers. Despite the significant efforts made recently for development of immunotherapeutic strategies including using immune checkpoint inhibitors and cancer vaccines, the clinical outcomes are unsatisfying. Different factors affect efficient cancer immunotherapy such as side-effects, immunosuppressive tumor microenvironment, and tumor heterogeneity. In the past decades, various nanotechnology-based approaches have been developed to enhance the efficacy of cancer immunotherapy, in addition to diminishing the toxicity associated with it. Several studies have shown that proper application of nanomaterials can revolutionize the outcome of immunotherapy in diverse melanoma models. This review summarizes the recent advancement in the integration of nanotechnology and cancer immunotherapy in melanoma treatment. The importance of nanomaterials and their therapeutic advantages for patients with melanoma are also discussed.
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Affiliation(s)
- Amirhossein Bahreyni
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada; Department of Pathology and Laboratory of Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
| | - Yasir Mohamud
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada; Department of Pathology and Laboratory of Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
| | - Honglin Luo
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada; Department of Pathology and Laboratory of Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada.
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16
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Chauhan M, Dhar ZA, Gorki V, Sharma S, Koul A, Bala S, Kaur R, Kaur S, Sharma M, Dhingra N. Exploration of anticancer potential of Lantadenes from weed Lantana camara: Synthesis, in silico, in vitro and in vivo studies. PHYTOCHEMISTRY 2023; 206:113525. [PMID: 36442578 DOI: 10.1016/j.phytochem.2022.113525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 06/16/2023]
Abstract
Naturally occurring pentacyclic triterpenoids and their semisynthetic analogues have engrossed increasing attention for their anticancer potential and exhibiting promising role in discovery of new anticancer agents. Present study include the semi synthetic modifications of Lantadenes from the weed Lantana carama and their structures delineation by FT-IR, 1H-NMR, 13C-NMR & mass spectroscopy. All the compounds were scrutinized for in vitro cytotoxicity, ligand receptor interaction and in vivo anticancer studies. Most of the novel analogues displayed potent antiproliferative activity against A375 & A431 cancer cell lines and found superior to parent Lantadenes. In particular, 3β-(4-Methoxybenzoyloxy)-22β-senecioyloxy-olean-12-en-28-oic acid was found to be most suitable compound, with IC50 value of 3.027 μM aganist A375 cell line having least docking score (-69.40 kcal/mol). Promising anticancer potential of the lead was further indicated by significant reduction in tumor volume and burden in two stage carcinoma model. These findings suggests that the Lantadene derivatives may hold promising potential for the intervention of skin cancers.
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Affiliation(s)
- Monika Chauhan
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India; School of Health Sciences and Technology, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, 248007, India.
| | - Zahid Ahmad Dhar
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Varun Gorki
- Parasitology Laboratory, Department of Zoology, Panjab University, Chandigarh, 160014, India
| | - Sonia Sharma
- Department Cum National Centre for Human Genome Studies and Research, Punjab University, Chandigarh, 160014, India
| | - Ashwani Koul
- Department of Biophysics, Panjab University, Chandigarh, 160014, India
| | - Shashi Bala
- Department of Biophysics, Panjab University, Chandigarh, 160014, India
| | - Ramandeep Kaur
- Department Cum National Centre for Human Genome Studies and Research, Punjab University, Chandigarh, 160014, India
| | - Sukhbir Kaur
- Parasitology Laboratory, Department of Zoology, Panjab University, Chandigarh, 160014, India
| | - Manu Sharma
- National Forensic Science University, Delhi Campus, India
| | - Neelima Dhingra
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
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17
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Liu S, Che N, Ou W, Yan M, Liao Y, Cheng Y. Bullatine A exerts anti-inflammatory effects by inhibiting the ROS/JNK/NF-κB pathway and attenuating systemic inflammatory responses in mice. PHARMACEUTICAL BIOLOGY 2022; 60:1840-1849. [PMID: 36200648 PMCID: PMC9553175 DOI: 10.1080/13880209.2022.2121410] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 08/03/2022] [Accepted: 08/31/2022] [Indexed: 06/16/2023]
Abstract
CONTEXT Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao) is a traditional Chinese herbal medicine that is capable of anti-analgesic and anti-inflammatory effects. Bullatine A (BA) is one of the major active ingredients of this plant, and most of the previous studies reported that it has anti-analgesic effects. However, the mechanism of BA anti-inflammatory remains unclear. OBJECTIVE This study investigates the anti-inflammatory activities of BA, both in vitro and in vivo, and elucidates its mechanism. MATERIALS AND METHODS In vitro, BA (10, 20, 40 and 80 μM) was added to 1 µg/mL of lipopolysaccharide (LPS)-activated microglia BV2 cells and immortalized murine bone marrow-derived macrophages, respectively. After 6 h, the mRNA and protein levels of inflammatory factors were determined by real-time quantitative PCR and western blotting. In vivo, C57BL/6 mice were randomly divided into control, model (5 mg/kg dose of LPS) and treated groups (LPS with 5, 10 or 20 mg/kg dose of BA) to evaluate the anti-inflammatory efficacy of BA. RESULTS BA significantly inhibited LPS-induced expression of inflammatory factors, such as IL-1β, IL-6, TNF-α, inducible nitric oxide synthase (iNOS) and COX-2. Further investigations showed that BA reduced the translocation of NF-κB p65 (38.5%, p < 0.01). BA also reduced the phosphorylation of c-Jun N-terminal kinase (JNK) (11.2%, p < 0.05) and reactive oxygen species (ROS) generation (24.2%, p < 0.01). Furthermore, BA treatment attenuated the LPS-primed inflammatory response and liver and lung damage in vivo. CONCLUSIONS BA can inhibit the inflammatory response in part through the ROS/JNK/NF-κB signalling pathway, providing a theoretical basis for the clinical application of BA in the treatment of periphery inflammatory diseases.
