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Liu L, Liu W, Deng W. Amylin inhibits gastric cancer progression by targeting CCN1 and affecting the PI3K/AKT signalling pathway. Ann Med 2025; 57:2480754. [PMID: 40165038 DOI: 10.1080/07853890.2025.2480754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 02/22/2025] [Accepted: 03/10/2025] [Indexed: 04/02/2025] Open
Abstract
METHODS This study used a combination of in vitro and in vivo experiments to investigate the role of amylin in the progression of GC. The expression of amylin in GC and its clinical correlation were evaluated using 38 pairs of GC and healthy human clinical samples. In vitro studies, human GC cell lines were treated with amylin to evaluate the effects of amylin on the proliferation, apoptosis and migration of GC cells. In in vivo studies, xenograft mouse models were established by subcutaneous injection of GC cells into nude mice, followed by treatment with amylin to assess tumor growth. Finally, Next-Generation Sequencing Technology (RNA-seq) was used to explore the potential mechanism of amylin on GC. RESULTS We found that amylin expression was reduced in GC compared to adjacent normal gastric tissues and that elevated amylin expression was negatively correlated with adverse pathological factors (p < 0.05). Additionally, we demonstrated that amylin impeded the growth, invasion, migration, and colony formation of GC cells and suppressed the epithelial-to-mesenchymal transformation of these cells (p < 0.05). Tumour xenograft model experiments confirmed the tumour-suppressive effect of amylin in subcutaneous tumours in nude mice (p < 0.05). Transcriptome sequencing (RNA-seq) revealed that amylin significantly down-regulated CCN1 gene expression in GC cells (p < 0.001). Further intervention targeting CCN1 verified its significance as a target of amylin's anti-carcinogenic function in GC. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that amylin exerted its oncogenic effects by inhibiting the PI3K/Akt signalling pathway (p < 0.05). CONCLUSIONS Our findings demonstrate that amylin plays a crucial role in suppressing gastric cancer progression by targeting CCN1 and inhibiting the PI3K/Akt signalling pathway. These results suggest that amylin could serve as a potential therapeutic agent for GC treatment.
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Affiliation(s)
- Li Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Wenxuan Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 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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Wang H, Cheng G, Zhang S, Qu H, Zhao X, Yang A, Sun X, Pan H. Sevoflurane: A dual modulator of miR‑211‑5p and mitochondrial apoptosis in glioma therapy. Mol Med Rep 2025; 32:179. [PMID: 40280112 PMCID: PMC12046963 DOI: 10.3892/mmr.2025.13544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 01/07/2025] [Indexed: 04/29/2025] Open
Abstract
The present study aimed to investigate how sevoflurane (SEV) regulated the apoptosis of glioma cells through the mitochondrial apoptosis pathway. First, an evaluation was performed on the viability, apoptosis, mitochondrial reactive oxygen species levels, mitochondrial membrane potential and apoptosis and autophagy‑related protein expression of glioma cells according to experimental groups. Next, the expression of microRNA‑211‑5p (miR‑211‑5p), silent information regulator 1 (SIRT1) and phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway was detected by reverse transcription‑quantitative PCR or western blotting. Dual luciferase reporter gene assay confirmed the targeting relationship between miR‑211‑5p and SIRT1. In addition, SEV suppressed the proliferation and induced the apoptosis in human glioma cell line cells via the mitochondrial apoptosis pathway. In mechanistic analysis, the miR‑211‑5p level in glioma cells was low, while following SEV treatment, it was increased. Furthermore, SEV regulated SIRT1 by upregulating miR‑211‑5p expression, thereby blocking the PI3K/AKT signaling pathway activation. Moreover, functional rescue experiments showed that downregulation of SIRT1 or miR‑211‑5p could reverse the effects of SEV on glioma cells. Collectively, SEV promoted apoptosis in glioma cells by inducing miR‑211‑5p, which regulated SIRT1/PI3K/AKT pathway, mediating mitochondria‑dependent apoptosis pathway. This finding may open new possibilities for SEV as a potential treatment for glioma in the future.
