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Shi G, Tian H, Chu S, Liu D, Yan Z, Yang M, Xu H. Design, synthesis and evaluation of a fluorescent PI3K inhibitor as a dual-function agent toward Cancer Theranostics. Bioorg Med Chem Lett 2025; 124:130255. [PMID: 40286989 DOI: 10.1016/j.bmcl.2025.130255] [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: 02/22/2025] [Revised: 04/03/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
The development of PI3K-targeted therapeutics has advanced significantly, yet molecular tools capable of simultaneous kinase inhibition and real-time visualization of drug distribution remain limited. Herein, we describe the rational design, synthesis, and biological evaluation of a novel fluorescent PI3K inhibitor (compound 1) that incorporates a 4-methylquinazoline pharmacophore conjugated to fluorescein isothiocyanate (FITC) through a piperazine linker. 1 demonstrated potent PI3K enzymatic inhibition and exhibited significant antiproliferative effects against HGC-27 and MCF-7 cancer cell lines. Mechanistic investigations revealed that 1 effectively suppresses DNA synthesis, triggers G0/G1 cell cycle arrest, and disrupts mitochondrial architecture. Fluorescence-based cellular and in vivo imaging studies demonstrated the compound's preferential cytoplasmic localization and tumor-targeting properties. This dual-function inhibitor not only advances PI3K-targeted drug discovery but also provides a valuable tool for real-time monitoring of drug distribution, representing a promising addition to the growing field of cancer theranostics.
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Affiliation(s)
- Ge Shi
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Hua Tian
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Shiji Chu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Dan Liu
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zheng Yan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Min Yang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beiiing 100050, China.
| | - Heng Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
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2
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Hou B, Jia G, Li Z, Jiang Y, Chen Y, Li X. Discovery of hydrazide-based PI3K/HDAC dual inhibitors with enhanced pro-apoptotic activity in lymphoma cells. Eur J Med Chem 2025; 292:117658. [PMID: 40300459 DOI: 10.1016/j.ejmech.2025.117658] [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: 02/12/2025] [Revised: 04/08/2025] [Accepted: 04/18/2025] [Indexed: 05/01/2025]
Abstract
PI3K and HDAC are concurrently upregulated in a variety of cancers, and simultaneous inhibition of PI3K and HDAC may synergistically inhibit tumor proliferation and induce apoptosis, providing a rationale for the study of dual-target PI3K/HDAC inhibitors. In this study, we rationally designed and synthesized a series of novel PI3K/HDAC dual-target inhibitors by combining the morpholino-triazine pharmacophore of PI3K inhibitor ZSTK474 with the hydrazide moiety of HDAC1-3 selective inhibitor 11h. Representative compound 31f possessed both PI3K (IC50 = 2.5-80.5 nM for PI3Kα, β, γ, and δ) and HDAC1-3 inhibitory activities (IC50 = 1.9-75.5 nM for HDAC1-3). 31f showed potent antiproliferative activity against a variety of tumor cell lines. Meanwhile, we designed and synthesized tool molecule 39a, a HDAC inhibitor structurally similar to 31f. In the mantle cell lymphoma Jeko-1 cell line, 31f showed significantly greater efficacy than the single inhibitors in inducing apoptosis. In conclusion, this study provided insights into the development of novel hydrazide-based dual HDAC/PI3K inhibitors.
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Affiliation(s)
- Baogeng Hou
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Geng Jia
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Zhongqiang Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yuqi Jiang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yuxin Chen
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Xiaoyang Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.
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3
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Jiang M, Ma S, Xuan Y, Chen K. Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy. Eur J Med Chem 2025; 291:117626. [PMID: 40252381 DOI: 10.1016/j.ejmech.2025.117626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/21/2025]
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in various cancers, including pancreatic, colorectal, and non-small cell lung cancer (NSCLC). Targeting KRAS has long been considered a difficult challenge due to its high affinity for guanosine triphosphate (GTP) and the lack of a druggable binding site. However, recent advancements in small-molecule inhibitor design have led to the development of targeted therapies aimed at KRAS mutations, particularly the KRASG12C mutation. Inhibitors such as Sotorasib and Adagrasib have shown promise in preclinical and clinical studies by irreversibly binding to the mutant KRAS protein, locking it in an inactive state and disrupting downstream signaling pathways critical for tumor growth and survival. These inhibitors have demonstrated clinical efficacy in treating patients with KRASG12C-mutated cancers, leading to tumor regression, prolonged progression-free survival, and improved patient outcomes. This review discusses the synthetic strategies employed to develop these KRAS inhibitor and also examines the clinical application of these inhibitors, highlighting the challenges and successes encountered during clinical trials. Ultimately, KRAS inhibitors represent a breakthrough in cancer therapy, offering a promising new treatment option for patients with KRAS-driven tumors.
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Affiliation(s)
- Min Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Shaowei Ma
- Department of Interventional Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Xuan
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Kuanbing Chen
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
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4
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Zhong Y, Jiao P, Wang Y, Mao B, Huang H, Shi C, Sun X, Liu Z, Zhang L. Discovery of novel PI3KC2γ inhibitors with high potency, selectivity, and favorable pharmacokinetics for glycogen metabolism regulation. Eur J Med Chem 2025; 291:117621. [PMID: 40262302 DOI: 10.1016/j.ejmech.2025.117621] [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: 01/17/2025] [Revised: 03/11/2025] [Accepted: 04/09/2025] [Indexed: 04/24/2025]
Abstract
Phosphatidylinositol 3-kinase Class IIγ (PI3KC2γ) is a critical regulator of PI(3,4)P2 production on endosomal membranes, linking its activity to metabolic disorders such as diabetes, glycogen storage diseases, and hyperlipidemia. Despite its importance, selective inhibitors targeting PI3KC2γ remain underexplored. In this study, we developed novel scaffolds for PI3KC2γ inhibitors using structure-based design. A series of inhibitors were synthesized, among which compound 23 was identified as the most potent PI3KC2γ inhibitor reported to date. Functional assays confirmed that compound 23 effectively inhibits insulin-stimulated PI(3,4)P2 formation, blocks glucose-to-glycogen conversion, and reduces excessive liver glycogen accumulation by downregulating the Akt2-glycogen synthase pathway. This study highlights the therapeutic potential of PI3KC2γ inhibition in glycogen storage diseases and provides efficient tool molecules for further drug development.
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Affiliation(s)
- Yi Zhong
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Peili Jiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yuxi Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Beibei Mao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Han Huang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Cheng Shi
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xiaojiao Sun
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
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5
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Li L, Liu Q, Shao Y, Wang S, Liu S, Wang X, Wang S, Ren D. Gaudichaudion H inhibits KRAS-mutant pancreatic cancer cell growth through interfering PDEδ-KRAS interaction. Chem Biol Interact 2025; 415:111529. [PMID: 40288433 DOI: 10.1016/j.cbi.2025.111529] [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: 10/28/2024] [Revised: 04/03/2025] [Accepted: 04/25/2025] [Indexed: 04/29/2025]
Abstract
KRAS mutation results in higher proliferation rates and miserable prognosis of cancers. Targeting the interaction between KRAS and PDE6D provided an alternative strategy to overcome KRAS-mutant pancreatic cancers. Gaudichaudione H (GH) is a prenylated caged xanthone isolated from Garcinia oligantha. In this work, GH was selected as a potential anti-cancer compound by MTT screening of twelve prenylated xanthonoids from G. oligantha. Further studies demonstrated that GH inhibited proliferation of a panel of cancer cell lines and induced pancreatic cancer cell apoptosis. GH suppressed xenograft tumor growth accompanied with decreased phosphorylation of ERK and AKT. Binding with PDEδ and thus interfering the KRAS-PDEδ interaction was verified as the possible mechanism of GH. These findings implicated GH as a promising candidate for the treatment of pancreatic cancers with KRAS mutation, provided novel insight into the underlying mechanisms of GH-induced anticancer effects.
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Affiliation(s)
- Lingyu Li
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Qingying Liu
- School of Pharmaceutical Sciences, Shandong Xiandai University, PR China
| | - Yuyu Shao
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Shuo Wang
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Shuangyu Liu
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Xiaoning Wang
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Shuqi Wang
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China
| | - Dongmei Ren
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, PR China.
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6
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Wang X, Wang Z, Liu Z, Huang F, Pan Z, Zhang Z, Liu T. Nutritional strategies in oncology: The role of dietary patterns in modulating tumor progression and treatment response. Biochim Biophys Acta Rev Cancer 2025; 1880:189322. [PMID: 40228747 DOI: 10.1016/j.bbcan.2025.189322] [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: 02/10/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 04/16/2025]
Abstract
Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.
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Affiliation(s)
- Xueying Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zeyao Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zihan Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Fanxuan Huang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zhaoyu Pan
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
| | - Zhiren Zhang
- Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China; Departments of Cardiology and Pharmacy and Breast Cancer surgery, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang Key Laboratory for Metabolic Disorder and Cancer Related Cardiovascular Diseases, Harbin, China.
| | - Tong Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China; Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China.
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7
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Goloudina A, Le Chevalier F, Authié P, Charneau P, Majlessi L. Shared neoantigens for cancer immunotherapy. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200978. [PMID: 40256120 PMCID: PMC12008704 DOI: 10.1016/j.omton.2025.200978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/22/2025]
Abstract
Exploration of neoantigens holds the potential to be productive in immuno-oncotherapy. Among tumor-specific antigens, neoantigens result from genetic instability that gives rise to non-synonymous somatic mutations, highly specific to tumor cells. In addition to point mutations, gene rearrangements, indels leading to frameshifts, chromosomal translocations or inversions that may lead to fusion proteins, alternative mRNA splicing, and integration of genetic material of oncogenic viruses into the host genome provide consistent sources of neoantigens that are absent in healthy tissues. Out of these alterations, 2%-3% may generate T cell neoepitopes, possibly detectable by TCRs. Neoantigens are absent in healthy tissues and are thus at low risk of triggering autoimmunity. In addition, the host lymphocytes have not been rendered tolerant toward them and it is possible to induce immune responses against them. Here, we overview the two categories of neoantigens, i.e., private and shared, and their use in immuno-oncotherapy in selected pre-clinical and clinical studies. The vast majority of commonly occurring tumor-specific mutations are cancer causing and are permanently expressed by all malignant tumor cells, preventing the latter from escaping vaccine-induced anti-neoantigen immunity. The use of public neoantigens combined with efficient vaccine platforms can provide non-personalized "off-the-shelf" therapeutic vaccine candidates for broad-spectrum immunotherapy purposes.
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Affiliation(s)
- Anastasia Goloudina
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Fabien Le Chevalier
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Pierre Authié
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Pierre Charneau
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
| | - Laleh Majlessi
- Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université de Paris, Virology Department, 28 rue du Dr. Roux, 75015 Paris, France
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8
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Xiong X, Du Y, Liu P, Li X, Lai X, Miao H, Ning B. Unveiling EIF5A2: A multifaceted player in cellular regulation, tumorigenesis and drug resistance. Eur J Pharmacol 2025; 997:177596. [PMID: 40194645 DOI: 10.1016/j.ejphar.2025.177596] [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: 02/11/2025] [Revised: 03/28/2025] [Accepted: 04/02/2025] [Indexed: 04/09/2025]
Abstract
The eukaryotic initiation factor 5A2 gene (EIF5A2) is a highly conserved and multifunctional gene that significantly influences various cellular processes, including translation elongation, RNA binding, ribosome binding, protein binding and post-translational modifications. Overexpression of EIF5A2 is frequently observed in multiple cancers, where it functions as an oncoprotein. Additionally, EIF5A2 is implicated in drug resistance through the regulation of various molecular pathways. In the review, we describe the structure and functions of EIF5A2 in normal cells and its role in tumorigenesis. We also elucidate the molecular mechanisms associated with EIF5A2 in the context of tumorigenesis and drug resistance. We propose that the biological roles of EIF5A2 in regulating diverse cellular processes and tumorigenesis are clinically significant and warrant further investigation.
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Affiliation(s)
- Xifeng Xiong
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China; Guangzhou Institute of Burn Clinical Medicine, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Yanli Du
- Guangdong Medical University, Zhanjiang, 524023, Guangdong, China; Department of Orthopedic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Peng Liu
- Departments of Burn and Plastic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Xinye Li
- Guangdong Medical University, Zhanjiang, 524023, Guangdong, China; Department of Orthopedic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Xudong Lai
- Department of infectious disease, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Haixiong Miao
- Department of Orthopedic, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China.
| | - Bo Ning
- Department of Neurosurgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China.
