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Zheng H, Chen Y, Luo W, Han S, Sun M, Lin M, Wu C, Gao L, Xie T, Kong N. Integration of active ingredients from traditional Chinese medicine with nano-delivery systems for tumor immunotherapy. J Nanobiotechnology 2025; 23:357. [PMID: 40382641 PMCID: PMC12085060 DOI: 10.1186/s12951-025-03378-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 04/07/2025] [Indexed: 05/20/2025] Open
Abstract
Tumor immune escape presents a significant challenge in cancer treatment, characterized by the upregulation of immune inhibitory molecules and dysfunction of immune cells. Tumor immunotherapy seeks to restore normal anti-tumor immune responses to control and eliminate tumors effectively. The active ingredients of traditional Chinese medicine (TCM) demonstrate a variety of anti-tumor activities and mechanisms, including the modulation of immune cell functions and inhibiting tumor-related suppressive factors, thereby potentially enhancing anti-tumor immune responses. Furthermore, nano-delivery systems function as efficient carriers to enhance the bioavailability and targeted delivery of TCM active ingredients, augmenting therapeutic efficacy. This review comprehensively analyzes the impact of TCM active ingredients on the immune system and explores the synergistic application of nano-delivery systems in combination with TCM active ingredients for enhancing tumor immunotherapy.
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Affiliation(s)
- Hao Zheng
- Department of Neurology, The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fuzhou, Fujian, China
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Yiquan Chen
- Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 311121, Zhejiang, China
| | - Wei Luo
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Shiqi Han
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
- Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 311121, Zhejiang, China
| | - Mengjuan Sun
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
- Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 311121, Zhejiang, China
| | - Min Lin
- Department of Neurology, The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fuzhou, Fujian, China
| | - Chenghan Wu
- Department of Neurology, The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fuzhou, Fujian, China
| | - Lili Gao
- Department of Neurology, The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fuzhou, Fujian, China.
| | - Tian Xie
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China.
| | - Na Kong
- Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 311121, Zhejiang, China.
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2
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Ren C, Zi Y, Zhang X, Liao X, Chen H. Basal and AT2 cells promote IPF-lung cancer co-occurrence via EMT: Single-cell analysis. Exp Cell Res 2025; 448:114578. [PMID: 40294812 DOI: 10.1016/j.yexcr.2025.114578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 04/22/2025] [Accepted: 04/25/2025] [Indexed: 04/30/2025]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease. With IPF, the probability of complication with lung cancer (LCA) increases considerably, and the prognosis is worse than that of simple IPF. To understand the pathological mechanisms and molecular pathways shared by these two diseases, we used the single-cell analysis from the Gene Expression Omnibus (GEO) database, and find that basal cells (BCs) and alveolar type 2 cells (AT2 cells) are important components of lung epithelial cells. Changes in molecular pathways in BCs and AT2 cells may be involved in the common pathogenesis of IPF and LCA. KRT17 and S100A14 in BCs may promote the IPF co-occurrence with LCA by mediating the EMT. WFDC2 and KRT19 may be the elements in AT2 cells that activate the EMT process to promote IPF co-occurrence with LCA. In both IPF and LCA, FN1-WNT axis may be involved in the interaction between BCs and AT2 cells. Importantly, the results of immunofluorescence colocalization experiments on tissue samples from patients with IPF and LCA were consistent with these conclusions. Basal-macrophage interactions may have also induced the IPF co-occurrence with LCA via the CYBA-ERK1/2 axis. The regulation of M2 macrophage polarization by JUN/SOD2-glycolysis axis may therefore be involved in the co-morbidity mechanism of IPF and LCA. Therefore, our results suggest that molecular changes in BCs, AT2 cells and macrophages may play important roles in the pathogenesis of IPF co-occurrence with LCA, and the cellular interactions between these cells may be critical for the progression of both diseases.
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Affiliation(s)
- Cheng Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing, 400016, China; Department of Respiratory and Critical Care Medicine, Chongqing University Fuling Hospital, Fuling, Chongqing, 408000, China
| | - Yawan Zi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing, 400016, China
| | - Xiaobin Zhang
- Department of Respiratory and Critical Care Medicine, Chongqing University Fuling Hospital, Fuling, Chongqing, 408000, China
| | - Xiuqing Liao
- Department of Respiratory and Critical Care Medicine, Chongqing University Fuling Hospital, Fuling, Chongqing, 408000, China
| | - Hong Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing, 400016, China.
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Liu R, Guo L, Shi D, Sun X, Shang M, Zhao Y, Wang X, Yang Y, Xiao S, Li J. Multilayer cascade-response nanoplatforms as metabolic symbiotic disruptors to reprogram the immunosuppressive microenvironment. J Control Release 2025; 383:113797. [PMID: 40318807 DOI: 10.1016/j.jconrel.2025.113797] [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: 02/05/2025] [Revised: 04/22/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025]
Abstract
Nanomedicine is extensively utilized in tumor treatment, however, the restricted permeability of nanomaterials within tumor tissues, along with the inherent metabolic complexity of these tissues, have hindered effective control of tumor progression. Hypoxic and normoxic tumor cells utilize monocarboxylic acid transporters (MCTs) for the rapid reutilization of lactate, facilitating accelerated tumor growth. Here, cascade-response nanoplatforms (NPs) with contrast-enhanced ultrasound imaging (CEUI) capability had been established, incorporating basigin siRNA internally and featuring hyaluronidase (HAase) and γ-glutamyltranspeptidase (GGT)-responsive lipid coatings externally (GHB NPs). The GHB NPs took advantage of GGT-responsive HAase release to facilitate deep tumor penetration. Furthermore, ultrasound (US) irradiation decreased the expression of glycolysis-related proteins through the modulation of the β-catenin/c-Myc pathway, and US irradiation induced mitochondrial damage, leading to a low-energy state in tumor cells. On this basis, GHB NPs was paired with US stimulation to provide a combination therapy that disturbed tumor cell metabolic symbiosis and remodeled the immunosuppressive tumor microenvironment. This study formulates an effective therapeutic approach for metabolic-immunotherapy, potentially offering a viable candidate for tumor treatment.