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Affiliation(s)
- Haili Wang
- Department of Anesthesiology, Sanmenxia Central Hospital of Henan University of Science and Technology, Sanmenxia, Henan 472000, P.R. China
| | - Guofang Cheng
- Department of Orthopedics, Sanmenxia Orthopedic Hospital, Sanmenxia, Henan 472000, P.R. China
| | - Shuyuan Zhang
- Department of Anesthesiology, Sanmenxia Central Hospital of Henan University of Science and Technology, Sanmenxia, Henan 472000, P.R. China
| | - Haibo Qu
- Department of Anesthesiology, Sanmenxia Central Hospital of Henan University of Science and Technology, Sanmenxia, Henan 472000, P.R. China
| | - Xibo Zhao
- Department of Anesthesiology, Sanmenxia Central Hospital of Henan University of Science and Technology, Sanmenxia, Henan 472000, P.R. China
| | - Ailing Yang
- Department of Anesthesiology, Sanmenxia Central Hospital of Henan University of Science and Technology, Sanmenxia, Henan 472000, P.R. China
| | - Xuejia Sun
- Department of Anesthesiology, Sanmenxia Central Hospital of Henan University of Science and Technology, Sanmenxia, Henan 472000, P.R. China
| | - Hua Pan
- Department of Anesthesiology, Sanmenxia Central Hospital of Henan University of Science and Technology, Sanmenxia, Henan 472000, P.R. China
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Hua YQ, Guo KX, Ni P, Wang D, An TY, Gao YY, Zhang RG. RPF2 regulates the protein kinase B/mammalian target of rapamycin pathway in the pathogenesis of Helicobacter pylori. World J Gastrointest Oncol 2025; 17:105664. [DOI: 10.4251/wjgo.v17.i6.105664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/25/2025] [Accepted: 05/12/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND RPF2 is a crucial factor in ribosome synthesis, which has been linked to the development of several cancers. However, the mechanism of RPF2 in gastric carcinogenesis is unclear.
AIM To explore the role and mechanism of RPF2 in the pathogenesis of Helicobacter pylori (H. pylori) infection.
METHODS GES-1 was co-cultured with H. pylori in vitro to detect changes in the expression of RPF2. Overexpression and silencing of RPF2 were performed. Quantitative real-time polymerase chain reaction (q-PCR) and Western blot (WB) were used to determine mRNA and protein expression of RPF2, protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and epithelial-mesenchymal transition-related factors MMP2 and MMP9; cell counting kit 8 and wound healing assays were utilized to evaluate cell viability and migratory capacity; q-PCR, WB, and immunohistochemistry were employed to establish RPF2 expression in cancer tissues.
RESULTS H. pylori facilitated RPF2 expression and triggered AKT/mTOR signaling pathway. Functional experiments showed that RPF2 overexpression could promote a series of malignant transformations such as cell proliferation, cell migration and invasion, and further enhance AKT/mTOR signaling pathway activation. RPF2 knockdown had the opposite effect. In addition, RPF2 expression was higher in gastric cancer tissues than in adjacent tissues.
CONCLUSION RPF2 plays a significant role in the pathogenic mechanism of H. pylori infection and may be useful in the detection and management of gastric cancer caused by H. pylori infection.