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9
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Wang X, Xu T, Ou A, Hu Z, Li M, Wu L, Jiang J, Wang L. Design, synthesis and in vitro and in vivo biological evaluation of matrine derivatives as efficient anticancer agents with the characteristics of endoplasmic reticulum stress induction and apoptosis activation. Bioorg Chem 2025; 160:108482. [PMID: 40273706 DOI: 10.1016/j.bioorg.2025.108482] [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: 02/26/2025] [Revised: 04/10/2025] [Accepted: 04/14/2025] [Indexed: 04/26/2025]
Abstract
Natural products have made significant contributions to the prevention and treatment of malignant tumors. However, natural products often suffer from low efficacy and potential toxicity. Therefore, modifying and optimizing lead compounds derived from natural products is a crucial strategy in drug development. In this study, we used matrine as an ideal lead compound and synthesized 27 matrine derivatives by incorporating indole structures with known antitumor activity. The antiproliferative effects of these derivatives were evaluated against human cancer cell lines (A549, HeLa, and Huh-7) and normal human liver cells (LO2). Compared to matrine, most of the derivatives exhibited superior antiproliferative activity. Notably, compound 9q showed significant antiproliferative activity against HeLa cells, with an IC50 value of 4.48 μM, demonstrating approximately 1500-fold greater potency than matrine (IC50 = 6756 μM). Further mechanistic studies revealed that compound 9q inhibited HeLa cell proliferation by modulating the expression of PI3K/AKT and Activating transcription factor 4 (ATF4) proteins. The upregulation of ATF4 promoted the expression of the key endoplasmic reticulum stress (ER stress) protein C/EBP homologous protein (CHOP). In the HeLa xenograft mouse model, compound 9q demonstrated significant anticancer efficacy. Therefore, compound 9q holds promise as a potential lead compound for the development of novel anticancer drugs.
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Affiliation(s)
- Xingdong Wang
- School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China
| | - Tingguo Xu
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Anqi Ou
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Zhouxing Hu
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Manqi Li
- School of Medicine, Guangxi University, Nanning 530004, China
| | - Lichuan Wu
- School of Medicine, Guangxi University, Nanning 530004, China.
| | - Jun Jiang
- School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China.
| | - Lisheng Wang
- School of Medicine, Guangxi University, Nanning 530004, China.
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10
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Doke R, Lokhande R, Chande K, Vinchurkar K, Prajapati BG. Recent advances in therapeutic strategies of Erdheim-Chester disease. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:6407-6428. [PMID: 39836251 DOI: 10.1007/s00210-024-03769-2] [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: 10/18/2024] [Accepted: 12/26/2024] [Indexed: 01/22/2025]
Abstract
Erdheim-Chester disease (ECD) is a rare form of non-LCH characterized by excessive accumulation of histiocytes in various tissues, leading to significant morbidity. The estimated prevalence of ECD is low, with fewer than 1000 cases reported globally, yet it presents considerable clinical challenges due to its heterogeneous manifestations, which include bone pain, cardiovascular complications, and neurological symptoms. Traditional treatment approaches, primarily involving corticosteroids and chemotherapy, have limitations, including inconsistent responses and significant side effects. Recent advances in understanding the pathogenesis of ECD, particularly the role of the BRAF V600E mutation, have led to the exploration of novel therapeutic strategies, such as targeted BRAF inhibitors, MEK and mTOR inhibitors, and other immunotherapies, which offer promise in improving patient outcomes. The review further explores clinical manifestations, and radiographic features of Erdheim-Chester disease, and discusses treatment strategies, current clinical studies in the field of ECD. By integrating these aspects, this review aims to provide a thorough understanding of ECD and its evolving treatment landscape, ultimately contributing to improved patient outcomes.
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Affiliation(s)
- Rohit Doke
- Jaihind College of Pharmacy, Vadgaon Sahani, Pune, Maharashtra, 412401, India
| | - Rahul Lokhande
- Samarth Institute of Pharmacy, Belhe, Pune, Maharashtra, 412410, India
| | - Kalyani Chande
- Dr. DY Patil College of Pharmacy Akurdi, Pune, Maharashtra, 411044, India
| | - Kuldeep Vinchurkar
- Sandip Foundation's Sandip Institute of Pharmaceutical Sciences (SIPS), Nashik, Maharashtra, 422213, India.
| | - Bhupendra G Prajapati
- Department of Pharmaceutical Technology, Shree S K Patel College of Pharmaceutical Education and Research, Ganpat University, 384012, Mahesana, Gujarat, India.
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11
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Lyu Z, Yang J, Xu Z, Wang W, Cheng W, Tsui KL, Zhang Q. Predicting the risk of ischemic stroke in patients with atrial fibrillation using heterogeneous drug-protein-disease network-based deep learning. APL Bioeng 2025; 9:026104. [PMID: 40191603 PMCID: PMC11970939 DOI: 10.1063/5.0242570] [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: 10/05/2024] [Accepted: 02/11/2025] [Indexed: 04/09/2025] Open
Abstract
Current risk assessment models for predicting ischemic stroke (IS) in patients with atrial fibrillation (AF) often fail to account for the effects of medications and the complex interactions between drugs, proteins, and diseases. We developed an interpretable deep learning model, the AF-Biological-IS-Path (ABioSPath), to predict one-year IS risk in AF patients by integrating drug-protein-disease pathways with real-world clinical data. Using a heterogeneous multilayer network, ABioSPath identifies mechanisms of drug actions and the propagation of comorbid diseases. By combining mechanistic pathways with patient-specific characteristics, the model provides individualized IS risk assessments and identifies potential molecular pathways involved. We utilized the electronic health record data from 7859 AF patients, collected between January 2008 and December 2009 across 43 hospitals in Hong Kong. ABioSPath outperformed baseline models in all evaluation metrics, achieving an AUROC of 0.7815 (95% CI: 0.7346-0.8283), a positive predictive value of 0.430, a negative predictive value of 0.870, a sensitivity of 0.500, a specificity of 0.885, an average precision of 0.409, and a Brier score of 0.195. Cohort-level analysis identified key proteins, such as CRP, REN, and PTGS2, within the most common pathways. Individual-level analysis further highlighted the importance of PIK3/Akt and cytokine and chemokine signaling pathways and identified IS risks associated with less-studied drugs like prochlorperazine maleate. ABioSPath offers a robust, data-driven approach for IS risk prediction, requiring only routinely collected clinical data without the need for costly biomarkers. Beyond IS, the model has potential applications in screening risks for other diseases, enhancing patient care, and providing insights for drug development.
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Affiliation(s)
| | - Jiannan Yang
- Musketeers Foundation Institute of Data Science, The University of Hong Kong, Hong Kong SAR, China
| | - Zhongzhi Xu
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Weilan Wang
- Centre for Healthy Longevity, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Kwok-Leung Tsui
- Department of Manufacturing, Systems, and Industrial Engineering, University of Texas, Arlington, Texas 76019, USA
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12
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Cazzola M, Page C, Rogliani P, Calzetta L, Matera MG. PI3K Inhibitors as Potential Therapeutic Agents for the Treatment of COPD with Associated Atherosclerosis. Drugs 2025; 85:741-753. [PMID: 40214902 PMCID: PMC12098434 DOI: 10.1007/s40265-025-02179-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 05/24/2025]
Abstract
Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) share a complex and multifactorial relationship characterized by overlapping risk factors, systemic inflammation, and intertwined pathophysiological mechanisms, with atherosclerosis emerging as a central inflammatory process connecting COPD and CVD, driven by systemic inflammation, oxidative stress, and endothelial dysfunction. While systemic inflammation is recognized as a critical link between these conditions, the precise pathways through which inflammation arises remain under investigation. There is therefore a need for therapeutic strategies to mitigate cardiovascular risks in patients with COPD. Among the pathways contributing to this interplay, the phosphoinositide 3-kinase (PI3K) signaling pathway has gained significant attention. Dysregulated PI3K signaling contributes to inflammation, oxidative stress, and endothelial dysfunction, which are key drivers of both COPD and CVD. Consequently, PI3K inhibitors have emerged as a promising therapeutic approach to mitigate inflammation and oxidative damage, offering a targeted strategy to address the shared pathological mechanisms underlying these diseases. A comprehensive understanding of the role of PI3K signaling and its inhibitors could facilitate the development of novel interventions to reduce cardiovascular risk in patients with COPD.
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Affiliation(s)
- Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00131, Rome, Italy.
| | - Clive Page
- Institute of Pharmaceutical Science, King's College London, London, UK
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00131, Rome, Italy
| | - Luigino Calzetta
- Unit of Respiratory Diseases and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy
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13
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Tracy PD, Bopp E, Milner E, Garrido-Castro AC, Giordano A, Mayer EL, Tolaney SM, Tarantino P, Schlam I. Management of Metastatic Hormone Receptor-Positive Breast Cancer Beyond CDK4/6 Inhibitors. Curr Oncol Rep 2025:10.1007/s11912-025-01689-9. [PMID: 40434676 DOI: 10.1007/s11912-025-01689-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2025] [Indexed: 05/29/2025]
Abstract
PURPOSE OF REVIEW Since the introduction of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) as the first-line treatment for metastatic hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-) breast cancer, there has been a significant expansion in the number of therapeutic options for subsequent lines of therapy. Many new agents are being studied, with potential for future regulatory approval. The increased number of therapeutic options raises questions about the optimal selection and sequencing of therapies for individual patients. These advances represent an important clinical challenge in this rapidly evolving field, given the introduction of new therapies targeting various pathways (alone or in combination) and new therapeutic classes being studied. RECENT FINDINGS Recently approved targeted therapies have demonstrated improvements in progression free survival (PFS) for patients whose cancer harbors mutations in the PI3K/AKT pathway, ESR1, BRCA1/2, and/or PALB2. Data to support continuation of CDK4/6 inhibition after progression on a prior CDK4/6i remains mixed, though some studies suggest a subset of patients may benefit from this approach. Several agents with unique mechanisms of action have shown promise in data from early phase trials, and have the potential to enter the treatment lexicon in the coming years. Examples include CDK2- and CDK4-selective inhibitors, complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and next-generation PI3K pathway inhibitors. In this narrative review, we summarize the current and upcoming treatments for metastatic HR+/HER2- breast cancer after progression on a CDK4/6i plus ET, with a focus on the following: an overview of first-line regimens of CDK4/6i plus ET and observed mechanisms of resistance; currently approved second-line therapy options; and upcoming options currently under exploration in clinical trials. We focus primarily on new therapy classes that may offer therapeutic options beyond currently available treatments.
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Affiliation(s)
- Philip D Tracy
- Department of Hematology/Oncology, Tufts Medical Center, Boston, MA, 02111, USA
- Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Emily Bopp
- Department of Medicine, Tufts Medical Center, Boston, MA, 02111, USA
| | - Emily Milner
- Department of Medicine, Tufts Medical Center, Boston, MA, 02111, USA
| | - Ana C Garrido-Castro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Antonio Giordano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Erica L Mayer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Paolo Tarantino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
- Harvard Medical School, Boston, MA, 02115, USA.
- Department of Oncology and Onco-Hematology, University of Milan, Milan, 20122, Italy.
| | - Ilana Schlam
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
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14
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Xu W, Li X, He F, Zhao H, Wu J, Li M, Dai X, Li Y, Hu X, Li X, Cen J, Guo P, Duan S. Folate receptor-targeted pH-sensitive liposomes loaded with TGX-221 against prostate cancer by inhibiting PI3K/110β signaling. NANOSCALE ADVANCES 2025; 7:3267-3280. [PMID: 40212450 PMCID: PMC11979785 DOI: 10.1039/d5na00009b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/05/2025] [Indexed: 05/29/2025]
Abstract
Prostate cancer (PCa) is the most common cancer in men and the leading cause of cancer death worldwide. Overactivation of PI3K signaling has been reported to be associated with PCa. TGX221 is an effective specific inhibitor of PI3K, but its clinical application is greatly limited due to its poor solubility. Herein, by using folic acid-PEG-cholesterol semi-succinate (FA-PEG-CHEMS) as the targeting component, we developed a folate receptor-targeted pH-sensitive liposomal delivery system loaded with TGX221 (FA-Lip-TGX221) that could realize effective delivery and controlled release of drugs in the tumor. The prepared liposomes exhibited a uniform particle size and high stability. In addition, FA-Lip-TGX221 could be effectively internalized by PC-3 cells due to its ability to target folate receptors, thereby accumulating in tumor tissues. Meanwhile, in vitro and in vivo experiments suggested that FA-Lip-TGX221 could activate the PERK-ATF4-CHOP signaling pathway by inhibiting PI3K/110β signaling in PCa, thus significantly promoting endoplasmic reticulum (ER) stress-mediated cancer cell death. In conclusion, FA-Lip-TGX221 is a promising nano-delivery vehicle for the treatment of PCa, and also provide valuable references for all tumors overexpressing folate receptors.