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Affiliation(s)
- Rui Liu
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Lu Guo
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Dandan Shi
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Xiao Sun
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Mengmeng Shang
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Yading Zhao
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Xiaoxuan Wang
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Yuanyuan Yang
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Shan Xiao
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Jie Li
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Department of Ultrasound, Qilu Hospital (Qingdao) of Shandong University, Qingdao, Shandong 266035, China.
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Huimin W, Xin W, Shan Y, Junwang Z, Jing W, Yuan W, Qingtong L, Xiaohui L, Jia Y, Lili Y. Lactate promotes the epithelial-mesenchymal transition of liver cancer cells via TWIST1 lactylation. Exp Cell Res 2025; 447:114474. [PMID: 39993459 DOI: 10.1016/j.yexcr.2025.114474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/15/2025] [Accepted: 02/16/2025] [Indexed: 02/26/2025]
Abstract
Elevated lactate levels increase the risk of liver cancer progression. However, the mechanisms by which lactate promotes liver cancer progression remain poorly understood. Epithelial-mesenchymal transition (EMT), characterized by the loss of epithelial cells polarity and cell-cell adhesion, leading to the acquisition of mesenchymal-like phenotypes, is widely recognized as a key contributor to liver cancer progression. TWIST1 (Twist Family BHLH Transcription Factor 1) plays a central role in inducing EMT. Here, we investigated the role of lactate in promoting EMT in liver cancer and the underlying regulatory mechanisms. High levels of lactate significantly promoted EMT progression in liver cancer cells. Mechanistically, lactate-induced lactylation of TWIST1 in vivo and in vitro. Mutation assay confirmed that Lysine 33 (K33) is the major site of TWIST1 lactylation. Moreover, cell fractionation & luciferase reporter assay results identified that TWIST1-K33R mutant impaired the EMT process via inhibiting nuclear import and the transcriptional activity. Thus, our findings provide novel insights into the regulatory role of lactate in EMT in liver cancer pathogenesis. Additionally, targeting of lactate-driven lactylation of TWIST1 may boost the therapeutic strategy for liver cancer.
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Affiliation(s)
- Wang Huimin
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Wu Xin
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Yu Shan
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Zhang Junwang
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Wen Jing
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Wang Yuan
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Liu Qingtong
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Li Xiaohui
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Yao Jia
- Department of Gastroenterology, Shanxi Bethune Hospital, No.99 Longcheng Road, Taiyuan, 030032, China
| | - Yuan Lili
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China.
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Cui W, Hao M, Yang X, Yin C, Chu B. Gut microbial metabolism in ferroptosis and colorectal cancer. Trends Cell Biol 2025; 35:341-351. [PMID: 39261152 DOI: 10.1016/j.tcb.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/14/2024] [Accepted: 08/16/2024] [Indexed: 09/13/2024]
Abstract
Ferroptosis is programmed cell death induced by iron-driven lipid peroxidation. Numerous studies have shown that ferroptosis is implicated in the progression of colorectal cancer (CRC) and has emerged as a promising strategy to combat therapy-resistant CRC. While the intrinsic antiferroptotic and proferroptotic pathways in CRC cells have been well characterized, extrinsic metabolism pathways regulating ferroptosis in CRC pathogenesis remain less understood. Emerging evidence shows that gut microbial metabolism is tightly correlated with the progression of CRC. This review provides an overview of gut microbial metabolism and discusses how these metabolites derived from intestinal microflora contribute to cancer plasticity through ferroptosis. Targeting gut microbe-mediated ferroptosis is a potential approach for CRC treatment.
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Affiliation(s)
- Weiwei Cui
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Meng Hao
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518107, China
| | - Xin Yang
- Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China.
| | - Chengqian Yin
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518107, China.
| | - Bo Chu
- Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
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Qian W, Xu CY, Hong W, Li ZM, Xu DG. Transmembrane protein 176B promotes epithelial-mesenchymal transition in colorectal cancer through inflammasome inhibition. World J Gastrointest Oncol 2025; 17:97673. [PMID: 40092936 PMCID: PMC11866255 DOI: 10.4251/wjgo.v17.i3.97673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 10/30/2024] [Accepted: 12/04/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Activation of the epithelial-mesenchymal transition (EMT), a pivotal process in tumor metastasis and evasion, as well as the NLRP3 inflammasome, both promote colorectal cancer (CRC) progression. Recent studies have shown that Transmembrane protein 176B (TMEM176B) regulates NLRP3 and promotes CRC malignant phenotypes. AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC. METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells, BALB/c mice, and primary cultured mouse natural killer (NK) cells. Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells. Fluorescence imaging, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, immunohistochemistry staining, flow cytometry, and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis, apoptosis, and EMT indicators. RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis, proliferation, and EMT, while activating apoptosis, NLRP3 inflammasome, and NK cell activity. Furthermore, silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion, and promoted apoptosis. The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65, matrix metallopeptidase 9, and transforming growth factor-β. CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.