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Affiliation(s)
- Shuhan Liu
- College of Life and Environmental Sciences, Center on Translational Neuroscience, Minzu University of China, Beijing, China
| | - Na Che
- College of Life and Environmental Sciences, Center on Translational Neuroscience, Minzu University of China, Beijing, China
| | - Wen Ou
- Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Meichen Yan
- College of Life and Environmental Sciences, Center on Translational Neuroscience, Minzu University of China, Beijing, China
| | - Yajin Liao
- Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
- Department of Neurology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, PR China
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Yong Cheng
- College of Life and Environmental Sciences, Center on Translational Neuroscience, Minzu University of China, Beijing, China
- Institute of National Security, Minzu University of China, Beijing, China
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18
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Hunter JE, Campbell AE, Butterworth JA, Sellier H, Hannaway NL, Luli S, Floudas A, Kenneth NS, Moore AJ, Brownridge PJ, Thomas HD, Coxhead J, Taylor L, Leary P, Hasoon MS, Knight AM, Garrett MD, Collins I, Eyers CE, Perkins ND. Mutation of the RelA(p65) Thr505 phosphosite disrupts the DNA replication stress response leading to CHK1 inhibitor resistance. Biochem J 2022; 479:2087-2113. [PMID: 36240065 PMCID: PMC9704643 DOI: 10.1042/bcj20220089] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 07/22/2022] [Accepted: 08/19/2022] [Indexed: 12/14/2022]
Affiliation(s)
- Jill E. Hunter
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
| | - Amy E. Campbell
- Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Jacqueline A. Butterworth
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
| | - Helene Sellier
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
| | - Nicola L. Hannaway
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
| | - Saimir Luli
- Newcastle University Clinical and Translational Research Institute, Preclinical In Vivo Imaging, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
| | - Achilleas Floudas
- Newcastle University Clinical and Translational Research Institute, Preclinical In Vivo Imaging, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
| | - Niall S. Kenneth
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Adam J. Moore
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
| | - Philip J. Brownridge
- Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Huw D. Thomas
- Newcastle University Clinical and Translational Research Institute, Preclinical In Vivo Imaging, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
| | - Jonathan Coxhead
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
| | - Leigh Taylor
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
| | - Peter Leary
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Megan S.R. Hasoon
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Andrew M. Knight
- Newcastle University Clinical and Translational Research Institute, Preclinical In Vivo Imaging, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
| | - Michelle D. Garrett
- School of Biosciences, University of Kent, Stacey Building, Canterbury, Kent CT2 7NJ, U.K
| | - Ian Collins
- Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton SM2 5NG, U.K
| | - Claire E. Eyers
- Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Neil D. Perkins
- Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K
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19
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Lv C, Ren C, Yu Y, Yin H, Huang C, Yang G, Hong Y. Wentilactone A Reverses the NF-κB/ECM1 Signaling-Induced Cisplatin Resistance through Inhibition of IKK/IκB in Ovarian Cancer Cells. Nutrients 2022; 14:nu14183790. [PMID: 36145166 PMCID: PMC9504226 DOI: 10.3390/nu14183790] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Wentilactone A (WA) is a tetranorditerpenoid isolated from marine algae. We previously found that WA inhibited cancer cell proliferation with little toxicity. In this study, we show that high expression of extracellular matrix protein-1 (ECM1) promotes cancer cell cisplatin resistance, and the secreted ECM1 activates normal fibroblasts (NFs) to transform cells with characteristics of cancer-associated fibroblasts (CAFs). Transcription of the ECM1 gene is regulated largely by NF-κB through EP881C/T-EP266C binding sites. WA supresses the phosphorylation of NF-κB through inhibition of the upstream IKK/IκB phoshorylation to block the expression of ECM1, which reverses the cisplatin-induced activation of NF-κB/ECM1. On the contrary, cisplatin facilitates phosphorylation of NF-κB to enhance the expression of ECM1. These results highlight ECM1 as a potential target for treatment of cisplatin-resistant cancers associated with the ECM1 activated signaling. In addition, WA reverses cisplatin resistance by targeting both tumor cells and the tumor microenvironment through IKK/IκB/NF-κB signaling to reduce the expression of the ECM1 protein.
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Affiliation(s)
- Cuiting Lv
- Central Laboratory, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Chunxia Ren
- Center for Reproductive Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yinjue Yu
- Department of Radiotherapy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Huijing Yin
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Caiguo Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical, Navy Medical University, Shanghai 200433, China
- Correspondence: (C.H.); (G.Y.); (Y.H.)
| | - Gong Yang
- Central Laboratory, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai 200240, China
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China
- Correspondence: (C.H.); (G.Y.); (Y.H.)
| | - Yang Hong
- Central Laboratory, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai 200240, China
- Department of Orthopedics, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai 200240, China
- Correspondence: (C.H.); (G.Y.); (Y.H.)
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Poudel M, Bhattarai PY, Shrestha P, Choi HS. Regulation of Interleukin-36γ/IL-36R Signaling Axis by PIN1 in Epithelial Cell Transformation and Breast Tumorigenesis. Cancers (Basel) 2022; 14:cancers14153654. [PMID: 35954317 PMCID: PMC9367291 DOI: 10.3390/cancers14153654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/15/2022] [Accepted: 07/22/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Members of the interleukin (IL)-1 cytokine family exhibit dual functions in the regulation of inflammation and cancer. Recent studies have shown the critical role of IL-36γ, the newly identified IL-1 family member, in the regulation of cellular processes implicated in the progression of cancer. Therefore, the underlying mechanism of IL-36γ in tumor development is of considerable interest. Here, we identified the pivotal role of IL-36γ in the proliferation of breast cancer cells. Consistently, IL-36γ was found to promote epithelial cell transformation via the activation of c-Fos, c-Jun, and AP-1 transcription factors, followed by the IL36R-mediated MEK/ERK and JNK/c-Jun cascades. Furthermore, our findings demonstrate the critical role of PIN1 in the regulation of IL-36γ-induced mammary gland tumorigenesis. Abstract Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the IL-36γ/IL-36R axis during breast cancer progression, which has not yet been elucidated. Initially, we determined the effects of IL-36γ on the proliferation and epithelial cell transformation of JB6 Cl41 mouse epidermal and MCF7 human breast cancer cells using BrdU incorporation and anchorage-independent growth assays. We found that treatment with IL-36γ increased the proliferation and colony formation of JB6 Cl41 and MCF7 cells. Analysis of the mechanism underlying the neoplastic cell transformation revealed that IL-36γ induced IL-36R-mediated phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun, resulting in increased c-Fos, c-Jun, and AP-1 activities in JB6 Cl41 and MCF7 cells. Furthermore, the IL-36γ-induced tumorigenic capacity of MCF7 cells was considerably enhanced by PIN1, following MEK/ERK and JNK/c-Jun signaling. Interestingly, blocking PIN1 activity using juglone suppressed the IL-36γ-induced increase in the anchorage-independent growth of 4T1 metastatic mouse breast cancer cells. Finally, in a syngeneic mouse model, IL-36γ-induced tumor growth in the breast mammary gland was significantly inhibited following PIN1 knockout.
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Affiliation(s)
| | | | | | - Hong Seok Choi
- Correspondence: ; Tel.: +82-622306379; Fax: +82-622225414
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21
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Yang C, Cui Y, Ren X, Li M, Yu K, Shen S, Jiang H, Li M, Zhang X, Zhao X, Zhu Q, Lin S. Orelabrutinib Combined With Lenalidomide and Immunochemotherapy for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Retrospective Analysis of Case Series. Front Oncol 2022; 12:901797. [PMID: 35785180 PMCID: PMC9243261 DOI: 10.3389/fonc.2022.901797] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/09/2022] [Indexed: 12/16/2022] Open
Abstract
Background Relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL) is an intractable situation without sound treatment. Bruton’s tyrosine kinase (BTK) represents an attractive drug target in PCNSL. Orelabrutinib is a new-generation BTK inhibitor with high cerebrospinal fluid (CSF) concentration. This study aimed to evaluate the efficacy and safety of orelabrutinib-containing combination therapy in patients with r/r PCNSL. Methods We retrospectively analyzed r/r PCNSL patients who received combination therapy with rituximab, high-dose methotrexate, temozolomide, orelabrutinib and lenalidomide, and further explored the relationship between the efficacy and genetic characteristics. Results A total of fifteen patients were included in this retrospective study. The overall response rate (ORR) was 86.7%, the complete remission (CR) rate was 73.3% and the disease control rate (DCR) was 93.3%. Among 13 responders, 9 patients are still receiving oral orelabrutinib and lenalidomide. The most common adverse event (AEs) was transaminase increase (66.7%). No grade 4 AE or drug-related death was reported. Genomic sequencing showed that patients who responded to orelabrutinib had abnormal NF-κB activation, while those who had no response were mainly enriched with transcriptional misregulation. Patients who had mutations in TLR, BCR, or NF-κB pathway achieved complete or partial response to the orelabrutinib-containing therapy. Moreover, the blood and cerebrospinal fluid circulating tumor DNA (ctDNA) were closely associated with tumor recurrence and treatment response and sustained tumor responses correlated with the clearance of ctDNA. Conclusion Orelabrutinib-containing regimen was effective and well-tolerated in patients with r/r PCNSL. Genome sequencing of tumor samples could help to screen patients who may respond to the orelabrutinib-containing regimen, and liquid biopsy may contribute to tracing tumor burden and monitoring treatment response.