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Affiliation(s)
- Weibo Xu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 China
- Medical School, Henan University Kaifeng 475004 China
| | - Xiaohan Li
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Fujin He
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Han Zhao
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Jing Wu
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Mengyu Li
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Xiaoying Dai
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Yanmin Li
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Xiaojiao Hu
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
| | - Xiaodong Li
- Medical School, Henan University Kaifeng 475004 China
| | - Juan Cen
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
- The First Affiliated Hospital of Henan University Kaifeng Henan 475004 PR China
| | - Peng Guo
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 China
| | - Shaofeng Duan
- Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University Kaifeng Henan 475004 PR China
- The First Affiliated Hospital of Henan University Kaifeng Henan 475004 PR China
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15
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Liu Z, Liao X, Zhao H, Ruan B, Jia F, He X, Long R. miR-29a-3p compositely regulates the COL6A6/PTEN-PI3K/Akt/CUX1 feedback loop to participate in the proliferation and invasion of pituitary adenomas. J Mol Histol 2025; 56:172. [PMID: 40419838 DOI: 10.1007/s10735-025-10436-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/21/2025] [Indexed: 05/28/2025]
Abstract
Pituitary adenoma (PA) is one of the most common intracranial tumors, and owing to its special biological morphology and behavior, there is currently no effective treatment. miRNAs play crucial roles as diagnostic indicators and targets for the treatment of numerous cancer types. The objective of this research was to explore how miR-29a-3p influences the development of PA. We collected 25 pairs of PA tissue and normal pituitary tissue, followed by the subcutaneous injection of 5 × 107 HP75 cells into the left axilla of nude mice, creating a heterotopic PA xenograft tumor model for experimental study. TtT/GF and HP75 cell proliferation and tumor growth in nude mice were assessed using CCK-8, Transwell, and immunohistochemistry tests. Western blotting, RT‒qPCR and RIP were used to detect the expression and interaction of related proteins and genes. The expression of miR-29a-3p was upregulated in PA. Knockdown of miR-29a-3p can inhibit the proliferation, invasion and migration of TtT/GF and HP75 cells and reduce the epithelial mesenchymal transformation (EMT) of these cells. Furthermore, reducing miR-29a-3p levels suppressed the expression of Ki-67 in the PA tissues of nude mice and slowed tumor growth. From a mechanistic standpoint, miR-29a-3p can target COL6A6 and PTEN. Knockdown of miR-29a-3p inhibits the PI3K/Akt/CUX1 signaling pathway through simultaneously increasing COL6A6 and PTEN expression, thus inhibiting the proliferation, invasion, migration and EMT of PA cells and alleviating the progression of PA. Conversely, CUX1 can promote the expression of miR-29a-3p through a positive feedback loop and accelerate the development of PA. Our study suggests that downregulating the expression of miR-29a-3p may be a new target for the treatment of PA.
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Affiliation(s)
- Zhuohui Liu
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Xiufu Liao
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
- Department of Otolaryngology, Chongqing General Hospital, Chongqing, 401147, Chongqing, China
| | - Hexiang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Biao Ruan
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Fengfeng Jia
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Xuzhi He
- Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, 400042, Chongqing, China.
| | - Ruiqing Long
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China.
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16
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Zhou H, Fu F, Huang R, Yu Q, Yan S, Lu J, Guo F, Ma C, Chen H, Liu L, Zhang Y, Jing X, Li F, Chen G, Li L, Lei T, Deng Q, Mei S, Chen C, Han J, Li R, Liao C. Prenatal Exome Sequencing for Fetal Macrocephaly: A Large Prospective Observational Cohort Study. Prenat Diagn 2025. [PMID: 40404351 DOI: 10.1002/pd.6818] [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: 02/12/2025] [Revised: 05/06/2025] [Accepted: 05/10/2025] [Indexed: 05/24/2025]
Abstract
OBJECTIVE To assess the diagnostic utility of exome sequencing (ES) in macrocephalic fetuses. METHODS Fetuses with macrocephaly (head circumference (HC) ≥ +2 SD) and negative chromosomal microarray results were included, who had available trio-ES data. Molecular diagnoses were systematically analyzed. Subgroup analyses were performed on the ES diagnostic yield based on gestational age, HC Z-scores, associated anomalies, and growth parameters. RESULTS Molecular diagnoses were established in 34 out of 87 macrocephalic fetuses (39.1%) through trio-ES. These diagnoses revealed that the variants predominantly affect key signaling pathways, including mTOR, RASopathies and Sotos syndrome. The detection rate was significantly higher in non-isolated compared to isolated macrocephaly cases (65.0%, 26/40 vs. 17.0%, 8/47; p < 0.001). The most frequent anomalies associated with genetic diagnoses included micromelia (100.0%, 14/14), megalencephaly (100.0%, 2/2), and ventriculomegaly (60.0%, 6/10). Subgroup analysis identified higher diagnostic yields in fetuses diagnosed before 32 gestational weeks, with HC Z-scores ≥ +3 SD, micromelia, and absence of large-for-gestational-age (LGA). CONCLUSIONS Exome sequencing significantly enhances the detection of monogenic disorders in macrocephalic fetuses compared with CMA, irrespective of isolated or non-isolated cases. These clinical features and phenotypes are essential for assessing monogenic disorders and for prenatal counseling and evaluations of macrocephalic fetuses.
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Affiliation(s)
- Hang Zhou
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fang Fu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ruibin Huang
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Qiuxia Yu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shujuan Yan
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jianqin Lu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fei Guo
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Chunling Ma
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
- The First Clinical Medical College, Southern Medical University, Guangzhou, China
| | - Huanyi Chen
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Liyuan Liu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
- The First Clinical Medical College, Southern Medical University, Guangzhou, China
| | - Yongling Zhang
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiangyi Jing
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fucheng Li
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Guilan Chen
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Lushan Li
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Tingying Lei
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Qiong Deng
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shanshan Mei
- Obstetrical Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Chen Chen
- Respiratory Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jin Han
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ru Li
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Can Liao
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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17
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Wu J, Lai J, Zhao X, Wang Z, Zhang Y, Wang L, Su Y, He Y, Li S, Jiang Y, Han J. DeepCCDS: Interpretable Deep Learning Framework for Predicting Cancer Cell Drug Sensitivity through Characterizing Cancer Driver Signals. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2416958. [PMID: 40397390 DOI: 10.1002/advs.202416958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 04/18/2025] [Indexed: 05/22/2025]
Abstract
Accurate characterization of cellular states is the foundation for precise prediction of drug sensitivity in cancer cell lines, which in turn is fundamental to realizing precision oncology. However, current deep learning approaches have limitations in characterizing cellular states. They rely solely on isolated genetic markers, overlooking the complex regulatory networks and cellular mechanisms that underlie drug responses. To address this limitation, this work proposes DeepCCDS, a Deep learning framework for Cancer Cell Drug Sensitivity prediction through Characterizing Cancer Driver Signals. DeepCCDS incorporates a prior knowledge network to characterize cancer driver signals, building upon the self-supervised neural network framework. The signals can reflect key mechanisms influencing cancer cell development and drug response, enhancing the model's predictive performance and interpretability. DeepCCDS has demonstrated superior performance in predicting drug sensitivity compared to previous state-of-the-art approaches across multiple datasets. Benefiting from integrating prior knowledge, DeepCCDS exhibits powerful feature representation capabilities and interpretability. Based on these feature representations, we have identified embedding features that could potentially be used for drug screening in new indications. Further, this work demonstrates the applicability of DeepCCDS on solid tumor samples from The Cancer Genome Atlas. This work believes integrating DeepCCDS into clinical decision-making processes can potentially improve the selection of personalized treatment strategies for cancer patients.
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Affiliation(s)
- Jiashuo Wu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Jiyin Lai
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Xilong Zhao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Ziyi Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yongbao Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Liqiang Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yinchun Su
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yalan He
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Siyuan Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Ying Jiang
- College of Basic Medical Science, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Junwei Han
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
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18
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AlKharboush DF, Khayat MT, Jamal A, El-Araby ME, Awaji AA, Khan MI, Omar AM. Exploring a kinase inhibitor targeting PI3KCA mutant cancer cells. J Biomol Struct Dyn 2025:1-18. [PMID: 40390333 DOI: 10.1080/07391102.2025.2502137] [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: 12/18/2023] [Accepted: 05/04/2024] [Indexed: 05/21/2025]
Abstract
The PI3K/mTOR signaling pathway is often disrupted in human cancers, with PI3Kα being one of the most mutated kinases. There has been considerable interest in developing small-molecule inhibitors aimed at blocking the mutant PI3Kα-driven phosphatidylinositol 3-kinase (PI3K) signaling pathway as a potential treatment for cancer. In this study, we describe our effort to identify a compound, phenylacetamide-1H-imidazol-5-one (KIM-161), from our in-house oncogenic kinase-targeting inhibitors. KIM-161 showed excellent anti-proliferative activities at sub-nanomolar concentrations, primarily against mutant PI3Kα breast cancer cell lines, when compared with wild-type PI3Kα breast cancer cell lines, producing both dose- and time-dependent effects with an IC50 range of 1.42 - 0.064 µM. Next, we observed that KIM-161 was able to induce ROS production by modulating breast cancer metabolism, suggesting its broad effects on mutant PI3Kα regulated downstream pathways. We also computationally analyzed the binding interactions between KIM-161 and PI3K-alpha (PDB ID: 8EXL). Molecular docking showed that KIM-161 had a docking score of -7.44 Kcal/mol, compared to the reference compound, which had a docking score of -7.67 Kcal/mol. Moreover, molecular dynamics simulation studies demonstrated that the PI3Ka-KIM-161 complex remained stable throughout the 100 ns simulation, when compared to the PI3Ka complex with the co-crystallized inhibitor. These findings present KIM-161 as a promising lead, providing valuable insights into treatment approaches and resistance mechanisms associated with PI3K inhibitors in specific PIK3CA-mutant cancer subtypes.
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Affiliation(s)
- Dana F AlKharboush
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Maan T Khayat
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Alam Jamal
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Moustafa E El-Araby
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Aeshah A Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad Imran Khan
- Research Center, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Abdelsattar M Omar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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19
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Wang H, Zhu J, Wang H, Zheng W, Wang L, Zhu J, Wang Z, Du Q. The role of FAM111B in the malignant progression and molecular regulation of human glioma through the PI3K/Akt pathway. Chin Neurosurg J 2025; 11:9. [PMID: 40390043 PMCID: PMC12087166 DOI: 10.1186/s41016-025-00395-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 04/14/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Gliomas represent the most prevalent primary neoplasm in the adult central nervous system. Despite advancements in therapeutic modalities, such as surgical intervention, radiotherapy, chemotherapy, and tumor treatment, the 5-year survival rate of glioma patients remains low. Therefore, there is an urgent need to develop additional treatment methods. Recent studies have suggested that FAM111B is involved in DNA repair, cell cycle regulation, and apoptosis. FAM111B mutations and overexpression are related to cancer. METHODS We found that FAM111B was significantly overexpressed in glioma tissues compared to the adjacent tissues by analyzing data from the TCGA_GBM&LGG and CGGA databases. Moreover, overexpression of FAM111B was associated with shorter overall survival, and disease-specific survival and tended to increase with disease stage progression. Cellular experiments confirmed these results. These results suggest that overexpression of FAM111B promotes the proliferation, migration, and invasion of glioma cells, whereas the knockdown of FAM111B inhibits these activities. We also found that FAM111B regulated glioma cell proliferation, migration, and invasion via the PI3K/AKT pathway. RESULTS FAM111B is capable of enhancing the proliferation, invasion, and migration capabilities of glioma cells and promotes the malignant progression of glioma via the PI3K/Akt signaling pathway. CONCLUSIONS This is the first study to demonstrate that FAM111B plays a crucial role in the proliferation, migration, and invasion of glioma cells. The malignant phenotype of FAM111B has also been shown to be closely associated with the PI3K/AKT pathway. FAM111B may be a predictive biomarker and a potential therapeutic target for gliomas.