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Affiliation(s)
- Wei Qian
- Department of Proctology, Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Wenling 317500, Zhejiang Province, China
| | - Chong-Yi Xu
- Department of Proctology, Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Wenling 317500, Zhejiang Province, China
| | - Wei Hong
- Department of Proctology, Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Wenling 317500, Zhejiang Province, China
| | - Zhe-Ming Li
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
| | - Dao-Gun Xu
- Department of Proctology, Wenling Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Wenling 317500, Zhejiang Province, China
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Ding X, Mei T, Xi X, Wang J, Wang W, Chen Y, Lu Y, Qin T, Huang D. ACT001 Suppresses the Malignant Progression of Small-Cell Lung Cancer by Inhibiting Lactate Production and Promoting Anti-Tumor Immunity. Thorac Cancer 2025; 16:e70028. [PMID: 40016971 PMCID: PMC11868026 DOI: 10.1111/1759-7714.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/12/2025] [Accepted: 02/16/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Improving the "cold" tumor immune microenvironment (TIME) of small-cell lung cancer (SCLC) represents a promising therapeutic approach. The metabolite lactate plays a crucial role in shaping the immune-cold tumor microenvironment (TME) and facilitating tumor progression. Phosphoglycerate kinase 1 (PGK1) is a key enzyme involved in tumor lactate metabolism. This study demonstrates that ACT001 improves the TIME of SCLC through inhibiting lactate production by targeting PGK1. METHODS The cytotoxic effects of ACT001 on SCLC cell lines NCI-H1688 and NCI-H446 were evaluated using MTT assay, clone formation, EdU incorporation, wound healing, and invasion assays. To elucidate the mechanism of action of ACT001, proteomic techniques, pull-down assays, LC-MS/MS, surface plasmon resonance, immunofluorescence, lactate generation, glucose uptake, and western blot assays were conducted. A xenograft model was used to assess the in vivo anti-tumor activity of ACT001. RESULTS ACT001 inhibited the proliferation, invasion, and metastasis of SCLC both in vitro and in vivo. Additionally, it reduced lactate accumulation and M2 macrophage polarization. Mechanistically, ACT001 released micheliolide, which covalently modified Cys316 of PGK1 under physiological conditions. This suppressed PGK1 activity and restored the distribution of PGK1 in mitochondria and the cytoplasm under hypoxic conditions. CONCLUSIONS ACT001 inhibits the malignant progression of SCLC by suppressing lactate production, modulating macrophage polarization, and restraining tumor metastasis through PGK1 targeting.
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Affiliation(s)
| | - Ting Mei
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
| | - Xiao‐Nan Xi
- College of PharmacyNankai UniversityTianjinChina
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjinChina
| | - Jing‐Ya Wang
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
| | | | - Yue Chen
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjinChina
- College of ChemistryNankai UniversityTianjinChina
| | - Ya‐Xin Lu
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjinChina
- College of ChemistryNankai UniversityTianjinChina
| | - Ting‐Ting Qin
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
| | - Ding‐Zhi Huang
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
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Umar AK, Limpikirati PK, Rivai B, Ardiansah I, Sriwidodo S, Luckanagul JA. Complexed hyaluronic acid-based nanoparticles in cancer therapy and diagnosis: Research trends by natural language processing. Heliyon 2025; 11:e41246. [PMID: 39811313 PMCID: PMC11729671 DOI: 10.1016/j.heliyon.2024.e41246] [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: 08/11/2024] [Revised: 12/10/2024] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
Hyaluronic acid (HA) is a popular surface modifier in targeted cancer delivery due to its receptor-binding abilities. However, HA alone faces limitations in lipid solubility, biocompatibility, and cell internalization, making it less effective as a standalone delivery system. This comprehensive study aimed to explore a dynamic landscape of complexation in HA-based nanoparticles in cancer therapy, examining diverse aspects from influential modifiers to emerging trends in cancer diagnostics. We discovered that certain active substances, such as 5-aminolevulinic acid, adamantane, and protamine, have been on trend in terms of their usage over the past decade. Dextran, streptavidin, and catechol emerge as intriguing conjugates for HA, coupled with nanostar, quantum dots, and nanoprobe structures for optimal drug delivery and diagnostics. Strategies like hypoxic conditioning, dual responsiveness, and pulse laser activation enhance controlled release, targeted delivery, and real-time diagnostic techniques like ultrasound imaging and X-ray computed tomography (X-ray CT). Based on our findings, conventional bibliometric tools fail to highlight relevant topics in this area, instead producing merely abstract and broad-meaning keywords. Extraction using Named Entity Recognition and topic search with Latent Dirichlet Allocation successfully revealed five representative topics with the ability to exclude irrelevant keywords. A shift in research focuses from optimizing chemical toxicity to particular targeting tactics and precise release mechanisms is evident. These findings reflect the dynamic landscape of HA-based nanoparticle research in cancer therapy, emphasizing advancements in targeted drug delivery, therapeutic efficacy, and multimodal diagnostic approaches to improve overall patient outcomes.
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Affiliation(s)
- Abd Kakhar Umar
- Pharmaceutical Sciences and Technology Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Medical Informatics Laboratory, ETFLIN, Palu City, 94225, Indonesia
| | - Patanachai K. Limpikirati
- Pharmaceutical Sciences and Technology Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Metabolomics for Life Sciences Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Bachtiar Rivai
- Pharmaceutical Sciences and Technology Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Medical Informatics Laboratory, ETFLIN, Palu City, 94225, Indonesia
| | - Ilham Ardiansah
- Department of Animal Husbandry, Faculty Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
- Medical Informatics Laboratory, ETFLIN, Palu City, 94225, Indonesia
| | - Sriwidodo Sriwidodo
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia
| | - Jittima Amie Luckanagul
- Pharmaceutical Sciences and Technology Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Center of Excellence in Plant-produced Pharmaceuticals, Chulalongkorn University, Bangkok, 10330, Thailand
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9
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Wang H, Zhou F, Qin W, Yang Y, Li X, Liu R. Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies. Theranostics 2025; 15:2159-2184. [PMID: 39990210 PMCID: PMC11840731 DOI: 10.7150/thno.105276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/11/2024] [Indexed: 02/25/2025] Open
Abstract
Cancer remains a major challenge to global public health, with rising incidence and high mortality rates. The tumor microenvironment (TME) is a complex system of immune cells, fibroblasts, extracellular matrix (ECM), and blood vessels that form a space conducive to cancer cell proliferation. Myeloid-derived suppressor cells (MDSCs) are abundant in tumors, and they drive immunosuppression through metabolic reprogramming in the TME. This review describes how metabolic pathways such as glucose metabolism, lipid metabolism, amino acid metabolism, and adenosine metabolism have a significant impact on the function of MDSCs by regulating their immunosuppressive activity and promoting their survival and expansion in tumors. The review also explores key metabolic targets in MDSCs and strategies to modulate MDSC metabolism to improve the tumor immune microenvironment and enhance anti-tumor immune responses. Understanding these pathways can provide insight into potential therapeutic targets for modulating MDSC activity and improving outcomes of cancer immunotherapies.