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Affiliation(s)
- Chuanwei Yang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Department of Neurosurgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou University, Henan, China
| | - Yong Cui
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Xiaohui Ren
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Ming Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Kefu Yu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shaoping Shen
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Haihui Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Mingxiao Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Xiaokang Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Xuzhe Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Qinghui Zhu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Song Lin
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Key Laboratory of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China
- *Correspondence: Song Lin,
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22
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Zhou M, Zhao G, Zhou X, Xuan R, Chen Y, Wang Y. Clinicopathological analysis and prognostic significance of NF-κB p65 and IKKβ protein and mRNA expression in nasopharyngeal carcinoma. J Int Med Res 2022; 50:3000605211069195. [PMID: 34994235 PMCID: PMC8743962 DOI: 10.1177/03000605211069195] [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] [Indexed: 11/20/2022] Open
Abstract
Objective To investigate the clinicopathological significance of NF-κB p65 and IKKβ protein and mRNA expression in nasopharyngeal carcinoma (NPC) patients from Guangdong Province, China. Methods Data and tissues from patients with NPC were retrospectively studied. Immunohistochemical staining and quantitative reverse transcription polymerase chain reaction were used to evaluate and compare NF-κB p65 and IKKβ protein and mRNA levels, respectively, in 60 NPC and 30 nasopharyngitis tissue samples. Statistical analysis was conducted to determine correlations between NF-κB p65 and IKKβ protein and mRNA levels with clinicopathological characteristics and prognoses of NPC patients. Results NF-κB p65 and IKKβ protein and mRNA expression in NPC were significantly correlated with tumor size, lymph node metastasis, and TNM stage. NF-κB p65 and IKKβ protein and mRNA levels were significantly increased in NPC patients with deep tumor invasion (T3–4), lymph node metastasis, and stage III/IV disease; high NF-κB p65 and IKKβ mRNA expression were associated with significantly shorter disease-free survival rates compared with cases showing low NF-κB p65 and IKKβ mRNA expression. Conclusions NF-κB p65 and IKKβ may affect the prognosis of NPC patients and could be potential therapeutic targets for this disease.
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Affiliation(s)
- Mei Zhou
- Department of Pathology, Traditional Chinese Medical Hospital, Zhongshan, Guangdong, China
| | - Gang Zhao
- Department of Ultrasonography, Traditional Chinese Medical Hospital, Zhongshan, Guangdong, China
| | - Xiaojun Zhou
- Department of Otorhinolaryngology, Traditional Chinese Medical Hospital, Zhongshan, Guangdong, China
| | - Ruixia Xuan
- Department of Pathology, Traditional Chinese Medical Hospital, Zhongshan, Guangdong, China
| | - Yuwei Chen
- Department of Pathology, Traditional Chinese Medical Hospital, Zhongshan, Guangdong, China
| | - Yun Wang
- Department of Pathology, Traditional Chinese Medical Hospital, Zhongshan, Guangdong, China
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RSL3 Drives Ferroptosis through NF- κB Pathway Activation and GPX4 Depletion in Glioblastoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2021:2915019. [PMID: 34987700 PMCID: PMC8720588 DOI: 10.1155/2021/2915019] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/16/2021] [Accepted: 12/03/2021] [Indexed: 12/21/2022]
Abstract
Glioblastoma, the most aggressive form of malignant glioma, is very difficult to treat because of its aggressively invasive nature and high recurrence rates. RAS-selective lethal 3 (RSL3), a well-known inhibitor of glutathione peroxidase 4 (GPX4), could effectively induce oxidative cell death in glioblastoma cells through ferroptosis, and several signaling pathways are involved in this process. However, the role of the nuclear factor kappa-B (NF-κB) pathway in glioblastoma cell ferroptosis has not yet been investigated. Therefore, we aimed to clarify the underlying mechanism of the NF-κB pathway in RSL3-induced ferroptosis in glioblastoma cells. We found that RSL3 led to an increase in lipid ROS concentration and downregulation of ferroptosis-related proteins such as GPX4, ATF4, and SLC7A11 (xCT) in glioblastoma cells. Additionally, the NF-κB pathway was activated by RSL3, and its inhibition by BAY 11-7082 could alleviate ferroptosis. The murine xenograft tumor model indicated that NF-κB pathway inhibition could mitigate the antitumor effects of RSL3 in vivo. Furthermore, we found that GPX4 knockdown could not effectively induce ferroptosis. However, NF-κB pathway activation coupled with GPX4 silencing induced ferroptosis. Additionally, ATF4 and xCT expression might be regulated by the NF-κB pathway. Collectively, our results revealed that the NF-κB pathway plays a novel role in RSL3-induced ferroptosis in glioblastoma cells and provides a new therapeutic strategy for glioblastoma treatment.
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24
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Biancalana M, Natan E, Lenardo MJ, Fersht AR. NF-κB Rel subunit exchange on a physiological timescale. Protein Sci 2021; 30:1818-1832. [PMID: 34089216 PMCID: PMC8376415 DOI: 10.1002/pro.4134] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 12/21/2022]
Abstract
The Rel proteins of the NF-κB complex comprise one of the most investigated transcription factor families, forming a variety of hetero- or homodimers. Nevertheless, very little is known about the fundamental kinetics of NF-κB complex assembly, or the inter-conversion potential of dimerised Rel subunits. Here, we examined an unexplored aspect of NF-κB dynamics, focusing on the dissociation and reassociation of the canonical p50 and p65 Rel subunits and their ability to form new hetero- or homodimers. We employed a soluble expression system to enable the facile production of NF-κB Rel subunits, and verified these proteins display canonical NF-κB nucleic acid binding properties. Using a combination of biophysical techniques, we demonstrated that, at physiological temperatures, homodimeric Rel complexes routinely exchange subunits with a half-life of less than 10 min. In contrast, we found a dramatic preference for the formation of the p50/p65 heterodimer, which demonstrated a kinetic stability of at least an order of magnitude greater than either homodimer. These results suggest that specific DNA targets of either the p50 or p65 homodimers can only be targeted when these subunits are expressed exclusively, or with the intervention of additional post-translational modifications. Together, this work implies a new model of how cells can modulate NF-κB activity by fine-tuning the relative proportions of the p50 and p65 proteins, as well as their time of expression. This work thus provides a new quantitative interpretation of Rel dimer distribution in the cell, particularly for those who are developing mathematical models of NF-κB activity.
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Affiliation(s)
- Matthew Biancalana
- Medical Research Council Laboratory of Molecular BiologyCambridge Biomedical CampusCambridgeUK
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaMarylandUSA
| | | | - Michael J. Lenardo
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaMarylandUSA
| | - Alan R. Fersht
- Medical Research Council Laboratory of Molecular BiologyCambridge Biomedical CampusCambridgeUK
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Thoms HC, Stark LA. The NF-κB Nucleolar Stress Response Pathway. Biomedicines 2021; 9:biomedicines9091082. [PMID: 34572268 PMCID: PMC8471347 DOI: 10.3390/biomedicines9091082] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/09/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate cell growth and death. In this review, we will provide insight into the NF-κB nucleolar stress response pathway. We will discuss apoptosis mediated by nucleolar sequestration of RelA and new data demonstrating a role for p62 (sequestosome (SQSTM1)) in this process. We will also discuss activation of NF-κB signalling by degradation of the RNA polymerase I (PolI) complex component, transcription initiation factor-IA (TIF-IA (RRN3)), and contexts where TIF-IA-NF-κB signalling may be important. Finally, we will discuss how this pathway is targeted by aspirin to mediate apoptosis of colon cancer cells.