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Affiliation(s)
- Heng Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Junrou Zhu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Haiyang Wang
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Wenhao Zheng
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Linjie Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Jinhao Zhu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Zheng Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Quan Du
- Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
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Wang Y, Yu DH, Quan W, Lan T, Tang F, Ma C, Li ZQ, Hong K, Wang ZF. Marine-derived fungal metabolite MHO7 promotes glioblastoma cell apoptosis as a novel Akt inhibitor by targeting membrane phosphatidylethanolamine. Int Immunopharmacol 2025; 155:114656. [PMID: 40233448 DOI: 10.1016/j.intimp.2025.114656] [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: 02/13/2025] [Revised: 03/28/2025] [Accepted: 04/08/2025] [Indexed: 04/17/2025]
Abstract
Temozolomide (TMZ) chemoresistance is a major challenge in the management of glioblastoma (GBM). Marine-derived fungal metabolites are a significant source of potential chemotherapeutic candidates. This study aimed to investigate the cytotoxic effect of MHO7 (6-epi-ophiobolin G) on GBM cells. MHO7 inhibited GBM cell proliferation and promoted apoptosis, accompanied by a reduction in Akt activity and membrane phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) content. We verified that MHO7 could react with phosphatidylethanolamine (PE), the second most abundant phospholipid in the plasma membrane, to form a covalent adduct. Pre-incubation with exogenous PE significantly alleviated the pro-apoptotic effect of MHO7, with a concomitant increase in Akt activity and membrane PIP2 and PIP3 content. Since binding to PIP3 is a key step in Akt activation, our results indicate that MHO7 can function as a novel Akt inhibitor. Additionally, MHO7 has a synergistic pro-apoptotic effect with TMZ, and TMZ-resistant GBM cells remain sensitive to MHO7. MHO7 had little cytotoxicity against normal neuronal cells. The anti-growth effect of MHO7 was also observed in an orthotopic glioma mice model. Therefore, MHO7 is a promising chemotherapeutic agent for GBM. This study also indicated that membrane lipid-targeted therapy may be a novel and effective strategy for tumor treatment.
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Affiliation(s)
- Yi Wang
- Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Dong-Hu Yu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wei Quan
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Tian Lan
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Feng Tang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chao Ma
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhi-Qiang Li
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Kui Hong
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
| | - Ze-Fen Wang
- Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
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21
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Gao M, Cheng Z, Yan W, Zhang Z, Zhang L, Geng H, Xu Y, Li C. Tyrosine kinase inhibitors induce cardiotoxicity by causing Ca 2+ overload through the inhibition of phosphoinositide 3-kinase activity. Biochem Biophys Res Commun 2025; 771:152027. [PMID: 40403685 DOI: 10.1016/j.bbrc.2025.152027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/24/2025] [Accepted: 05/14/2025] [Indexed: 05/24/2025]
Abstract
BACKGROUND Tyrosine kinase inhibitors (TKIs) are commonly used in cancer treatment, but their off-target effects can lead to serious cardiotoxicity. Our previous studies have revealed that upregulation of phosphoinositide 3-kinase (PI3K) confers considerable protection against calcium (Ca2+) disorders and cardiac dysfunction induced by sunitinib. However, the involvement of PI3K inhibition in the prevention of cardiomyocyte contraction induced by other TKIs remains unclear. METHODS Herein, we selected three TKIs with different targets and mechanisms, namely, sunitinib, imatinib, and trametinib, and assessed their myocardial toxicity, PI3K activity, and Ca2+ regulation in AC16 cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). RESULTS All three TKIs induced AC16 cell damage and reduced PI3K expression. These drugs also caused hiPSC-CM injury, increased reactive oxygen species (ROS) release, induced cytoplasmic Ca2+ overload, and inhibited cell contraction. Phosphatidylinositol (3,4,5)-trisphosphate pretreatment and adenovirus-mediated p110α overexpression activated PI3K, prevented TKI-induced Ca2+ overload and ROS release, and reduced TKI-induced myocardial injury and contraction inhibition. CONCLUSIONS All three TKIs induced cardiotoxicity by inhibiting PI3K activity.
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Affiliation(s)
- Meiling Gao
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China; Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China
| | - Zhiling Cheng
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China; Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China
| | - Wei Yan
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China
| | - Zhihan Zhang
- Department of Nutrition, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ling Zhang
- Department of Pharmacy, Hebei Chest Hospital, Shijiazhuang, Hebei, China
| | - Hui Geng
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China
| | - Yanfang Xu
- Hebei Medical University, No. 361 Zhongshan East Road, Chang'an District, Shijiazhuang, Hebei, China.
| | - Congxin Li
- Department of Pharmacy, Hebei Medical University Third Hospital, No. 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, Hebei, China.
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22
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Sahm F, Bertero L, Brandner S, Capper D, Goldbrunner R, Jenkinson MD, Kalamarides M, Lamszus K, Albert NL, Mair MJ, Berghoff AS, Mawrin C, Wirsching HG, Maas SLN, Raleigh DR, Reifenberger G, Schweizer L, Suwala AK, Tabatabai G, Tabouret E, Short S, Wen PY, Weller M, Le Rhun E, Wesseling P, van den Bent M, Preusser M. European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection. Neuro Oncol 2025; 27:869-883. [PMID: 39577862 PMCID: PMC12083233 DOI: 10.1093/neuonc/noae253] [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: 08/25/2024] [Indexed: 11/24/2024] Open
Abstract
Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.
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Affiliation(s)
- Felix Sahm
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg Gemany and CCU Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Luca Bertero
- Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sebastian Brandner
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and Division of Neuropathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David Capper
- German Cancer Consortium (DKTK), partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Roland Goldbrunner
- Department of Neurosurgery, University Hospital Cologne, Cologne, Germany
| | - Michael D Jenkinson
- Department of Neurosurgery, University of Liverpool and Walton Centre, Liverpool, UK
| | - Michel Kalamarides
- Department of Neurosurgery, Pitie-Salpetriere Hospital, AP-HP Sorbonne Université, Paris, France
| | - Katrin Lamszus
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nathalie L Albert
- Department of Nuclear Medicine, LMU Hospital, LMU Munich, Munich, Germany
| | - Maximilian J Mair
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
- Department of Nuclear Medicine, LMU Hospital, LMU Munich, Munich, Germany
| | - Anna S Berghoff
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Christian Mawrin
- Department of Neuropathology, University Hospital Magdeburg, Magdeburg, Germany
| | - Hans-Georg Wirsching
- Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Sybren L N Maas
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
| | - David R Raleigh
- Departments of Radiation Oncology, Neurological Surgery, and Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Guido Reifenberger
- Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
| | - Leonille Schweizer
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | - Abigail K Suwala
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg Gemany and CCU Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Ghazaleh Tabatabai
- Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, DKTK partner site Tübingen, University of Tübingen, Germany
| | - Emeline Tabouret
- Aix-Marseille Universite, APHM, CNRS, INP, Institut Neurophysiopathol, GlioME Team, Plateforme PETRA, CHU Timone, Service de Neurooncologie, Marseille, France
| | - Susan Short
- Department of Oncology, Leeds Institute of Medical Research at St James’s Hospital, Leeds, UK
| | - Patrick Y Wen
- Center For Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Michael Weller
- Department of Neurology, Brain Tumor Center & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Emilie Le Rhun
- Department of Medical Oncology and Hematology, Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Pieter Wesseling
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands
| | - Martin van den Bent
- The Brain Tumor Center at Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Zhou Y, Wang F, Feng S, Li M, Zhu M. USP39 promote post-translational modifiers to stimulate the progress of cancer. Discov Oncol 2025; 16:749. [PMID: 40358671 PMCID: PMC12075731 DOI: 10.1007/s12672-025-02573-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
Deubiquitinating enzymes (DUBs) are a class of crucial peptidyl hydrolases within the ubiquitin system, playing a significant role in reversing and strictly regulating ubiquitination, which is essential for various biological processes such as protein stability and cellular signal transduction. Ubiquitin-specific protease 39 (USP39) is an important member of the DUBs family. Recent studies have revealed that USP39 is involved in the regulation of multiple cellular activities including cell proliferation, migration, invasion, apoptosis, and DNA damage repair. USP39 also plays a significant role in the development and progression of various cancers. It is believed that USP39 is a unique enzyme that controls the ubiquitin process and is closely associated with the occurrence and progression of many cancers, including hepatocellular, lung, gastric, breast, and ovarian cancer. This review summarizes the structural and functional aspects of USP39 and its research advancements in tumors, investigates the key molecular mechanisms related to USP39, and provides references for tumor diagnosis and treatment.
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Affiliation(s)
- Yuli Zhou
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Fang Wang
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Siren Feng
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Mengsen Li
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570216, China.
| | - Mingyue Zhu
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
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24
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Tyrakis PA, Kampjut D, Steele GF, Lindström HJG, Chirnomas D, Hopkins BD, Goncalves MD, Mukherjee S, Cantley LC, Maddocks ODK. Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models. Br J Cancer 2025:10.1038/s41416-025-03035-z. [PMID: 40360883 DOI: 10.1038/s41416-025-03035-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 04/11/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND While PI3K/AKT/mTOR signalling plays a critical role in cancer, targeting this pathway with single node inhibitors has limited efficacy due to several known factors such as pathway feedback reactivation, co-occurring pathway mutations, and systemic glucose dysregulation leading to hyperinsulinemia. While multi-node inhibition approaches have shown promising clinical efficacy, they require further mechanistic characterisation. METHODS Using models of endometrial and breast cancer, we evaluated the efficacy of a multi-node PI3K/AKT/mTOR pathway inhibitor approach utilising the dual mTORC1/mTORC2 inhibitor sapanisertib, PI3Kα inhibitor serabelisib and an insulin-supressing diet. Pathway signalling inhibition versus a range of single-node inhibitors was measured via S6, AKT and 4E-BP1 phosphorylation. RESULTS The serabelisib-sapanisertib combination more effectively suppressed PI3K/AKT/mTOR pathway signalling, particularly 4E-BP1, than single-node inhibitors, including alpelisib, capivasertib, inavolisib, everolimus and mutant-specific PI3K inhibitors RLY-2608 and STX-478. Serabelisib plus sapanisertib combined effectively with a range of other therapeutics, such as chemotherapies, hormone targeted therapies and CDK4/6 inhibitors. In xenograft models, sapanisertib, serabelisib plus paclitaxel/insulin supressing diet achieved complete inhibition of tumour growth/tumour regression. CONCLUSION Multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast cancer, supporting continued clinical development in these and other solid tumours.
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Affiliation(s)
- Petros A Tyrakis
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Domen Kampjut
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Georgina F Steele
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - H Jonathan G Lindström
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Deborah Chirnomas
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Benjamin D Hopkins
- Englander Institute for Precision Medicine, Meyer Cancer Center, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | | | - Siddhartha Mukherjee
- Department of Medicine, Columbia University Irving Cancer Research Center, Columbia University, New York, NY, 10032, USA
| | - Lewis C Cantley
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Oliver D K Maddocks
- Faeth Therapeutics R&D, CRUK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
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25
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Liu L, Wuyun T, Sun X, Zhang Y, Cha G, Zhao L. Therapeutic efficacy of TMTP1-modified EVs in overcoming bone metastasis and immune resistance in PIK3CA mutant NSCLC. Cell Death Dis 2025; 16:367. [PMID: 40328748 PMCID: PMC12055990 DOI: 10.1038/s41419-025-07685-y] [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: 10/20/2024] [Revised: 04/08/2025] [Accepted: 04/17/2025] [Indexed: 05/08/2025]
Abstract
Non-small cell lung cancer (NSCLC) with PIK3CA mutations demonstrates significant challenges in treatment due to enhanced bone metastasis and immune checkpoint resistance. This study investigates the efficacy of tumor-targeting peptide 1-modified cancer stem cell-derived extracellular vesicles (TMTP1-TSRP-EVs) in reshaping the tumor microenvironment and reversing immune checkpoint resistance in NSCLC. By integrating TMTP1-TSRP into EVs, we aim to specifically deliver therapeutic agents to NSCLC cells, focusing on inhibiting the PI3K/Akt/mTOR pathway, a crucial driver of oncogenic activity and immune evasion in PIK3CA-mutated cells. Our comprehensive in vitro and in vivo analyses show that TMTP1-TSRP-EVs significantly inhibit tumor growth, reduce PD-L1 expression, and enhance CD8+ T cell infiltration, effectively reversing the immune-suppressive microenvironment. Moreover, the in vivo models confirm that our approach not only suppresses bone metastases but also overcomes primary resistance to immune checkpoint inhibitors by modulating the expression of key immunological markers. These findings suggest that targeted delivery of TMTP1-TSRP-EVs could provide a novel therapeutic strategy for treating PIK3CA-mutant NSCLC, offering significant improvements over traditional therapies by directly targeting the molecular pathogenesis of tumor resistance and metastasis. Molecular Mechanisms Reshaping the TME to Halt PI3K-Mutant Bone Metastasis of NSCLC and Overcoming Primary ICI Resistance. (Created by BioRender).