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Affiliation(s)
- Hong Wang
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Fei Zhou
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Wenqing Qin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Yun Yang
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China
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10
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He Y, Huang Y, Peng P, Yan Q, Ran L. Lactate and lactylation in gastrointestinal cancer: Current progress and perspectives (Review). Oncol Rep 2025; 53:6. [PMID: 39513579 PMCID: PMC11574708 DOI: 10.3892/or.2024.8839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 10/14/2024] [Indexed: 11/15/2024] Open
Abstract
Gastrointestinal (GI) cancers, which have notable incidence and mortality, are impacted by metabolic reprogramming, especially the increased production and accumulation of lactate. Lactylation, a post‑translational modification driven by lactate, is a crucial regulator of gene expression and cellular function in GI cancer. The present review aimed to examine advancements in understanding lactate and lactylation in GI cancer. The mechanisms of lactate production, its influence on the tumor microenvironment and the clinical implications of lactate levels as potential biomarkers were explored. Furthermore, lactylation was investigated, including its biochemical foundation, primary targets and functional outcomes. The present review underscored potential therapeutic strategies targeting lactate metabolism and lactylation. Challenges and future directions emphasize the potential of lactate and lactylation as innovative therapeutic targets in GI cancer to improve clinical outcomes.
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Affiliation(s)
- Yufen He
- Department of Gastroenterology and Hepatology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, Chongqing 400014, P.R. China
| | - Yaxi Huang
- Department of Gastroenterology and Hepatology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, Chongqing 400014, P.R. China
| | - Peng Peng
- Department of Gastroenterology and Hepatology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, Chongqing 400014, P.R. China
| | - Qi Yan
- Department of Gastroenterology and Hepatology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, Chongqing 400014, P.R. China
| | - Lidan Ran
- Department of Intensive Care Unit, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, Chongqing 400014, P.R. China
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11
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Wei J, Li W, Zhang P, Guo F, Liu M. Current trends in sensitizing immune checkpoint inhibitors for cancer treatment. Mol Cancer 2024; 23:279. [PMID: 39725966 DOI: 10.1186/s12943-024-02179-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/20/2024] [Indexed: 12/28/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have dramatically transformed the treatment landscape for various malignancies, achieving notable clinical outcomes across a wide range of indications. Despite these advances, resistance to immune checkpoint blockade (ICB) remains a critical clinical challenge, characterized by variable response rates and non-durable benefits. However, growing research into the complex intrinsic and extrinsic characteristics of tumors has advanced our understanding of the mechanisms behind ICI resistance, potentially improving treatment outcomes. Additionally, robust predictive biomarkers are crucial for optimizing patient selection and maximizing the efficacy of ICBs. Recent studies have emphasized that multiple rational combination strategies can overcome immune checkpoint resistance and enhance susceptibility to ICIs. These findings not only deepen our understanding of tumor biology but also reveal the unique mechanisms of action of sensitizing agents, extending clinical benefits in cancer immunotherapy. In this review, we will explore the underlying biology of ICIs, discuss the significance of the tumor immune microenvironment (TIME) and clinical predictive biomarkers, analyze the current mechanisms of resistance, and outline alternative combination strategies to enhance the effectiveness of ICIs, including personalized strategies for sensitizing tumors to ICIs.
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Grants
- ZYJC21043 the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
- ZYJC21043 the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
- ZYJC21043 the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
- ZYJC21043 the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
- ZYJC21043 the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
- 2023YFS0111 Social Development Science and Technology Project of Sichuan Province on Science and Technology
- 2023YFS0111 Social Development Science and Technology Project of Sichuan Province on Science and Technology
- 2023YFS0111 Social Development Science and Technology Project of Sichuan Province on Science and Technology
- 2023YFS0111 Social Development Science and Technology Project of Sichuan Province on Science and Technology
- 2023YFS0111 Social Development Science and Technology Project of Sichuan Province on Science and Technology
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Affiliation(s)
- Jing Wei
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Wenke Li
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Pengfei Zhang
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Fukun Guo
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA
| | - Ming Liu
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
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Chen J, Liu J, Nie W, Hou X, Zhang X, Liu C, Si L, Zhang M, Xu S, Xie Q, Liang J, Li Y. Research progress on the structural and anti-colorectal malignant tumor properties of Shikonin. J Cancer Res Ther 2024; 20:1957-1963. [PMID: 39792404 DOI: 10.4103/jcrt.jcrt_933_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/17/2024] [Indexed: 01/12/2025]
Abstract
ABSTRACT Colorectal cancer is the third most prevalent malignant tumor worldwide. Despite the advancements in surgical procedures and treatment options, CRC remains a considerable cause of cancer-related mortality. Shikonin is a naphthoquinone compound that exhibits multiple biological activities, including anti-inflammatory and anti-tumor effects as well as wound healing promotion. Recently, Shikonin has been increasingly used in basic research on colorectal malignant tumors. Therefore, we explored the mechanisms of action and structural improvements of Shikonin in colorectal cancer through a literature review to provide valuable insights for the advancement of research and development of related pharmaceuticals.