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26
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Wang L, Gu J, Zong M, Zhang Q, Li H, Li D, Mou X, Liu P, Liu Y, Qiu F, Zhao F. Anti-inflammatory action of physalin A by blocking the activation of NF-κB signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 267:113490. [PMID: 33091501 DOI: 10.1016/j.jep.2020.113490] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 10/13/2020] [Accepted: 10/16/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Physalis Calyx seu Fructus is typically used to treat inflammatory diseases such as upper respiratory tract infection and acute tonsillitis in clinical practice of China. Physalin A, a main active ingredient of this traditional Chinese medicine (TCM), has been reported for its significant anti-tumor activity. However, most reports focused on the studies of its anti-tumor activity, the anti-inflammatory activity of physalin A and its molecular mechanism are still not elucidated clearly. AIM OF THE STUDY The aim of the study was to investigate the anti-inflammatory activities both in vitro and in vivo and molecular mechanism of physalin A. MATERIALS AND METHODS The potential anti-inflammatory properties of physalin A were evaluated in vitro by lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells, and in vivo via two typical acute inflammation murine models. Some important inflammation-related molecules were analyzed by enzyme-linked immuno sorbent assay (ELISA) and Western blotting. RESULTS The results showed that physalin A inhibited carrageenan-induced paw edema of rats and capillary permeability of mice induced by acetic acid in vivo. Furthermore, physalin A also significantly reduced the release of inflammatory mediators nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in RAW 264.7 in vitro. Further investigations indicated that physalin A can down-regulate the high expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose-dependent manner. Physalin A remarkably blocked the degradation of inhibitor of nuclear factor kappa B alpha (IκB-α) and the nuclear translocation of nuclear factor-κB (NF-κB) p65 induced by LPS in RAW 264.7 cells. However, physalin A did not significantly inhibit the phosphorylation of mitogen-activated protein kinases (MAPKs) family proteins c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) or p38. CONCLUSIONS All the results clearly illustrated that the anti-inflammatory action of physalin A is due to the inactivation of NF-κB signal pathway, but is irrelevant to the MAPKs pathway.
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Affiliation(s)
- Liying Wang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Jinpo Gu
- Department of General Surgery, Yantai Hospital of Traditional Chinese Medicine, Yantai, 264000, PR China
| | - Mingyue Zong
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Qingran Zhang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Huixiang Li
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Danna Li
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Xiaofeng Mou
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Pan Liu
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Yanan Liu
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China
| | - Feng Qiu
- Tianjin State Key Laboratory of Modern Chinese Medicine, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, PR China.
| | - Feng Zhao
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, PR China.
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27
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Hu TY, Zhang H, Chen YY, Jiao WH, Fan JT, Liu ZQ, Lin HW, Cheng BH. Dysiarenone from Marine Sponge Dysidea arenaria Attenuates ROS and Inflammation via Inhibition of 5-LOX/NF-κB/MAPKs and Upregulation of Nrf-2/OH-1 in RAW 264.7 Macrophages. J Inflamm Res 2021; 14:587-597. [PMID: 33664584 PMCID: PMC7921866 DOI: 10.2147/jir.s283745] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/10/2021] [Indexed: 01/15/2023] Open
Abstract
Background Marine natural products harbor a variety of pharmacological activities, and the sea species have been becoming a main source of new drug candidate. In pursuit of safer and more effective anti-inflammation drug, the anti-inflammatory activities, anti-oxygenation effects and underlying molecular mechanisms of compound dysiarenone from Dysidea arenaria were investigated via LPS-induced RAW 264.7 cell model. Methods Firstly, RAW 264.7 cells have been stimulated with LPS and treated with dysiarenone, and the cell viability of the LPS-treated RAW 264.7 cells was examined. One-step method, DCFH-DA fluorescence probe method was used to detect reactive oxygen species (ROS). The modulation of dysiarenone on anti-inflammation was detected by enzyme-linked immunosorbent assay by measuring the release of inflammatory cytokines (TNF-α and IL-6), and inflammatory mediators (LTB4). Further, the underlying anti-inflammatory mechanism of dysiarenone was explored by determining the expression of inducible 5-LOX, MAPKs, p-Akt, and p-NF-κB p65. Oxidative stress is tightly connected with inflammation, which was also evaluated through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (OH-1) signaling pathway. Results Our study unraveled that dysiarenone between 2 and 8 µM reduces the inflammation responses via suppressing the production of inflammatory cytokines (TNF-α and IL-6) and inflammatory mediators (LTB4). Dysiarenone down-regulated the protein levels of inducible 5-LOX via the inhibition of phosphorylation of MAPKs (including p38, ERK), Akt and NF-κB p65. Additionally, dysiarenone decreases ROS accumulation by upregulating HO-1 expression via nuclear translocation of Nrf2. Conclusion In conclusion, we demonstrated that dysiarenone possesses anti-inflammation and anti-oxidation activity via inhibiting 5-LOX/NF-κB/MAPK and Nrf2/HO-1 signaling pathway. Dysiarenone might be a promising lead compound for inflammatory diseases.
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Affiliation(s)
- Tian-Yong Hu
- Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, 518172, People's Republic of China
| | - Hua Zhang
- Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, 518172, People's Republic of China
| | - Yan-Yan Chen
- Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, 518172, People's Republic of China
| | - Wei-Hua Jiao
- Research Center for Marine Drugs, State Key Laboratory of Oncogene and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jun-Ting Fan
- Department of Pharmaceutical Analysis, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China
| | - Zhi-Qiang Liu
- Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, 518172, People's Republic of China
| | - Hou-Wen Lin
- Research Center for Marine Drugs, State Key Laboratory of Oncogene and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Bao-Hui Cheng
- Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, 518172, People's Republic of China
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28
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Campbell AE, Ferraz Franco C, Su LI, Corbin EK, Perkins S, Kalyuzhnyy A, Jones AR, Brownridge PJ, Perkins ND, Eyers CE. Temporal modulation of the NF-κB RelA network in response to different types of DNA damage. Biochem J 2021; 478:533-551. [PMID: 33438746 PMCID: PMC7886319 DOI: 10.1042/bcj20200627] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 12/30/2022]
Abstract
Different types of DNA damage can initiate phosphorylation-mediated signalling cascades that result in stimulus specific pro- or anti-apoptotic cellular responses. Amongst its many roles, the NF-κB transcription factor RelA is central to these DNA damage response pathways. However, we still lack understanding of the co-ordinated signalling mechanisms that permit different DNA damaging agents to induce distinct cellular outcomes through RelA. Here, we use label-free quantitative phosphoproteomics to examine the temporal effects of exposure of U2OS cells to either etoposide (ETO) or hydroxyurea (HU) by monitoring the phosphorylation status of RelA and its protein binding partners. Although few stimulus-specific differences were identified in the constituents of phosphorylated RelA interactome after exposure to these DNA damaging agents, we observed subtle, but significant, changes in their phosphorylation states, as a function of both type and duration of treatment. The DNA double strand break (DSB)-inducing ETO invoked more rapid, sustained responses than HU, with regulated targets primarily involved in transcription, cell division and canonical DSB repair. Kinase substrate prediction of ETO-regulated phosphosites suggest abrogation of CDK and ERK1 signalling, in addition to the known induction of ATM/ATR. In contrast, HU-induced replicative stress mediated temporally dynamic regulation, with phosphorylated RelA binding partners having roles in rRNA/mRNA processing and translational initiation, many of which contained a 14-3-3ε binding motif, and were putative substrates of the dual specificity kinase CLK1. Our data thus point to differential regulation of key cellular processes and the involvement of distinct signalling pathways in modulating DNA damage-specific functions of RelA.