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Affiliation(s)
- Liwen Liu
- Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tanghesi Wuyun
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Sun
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Zhang
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Geqi Cha
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ling Zhao
- The Second Department of Respiratory, Harbin Medical University Cancer Hospital, Harbin, China.
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26
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Cartwright D, Kidd AC, Ansel S, Ascierto ML, Spiliopoulou P. Oncogenic Signalling Pathways in Cancer Immunotherapy: Leader or Follower in This Delicate Dance? Int J Mol Sci 2025; 26:4393. [PMID: 40362630 PMCID: PMC12072740 DOI: 10.3390/ijms26094393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/01/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.
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Affiliation(s)
- Douglas Cartwright
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Andrew C. Kidd
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Sonam Ansel
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Maria Libera Ascierto
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
| | - Pavlina Spiliopoulou
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; (D.C.); (A.C.K.); (S.A.); (M.L.A.)
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
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Tiwari V, Kamboj A, Sheoran B, Chaudhary E, Yadav M, Kumari A, Krishania M, Ali U, Tiwari A, Garg M, Bhatnagar A. Anthocyanin-rich black wheat as a functional food for managing type 2 diabetes mellitus: a study on high fat diet-streptozotocin-induced diabetic rats. Food Funct 2025; 16:3273-3295. [PMID: 39688703 DOI: 10.1039/d4fo05065g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Background: Type 2 Diabetes Mellitus (T2DM) is associated with insulin resistance, hyperglycemia, and hyperlipidemia. Anthocyanins, which are natural antioxidants, have been reported to manage T2DM-related complications. However, the potential of anthocyanin-rich black wheat as a functional food for managing diabetes remains unexplored. Aim: This study aimed to investigate the effects of anthocyanin-rich black wheat on glucose metabolism, insulin sensitivity, lipid profile, oxidative stress, inflammation, and organ protection in high fat diet-streptozotocin (HFD-STZ) induced T2DM rats. Methods: T2DM was induced in rats using HFD-STZ. The rats were fed with either white wheat or anthocyanin-rich black wheat chapatti. Glucose metabolism, insulin sensitivity, lipid profile, antioxidant enzymes, inflammatory markers, and glucose transporters were assessed. Histopathological analysis of the liver, kidneys, and spleen was performed. Results: Compared to white wheat chapatti, black wheat chapatti exhibited higher α-amylase and α-glucosidase inhibitory activities. Black wheat chapatti consumption significantly reduced blood glucose and HbA1c levels, and improved insulin sensitivity, oral glucose tolerance, and insulin tolerance. Antioxidant enzyme (superoxide dismutase and catalase) activities were enhanced. Atherogenic dyslipidemia was attenuated, with improved high-density lipoprotein cholesterol levels. Inflammatory markers (TNF-α, IL-1β, leptin, resistin and cortisol) were reduced, while adiponectin (Acrp-30) levels increased. Black wheat chapatti activated adiponectin-AMPK and PI3K-AKT pathways, upregulating glucose transporters (GLUT-2 and GLUT-4). Histopathology revealed protective effects on the liver, kidneys, and spleen. Conclusions: Anthocyanin-rich black wheat chapatti ameliorates insulin resistance and associated complications in HFD-STZ-induced T2DM rats. It modulates key signaling pathways and glucose transporters, demonstrating its potential as a functional food for managing T2DM and its complications.
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Affiliation(s)
- Vandita Tiwari
- Department of Biochemistry, Panjab University, Chandigarh, India
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Akhil Kamboj
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Bhawna Sheoran
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
- Regional Centre for Biotechnology, Faridabad, Haryana (NCR), Delhi, India
| | - Era Chaudhary
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
- Regional Centre for Biotechnology, Faridabad, Haryana (NCR), Delhi, India
| | - Mona Yadav
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
- Regional Centre for Biotechnology, Faridabad, Haryana (NCR), Delhi, India
| | - Anita Kumari
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Meena Krishania
- Center of Innovative and Applied Bioprocessing, Mohali, Punjab, India
| | - Usman Ali
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Apoorv Tiwari
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
| | - Monika Garg
- National Agri-Food Biotechnology Institute (NABI), Mohali, Punjab, India.
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Yan H, Zhao L, He K, Liu H, Zhang C, Liu Q, Song K, Yang H, Xu T, Yang S. EPO Enhances Adaptation to Hypoxic Environment in the Freshwater Teleost ( Micropterus salmoides) through the PI3K/AKT Pathway. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:8402-8416. [PMID: 40239033 DOI: 10.1021/acs.est.5c00093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
Hypoxia has become one of the most common environmental stress events in the life history of aquatic organisms due to accelerated global warming. Exploring the adaptation mechanisms of aquatic organisms in hypoxic environments is important to deepen our understanding of environmental toxicology and to design breeding programs. In this study, the largemouth bass Micropterus salmoides exhibited greater hypoxic adaptability after 4 weeks of intermittent hypoxic exposure (IHE), with the O2 tension for loss of equilibrium decreased from 1.17 ± 0.20 to 0.66 ± 0.10 mg/L. Combined transcriptomics, biochemical detection, and immunostaining results revealed that the hypoxia-tolerant phenotype driven by IHE was strongly correlated with the activation of erythropoietin (EPO). EPO promoted phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling to alleviate hepatic damage under acute hypoxic exposure (AHE) by selectively regulating the expression of genes related to antioxidant defense, antiapoptosis, and cell proliferation, which plays an important role in regulating hypoxic adaptation. The inhibition of EPO impaired cell survival in hypoxic environments, but intervention with the PI3K agonist 740 Y-P reversed this process. This novel finding provides insights into exploring how aquatic organisms cope with the challenges of hypoxia under increasing environmental risks.
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Affiliation(s)
- Haoxiao Yan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Liulan Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Kuo He
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Hao Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Chengxian Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Qiao Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Kaige Song
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Hangyu Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Tianjun Xu
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Song Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
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Fang X, Li J, Pang H, Zheng H, Shi X, Feng L, Hu K, Zhou T. Xingxiao pills suppresses lung adenocarcinoma progression by modulating lipid metabolism and inhibiting the PLA2G4A-GLI1-SOX2 Axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156826. [PMID: 40339555 DOI: 10.1016/j.phymed.2025.156826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/20/2025] [Accepted: 05/02/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality due to resistance, metastasis, and recurrence. Unlike conventional cytotoxic therapies, Xingxiao Pills (XXP), a classic traditional Chinese medicine formula, offers a complementary approach to treating LUAD, while its non-cytotoxic anti-cancer mechanisms remain unclear. PURPOSE To investigate the effect and mechanism of XXP on LUAD progression and stemness via lipid metabolism regulation. METHOD UHPLC-MS/MS was used to analyze the chemical constituents of XXP. The effects of XXP on LUAD cell proliferation, migration, invasion, and stemness were evaluated using CCK-8, Transwell, and tumor sphere assays. A LUAD xenograft model confirmed XXP's anti-tumor effects. Transcriptomics, metabolomics, ELISA, qRT-PCR, and Western blot were used to investigate the underlying mechanisms. Kaplan-Meier (KM) survival analysis and stemness index scores were performed for LUAD patients based on the TCGA dataset. Statistical analyses were performed using Student's t-test, ANOVA, and KM survival analysis (p< 0.05 considered significant). RESULTS XXP inhibits LUAD progression in mouse and cell models by targeting lipid metabolism reprogramming. It suppresses FA synthesis, elongation, oxidation, and glycerophospholipid (GPL) metabolism while upregulating arachidonic acid (AA) metabolism. Mechanistic studies revealed that XXP attenuates tumor stemness by inhibiting PLA2G4A (cPLA2), lowering AA release, and disrupting SMO/GLI1/SOX2 signaling, an effect also observed with the cPLA2 inhibitor AACOCF3. KM analysis showed that higher PLA2G4A expression correlated with a worse 5-year prognosis in LUAD (p = 0.0047). The low GPL/high AA group (consistent with XXP's metabolic pattern) had better survival (p = 0.0028) and a lower stemness index (p< 0.0001) than the high GPL/low AA unrelated group. CONCLUSION Xingxiao Pill modulates GPL and AA metabolism and downregulates the PLA2G4A (cPLA2)-AA/SMO/GLI1/SOX2 axis. Through this mechanism, XXP effectively inhibits tumor growth and stemness by targeting lipid metabolism.
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Affiliation(s)
- Xueni Fang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - JingHua Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - HaoYue Pang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hao Zheng
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiang Shi
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Kaiwen Hu
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
| | - Tian Zhou
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
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30
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Zhou Y, Zhang X, Yin H. A Site-Specific Photo-Crosslinking Proteomics Approach Provides Insights into Noncanonical Pyroptotic Caspase-4 Substrates. Angew Chem Int Ed Engl 2025; 64:e202501535. [PMID: 40070324 DOI: 10.1002/anie.202501535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 03/09/2025] [Accepted: 03/11/2025] [Indexed: 03/26/2025]
Abstract
Inflammatory caspases (1/4/5) are key effectors in the process of pyroptosis by cleaving and activating the pore-forming protein gasdermin D (GSDMD). Unlike other caspases whose substrates have been well characterized, the substrates for caspase-4, which mediate noncanonical pyroptosis, remain poorly understood. Here, we combined noncanonical amino acids, photo-crosslinking, and proteomics to profile caspase-4 substrates, enabling the capture of transient protein interactions with activated caspase-4. A set of new substrates were identified by photo-crosslinking mass spectrometry, revealing the signaling pathway and biological process affected by pyroptosis. Notably, we found that AKT1 is cleaved at D108, which removes its autoinhibition and membrane localization domain, resulting in the release of activated AKT1. Our results also showed the precursor of caspase-5/12 could be cleaved by caspase-4 to form the p20/p10 active conformation, uncovering a previously unrecognized pyroptotic caspase cascade. Overall, this study presents an approach for identifying caspase-4 substrates and offers further understanding of noncanonical pyroptosis.
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Affiliation(s)
- Yi Zhou
- Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xinyu Zhang
- Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Hang Yin
- Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
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31
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Li Y, Sun Y, Yu K, Li Z, Miao H, Xiao W. Keratin: A potential driver of tumor metastasis. Int J Biol Macromol 2025; 307:141752. [PMID: 40049479 DOI: 10.1016/j.ijbiomac.2025.141752] [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: 10/08/2024] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/19/2025]
Abstract
Keratins, as essential components of intermediate filaments in epithelial cells, play a crucial role in maintaining cell structure and function. In various malignant epithelial tumors, abnormal keratin expression is frequently observed and serves not only as a diagnostic marker but also closely correlates with tumor progression. Extensive research has demonstrated that keratins are pivotal in multiple stages of tumor metastasis, including responding to mechanical forces, evading the immune system, reprogramming metabolism, promoting angiogenesis, and resisting apoptosis. Here we emphasize that keratins significantly enhance the migratory and invasive capabilities of tumor cells, making them critical drivers of tumor metastasis. These findings highlight the importance of targeting keratins as a strategic approach to combat tumor metastasis, thereby advancing our understanding of their role in cancer progression and offering new therapeutic opportunities.
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Affiliation(s)
- Yuening Li
- Army Medical University, Chongqing, China
| | - Yiming Sun
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Kun Yu
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Zhixi Li
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
| | - Hongming Miao
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China; Jinfeng Laboratory, Chongqing, China.
| | - Weidong Xiao
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
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Alharbi S, Merkle S, Hammill AM, Waters AM, Le Cras TD. RAS Pathway Mutations and Therapeutics in Vascular Anomalies. Pediatr Blood Cancer 2025; 72:e31605. [PMID: 39984187 DOI: 10.1002/pbc.31605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/30/2024] [Accepted: 02/02/2025] [Indexed: 02/23/2025]
Abstract
Vascular anomalies (VAs) are a diverse group of vascular tumors and vascular malformations (VMs). VMs are characterized by abnormal vessel development, overgrowth, and dysfunction. Coagulopathy, edema, and effusions can cause severe morbidity and mortality in children and adults with these diseases. Germline or somatic mutations in the RAS/RAF/MAPK pathway have been identified in multiple types of VAs. RAS genes (KRAS, NRAS, and HRAS) are small GTPase proteins that play an important role in normal development and cell function. In healthy cells, RAS proteins cycle between GDP (inactive) and GTP (active) states that regulate important functions such as proliferation, migration, and survival. "Hot spot" mutations in codons 12, 13, or 61 of RAS genes are found in multiple tumor types and VAs. RAS mutations often cause excessive MAP kinase signaling, driving unchecked cell proliferation. In this review, we discuss the different RAS pathway mutations discovered in VAs and the role that these may play using insights from cell and animal models. Current therapies targeting RAS pathways are presented. In the future, a better understanding of the role of RAS pathway mutations may advance therapeutic strategies for people with VAs.