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Affiliation(s)
- Jinghua Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Jie Liu
- Department of Pediatric Intensive Care Unit, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Weiwei Nie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Xingqin Hou
- South Ward, The Second Hospital of Shandong University, Jinan, China
| | - Xi Zhang
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Chao Liu
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Linxin Si
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Mingzhu Zhang
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Shutao Xu
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Jing Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Yan Li
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
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13
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Yang S, Li Y, Zhang Y, Wang Y. Impact of chronic stress on intestinal mucosal immunity in colorectal cancer progression. Cytokine Growth Factor Rev 2024; 80:24-36. [PMID: 39490234 DOI: 10.1016/j.cytogfr.2024.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/14/2024] [Accepted: 10/16/2024] [Indexed: 11/05/2024]
Abstract
Chronic stress is a significant risk factor that contributes to the progression of colorectal cancer (CRC) and has garnered considerable attention in recent research. It influences the distribution and function of immune cells within the intestinal mucosa through the "brain-gut" axis, altering cytokine and chemokine secretion and creating an immunosuppressive tumor microenvironment. The intestine, often called the "second brain," is particularly susceptible to the effects of chronic stress. Cytokines and chemokines in intestinal mucosal immunity(IMI) are closely linked to CRC cells' proliferation, metastasis, and drug resistance under chronic stress. Recently, antidepressants have emerged as potential therapeutic agents for CRC, possibly by modulating IMI to restore homeostasis and exert anti-tumor effects. This article reviews the role of chronic stress in promoting CRC progression via its impact on intestinal mucosal immunity, explores potential targets within the intestinal mucosa under chronic stress, and proposes new approaches for CRC treatment.
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Affiliation(s)
- Shengya Yang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yingru Zhang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yan Wang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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14
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Deng RZ, Zheng X, Lu ZL, Yuan M, Meng QC, Wu T, Tian Y. Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer. World J Gastrointest Oncol 2024; 16:4354-4368. [PMID: 39554751 PMCID: PMC11551631 DOI: 10.4251/wjgo.v16.i11.4354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/24/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role - immune checkpoints - and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Run-Zhi Deng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Xin Zheng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Zhong-Lei Lu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Ming Yuan
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Qi-Chang Meng
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Tao Wu
- Department of General Surgery, West China Hospital of Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Yu Tian
- Department of Thoracic Surgery, Yancheng No. 1 People’s Hospital, Affiliated Hospital of Nanjing University Medical School, The First People’s Hospital of Yancheng, Yancheng 224000, Jiangsu Province, China
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15
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Zhang Y, Shi J, Zhu J, Ding X, Wei J, Jiang X, Yang Y, Zhang X, Huang Y, Lai H. Immunometabolic rewiring in macrophages for periodontitis treatment via nanoquercetin-mediated leverage of glycolysis and OXPHOS. Acta Pharm Sin B 2024; 14:5026-5036. [PMID: 39664434 PMCID: PMC11628840 DOI: 10.1016/j.apsb.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/28/2024] [Accepted: 06/15/2024] [Indexed: 12/13/2024] Open
Abstract
Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in macrophages, specifically an increase in aerobic glycolysis, which is linked to heightened inflammatory responses. This suggests that targeting macrophage metabolism could offer a new therapeutic avenue. In this study, we developed an immunometabolic intervention using quercetin (Q) encapsulated in bioadhesive mesoporous polydopamine (Q@MPDA) to treat periodontitis. Our results demonstrated that Q@MPDA could reprogram inflammatory macrophages to an anti-inflammatory phenotype (i.e., from-M1-to-M2 repolarization). In a murine periodontitis model, locally administered Q@MPDA reduced the presence of inflammatory macrophages, and decreased the levels of inflammatory cytokines (IL-1β and TNF-α) and reactive oxygen species (ROS) in the periodontium. Consequently, it alleviated periodontitis symptoms, reduced alveolar bone loss, and promoted tissue repair. Furthermore, our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory macrophages while enhancing oxidative phosphorylation (OXPHOS), facilitating the shift from M1 to M2 macrophage subtype. Our findings suggest that Q@MPDA is a promising treatment for periodontitis via immunometabolic rewiring.
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Affiliation(s)
- Yi Zhang
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Junyu Shi
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Jie Zhu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xinxin Ding
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Jianxu Wei
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Xue Jiang
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Yijie Yang
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Xiaomeng Zhang
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Yongzhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
- NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China
| | - Hongchang Lai
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
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16
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Wei J, Xu S, Liu Y, Zhang L, Chen H, Li J, Duan M, Niu Z, Huang M, Zhang D, Zhou X, Xie J. TGF-β2 enhances glycolysis in chondrocytes via TβRI/p-Smad3 signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119788. [PMID: 38879132 DOI: 10.1016/j.bbamcr.2024.119788] [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: 12/07/2023] [Revised: 05/22/2024] [Accepted: 06/11/2024] [Indexed: 07/02/2024]
Abstract
Chondrocytes rely heavily on glycolysis to maintain the metabolic homeostasis and cartilage matrix turnover. Glycolysis in chondrocytes is remodeled by diverse biochemical and biomechanical factors due to the sporty joint microenvironment. Transforming growth factor-β2 (TGF-β2), one of the most abundant TGF-β superfamily members in chondrocytes, has increasingly attracted attention in cartilage physiology and pathology. Although previous studies have emphasized the importance of TGF-β superfamily members on cell metabolism, whether and how TGF-β2 modulates glycolysis in chondrocytes remains elusive. In the current study, we investigated the effects of TGF-β2 on glycolysis in chondrocytes and explored the underlying biomechanisms. The results showed that TGF-β2 could enhance glycolysis in chondrocytes by increasing glucose consumption, up-regulating liver-type ATP-dependent 6-phosphofructokinase (Pfkl) expression, and boosting lactate production. The TGF-β2 signal entered chondrocytes via TGF-β receptor type I (TβRI), and activated p-Smad3 signaling to regulate the glycolytic pathway. Subsequent experiments employing specific inhibitors of TβRI and p-Smad3 further substantiated the role of TGF-β2 in enhancement of glycolysis via TβRI/p-Smad3 axis in chondrocytes. The results provide new understanding of the metabolic homeostasis in chondrocytes induced by TGF-β superfamily and might shed light on the prevention and treatment of related osteoarticular diseases.