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Affiliation(s)
- Amy E. Campbell
- Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Catarina Ferraz Franco
- Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Ling-I Su
- Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
| | - Emma K. Corbin
- Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
| | - Simon Perkins
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Anton Kalyuzhnyy
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Andrew R. Jones
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Philip J. Brownridge
- Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K
| | - Neil D. Perkins
- Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
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Zozo B, Govender N, Moodley J, Naicker T. Expression of plasma nuclear factor-kappa B cells (NF-κB) and Inhibitory subunit kappa B alpha (IκB-α) in HIV-associated pre-eclampsia. Hypertens Pregnancy 2021; 40:15-20. [PMID: 33397161 DOI: 10.1080/10641955.2020.1854299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Objective:To investigate the expression of plasma NF-κB and the inhibitory subunit IκB-α in HIV-associated pre-eclampsia. Method: This retrospective study examined plasma NF-κB and IκB-α expression expressed as Mean Fluorescence Intensity (MFI) in normotensive (n = 32) and pre-eclamptic (n = 34) pregnant women stratified by HIV status. Results: A significant decrease in the level of plasma NF-κB expression between pre-eclamptic and normotensive pregnant women was observed, irrespective of HIV status (MFI = 82.8 vs 134.3; p = 0.03). Similarly, a significant decline in the level of plasma IκB-α expression was noted in the pre-eclamptic compared to normotensive pregnant women, irrespective of HIV status (MFI = 91.2 vs 120.1; p = 0.04). Plasma NF-κB (p = 0.7) and IκB-α (p = 0.8) expression was similar between HIV positive and HIV negative pregnant women, irrespective of pregnancy type. Conclusion: This study demonstrates decreased plasma NF-κB and IκB-α expression in preeclampsia compared to normotensive pregnant women irrespective of HIV status.
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Affiliation(s)
- Bambanani Zozo
- Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal , Durban, KwaZulu-Natal, South Africa
| | - Nalini Govender
- Women's Health and HIV Research Group, College of Health Sciences, University of KwaZulu-Natal , Durban, South Africa
| | - Jagidesa Moodley
- Dept of Basic Medical Sciences, Faculty of Health Sciences, Durban University of Technology , Durban, South Africa
| | - Thajasvarie Naicker
- Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal , Durban, KwaZulu-Natal, South Africa
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Fan X, Zhou J, Bi X, Liang J, Lu S, Yan X, Luo L, Yin Z. L-theanine suppresses the metastasis of prostate cancer by downregulating MMP9 and Snail. J Nutr Biochem 2020; 89:108556. [PMID: 33249185 DOI: 10.1016/j.jnutbio.2020.108556] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 08/26/2020] [Accepted: 11/21/2020] [Indexed: 12/18/2022]
Abstract
Prostate cancer (PCa) is a very prevalent male-specific malignancy; most PCa patients eventually die as a result of metastasis. L-theanine (C7H14N2O3), a nonprotein amino acid derivative from green tea leaves, has been demonstrated to act as an anticarcinogen through proapoptotic and antiproliferative effects. However, the antimetastatic effect of L-theanine in tumor cells and its underlying mechanism are still unclear. Here, we found that L-theanine could suppress invasion, migration, and increase cell-cell adhesion of prostate cancer cells in vitro and in vivo. We also found that L-theanine could inhibit the epithelial-mesenchymal transition process in PCa. Our study revealed that L-theanine could downregulate MMP9, N-cadherin, Vimentin, Snail, and upregulate E-cadherin. Furthermore, L-theanine suppressed the transcription of MMP9 and Snail by significantly inhibiting the ERK/NF-κB signaling pathway and the binding activity of p65 to the promoter regions of MMP9 and Snail. All of these findings suggest that L-theanine has therapeutic potential for metastatic PCa and may be considered a promising candidate for antimetastatic therapy of prostate cancer.
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Affiliation(s)
- Xirui Fan
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China
| | - Jinyi Zhou
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China
| | - Xiaowen Bi
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China
| | - Juanjuan Liang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China
| | - Shuai Lu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China
| | - Xintong Yan
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China
| | - Lan Luo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, People's Republic of China.
| | - Zhimin Yin
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China.
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31
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Song L, Chen X, Mi L, Liu C, Zhu S, Yang T, Luo X, Zhang Q, Lu H, Liang X. Icariin-induced inhibition of SIRT6/NF-κB triggers redox mediated apoptosis and enhances anti-tumor immunity in triple-negative breast cancer. Cancer Sci 2020; 111:4242-4256. [PMID: 32926492 PMCID: PMC7648025 DOI: 10.1111/cas.14648] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is closely implicated in triple-negative breast cancer growth, metastasis, and tumor immune escape. In this study, the anti-cancer effects of icariin, a natural flavonol glycoside, toward breast cancer cells and the underlying mechanisms were investigated. This investigation showed that icariin selectively inhibited proliferation and triggered apoptosis in breast cancer cells in a concentration- and time-dependent manner, but exhibited little cytotoxicity in normal breast cells. Moreover, icariin induced cell apoptosis via a mitochondria-mediated pathway, as indicated by the upregulated ratio of Bax/Bcl-2 and reactive oxygen species induction. Importantly, icariin impaired the activation of the NF-κB/EMT pathway, as evidenced by upregulation of SIRT6, resulting in inhibition of migration and invasion of breast cancer cells. Additionally, oss-128167, an inhibitor of SIRT6, dramatically attenuated anti-migration and anti-invasion effects of icariin. Transcriptomic analysis verified that impairment of NF-κB led to the selective function of icariin in breast cancer cells. Notably, icariin exhibited a significant tumor growth inhibition and anti-pulmonary metastasis effect in a tumor mouse model of MDA-MB-231 and 4T1 cells by regulating the tumor immunosuppressive microenvironment. Together, these results showed that icariin could effectively trigger apoptosis and inhibit the migration of breast cancer cells via the SIRT6/NF-κB signaling pathway, suggesting that icariin might serve as a potential candidate drug for the treatment of breast cancer.
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Affiliation(s)
- Linjiang Song
- School of Medical and Life Sciences/Reproductive & Women‐children HospitalChengdu University of Traditional Chinese MedicineChengduChina
| | - Xian Chen
- Department of PathologyHospital of Chengdu University of Traditional Chinese MedicineChengdu University of Traditional Chinese MedicineChengduChina
| | - Ling Mi
- School of Medical and Life Sciences/Reproductive & Women‐children HospitalChengdu University of Traditional Chinese MedicineChengduChina
| | - Chi Liu
- School of Medical and Life Sciences/Reproductive & Women‐children HospitalChengdu University of Traditional Chinese MedicineChengduChina
| | - Shaomi Zhu
- School of Medical and Life Sciences/Reproductive & Women‐children HospitalChengdu University of Traditional Chinese MedicineChengduChina
| | - Tianlin Yang
- Department of PathologyHospital of Chengdu University of Traditional Chinese MedicineChengdu University of Traditional Chinese MedicineChengduChina
| | - Xiaohong Luo
- School of Medical and Life Sciences/Reproductive & Women‐children HospitalChengdu University of Traditional Chinese MedicineChengduChina
| | - Qinxiu Zhang
- School of Medical and Life Sciences/Reproductive & Women‐children HospitalChengdu University of Traditional Chinese MedicineChengduChina
- Department of OtolaryngologyHospital of Chengdu University of Traditional Chinese MedicineChengdu University of Traditional Chinese MedicineChengduChina
| | - Hua Lu
- Innovative Institute of Liu‐minru Female Science InheritanceChengdu University of Traditional Chinese MedicineChengduChina
| | - Xin Liang
- School of Medical and Life Sciences/Reproductive & Women‐children HospitalChengdu University of Traditional Chinese MedicineChengduChina
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Singh A, Srivastava N, Yadav A, Ateeq B. Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma. Neoplasia 2020; 22:497-510. [PMID: 32896760 PMCID: PMC7481885 DOI: 10.1016/j.neo.2020.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 08/01/2020] [Accepted: 08/05/2020] [Indexed: 01/05/2023]
Abstract
Glioblastoma (GBM) represents the most aggressive malignancy of the central nervous system. Increased expression of Angiotensin II Receptor Type 1 (AGTR1) has been associated with proliferative and infiltrative properties of glioma cells. However, the underlying mechanism of AGTR1 upregulation in GBM is still unexplored. To understand the post-transcriptional regulation of AGTR1 in GBM, we screened 3'untranslated region (3'UTR) of AGTR1 for putative miRNA binding by using prediction algorithms. Interestingly, miR-155 showed conserved binding on the 3'UTR of AGTR1, subsequently confirmed by luciferase reporter assay. Furthermore, miR-155 overexpressing GBM cells show decrease in AGTR1 expression accompanied with reduced cell proliferation, invasion, foci formation and anchorage-independent growth. Strikingly, immunodeficient mice implanted with stable miR-155 overexpressing SNB19 cells show negligible tumor growth. Notably, miR-155 attenuates NF-κB signaling downstream of AGTR1 leading to reduced CXCR4 as well as AGTR1 levels. Mechanistically, miR-155 mitigates AGTR1-mediated angiogenesis, epithelial-to-mesenchymal transition, stemness, and MAPK signaling. Similar effects were observed by using pharmacological inhibitor of IκB Kinase (IKK) complex in multiple cell-based assays. Taken together, we established that miRNA-155 post-transcriptionally regulates AGTR1 expression, abrogates AGTR1/NF-κB/CXCR4 signaling axis and elicits pleiotropic anticancer effects in GBM. This study opens new avenues for using IKK inhibitors and miRNA-155 replacement therapies for the treatment of AGTR1-positive malignancies.