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Affiliation(s)
- Sara Alharbi
- Cancer and Cell Biology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Svatava Merkle
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Adrienne M Hammill
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Andrew M Waters
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Timothy D Le Cras
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Zhang ZL, Xu HN, Gong CM, Li YZ, Song XM, Li YM, Zhang DD, Wang R. Microorganism-Derived Bisindole Alkaloids With Anticancer Potential and Their Mechanisms: A Comprehensive Review. Chem Biodivers 2025; 22:e202402398. [PMID: 39714457 DOI: 10.1002/cbdv.202402398] [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: 09/23/2024] [Revised: 12/12/2024] [Accepted: 12/20/2024] [Indexed: 12/24/2024]
Abstract
Bisindole alkaloids constitute a significant class of natural compounds distinguished by their characteristic bisindole structure and renowned for their anticancer properties. Over the last six decades, researchers have isolated 425 microorganism-derived bisindole alkaloids (MDBAs). Among them, 187 MDBAs have demonstrated anticancer properties against various in vitro cancer cell lines, primarily by impeding the cell cycle, restraining cell proliferation, and inducing apoptosis and autophagy. These effects are mediated by regulating key targets and signaling pathways such as hypoxia-inducible factor (HIF)-1, MAPK, and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR. This review provides a comprehensive examination of the sources, chemical diversity, and anticancer properties of these compounds. Furthermore, it summarizes the structure-activity relationship (SAR), druggability, and the mechanisms underlying MDBAs' anticancer effects. Ultimately, this article aims to furnish a thorough overview of the advancements in the investigation of microorganism-derived bisindole alkaloids for their continued development and utilization.
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Affiliation(s)
- Zi-Long Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Hao-Nan Xu
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Chuan-Ming Gong
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Yu-Ze Li
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Xiao-Mei Song
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Yi-Ming Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Dong-Dong Zhang
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Rui Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
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Kamiki J, Gorgulho CM, Lérias JR, Maeurer MJ. Mucosal-associated invariant T-cells in pulmonary pathophysiology. Curr Opin Pulm Med 2025; 31:202-210. [PMID: 40104908 PMCID: PMC11957436 DOI: 10.1097/mcp.0000000000001163] [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] [Indexed: 03/20/2025]
Abstract
PURPOSE OF REVIEW Mucosal-associated invariant T-cells (MAIT) have been associated with lung cancer and pulmonary infections. The treatment of patients with cancer or infections includes host-directed therapies (HDTs). MAIT play a role in shaping the 'milieu interne' in cancer and infections and this review addresses the biology of MAIT in pulmonary pathophysiology. RECENT FINDINGS MAIT represent an attractive target for therapy in pulmonary malignancies and infections. T-cells are often difficult to exploit therapeutically due to the diversity of both T-cell receptor (TCR) repertoire and its ligandome. MAIT-cells are restricted by the major histocompatibility complex class I-related gene protein (MR1) that presents nondefined tumor-associated targets, bacterial products, vitamin and drug derivates. Due to their plasticity in gene expression, MAIT are able to conversely switch from IFN-γ to IL-17 production. Both cytokines play a key role in protective immune responses in infections and malignancies. MAIT-derived production of interleukin (IL)-17/TGF-β shapes the tumor micro-environment (TME), including tissue re-modelling leading to pulmonary fibrosis and recruitment of neutrophils. MAIT contribute to the gut-lung axis associated with clinical improved responses of patients with cancer to checkpoint inhibition therapy. MAIT are at the crossroad of HDTs targeting malignant and infected cells. Clinical presentations of overt inflammation, protective immune responses and tissue re-modeling are reviewed along the balance between Th1, Th2, Th9, and Th17 responses associated with immune-suppression or protective immune responses in infections. SUMMARY MAIT shape the TME in pulmonary malignancies and infections. Drugs targeting the TME and HDTs affect MAIT that can be explored to achieve improved clinical results while curbing overt tissue-damaging immune responses.
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Affiliation(s)
- Jéssica Kamiki
- ImmunoTherapy/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Lisbon, Portugal
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35
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Wang Z, Wang S, Liu Y, Wang X, Li W, Qi H, You H. 6PPD induces apoptosis and autophagy in SH-SY5Y cells via ROS-mediated PI3K/AKT/mTOR pathway: In vitro and in silico approaches. Toxicology 2025; 513:154091. [PMID: 39983890 DOI: 10.1016/j.tox.2025.154091] [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: 11/21/2024] [Revised: 02/04/2025] [Accepted: 02/16/2025] [Indexed: 02/23/2025]
Abstract
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), an extensively employed antioxidant in rubber materials, is considered as an emerging contaminant. 6PPD was proven to have potential neurotoxicity, which poses risks to human health. However, the research on its neurotoxicity is still limited. This work explored the neurotoxicity of 6PPD to SH-SY5Y cells and in-depth mechanisms with a combination of in vitro and in silico approaches. Our results indicated that 6PPD could reduce cell viability and cause oxidative damage by increasing reactive oxygen species (ROS) accumulation and altering the levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). 6PPD induced neuronal apoptosis of mitochondrial pathway and autophagy dysfunction, as characterized by the increased expressions of Cleaved caspase-3, Bax/Bcl-2, Beclin-1, LC3-II/I, and P62. 6PPD downregulated the expression of PI3K, p-AKT, and p-mTOR, while the PI3K inhibitor suppressed PI3K/AKT/mTOR pathway and promoted both apoptosis and autophagy, indicating that PI3K/AKT/mTOR pathway was involved in 6PPD-induced apoptosis and autophagy. The inhibition of this pathway was attributed to ROS accumulation in SH-SY5Y cells. Molecular docking analysis further revealed that 6PPD exhibits strong binding affinity to PI3K, AKT, and mTOR protein molecules, which could effectively interfere with downstream signaling pathways. These findings enrich the understanding of 6PPD-induced neurotoxicity and contribute to the evaluation of ecological risks associated with 6PPD.
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Affiliation(s)
- Ziwei Wang
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Shutao Wang
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China.
| | - Yingying Liu
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Xingyu Wang
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Wanlun Li
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Hong Qi
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
| | - Hou You
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, China
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Che X, Shang X, WeiXu, Xing M, Wei H, Li W, Li Z, Teng X, Geng L. Selenium-enriched Lactiplantibacillus plantarum alleviates alkalinity stress-induced selective hepatic insulin resistance in common carp. Int J Biol Macromol 2025; 305:141204. [PMID: 39986514 DOI: 10.1016/j.ijbiomac.2025.141204] [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: 10/08/2024] [Revised: 11/18/2024] [Accepted: 02/15/2025] [Indexed: 02/24/2025]
Abstract
Carbonate alkalinity is one of the primary factors limiting saline-alkaline water aquaculture, and high alkalinity can lead to respiratory alkalosis, which is hazardous to fish health. Selenium (Se) and Lactiplantibacillus plantarum (L. plantarum) can be used for the biosynthesis of organic selenium (selenium-enriched Lactiplantibacillus plantarum: SL), which has low toxicity, high bioavailability, and the promotion of metabolism. Additionally, it can be used as a feed additive in aquaculture. In the present study, we established a model of chronic alkalinity stress in common carp and added SL to the feed. We found that alkalinity stress can cause severe hepatic dysfunction in common carp, as well as disrupt the intestinal barrier, further contributing to the translocation of enterogenous lipopolysaccharides through portal circulation and exacerbating liver injury. SL alleviated glucose-lipid metabolism abnormalities of the liver while reducing serum LPS levels and reduction of enterogenous LPS translocation to the liver, thus significantly reducing the degree of intestinal villi damage, hepatocyte vacuolisation, and nuclear damage. The significantly increased activities of SOD, GSH-Px, CAT, and T-AOC revealed that SL improved the antioxidant capacity of common carp. SL inhibited the alkalinity stress-induced overexpression of genes related to lipid synthesis and gluconeogenesis by modulating the P13K/Akt/FoxO1 signalling pathway, thus alleviating selective hepatic insulin resistance. SL attenuated the inflammatory response by modulating the mRNA expression levels of IL-7, IL-6, TNF-α and IL-10. In addition, apparent increase in the abundance of pathogenic bacteria (Brevinema, Bosea, Luteolibacter, and Vibrio) and apparent reduction in the abundance of beneficial bacteria (Cetobacterium, ZOR0006, and Shewanella) were closely related to the hepato-intestinal circulation process in carp exposed to alkalinity stress. SL regulated the hepato-intestinal circulation, reduced the abundance of Brevinema, Bosea, Luteolibacter, and Vibrio, increased the abundance of Cetobacterium, ZOR0006, and Shewanella, alleviated alkalinity stress-induced damage to intestinal microvilli (villus height and width), and significantly restored normal liver and intestinal functions. This study reveals the physiological regulatory mechanism by which Se-enriched L. plantarum through liver-intestinal axis alleviates alkalinity stress-induced hepatic insulin resistance and may provide new ideas and a theoretical basis for protecting against alkalosis and treating insulin resistance.
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Affiliation(s)
- Xinghua Che
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Xinchi Shang
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China; College of Life Science, Northeast Agricultural University, Harbin 150036, China
| | - WeiXu
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Meiqi Xing
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Haiju Wei
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Wang Li
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
| | - Zhengwei Li
- Fisheries Technology Extension Station of Heilongjiang Province, Daqing 166299, China
| | - Xiaohua Teng
- College of Life Science, Northeast Agricultural University, Harbin 150036, China.
| | - Longwu Geng
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
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Lynch EB, Kapur N, Goretsky T, Bradford EM, Vekaria H, Bhogoju S, Hassan SA, Pauw E, Avdiushko MG, Lee G, Gao T, Sullivan PG, Barrett TA. Phosphatidylinositol 3-Kinase Signaling Enhances Intestinal Crypt Epithelial Cell Recovery after Radiation. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00151-8. [PMID: 40316215 DOI: 10.1016/j.ajpath.2025.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/24/2025] [Accepted: 04/10/2025] [Indexed: 05/04/2025]
Abstract
Intestinal stem cell (ISC) signaling maintains the balance of self-renewal and differentiation. The role of phosphatidylinositol 3-kinase (PI3K) signaling in ISC responses to radiation was interrogated using Villin-Cre pik3r1lox/lox (p85ΔIEC) mice and p85α-deficient human enteroids (shp85α). Lethal whole-body irradiation in mice was performed to monitor PI3K-mediated survival responses. Rectal biopsies from patients with radiation proctitis were examined by immunohistochemistry for the PI3K/Akt- and Wnt-target survivin. The intestinal epithelial cells (IECs) from p85ΔIEC mice showed increased protein levels of phosphorylated phosphatase and tensin homolog, phosphorylated AktSer473, survivin, cyclin D1, and ρ-β-cateninSer552, as well as increased mRNA for ISC/progenitor cell. In situ hybridization showed that enhanced PI3K signaling reduced Lgr5+ cells but expansion of Axin2+ cells. The shp85α enteroids showed increased mRNA expression of Wnt targets and transcription factor ASCL2, needed for dedifferentiation-mediated restoration of ablated ISCs. The p85α-deficient enteroids showed reduced HES1 mRNA and increases in secretory (ATOH1/MATH1) signaling determinants GFI1 and SPDEF, indicative of reduced NOTCH signaling. Seahorse analyses and phosphorylated p38 staining in IECΔp85 mice indicated that enhanced PI3K signaling led to increased IEC mitochondrial respiration and reactive oxygen species generation. Expression of survivin correlated with the radiation injury in patients. The current data indicate that PI3K signaling increases mitochondrial reactive oxygen species generation and ISC activation that improves IEC recovery from radiation-induced injury. The results suggest that increasing PI3K signaling and induced mitochondrial respiration may improve mucosal healing from radiation injury in patients.