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Affiliation(s)
- Yan-Qiao Hua
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Kai-Xin Guo
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Occupational Disease Control, Anyang Center for Disease Control and Prevention, Anyang 455000, Henan Province, China
| | - Peng Ni
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Di Wang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Tong-Yan An
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Yang-Ye Gao
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Rong-Guang Zhang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Heinz Mehhorn Academician Workstation, School of Public Health, Hainan Medical University, Haikou 571199, Hainan Province, China
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Ni C, Sun Q, Yin H. Comprehensive multi-omics analysis of histone acetylation modulators identifies ASH1L as a novel aggressive marker for osteosarcoma. Discov Oncol 2025; 16:1070. [PMID: 40504347 PMCID: PMC12162460 DOI: 10.1007/s12672-025-02920-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 06/05/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Osteosarcoma, a highly malignant bone tumor prevalent in children and adolescents, continues to have poor long-term survival rates, particularly in metastatic cases. While histone acetylation dysregulation has been implicated in cancer progression, the role of histone acetylation modification-related proteins (HAMRPs) in osteosarcoma immune infiltration and prognosis remains unclear. METHODS The expression patterns, prognostic implications, and clinical correlations of HAMRPs in osteosarcoma were analyzed using the TARGET, GEO, TISCH, and HPA databases. The effectiveness of HAMRPs in predicting the immune landscape of osteosarcoma was confirmed using CIBERSORT, ssGSEA, and ESTIMATE algorithms. The study employed GSEA analysis, wound healing assay, Transwell, and western blot to explore the role and regulatory mechanism of the key gene ASH1L in osteosarcoma progression. RESULTS Two distinct histone acetylation modification patterns were identified, showing significant differences in survival, clinical features, and immune landscape. Comprehensive clinical correlation analysis and Kaplan-Meier analysis of all HAMRPs used for two subtypes revealed that higher ASH1L expression was found in metastatic osteosarcoma cases and indicated poorer survival outcomes. In vitro experiments confirmed that ASH1L promoted osteosarcoma metastasis and epithelial-mesenchymal transition via the AKT/mTOR pathway. Additionally, an ASH1L-derived risk model was developed to aid personalized clinical decisions. CONCLUSIONS This study elucidates the prognostic and immunological significance of HAMRPs and highlights ASH1L as a novel aggressive marker in osteosarcoma.
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Affiliation(s)
- Chenlie Ni
- The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, China
| | - Qiwen Sun
- Haining Yuanhua Township Central Health Hospital, Jiaxing, 314000, China
| | - Haibo Yin
- The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, China.
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Qi GX, Zhao RX, Gao C, Ma ZY, Wang S, Xu J. Recent advances and challenges in colorectal cancer: From molecular research to treatment. World J Gastroenterol 2025; 31:106964. [DOI: 10.3748/wjg.v31.i21.106964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/22/2025] [Accepted: 05/26/2025] [Indexed: 06/06/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the top causes of cancer-related fatalities globally. Recent progress in genomics, proteomics, and bioinformatics has greatly improved our comprehension of the molecular underpinnings of CRC, paving the way for targeted therapies and immunotherapies. Nonetheless, obstacles such as tumor heterogeneity and drug resistance persist, hindering advancements in treatment efficacy. In this context, the integration of artificial intelligence (AI) and organoid technology presents promising new avenues. AI can analyze genetic and clinical data to forecast disease risk, prognosis, and treatment responses, thereby expediting drug development and tailoring treatment plans. Organoids replicate the genetic traits and biological behaviors of tumors, acting as platforms for drug testing and the formulation of personalized treatment approaches. Despite notable strides in CRC research and treatment - from genetic insights to therapeutic innovations - numerous challenges endure, including the intricate tumor microenvironment, tumor heterogeneity, adverse effects of immunotherapies, issues related to AI data quality and privacy, and the need for standardization in organoid culture. Future initiatives should concentrate on clarifying the pathogenesis of CRC, refining AI algorithms and organoid models, and creating more effective therapeutic strategies to alleviate the global impact of CRC.