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Affiliation(s)
- Jieya Wei
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Siqun Xu
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yang Liu
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Li Zhang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Hao Chen
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jiazhou Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Mengmeng Duan
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Zhixing Niu
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Minglei Huang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Demao Zhang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
| | - Jing Xie
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
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17
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Zhang Z, Li M, Zhang X, Zhou F. Novel Strategies for Tumor Treatment: Harnessing ROS-Inducing Active Ingredients from Traditional Chinese Medicine Through Multifunctional Nanoformulations. Int J Nanomedicine 2024; 19:9659-9688. [PMID: 39309188 PMCID: PMC11416109 DOI: 10.2147/ijn.s479212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 08/28/2024] [Indexed: 09/25/2024] Open
Abstract
Reactive oxygen species (ROS) encompass a diverse group of chemically reactive molecules or ions distinguished by their substantial oxidative potential. Empirical studies have shown that the targeted administration of high toxic concentrations of ROS can effectively induce tumor cell death in various types. Numerous bioactive ingredients derived from traditional Chinese medicine (TCM), recognized for their ROS-inducing properties, have demonstrated significant anti-tumor activity. Nonetheless, their clinical application has been hindered by challenges such as low solubility, limited bioavailability, and poor selectivity. Multifunctional nanoformulations possess the potential to overcome these challenges and enhance the anticancer efficacy of ROS-inducing active compounds. Through extensive searches of various academic databases and a thorough review and screening of relevant literature, this study aims to systematically summarize and generalize multiple active ingredients in TCM that induce ROS generation, along with their multifunctional nanoformulations, from various perspectives. The objective is to provide new insights and references for fundamental cancer research and clinical treatments. Furthermore, we acknowledge that although numerous active ingredients and their nanoformulations in TCM have demonstrated ROS-inducing and anti-tumor potentials, potentially offering novel strategies for tumor therapy, the underlying mechanisms require further comprehensive investigation.
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Affiliation(s)
- Zhengguang Zhang
- Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangsu, Nanjing, People’s Republic of China
- School of Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, People’s Republic of China
| | - Min Li
- Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangsu, Nanjing, People’s Republic of China
| | - Xiaolong Zhang
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Jiangsu, Nanjing, People’s Republic of China
| | - Fuqiong Zhou
- Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangsu, Nanjing, People’s Republic of China
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18
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Yu H, Liu S, Yuan Z, Huang H, Yan P, Zhu W. Targeted co-delivery of rapamycin and oxaliplatin by liposomes suppresses tumor growth and metastasis of colorectal cancer. Biomed Pharmacother 2024; 178:117192. [PMID: 39098178 DOI: 10.1016/j.biopha.2024.117192] [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: 04/30/2024] [Revised: 07/08/2024] [Accepted: 07/22/2024] [Indexed: 08/06/2024] Open
Abstract
The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC.
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Affiliation(s)
- Hang Yu
- Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Shengyao Liu
- Department of Spinal Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No. 250, Changgangdong Road, Guangzhou 510260, China
| | - Zhongwen Yuan
- Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Hanhui Huang
- Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Pengke Yan
- Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
| | - Wenting Zhu
- Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
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19
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Zeng W, Liu H, Mao Y, Jiang S, Yi H, Zhang Z, Wang M, Zong Z. Myeloid‑derived suppressor cells: Key immunosuppressive regulators and therapeutic targets in colorectal cancer (Review). Int J Oncol 2024; 65:85. [PMID: 39054950 PMCID: PMC11299769 DOI: 10.3892/ijo.2024.5673] [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: 02/19/2024] [Accepted: 06/03/2024] [Indexed: 07/27/2024] Open
Abstract
Globally, colorectal cancer (CRC) is the third most common type of cancer. CRC has no apparent symptoms in the early stages of disease, and most patients receive a confirmed diagnosis in the middle or late disease stages. The incidence of CRC continues to increase, and the affected population tends to be younger. Therefore, determining how to achieve an early CRC diagnosis and treatment has become a top priority for prolonging patient survival. Myeloid‑derived suppressor cells (MDSCs) are a group of bone marrow‑derived immuno‑negative regulatory cells that are divided into two subpopulations, polymorphonuclear‑MDSCs and monocytic‑MDSCs, based on their phenotypic similarities to neutrophils and monocytes, respectively. These cells can inhibit the immune response and promote cancer cell metastasis in the tumour microenvironment (TME). A large aggregation of MDSCs in the TME is often a marker of cancer and a poor prognosis in inflammatory diseases of the intestine (such as colonic adenoma and ulcerative colitis). In the present review, the phenotypic classification of MDSCs in the CRC microenvironment are first discussed. Then, the amplification, role and metastatic mechanism of MDSCs in the CRC TME are described, focusing on genes, gene modifications, proteins and the intestinal microenvironment. Finally, the progress in CRC‑targeted therapies that aim to modulate the quantity, function and structure of MDSCs are summarized in the hope of identifying potential screening markers for CRC and improving CRC prognosis and therapeutic options.