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MESH Headings
- Animals
- Apoptosis
- Brain Neoplasms/genetics
- Brain Neoplasms/metabolism
- Brain Neoplasms/pathology
- Cell Movement
- Cell Proliferation
- Female
- Gene Expression Regulation, Neoplastic
- Glioblastoma/genetics
- Glioblastoma/metabolism
- Glioblastoma/pathology
- Humans
- Mice
- Mice, Inbred NOD
- Mice, SCID
- MicroRNAs/genetics
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptors, CXCR4/genetics
- Receptors, CXCR4/metabolism
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Anukriti Singh
- Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India; Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Nidhi Srivastava
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Anjali Yadav
- Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India
| | - Bushra Ateeq
- Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India; Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India.
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Pastor-Fernández G, Mariblanca IR, Navarro MN. Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities. Cells 2020; 9:cells9092044. [PMID: 32906785 PMCID: PMC7563346 DOI: 10.3390/cells9092044] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/24/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
The interleukin 23 (IL-23) is a key pro-inflammatory cytokine in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators, such as IL-17, IL-22, granulocyte-macrophage colony-stimulating (GM-CSF), or the tumor necrosis factor (TNFα) by target populations, mainly Th17 and IL-17-secreting TCRγδ cells (Tγδ17). Due to their pivotal role in inflammatory diseases, IL-23 and its downstream effector molecules have emerged as attractive therapeutic targets, leading to the development of neutralizing antibodies against IL-23 and IL-17 that have shown efficacy in different inflammatory diseases. Despite the success of monoclonal antibodies, there are patients that show no response or partial response to these treatments. Thus, effective therapies for inflammatory diseases may require the combination of multiple immune-modulatory drugs to prevent disease progression and to improve quality of life. Alternative strategies aimed at inhibiting intracellular signaling cascades using small molecule inhibitors or interfering peptides have not been fully exploited in the context of IL-23-mediated diseases. In this review, we discuss the current knowledge about proximal signaling events triggered by IL-23 upon binding to its membrane receptor to bring to the spotlight new opportunities for therapeutic intervention in IL-23-mediated pathologies.
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Tundo GR, Sbardella D, Santoro AM, Coletta A, Oddone F, Grasso G, Milardi D, Lacal PM, Marini S, Purrello R, Graziani G, Coletta M. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges. Pharmacol Ther 2020; 213:107579. [PMID: 32442437 PMCID: PMC7236745 DOI: 10.1016/j.pharmthera.2020.107579] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 01/10/2023]
Abstract
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
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Affiliation(s)
- G R Tundo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
| | | | - A M Santoro
- CNR, Institute of Crystallography, Catania, Italy
| | - A Coletta
- Department of Chemistry, University of Aarhus, Aarhus, Denmark
| | - F Oddone
- IRCCS-Fondazione Bietti, Rome, Italy
| | - G Grasso
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - D Milardi
- CNR, Institute of Crystallography, Catania, Italy
| | - P M Lacal
- Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy
| | - S Marini
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - R Purrello
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - G Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - M Coletta
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.
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Chermnykh ES, Alpeeva EV, Vorotelyak EA. Transglutaminase 3: The Involvement in Epithelial Differentiation and Cancer. Cells 2020; 9:cells9091996. [PMID: 32872587 PMCID: PMC7563467 DOI: 10.3390/cells9091996] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/21/2020] [Accepted: 08/26/2020] [Indexed: 12/14/2022] Open
Abstract
Transglutaminases (TGMs) contribute to the formation of rigid, insoluble macromolecular complexes, which are essential for the epidermis and hair follicles to perform protective and barrier functions against the environment. During differentiation, epidermal keratinocytes undergo structural alterations being transformed into cornified cells, which constitute a highly tough outermost layer of the epidermis, the stratum corneum. Similar processes occur during the hardening of the hair follicle and the hair shaft, which is provided by the enzymatic cross-linking of the structural proteins and keratin intermediate filaments. TGM3, also known as epidermal TGM, is one of the pivotal enzymes responsible for the formation of protein polymers in the epidermis and the hair follicle. Numerous studies have shown that TGM3 is extensively involved in epidermal and hair follicle physiology and pathology. However, the roles of TGM3, its substrates, and its importance for the integument system are not fully understood. Here, we summarize the main advances that have recently been achieved in TGM3 analyses in skin and hair follicle biology and also in understanding the functional role of TGM3 in human tumor pathology as well as the reliability of its prognostic clinical usage as a cancer diagnosis biomarker. This review also focuses on human and murine hair follicle abnormalities connected with TGM3 mutations.
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36
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Yan Y, Lin HW, Zhuang ZN, Li M, Guo S. Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer. World J Gastrointest Oncol 2020; 12:877-892. [PMID: 32879665 PMCID: PMC7443842 DOI: 10.4251/wjgo.v12.i8.877] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/20/2020] [Accepted: 07/26/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B (NF-κB) pathway, resulting in the proliferation of tumor cells. Treatment with fluorouracil (5-FU) might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway.
AIM To detect whether interleukin (IL)-1 receptor antagonist (IL-1RA) could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells.
METHODS Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines. Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6, IL-8, IL-17, IL-21 and TLR4 in colon cancer cell lines. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1α feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth.
RESULTS IL-1 receptor antagonist could decrease the expression of IL-1α and IL-1β and downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells. Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line, and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line.
CONCLUSION Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs. IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.