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Affiliation(s)
- Gao-Xiu Qi
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Rui-Xia Zhao
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Chen Gao
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Zeng-Yan Ma
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Shang Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Jing Xu
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
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Li X, Wang S, Nie X, Hu Y, Liu O, Wang Y, Lin B. PSAT1 regulated by STAT4 enhances the proliferation, invasion and migration of ovarian cancer cells via the PI3K/AKT pathway. Int J Mol Med 2025; 55:88. [PMID: 40211693 PMCID: PMC12005366 DOI: 10.3892/ijmm.2025.5529] [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] [Accepted: 12/20/2024] [Indexed: 04/19/2025] Open
Abstract
Epithelial ovarian cancer, the most prevalent form of ovarian cancer, is a health concern worldwide. Phosphoserine aminotransferase 1 (PSAT1), as the rate‑limiting enzyme in serine synthesis, is key in the conversion of 3‑phosphoglycerate to serine. The present study explored the role of PSAT1 expression in epithelial ovarian tumors. Gene Expression Profiling Interactive Analysis was used for gene expression and survival analyses. The effects of PSAT1 overexpression and knockdown on invasion, migration, proliferation and cell cycle progression of ovarian cancer cell lines were investigated both in vitro and in vivo. Western blotting was conducted to assess alterations in PI3K/AKT signalling pathway proteins. Database and tissue sample data confirmed that PSAT1 was significantly upregulated in ovarian cancer. Preliminary functional investigations indicated that PSAT1 was involved in modulation of invasion and migration, demonstrating the capacity of PSAT1 to enhance expression of the PI3K/AKT signalling pathway. These findings suggested that PSAT1 served a critical role in the onset and progression of ovarian cancer, thereby offering a theoretical basis for early detection and therapeutic strategies.
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Affiliation(s)
- Xiao Li
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Shuang Wang
- Department of Obstetrics and Gynaecology, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin 300277, P.R. China
| | - Xin Nie
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yuexin Hu
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Ouxuan Liu
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yuxuan Wang
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Bei Lin
- Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Thakkar AB, Subramanian RB, Thakkar VR, Thakkar SS, Prajapati J, Goswami D, Thakor P. Biochanin A, an isoflavone isolated from Dalbergia sissoo Roxb. ex DC., leaves promote ROS-mediated and caspase-dependent apoptosis in lung adenocarcinoma cells. J Biomol Struct Dyn 2025:1-25. [PMID: 40432355 DOI: 10.1080/07391102.2025.2507820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 04/27/2024] [Indexed: 05/29/2025]
Abstract
The objective of this study was to isolate and characterize a cytotoxic compound from the hydromethanolic extract of Dalbergia sissoo Roxb. ex DC. leaves using the cold percolation technique. Thin-layer chromatography was employed to isolate the cytotoxic component from the crude plant extract, and its cytotoxicity against lung adenocarcinoma (A549) cells was evaluated using the MTT assay. The structure of the isolated cytotoxic compound was determined through FTIR, NMR, UV analysis, and LC-MS/MS methods. Through comprehensive characterization, a cytotoxic compound called Biochanin A (BA) was identified, exhibiting significant anticancer activity with an IC50 value of 21.92 ± 2.19 μM against A549 cells, while demonstrating lower cytotoxicity towards normal lung cells (WI-38) with an IC50 value of 285.12 ± 2.19 μM. Notably, BA induced morphological changes in A549 cells, leading to apoptotic alterations and the generation of reactive oxygen species (ROS), as confirmed by multiple techniques (AO/EB, DAPI, Giemsa). In silico molecular docking, ADMET, MMGBSA, and molecular dynamics simulation investigations support the RT-PCR and cell biology findings. As a result, BA's molecular mechanism of action involves ROS-induced apoptosis mediated by caspases 9 and 3.