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Affiliation(s)
- Wenjuan Zeng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- HuanKui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Haohan Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yuanhao Mao
- Fuzhou Medical College, Nanchang University, Fuzhou, Jiangxi 330006, P.R. China
| | - Shihao Jiang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Hao Yi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zitong Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- HuanKui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Menghui Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- HuanKui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Wang G, Zou X, Chen Q, Nong W, Miao W, Luo H, Qu S. The relationship and clinical significance of lactylation modification in digestive system tumors. Cancer Cell Int 2024; 24:246. [PMID: 39010066 PMCID: PMC11251390 DOI: 10.1186/s12935-024-03429-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/02/2024] [Indexed: 07/17/2024] Open
Abstract
Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance.
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Affiliation(s)
- Gang Wang
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Xiaosu Zou
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Qicong Chen
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Wenqian Nong
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Weiwei Miao
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Honglin Luo
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China.
| | - Shenhong Qu
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China.
- Department of Otolaryngology & Head and Neck, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China.
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21
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Qi K, Li J, Hu Y, Qiao Y, Mu Y. Research progress in mechanism of anticancer action of shikonin targeting reactive oxygen species. Front Pharmacol 2024; 15:1416781. [PMID: 39076592 PMCID: PMC11284502 DOI: 10.3389/fphar.2024.1416781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 06/13/2024] [Indexed: 07/31/2024] Open
Abstract
Excessive buildup of highly reactive molecules can occur due to the generation and dysregulation of reactive oxygen species (ROS) and their associated signaling pathways. ROS have a dual function in cancer development, either leading to DNA mutations that promote the growth and dissemination of cancer cells, or triggering the death of cancer cells. Cancer cells strategically balance their fate by modulating ROS levels, activating pro-cancer signaling pathways, and suppressing antioxidant defenses. Consequently, targeting ROS has emerged as a promising strategy in cancer therapy. Shikonin and its derivatives, along with related drug carriers, can impact several signaling pathways by targeting components involved with oxidative stress to induce processes such as apoptosis, necroptosis, cell cycle arrest, autophagy, as well as modulation of ferroptosis. Moreover, they can increase the responsiveness of drug-resistant cells to chemotherapy drugs, based on the specific characteristics of ROS, as well as the kind and stage of cancer. This research explores the pro-cancer and anti-cancer impacts of ROS, summarize the mechanisms and research achievements of shikonin-targeted ROS in anti-cancer effects and provide suggestions for designing further anti-tumor experiments and undertaking further experimental and practical research.
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Affiliation(s)
- Ke Qi
- Department of Diagnostic Clinical Laboratory Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Jiayi Li
- Department of Clinical Test Center, Medical Laboratory, Peking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Yang Hu
- Department of Diagnostic Clinical Laboratory Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Yiyun Qiao
- Department of Clinical Test Center, Peking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Yongping Mu
- Department of Clinical Test Center, Peking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
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22
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Wang Y, Zeng Y, Yang W, Wang X, Jiang J. Targeting CD8 + T cells with natural products for tumor therapy: Revealing insights into the mechanisms. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155608. [PMID: 38642413 DOI: 10.1016/j.phymed.2024.155608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 03/27/2024] [Accepted: 04/07/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND Despite significant advances in cancer immunotherapy over the past decades, such as T cell-engaging chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockade (ICB), therapeutic failure resulting from various factors remains prevalent. Therefore, developing combinational immunotherapeutic strategies is of great significance for improving the clinical outcome of cancer immunotherapy. Natural products are substances that naturally exist in various living organisms with multiple pharmacological or biological activities, and some of them have been found to have anti-tumor potential. Notably, emerging evidences have suggested that several natural compounds may boost the anti-tumor effects through activating immune response of hosts, in which CD8+ T cells play a pivotal role. METHODS The data of this review come from PubMed, Web of Science, Google Scholar, and ClinicalTrials (https://clinicaltrials.gov/) with the keywords "CD8+ T cell", "anti-tumor", "immunity", "signal 1", "signal 2", "signal 3", "natural products", "T cell receptor (TCR)", "co-stimulation", "co-inhibition", "immune checkpoint", "inflammatory cytokine", "hesperidin", "ginsenoside", "quercetin", "curcumin", "apigenin", "dendrobium officinale polysaccharides (DOPS)", "luteolin", "shikonin", "licochalcone A", "erianin", "resveratrol", "procyanidin", "berberine", "usnic acid", "naringenin", "6-gingerol", "ganoderma lucidum polysaccharide (GL-PS)", "neem leaf glycoprotein (NLGP)", "paclitaxel", "source", "pharmacological activities", and "toxicity". These literatures were published between 1993 and 2023. RESULTS Natural products have considerable advantages as anti-tumor drugs based on the various species, wide distribution, low price, and few side effects. This review summarized the effects and mechanisms of some natural products that exhibit anti-tumor effects via targeting CD8+ T cells, mainly focused on the three signals that activate CD8+ T cells: TCR, co-stimulation, and inflammatory cytokines. CONCLUSION Clarifying the role and underlying mechanism of natural products in cancer immunotherapy may provide more options for combinational treatment strategies and benefit cancer therapy, to shed light on identifying potential natural compounds for improving the clinical outcome in cancer immunotherapy.
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Affiliation(s)
- Yuke Wang
- West China School of Public Health and West China Fourth Hospital, West China School of Basic Medical Sciences & Forensic Medicine and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Neurosurgery, Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, China
| | - Yan Zeng
- West China School of Public Health and West China Fourth Hospital, West China School of Basic Medical Sciences & Forensic Medicine and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wenyong Yang
- Department of Neurosurgery, Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, China
| | - Xiuxuan Wang
- Research and Development Department, Beijing DCTY Biotech Co., Ltd., Beijing, China
| | - Jingwen Jiang
- West China School of Public Health and West China Fourth Hospital, West China School of Basic Medical Sciences & Forensic Medicine and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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23
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Lin TT, Xiong W, Chen GH, He Y, Long L, Gao XF, Zhou JL, Lv WW, Huang YZ. Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages. Acta Pharmacol Sin 2024; 45:867-878. [PMID: 38114644 PMCID: PMC10943229 DOI: 10.1038/s41401-023-01205-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 11/19/2023] [Indexed: 12/21/2023]
Abstract
Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.