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Affiliation(s)
- Yan Yan
- Department of Operating Room, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Hong-Wei Lin
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University, Beijing 102200, China
| | - Zhuo-Nan Zhuang
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University, Beijing 102200, China
| | - Ming Li
- Department of General Surgery, Zouping Traditional Chinese Medicine Hospital, Zhouping 256200, Shandong Province, China
| | - Sen Guo
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
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Non-Thermal Plasma Couples Oxidative Stress to TRAIL Sensitization through DR5 Upregulation. Int J Mol Sci 2020; 21:ijms21155302. [PMID: 32722598 PMCID: PMC7432737 DOI: 10.3390/ijms21155302] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/23/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells without affecting most normal cells. Despite being in clinical testing, novel strategies to induce TRAIL-mediated apoptosis are in need to overcome cancer cell unresponsiveness and resistance. Plasma-activated medium (PAM) markedly stimulates reactive oxygen/nitrogen species (ROS/RNS)-dependent apoptosis in cancer cells. We investigate the capability of PAM and TRAIL (PAM/TRAIL) combination therapy to overcome TRAIL resistance and improve the anticancer efficacy of TRAIL. The combinatorial treatment of PAM and TRAIL shows synergistic effects on growth inhibition in TRAIL-resistant cancer cells via augmented apoptosis by two attributes. DR5 (TRAIL-R2) transcription by CHOP is upregulated in a PAM-generated ROS/RNS-dependent manner, and PAM itself upregulates PTEN expression mediated by suppression of miR-425 which is involved in Akt inactivation, leading to increased apoptosis induction. Treatment of cancer cell lines with the antioxidant N-acetylcysteine reduces the extent of membrane dysfunction and the expression of both CHOP-DR5 and miR-425-PTEN axes, attenuating PAM/TRAIL-induced cancer cell apoptosis. These data suggest that PAM/TRAIL treatment is a novel approach to sensitizing cancer cells to TRAIL-induced apoptosis and overcoming TRAIL resistance. PAM is a promising candidate for further investigations as a chemotherapeutic sensitizer in the treatment of cancer.
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38
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Menezes SV, Fouani L, Huang MLH, Geleta B, Maleki S, Richardson A, Richardson DR, Kovacevic Z. The metastasis suppressor, NDRG1, attenuates oncogenic TGF-β and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells. Carcinogenesis 2020; 40:805-818. [PMID: 30561520 DOI: 10.1093/carcin/bgy178] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 11/18/2018] [Accepted: 12/13/2018] [Indexed: 01/04/2023] Open
Abstract
The metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and β-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and β-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/β and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-β signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.
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Affiliation(s)
- Sharleen V Menezes
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Leyla Fouani
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Michael L H Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Bekesho Geleta
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Sanaz Maleki
- Histopathology Laboratory, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia
| | - Alexander Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.,Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia
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Vahid F, Davoodi SH. Nutritional Factors Involved in the Etiology of Gastric Cancer: A Systematic Review. Nutr Cancer 2020; 73:376-390. [PMID: 32336147 DOI: 10.1080/01635581.2020.1756353] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CONTEXT Since treatment options for GC are limited, the best and most effective way is to try to reduce the incidences and understanding prevention strategies. OBJECTIVE The success in prevention strategies depends on understanding etiologic mechanisms. Our goal is to identify the major nutritional risk factors for GC, and we will examine the controversial evidence. DATA SOURCES We used Pub Med, Google Scholar, Scopus, Science Direct, Elsevier, Springer, and MEDLINE databases for extracting articles. DATA EXTRACTION Human studies published in English from 1997to2018 were included. Two reviewers other than authors initially assessed abstract of 742 papers and 248papers were selected for future assessments. After full review and consideration of the inclusion and exclusion criteria, we used 85 articles. RESULTS Dietary salt is a strong independent risk for GC whereas alcohol is most likely a risk only in the presence of heavy alcohol consumption. Red meat and high-fat diet increase the risk of developing GC but fresh fruits, vegetables and certain micronutrients like selenium and vitamin C are protective. CONCLUSION Some nutrients such as selenium, vitamin C, folate, iron, and zinc are involved in the etiology of GC. On the other hand; salt, fats, alcohol, red meat, and pepper were reported to be risk factors for GC. Since the GC is a heterogeneous malignancy and multiple factors are involved in its genesis.
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Affiliation(s)
- Farhad Vahid
- Department of Nutritional Sciences, School of Health, Arak University of Medical Sciences, Arak, Iran
| | - Sayed Hossein Davoodi
- Faculty of Nutrition Sciences and Food Technology, Department of Nutritional Sciences, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Hassannia B, Logie E, Vandenabeele P, Vanden Berghe T, Vanden Berghe W. Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug. Biochem Pharmacol 2020; 173:113602. [DOI: 10.1016/j.bcp.2019.08.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 08/05/2019] [Indexed: 12/26/2022]
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41
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Zhu D, Zheng S, Fang C, Guo X, Han D, Tang M, Fu H, Jiang M, Xie N, Nie Y, Yao X, Chen Y. Dysbindin promotes pancreatic ductal adenocarcinoma metastasis by activating NF-κB/MDM2 via miR-342-3p. Cancer Lett 2020; 477:107-121. [PMID: 32120026 DOI: 10.1016/j.canlet.2020.02.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/11/2020] [Accepted: 02/26/2020] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid tumours and has the highest cancer-related mortality rate. Despite intense investigation, the molecular mechanisms underlying the invasiveness and aetiology of PDAC remain elusive. MicroRNAs (miRNAs) are key regulators of tumour cell plasticity, but their roles in PDAC metastasis have not been characterized. Our early studies showed that dysbindin protein levels are elevated in PDAC patients compared with control individuals and that dysbindin upregulation elicits PDAC cell proliferation via the PI3K pathway. Here, we show that dysbindin promoted PDAC metastasis via the NF-κB/MDM2 signalling axis. Increased dysbindin levels correlated with aggressive features in PDAC, and the overexpression of dysbindin significantly promoted PDAC metastasis and invasion in vitro and in vivo. Surprisingly, dysbindin was identified as a direct target of miR-342-3p, which promotes NF-κB activation and PDAC metastasis. Thus, dysbindin-mediated NF-κB activation via miR-342-3p represents a context-dependent switch that enables PDAC cell proliferation and metastasis. Our data suggest that dysbindin and miR-342-3p are potential leads for the development of targeted therapy for PDAC.
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Affiliation(s)
- Donglie Zhu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Shi Zheng
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Cheng Fang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Xin Guo
- Department of Endoscopic Surgery, 986th Military Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710054, China
| | - Dandan Han
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Mingyao Tang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Hang Fu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Mingzuo Jiang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Ning Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
| | - Xuebiao Yao
- Department of Hefei Laboratory for Physical Sciences at Microscale, School of Life Science, University of Science and Technology of China, Hefei, China.
| | - Yong Chen
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
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ADP-dependent glucokinase regulates energy metabolism via ER-localized glucose sensing. Sci Rep 2019; 9:14248. [PMID: 31582762 PMCID: PMC6776650 DOI: 10.1038/s41598-019-50566-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 09/05/2019] [Indexed: 12/21/2022] Open
Abstract
Modulation of energy metabolism to a highly glycolytic phenotype, i.e. Warburg effect, is a common phenotype of cancer and activated immune cells allowing increased biomass-production for proliferation and cell division. Endoplasmic reticulum (ER)-localized ADP-dependent glucokinase (ADPGK) has been shown to play a critical role in T cell receptor activation-induced remodeling of energy metabolism, however the underlying mechanisms remain unclear. Therefore, we established and characterized in vitro and in vivo models for ADPGK-deficiency using Jurkat T cells and zebrafish. Upon activation, ADPGK knockout Jurkat T cells displayed increased cell death and ER stress. The increase in cell death resulted from a metabolic catastrophe and knockout cells displayed severely disturbed energy metabolism hindering induction of Warburg phenotype. ADPGK knockdown in zebrafish embryos led to short, dorsalized body axis induced by elevated apoptosis. ADPGK hypomorphic zebrafish further displayed dysfunctional glucose metabolism. In both model systems loss of ADPGK function led to defective N- and O-glycosylation. Overall, our data illustrate that ADPGK is part of a glucose sensing system in the ER modulating metabolism via regulation of N- and O-glycosylation.
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43
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Anti-inflammatory action of YHQ by regulating 5-LOX/COX-2/NF-κB/MAPKs/Akt signaling pathways in RAW 264.7 macrophage cells. J Herb Med 2019. [DOI: 10.1016/j.hermed.2019.100269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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44
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Shanmugapriya, Othman N, Sasidharan S. Prediction of genes and protein-protein interaction networking for miR-221-5p using bioinformatics analysis. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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45
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Tang C, Zhu G. Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways. Curr Stem Cell Res Ther 2019; 14:219-225. [PMID: 30033874 DOI: 10.2174/1574888x13666180723104340] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 01/03/2023]
Abstract
The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.