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Affiliation(s)
- Evan B Lynch
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky; Division of Plastic Surgery, Department of Surgery, University of Kentucky, Lexington, Kentucky; Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Neeraj Kapur
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Tatiana Goretsky
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Emily M Bradford
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Hemendra Vekaria
- Lexington VA Healthcare System, Lexington, Kentucky; Department of Neuroscience, University of Kentucky, Lexington, Kentucky
| | - Sarayu Bhogoju
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Syed A Hassan
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Emily Pauw
- College of Medicine, University of Kentucky, Lexington, Kentucky
| | - Margarita G Avdiushko
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Goo Lee
- The University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, Alabama
| | - Tianyan Gao
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky
| | - Patrick G Sullivan
- Lexington VA Healthcare System, Lexington, Kentucky; Department of Neuroscience, University of Kentucky, Lexington, Kentucky
| | - Terrence A Barrett
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky.
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Esposto MP, Mahlaoui N, Abolhassani H, Van Aerde K, Cesaro S, Chandra A, Ehl S, Kracker S, Suarez F, Barlogis V, Parisi A, Maccari ME, Chinello M. Case Report: Activated PI3-kinase-δ syndrome and ovarian malignancies: a case series from the European ESID-APDS registry. Front Immunol 2025; 16:1572194. [PMID: 40370432 PMCID: PMC12075536 DOI: 10.3389/fimmu.2025.1572194] [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: 02/06/2025] [Accepted: 04/07/2025] [Indexed: 05/16/2025] Open
Abstract
Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.
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Affiliation(s)
- Maria Pia Esposto
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Nizar Mahlaoui
- Pediatric Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Hassan Abolhassani
- Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Koen Van Aerde
- Department of pediatric infectious disease and immunology, Amalia Children’s Hospital, Radboudumc, Nijmegen, Netherlands
| | - Simone Cesaro
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Anita Chandra
- Department of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Stephan Ehl
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sven Kracker
- Laboratory of Lymphocyte Activation and Susceptibility to Epstein Barr Virus (EBV) infection, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France
| | - Felipe Suarez
- Université Paris Cité, Inserm U-1163, Institut Imagine, Laboratoire of Hematological Disorders, Paris, France
- Service d’Hématologie Adulte and Centre de référence des déficits immunitaires héréditaires (CEREDIH), AP-HP, Hôpital Necker-Enfants Malades, Paris, France
| | - Vincent Barlogis
- Department of Pediatric Hematology, Immunology and Oncology, APHM, Hôpital de la Timone Enfants, Marseille, France
- CEReSS Research Unit EA 3279 and Department of Public Health, Aix Marseille University, School of Medicine, Marseille, France
- Aix Marseille University, School of Medicine, Marseille, France
| | - Alice Parisi
- Department of Pathological Anatomy, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Maria Elena Maccari
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children’s Hospital, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Matteo Chinello
- Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
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39
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Ge H, Guo N, Liu Y, Lang B, Yin X, Yu X, Zhang Z, Fu Y, Ding H, Hu Q, Han X, Geng W, Shang H, Jiang Y. The inhibitory receptor LAG3 affects NK cell IFN-γ production through glycolysis and the PSAT1/STAT1/IFNG pathway. mBio 2025:e0023025. [PMID: 40298450 DOI: 10.1128/mbio.00230-25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 02/26/2025] [Indexed: 04/30/2025] Open
Abstract
Natural killer (NK) cells are integral to the innate immune system and crucial for antiviral defense. NK cell activation and functional state are suppressed by inhibitory receptors. Lymphocyte activation gene 3 (LAG3) is an important inhibitory receptor, but the associated signaling pathways that regulate lymphocyte function remain to be elucidated. In addition, the effect of LAG3 on NK cell function during HIV infection and its specific mechanisms are unclear. In this study, we observed that LAG3 expression by NK cells is elevated in HIV-infected individuals and inversely correlated with CD4/CD8 ratio and CD4+ T cell count. LAG3+ NK cells produce lower levels of interferon-gamma (IFN-γ), but LAG3-Fc protein significantly enhances NK cell function. The activation of LAG3 significantly inhibits IFN-γ production and Ki67 expression by NK cells. Our transcriptome sequencing and in vitro data show for the first time that LAG3 not only regulates the transcription of MYC and several glycolysis-related enzyme genes via the PI3K/AKT/mTOR signaling pathway to inhibit glycolysis in NK cells but also suppresses the STAT1/IFNG pathway by upregulating PSAT1 expression, thus limiting IFN-γ production by NK cells via these two different pathways. Overall, these results provide new insights and identify potential targets for immunotherapy of HIV infection. IMPORTANCE We demonstrate that lymphocyte activation gene 3 (LAG3) expression is upregulated on natural killer (NK) cells during HIV infection. LAG3 inhibits glycolysis in NK cells and also upregulates PSAT1 expression to suppress activation of the STAT1/IFNG pathway, thus restricting interferon-gamma production by NK cells. These results provide new clues to study the effects of LAG3 on the metabolism and functional exhaustion of NK cells and offer a potential target for the treatment of HIV.
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Affiliation(s)
- Hongchi Ge
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Nan Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Yufei Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Bin Lang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Xiaowan Yin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Xiaowen Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Zining Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Yajing Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Haibo Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Qinghai Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Xiaoxu Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Wenqing Geng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Hong Shang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
| | - Yongjun Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China
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40
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Timilsina S, Huang JY, Abdelfattah N, Medina D, Singh D, Abdulsahib S, Subbarayalu P, Do TP, Venkata PP, Nirzhor S, Prochnau J, Bhandari M, Zheng S, Chen Y, Huang G, Mukherjee N, Hromas R, Sung P, Kaklamani V, Vadlamudi R, Zhang N, Rao MK. Epigenetic silencing of DNA sensing pathway by FOXM1 blocks stress ligand-dependent antitumor immunity and immune memory. Nat Commun 2025; 16:3967. [PMID: 40295473 PMCID: PMC12037779 DOI: 10.1038/s41467-025-59186-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 04/14/2025] [Indexed: 04/30/2025] Open
Abstract
The interplay between tumor cells and the microenvironment significantly influences cancer progression. Here, we report a significant role of the transcription factor FOXM1 in shaping the tumor immune landscape. Single-cell sequencing reveals that tumor-intrinsic FOXM1 creates an immune-suppressive tumor microenvironment by inhibiting expression of stress ligands (including ULBP1) on cancer cells, thereby blocking NKG2D-NKG2DL interactions critical for priming natural killer- and T cell-mediated cytotoxicity of cancer cells. FOXM1 suppresses ULBP1 expression by epigenetically silencing the DNA-sensing protein STING using a DNMT1-UHRF1 complex, which in turn inhibits the unfolded protein response protein CHOP from activating ULBP1. Importantly, cancer patients with higher levels of FOXM1 and DNMT1, and lower levels of STING and ULBP1, have worse survival and are less responsive to immunotherapy. Collectively, our findings provide key insight into how a tumor-intrinsic transcription factor epigenetically shapes the tumor immune microenvironment, with strong implications for refining existing and designing new cancer immunotherapies.
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Affiliation(s)
| | - Jian Yu Huang
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
| | - Nourhan Abdelfattah
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA
| | - Daisy Medina
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Deepika Singh
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Shahad Abdulsahib
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Panneerdoss Subbarayalu
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Trong Phat Do
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Prabhakar Pitta Venkata
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Saif Nirzhor
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Jack Prochnau
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
| | - Mukund Bhandari
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Siyuan Zheng
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA
| | - Yidong Chen
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA
| | - Gang Huang
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | | | - Robert Hromas
- Department of Medicine, UT Health, San Antonio, TX, USA
| | - Patrick Sung
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA
- Department of Biochemistry & Structural Biology, UT Health San Antonio, San Antonio, TX, USA
| | | | - Ratna Vadlamudi
- Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, USA
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Nu Zhang
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA
- Department of Microbiology, Immunology & Molecular Genetics, UT Health, San Antonio, TX, USA
| | - Manjeet K Rao
- Greehey Children's Cancer Research Institute, San Antonio, TX, USA.
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA.
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41
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Patil SB, Kuvalekar MB, Yaraguppi DA, Prasanth DSNBK, Halkavatagi SG, Tennalli GB, Javali MA, Khan TMY. Exploring the efficacy of Benincasa hispida extract on obesity linked inflammatory bowel disease by integrating computational analysis and experimental validations. Sci Rep 2025; 15:14426. [PMID: 40281051 PMCID: PMC12032220 DOI: 10.1038/s41598-025-99256-6] [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: 10/29/2024] [Accepted: 04/18/2025] [Indexed: 04/29/2025] Open
Abstract
The association of obesity with inflammatory bowel disease (IBD) can be understood by the intricate role of pro- and anti-inflammatory cytokines, especially adipokines, which are secreted by adipose tissue and are responsible for IBD because of their structural similarity with tumor necrosis factor-alpha (TNF-α), an important cytokine involved in IBD pathogenesis. The current study was carried out to evaluate the therapeutic potential of Benincasa hispida in obesity-associated IBD. Approximately 18 compounds sourced from Benincasa hispida (Thunb.) were comprehensively analyzed, among which 11 presented favorable drug-likeness scores and adherence to Lipinski's Rule of Five. Various methodologies, including compound-gene set pathway enrichment analysis, network pharmacology, docking studies, and molecular dynamics simulations, have been employed. Safety assessments via Protox confirmed the nontoxic nature of these compounds, which is crucial for their therapeutic potential. Through Venn diagram analysis of the Gene Card and OMIM databases, proteins associated with obesity and IBD management were pinpointed. Pathway enrichment analysis revealed 810 targets across 192 distinct pathways, with 8 directly related to the pathogenesis of obesity and IBD. Notable therapeutic targets, such as MTOR, were identified through STRING and KEGG pathway database analyses, shedding light on the molecular pathways modulated by these protein targets. Interactions among compounds, proteins, and pathways were visualized via Cytoscape 3.6.1. Furthermore, the compounds were docked with the protein target via AutoDock 4.2, and the compound ajmalin exhibited the highest binding affinity with the MTOR protein, with a binding energy of -7.8 kcal/mol; later, a dynamic study was performed for the ajmaline and protein complex. These findings shed light on the potential efficacy of Benincasa hispida in targeting crucial pathways for managing obesity and IBD. Hence, in vivo studies involving Wistar rats exposed to microplastics and monosodium glutamate (MSG) were carried out to evaluate the potential of Benincasa hispida extracts in mitigating obesity-related IBD. Fecal lipid analysis revealed alterations associated with these conditions, whereas histopathological examinations of the liver and intestine revealed the inflammatory changes induced by MSG and microplastics. The protective effects of this extract on liver and intestinal histology suggest promising avenues for further investigations, emphasizing its potential as a therapeutic intervention for IBD and obesity.
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Affiliation(s)
| | | | - Deepak A Yaraguppi
- Department of Biotechnology, KLE Technological University, Hubballi, 580031, Karnataka, India.
| | - D S N B K Prasanth
- School of Pharmacy and Management, SVKM's Narsee Monjee Institute of Management Studies, Polepaly SEZ TSIIC, Jadcherla, Hyderabad, 509301, Mahbubnagar, Telangana, India
| | | | - Gururaj B Tennalli
- Department of Biotechnology, KLE Technological University, Hubballi, 580031, Karnataka, India
| | - Mukhatar Ahmed Javali
- Department of periodontics and community dental science, Division of Periodontics, College of Dentistry, Abha Asir Region, King Khalid University, Abha, Saudi Arabia
| | - T M Yunus Khan
- Central Labs, King Khalid University, P.O. Box 960, AlQuara'a, Abha, Saudi Arabia
- Department of Mechanical Engineering, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
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42
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Lacroix E, Momchilova EA, Chandhok S, Padavu M, Zapf R, Audas TE. PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc. Cell Rep 2025; 44:115617. [PMID: 40272983 DOI: 10.1016/j.celrep.2025.115617] [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: 09/05/2024] [Revised: 01/17/2025] [Accepted: 04/04/2025] [Indexed: 04/26/2025] Open
Abstract
In response to environmental stress, eukaryotic cells reversibly form functional amyloid aggregates called amyloid bodies (A-bodies). While these solid-like biomolecular condensates share many biophysical characteristics with pathological amyloids, A-bodies are non-toxic, and they induce a protective state of cellular dormancy. As a recently identified structure, the modulators of A-body biogenesis remain uncharacterized, with the seeding noncoding RNA being the only known regulatory factor. Here, we use an image-based high-throughput screening approach to identify candidate pathways regulating A-body biogenesis. Our data demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling axis meditates A-body formation during stress exposure, with AKT activation repressing glycogen synthase kinase-3 (GSK3)-mediated degradation of c-Myc. This enhances c-Myc binding to regulatory elements of the seeding noncoding RNA, upregulating the transcripts that nucleate A-body formation. Identifying a link between PI3K/AKT signaling, c-Myc, and physiological amyloid aggregates extends the range of activity for these well-established regulators while providing insight into cellular components whose dysregulation could underly amyloidogenic disorders.