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Affiliation(s)
- Ting-Ting Lin
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, 256603, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Wei Xiong
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Gui-Hua Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China
| | - Yang He
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Li Long
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xin-Fu Gao
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, 256603, China
| | - Jia-Lin Zhou
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Wen-Wen Lv
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, 256603, China.
| | - Yong-Zhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China.
- NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai, 201203, China.
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24
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Xue W, Yang L, Chen C, Ashrafizadeh M, Tian Y, Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cell Mol Life Sci 2024; 81:79. [PMID: 38334836 PMCID: PMC10857981 DOI: 10.1007/s00018-023-05099-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/09/2023] [Accepted: 12/20/2023] [Indexed: 02/10/2024]
Abstract
Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial-mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/β-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3β that destructs β-catenin, while ligand-receptor interaction impairs GSK-3β function to increase β-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/β-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance β-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/β-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/β-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression.
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Affiliation(s)
- Wenhua Xue
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Lin Yang
- Department of Hepatobiliary Surgery, Xianyang Central Hospital, Xianyang, 712000, Shaanxi, China
| | - Chengxin Chen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Milad Ashrafizadeh
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Yu Tian
- School of Public Health, Benedictine University, Lisle, USA.
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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25
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Zhu J, Wang R, Yang C, Shao X, Zhang Y, Hou J, Gao Y, Ou A, Chen M, Huang Y. Blocking tumor-platelet crosstalk to prevent tumor metastasis via reprograming glycolysis using biomimetic membrane-hybridized liposomes. J Control Release 2024; 366:328-341. [PMID: 38168561 DOI: 10.1016/j.jconrel.2023.12.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/26/2023] [Accepted: 12/29/2023] [Indexed: 01/05/2024]
Abstract
Activated platelets promote tumor progression and metastasis through active interactions with cancer cells, especially in promoting epithelial-mesenchymal transition (EMT) of tumor cells and shedding tumor cells into the blood. Blocking platelet-tumor cell interactions can be a potential strategy to inhibit tumor metastasis. Platelet activation requires energy produced from aerobic glycolysis. Based on this, we propose a platelet suppression strategy by reprogramming glucose metabolism of platelets, which has an advantage over conventional antiplatelet treatment that has a risk of serious hemorrhage. We develop a biomimetic delivery system using platelet membrane-hybridized liposomes (PM-Lipo) for codelivery of quercetin and shikonin to simultaneously inhibit lactate transporter MCT-4 and a glycolytic enzyme PKM2 for achieving metabolic reprogramming of platelets and suppressing platelet activation. Notably, PM-Lipo can also inhibit glycolysis in cancer cells, which actually takes "two-birds-one-stone" action. Consequently, the platelet-tumor cell interactions are inhibited. Moreover, PM-Lipo can bind with circulating tumor cells and reduce their seeding in the premetastatic microenvironment. The in vivo studies further demonstrated that PM-Lipo can effectively suppress primary tumor growth and reduce lung metastasis without affecting inherited functions of platelets. Reprogramming glycolysis of platelets can remodel the tumor immune microenvironment, including suppression of Treg and stimulation of CTLs.
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Affiliation(s)
- Jie Zhu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Rui Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; Nanchang University College of Pharmacy, 461 Bayi Rd, Nanchang 330006, China
| | - Chenxiao Yang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; Nanchang University College of Pharmacy, 461 Bayi Rd, Nanchang 330006, China
| | - Xinyue Shao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yi Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Jiazhen Hou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China
| | - Yanrong Gao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ante Ou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Meiwan Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, China
| | - Yongzhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Zhongshan Institute for Drug Discovery, The Institutes of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan 528437, China; NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China.
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26
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Dong H, Chang CD, Gao F, Zhang N, Yan XJ, Wu X, Wang YH. The anti-leukemia activity and mechanisms of shikonin: a mini review. Front Pharmacol 2023; 14:1271252. [PMID: 38026987 PMCID: PMC10651754 DOI: 10.3389/fphar.2023.1271252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Leukemia encompasses a group of highly heterogeneous diseases that pose a serious threat to human health. The long-term outcome of patients with leukemia still needs to be improved and new effective therapeutic strategies continue to be an unmet clinical need. Shikonin (SHK) is a naphthoquinone derivative that shows multiple biological function includes anti-tumor, anti-inflammatory, and anti-allergic effects. Numerous studies have reported the anti-leukemia activity of SHK during the last 3 decades and there are studies showing that SHK is particularly effective towards various leukemia cells compared to solid tumors. In this review, we will discuss the anti-leukemia effect of SHK and summarize the underlying mechanisms. Therefore, SHK may be a promising agent to be developed as an anti-leukemia drug.
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Affiliation(s)
- Han Dong
- Department of Geriatrics, Jilin Geriatrics Clinical Research Center, The First Hospital of Jilin University, Changchun, China
| | - Chun-Di Chang
- Department of Neurology, Jilin Province People’s Hospital, Changchun, China
| | - Fei Gao
- Endocrine Department, Qian Wei Hospital of Jilin Province, Changchun, China
| | - Na Zhang
- Electrodiagnosis Department, Jilin Province FAW General Hospital, Changchun, China
| | - Xing-Jian Yan
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Xue Wu
- Department of Geriatrics, Jilin Geriatrics Clinical Research Center, The First Hospital of Jilin University, Changchun, China
| | - Yue-Hui Wang
- Department of Geriatrics, Jilin Geriatrics Clinical Research Center, The First Hospital of Jilin University, Changchun, China
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