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Affiliation(s)
- Cong Tang
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Guodong Zhu
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
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46
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Using the Pleiotropic Characteristics of Curcumin to Validate the Potential Application of a Novel Gene Expression Screening Platform. Nutrients 2019; 11:nu11061397. [PMID: 31234318 PMCID: PMC6627093 DOI: 10.3390/nu11061397] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 06/12/2019] [Accepted: 06/18/2019] [Indexed: 12/12/2022] Open
Abstract
Curcumin is a polyphenol derived from curcumin longa that exhibits anticancer and anti-inflammatory properties. The consumption of foods at supernutritional levels to obtain health benefits may paradoxically result in negative health outcomes. In the present study, multiple targeting characteristics of curcumin were analyzed using our gene expression screening system, which utilized the gene expression signatures of curcumin from human hepatocellular carcinoma and colorectal cancer cells to query gene expression databases and effectively identify the molecular actions of curcumin. In agreement with prediction, curcumin inhibited NF-κB and Aurora-A, and induced G2/M arrest and apoptosis. Curcumin-suppressed NF-κB was identified through inhibition of PLCG1, PIK3R1, and MALT1 in the CD4-T-cell-receptor-signaling NF-κB cascade pathway. The results suggest that our novel gene expression screening platform is an effective method of rapidly identifying unknown biological functions and side effects of compounds with potential nutraceutical benefits.
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Liu M, Xiao CQ, Sun MW, Tan MJ, Hu LH, Yu Q. Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases. J Cell Mol Med 2019; 23:4301-4312. [PMID: 30993883 PMCID: PMC6533482 DOI: 10.1111/jcmm.14322] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/28/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022] Open
Abstract
Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor‐κB (NF‐κB) signalling pathways is associated with the development of cancer and inflammatory diseases. JAKs and IKKs are the key regulators in the STAT3 and NF‐κB signalling respectively. Therefore, the two families of kinases have been the major targets for developing drugs to regulate the two signalling pathways. Here, we report a natural compound xanthatin from the traditional Chinese medicinal herb Xanthium L. as a potent inhibitor of both STAT3 and NF‐κB signalling pathways. Our data demonstrated that xanthatin was a covalent inhibitor and its activities depended on its α‐methylene‐γ‐butyrolactone group. It preferentially interacted with the Cys243 of JAK2 and the Cys412 and Cys464 of IKKβ to inactivate their activities. In doing so, xanthatin preferentially inhibited the growth of cancer cell lines that have constitutively activated STAT3 and p65. These data suggest that xanthatin may be a promising anticancer and anti‐inflammation drug candidate.
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Affiliation(s)
- Man Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.,University of Chinese Academy of Sciences, Beijing, PR China
| | - Cheng-Qian Xiao
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China.,State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China
| | - Ming-Wei Sun
- University of Chinese Academy of Sciences, Beijing, PR China.,The Chemical Proteomics Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China
| | - Min-Jia Tan
- University of Chinese Academy of Sciences, Beijing, PR China.,The Chemical Proteomics Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China
| | - Li-Hong Hu
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Qiang Yu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.,University of Chinese Academy of Sciences, Beijing, PR China
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Mortezaee K, Najafi M, Farhood B, Ahmadi A, Shabeeb D, Musa AE. NF‐κB targeting for overcoming tumor resistance and normal tissues toxicity. J Cell Physiol 2019; 234:17187-17204. [DOI: 10.1002/jcp.28504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy School of Medicine, Kurdistan University of Medical Sciences Sanandaj Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department School of Paramedical Sciences, Kermanshah University of Medical Sciences Kermanshah Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology Faculty of Paramedical Sciences, Kashan University of Medical Sciences Kashan Iran
| | - Amirhossein Ahmadi
- Pharmaceutical Sciences Research Center Faculty of Pharmacy, Mazandaran University of Medical Sciences Sari Iran
| | - Dheyauldeen Shabeeb
- Department of Physiology College of Medicine, University of Misan Misan Iraq
| | - Ahmed E. Musa
- Department of Medical Physics Tehran University of Medical Sciences (International Campus) Tehran Iran
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Fouani L, Kovacevic Z, Richardson DR. Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment. Antioxid Redox Signal 2019; 30:1096-1123. [PMID: 29161883 DOI: 10.1089/ars.2017.7387] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE Nuclear factor kappa B (NF-κB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-κB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy. CRITICAL ISSUES As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-κB signaling, when in sublethal amounts; and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-κB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-κB and may stimulate oncogenesis and confer resistance. FUTURE DIRECTIONS Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-κB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox-active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-κB signaling inhibitor. It is proposed that targeting NF-κB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens.
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Affiliation(s)
- Leyla Fouani
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
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50
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Hu TY, Ju JM, Mo LH, Ma L, Hu WH, You RR, Chen XQ, Chen YY, Liu ZQ, Qiu SQ, Fan JT, Cheng BH. Anti-inflammation action of xanthones from Swertia chirayita by regulating COX-2/NF-κB/MAPKs/Akt signaling pathways in RAW 264.7 macrophage cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 55:214-221. [PMID: 30668431 DOI: 10.1016/j.phymed.2018.08.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 06/11/2018] [Accepted: 08/03/2018] [Indexed: 05/16/2023]
Abstract
BACKGROUND Swertia chirayita, has been commonly used under the name "Zang-yin-chen" for the treatment of liver infections, inflammation, abdominal pain, and bacterial infection in traditional Tibetan medicine. However, the bioactive components with anti-inflammatory activities and underlying mechanisms remain poorly evaluated. STUDY DESIGN/METHODS Repeated column chromatography yielded two main xanthones from petroleum ether (PE) and ethyl acetate fractions of whole plants of S. chirayita, and their structures were determined as bellidifolin (1) and swerchirin (2) on the basis of spectroscopic data and literature analysis. The anti-inflammatory activities and mechanisms of anti-inflammation of these two isolated xanthones were determined via enzyme-linked immunosorbent assay (ELISA) and western blot in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages in vitro. RESULTS Anti-inflammation assay demonstrated that 1 and 2 inhibit the production of the pro-inflammatory cytokines interleukin-6 (IL-6) and TNF-α in LPS-stimulated RAW 264.7 macrophages. Xanthone 1 also potently inhibited the production of prostaglandin E2 (PGE2) by suppressing the protein expression of cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 macrophages. Western blot showed that the phosphorylation of c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs were remarkably attenuated by 1 in a concentration-dependent manner. Particularly, Compound 1 suppressed the phosphorylation of the inhibitor κB kinase-β (IKK-β), Akt, and p65 subunit of nuclear factor-kappaB (NF-κB). CONCLUSION The potent suppressive effects of 1 from S. chirayita on inflammatory mediators by blocking the expression of COX-2 and phosphorylation of Akt, IKK-β, MAPK and NF-κB, activation in LPS-stimulated macrophages suggest that 1 can be a preventive therapeutic candidate for the management of inflammatory-mediated immune disorders.
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Affiliation(s)
- Tian-Yong Hu
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China
| | - Jian-Ming Ju
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Li-Hua Mo
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China
| | - Li Ma
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China
| | - Wen-Hui Hu
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China
| | - Rong-Rong You
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Xue-Qing Chen
- Anhui University of Chinese Medicine, Hefei 230031, China
| | - Yan-Yan Chen
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China
| | - Zhi-Qiang Liu
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China
| | - Shu-Qi Qiu
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China
| | - Jun-Ting Fan
- Department of Pharmaceutical Analysis, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
| | - Bao-Hui Cheng
- Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang ENT hospital, Shenzhen 518172, China.
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