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Affiliation(s)
- Emma Lacroix
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Evgenia A Momchilova
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Sahil Chandhok
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Mythili Padavu
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Richard Zapf
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
| | - Timothy E Audas
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada.
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43
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Rao K, Zhang X, Luo Y, Xia Q, Jin Y, He J. Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth. Cell Rep 2025; 44:115441. [PMID: 40106438 DOI: 10.1016/j.celrep.2025.115441] [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: 07/12/2024] [Revised: 01/06/2025] [Accepted: 02/26/2025] [Indexed: 03/22/2025] Open
Abstract
Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.
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Affiliation(s)
- Keqiang Rao
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China
| | - Xinchao Zhang
- Department of Pathology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China.
| | - Yuting Jin
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China.
| | - Jing He
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.
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44
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Jiang Q, Xue S, Pan X, Yu T, Wei X, Li L, Qi C, Shi W, Ren Z, Hu D, Fu H. Differential changes in the microglial transcriptome between neonatal and adult mice after spinal cord injury. Sci Rep 2025; 15:13708. [PMID: 40258965 PMCID: PMC12012053 DOI: 10.1038/s41598-025-98429-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/11/2025] [Indexed: 04/23/2025] Open
Abstract
Spinal cord injury (SCI) remains a significant therapeutic challenge, lacking effective treatment options. Related studies have found that neonatal microglia are more effective than adult microglia in promoting the recovery of SCI, but the reason why neonatal, not adult, microglia are more conducive to SCI recovery is not clear, the differences of gene expression and pathways between them are still worth exploring. Therefore, we examined changes in the microglial transcriptome after SCI in neonatal and adult mice. We identified hub genes or pathways that exhibited significant differential expression between the two groups. Four Gene sets were established for further analysis, named Gene set 1, Gene set 2, Gene set 3, Gene set 4, respectively. GO analysis revealed enrichment in categories critical for injury repair, including DNA metabolism, replication, recombination, meiotic cell cycle progression, regulation of cell-cell adhesion, megakaryocyte and endothelial development, modulation of the neuroinflammatory response, endocytosis, and regulation of cytokine production and cell migration. KEGG analysis revealed enrichment in pathways critical for various cellular processes, including the p53, TNF, PI3K-AKT, PPAR and B cell receptor signaling pathway, axon guidance, cytokine-cytokine receptor interaction. PPI and TF-hub gene-microRNA networks were constructed to elucidate the underlying gene regulatory mechanisms. Additionally, drug prediction was performed to identify potential therapeutic candidates. Finally, 11 hub genes (Chek1, RRM2, Lyve1, Mboat1, Clec4a3, Ccnd1, Cdk6, Zeb1, Igf1, Pparg, and Cd163) were selected from four Gene sets for further validation using qRT-PCR. We identified candidate genes and pathways involved in microglial transcriptome heterogeneity after SCI in neonatal and adult mice. These findings provide valuable insights into potential therapeutic targets for neonatal microglia in the treatment of SCI.
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Affiliation(s)
- Qi Jiang
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Qingdao Medical College of Qingdao University, Qingdao University, Qingdao, 266071, China
| | - Shiyuan Xue
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Qingdao Medical College of Qingdao University, Qingdao University, Qingdao, 266071, China
| | - Xiaojing Pan
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China
| | - Tengbo Yu
- Department of Orthopedic Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266071, China
| | - Xinyi Wei
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Qingdao Medical College of Qingdao University, Qingdao University, Qingdao, 266071, China
| | - Liping Li
- Department of Bone Surgery, Qingdao Central Hospital, Qingdao, 266000, China
| | - Chao Qi
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Weipeng Shi
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Qingdao Medical College of Qingdao University, Qingdao University, Qingdao, 266071, China
| | - Zhongkai Ren
- Department of Orthopedic Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266071, China
| | - Die Hu
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China.
| | - Haitao Fu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
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Balla T. Phosphatidylinositol 4-phosphate; A minor lipid with multiple personalities. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159615. [PMID: 40262701 DOI: 10.1016/j.bbalip.2025.159615] [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: 02/26/2025] [Revised: 04/08/2025] [Accepted: 04/18/2025] [Indexed: 04/24/2025]
Abstract
Phosphorylated products of phosphatidylinositol (PI), named Diphosphoinositide (DPI) and triphosphoinositide (TPI) were identified long time ago and found to exhibit high turnover rates based on their rapid 32P-phosphate labeling. The PI kinase activities that were responsible for their production were subsequently identified and found to be associated with different organelle membranes, including the plasma membrane. These activities were then linked with a certain group of cell surface receptors that activated phospholipase C enzymes to hydrolyze PI and used calcium or cGMP as a second messenger. This visionary concept was introduced in the seminal BBA review written by Robert Michell, exactly 50 years ago. The enzymology and functional diversity of PI 4-phosphate (PI4P) (the term that has replaced DPI) has since underwent an expansion that could not have been foreseen. In this review I will attempt to revisit this expansion with some historical reflections celebrating the 50th anniversary of the Michell review.
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Affiliation(s)
- Tamas Balla
- Section on Molecular Signal Transduction, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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46
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Villanueva JL, Vita AA, Zwickey H, Fitzgerald K, Hodges R, Zimmerman B, Bradley R. Dietary associations with reduced epigenetic age: a secondary data analysis of the methylation diet and lifestyle study. Aging (Albany NY) 2025; 17:994-1010. [PMID: 40266024 PMCID: PMC12074822 DOI: 10.18632/aging.206240] [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: 04/26/2024] [Accepted: 03/13/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND Aging is the primary risk factor for developing non-communicable chronic diseases, necessitating interventions targeting the aging process. Outcome measures of biological aging used in these interventions are mathematical algorithms applied to DNA methylation patterns, known as epigenetic clocks. The Methylation Diet and Lifestyle study was a pilot randomized controlled trial of a diet and lifestyle intervention that utilized epigenetic age as its primary outcome, measured using Horvath's clock. Significant reductions in epigenetic age post-intervention were observed but with notable variability. PURPOSE This research aimed to identify dietary components associated with epigenetic age change across groups. Contributing factors to variability, such as weight changes and baseline differences in chronological and epigenetic age, were explored. RESULTS In hierarchical linear regression, foods investigated as polyphenolic modulators of DNA methylation (green tea, oolong tea, turmeric, rosemary, garlic, berries) categorized in the original study as methyl adaptogens showed significant linear associations with epigenetic age change (B = -1.24, CI = [-2.80, -0.87]), after controlling for baseline epigenetic age acceleration and weight changes. Although the intervention group lost significantly more weight than the control group, these changes were not associated with epigenetic age changes in the regression model. These findings suggest that consuming foods categorized as methyl adaptogens may reduce markers of epigenetic aging.
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Affiliation(s)
- Jamie L. Villanueva
- School of Nursing, University of Washington, Seattle, WA 98195, USA
- Helfgott Research Institute, National University of Natural Medicine, Portland, OR 97201, USA
| | - Alexandra Adorno Vita
- Helfgott Research Institute, National University of Natural Medicine, Portland, OR 97201, USA
- Colorado State University, Department of Food Science and Human Nutrition, Fort Collins, CO 80526, USA
| | - Heather Zwickey
- Helfgott Research Institute, National University of Natural Medicine, Portland, OR 97201, USA
| | | | - Romilly Hodges
- College of Nutrition, Sonoran University, Tempe, AZ 85282, USA
| | - Benjamin Zimmerman
- Helfgott Research Institute, National University of Natural Medicine, Portland, OR 97201, USA
| | - Ryan Bradley
- Helfgott Research Institute, National University of Natural Medicine, Portland, OR 97201, USA
- Herbert Wertheim School of Public Health and Human Longevity Sciences, University of California, San Diego, CA 92093, USA
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Shin AE, Sugiura K, Kariuki SW, Cohen DA, Flashner SP, Klein-Szanto AJ, Nishiwaki N, De D, Vasan N, Gabre JT, Lengner CJ, Sims PA, Rustgi AK. LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models. J Clin Invest 2025; 135:e186035. [PMID: 39808497 PMCID: PMC11996871 DOI: 10.1172/jci186035] [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: 09/18/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer death because of metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present a comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using the FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (a ribosomal protein S6 kinase inhibitor) in CRC cell lines and mouse- and patient-derived organoids. Tissue microarrays from patients with CRC verified that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of patient-derived organoids in precision medicine in metastatic CRC.
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Affiliation(s)
- Alice E. Shin
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | - Kensuke Sugiura
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | | | - David A. Cohen
- Department of Surgery, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons; Columbia University Irving Medical Center, New York, New York, USA
| | | | | | | | - Dechokyab De
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | - Neil Vasan
- Division of Hematology and Oncology, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Joel T. Gabre
- Division of Digestive and Liver Diseases, Department of Medicine, and
| | - Christopher J. Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Peter A. Sims
- Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, and
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48
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Liu YH, Wang ZY, Du YF, Liu XH, Niu JB, Song J, Jin CY, Zhang SY. Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities. Bioorg Med Chem 2025; 121:118109. [PMID: 39955801 DOI: 10.1016/j.bmc.2025.118109] [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: 11/18/2024] [Revised: 01/23/2025] [Accepted: 02/10/2025] [Indexed: 02/18/2025]
Abstract
Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.
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Affiliation(s)
- Yun-He Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, China
| | - Zi-Yue Wang
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, China
| | - Yi-Fei Du
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xuan-Han Liu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jin-Bo Niu
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Cheng-Yun Jin
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
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Hou X, Chen Y, Carrillo ND, Cryns VL, Anderson RA, Sun J, Wang S, Chen M. Phosphoinositide signaling at the cytoskeleton in the regulation of cell dynamics. Cell Death Dis 2025; 16:296. [PMID: 40229242 PMCID: PMC11997203 DOI: 10.1038/s41419-025-07616-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/20/2025] [Accepted: 03/31/2025] [Indexed: 04/16/2025]
Abstract
The cytoskeleton, composed of microfilaments, intermediate filaments, and microtubules, provides the structural basis for cellular functions such as motility and adhesion. Equally crucial, phosphoinositide (PIPn) signaling is a critical regulator of these processes and other biological activities, though its precise impact on cytoskeletal dynamics has yet to be systematically investigated. This review explores the complex interplay between PIPn signaling and the cytoskeleton, detailing how PIPn modulates the dynamics of actin, intermediate filaments, and microtubules to shape cellular behavior. Dysregulation of PIPn signaling is implicated in various diseases, including cancer, highlighting promising therapeutic opportunities through targeted modulation of these pathways. Future research should aim to elucidate the intricate molecular interactions and broader cellular responses to PIPn signaling perturbations, particularly in disease contexts, to devise effective strategies for restoring cytoskeletal integrity.
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Affiliation(s)
- Xiaoting Hou
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Yu Chen
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Noah D Carrillo
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Vincent L Cryns
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Richard A Anderson
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Jichao Sun
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Critical Care Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital, Shenzhen, China
| | - Songlin Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
| | - Mo Chen
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
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50
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Jia W, Cheng X. In Silico Discovery of a Novel Natural Product Targeting PI3Kα for the Treatment of Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2025; 26:3565. [PMID: 40332095 PMCID: PMC12027195 DOI: 10.3390/ijms26083565] [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: 02/19/2025] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 05/08/2025] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a major health burden, with abnormal activation of phosphatidylinositol 3-kinase alpha (PI3Kα) strongly implicated in its pathogenesis. Targeting PI3Kα represents a promising therapeutic strategy. In this study, we employed structure-based virtual screening to identify natural small-molecule inhibitors of PI3Kα. A total of 12,800 molecules were screened, and five compounds were selected for further evaluation based on binding affinity and interaction patterns. Pharmacokinetic properties were assessed using ADMET predictions, and molecular dynamics (MD) simulations were conducted to validate the binding stability. Among the candidates, Apigetrin demonstrated favorable ADMET properties, a high safety profile, and stable binding within the ATP-binding pocket of PI3Kα. These findings suggest that Apigetrin is a promising natural PI3Kα inhibitor with potential therapeutic relevance for HNSCC.
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Affiliation(s)
- Wenqing Jia
- College of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250200, China
| | - Xianchao Cheng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
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