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Affiliation(s)
- Anjali B Thakkar
- P. G. Department of Biosciences, Sardar Patel Maidan, Satellite Campus, Sardar Patel University, Anand, Gujarat, India
- Department of Applied and Interdisciplinary Sciences, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
| | - Ramalingam B Subramanian
- P. G. Department of Biosciences, Sardar Patel Maidan, Satellite Campus, Sardar Patel University, Anand, Gujarat, India
| | - Vasudev R Thakkar
- P. G. Department of Biosciences, Sardar Patel Maidan, Satellite Campus, Sardar Patel University, Anand, Gujarat, India
| | - Sampark S Thakkar
- Akashganga, Shree Kamdhenu Electronics Pvt. Ltd, Vallabh Vidyanagar, Gujarat, India
| | - Jignesh Prajapati
- Department of Biochemistry & Forensic Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Dweipayan Goswami
- Department of Microbiology & Biotechnology, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Parth Thakor
- Bapubhai Desaibhai Patel Institute of Paramedical Sciences, Charotar University of Science and Technology, Changa, Gujarat, India
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Qu H, Sun A, Zhou Y, Ma C, Ye Y, Xu Y, Zhao H, Zhao C, Hu Y, Yang L, Peng L, Zheng S, Wang K. Hypocrellin B Exerts Its Antitumor Effect on Colorectal Cancer by Inhibiting the AKT Pathway. JOURNAL OF NATURAL PRODUCTS 2025. [PMID: 40392701 DOI: 10.1021/acs.jnatprod.4c01431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
Colorectal cancer is the fourth most common malignant cancer worldwide, with limited treatment options for advanced cases. The natural compound hypocrellin B has been shown to inhibit tumor growth, but its effects and specific mechanisms of action in colorectal cancer remain unclear. Here, we explore the anti-tumor effect of hypocrellin B on human colorectal cancer cells and identify molecular targets. We found that hypocrellin B significantly inhibits proliferation and migration and promotes apoptosis of colorectal cancer cells in vitro by targeting the AKT/STING signaling pathway. Hypocrellin B also inhibited tumor growth in vivo in a mouse xenograft model. In summary, hypocrellin B exerts an anticolorectal cancer effect by inhibiting the phosphorylation of AKT, thus blocking a key pathway of tumor growth and survival. These results indicate that hypocrellin B is a promising candidate for the treatment of colorectal cancer, warranting further investigation.
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Affiliation(s)
- Hongyan Qu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China
| | - Aofeng Sun
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Yi Zhou
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China
| | - Chunbo Ma
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Yihan Ye
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Yini Xu
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Haiyang Zhao
- The Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, People's Republic of China
| | - Chengguang Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China
| | - Yunming Hu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China
| | - Lehe Yang
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Lingcong Peng
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Suqing Zheng
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China
| | - Ke Wang
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, People's Republic of China
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Ma X, He Y, Yang Y, Lu T, Tang Z, Cui Y, Wang R. YY1-induced DDX18 modulates EMT via the AKT/mTOR pathway in esophageal cancer: a novel therapeutic target. J Transl Med 2025; 23:562. [PMID: 40394670 PMCID: PMC12090415 DOI: 10.1186/s12967-025-06555-7] [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: 12/11/2024] [Accepted: 04/30/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Esophageal cancer is the 11th most common malignancy and the 7th leading cause of cancer-related death globally. Identifying key molecules and underlying mechanisms in the progression of esophageal cancer represents an effective strategy for developing novel therapeutic approaches. METHODS DDX18 expression in clinical specimens was evaluated by immunohistochemistry and western blot analysis. Functional assays were performed in cells with either DDX18 knockdown or overexpression. Dual luciferase reporter assays and chromatin immunoprecipitation (ChIP) were conducted to validate the interaction between YY1 and the DDX18 promoter. A xenograft tumor model was utilized to investigate the role of DDX18 in vivo in esophageal cancer. RESULTS DDX18 was found to be markedly overexpressed in esophageal cancer, with its levels significantly higher in patients with pathological grade III compared to those with grades I-II. In vitro, DDX18 enhanced cell proliferation, migration, and invasion, while concurrently suppressing apoptosis. Furthermore, DDX18 promoted epithelial-mesenchymal transition (EMT) and activated the AKT/mTOR signaling pathway. The use of AKT inhibitors effectively abrogated the oncogenic effects of DDX18. Dual luciferase and ChIP assays confirmed that YY1 binds to and stimulates DDX18 transcription. In rescue experiments, YY1 countered the inhibitory effects of DDX18 knockdown on cell proliferation, EMT, and AKT/mTOR activation. In vivo, DDX18 knockdown resulted in reduced tumor growth. CONCLUSIONS The transcription of DDX18 was activated by YY1, and DDX18 promoted tumor cell growth and EMT through the AKT/mTOR signaling pathway in esophageal cancer cells.
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Affiliation(s)
- Xiaochao Ma
- Department of Thoracic Surgery, Organ Transplantation Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, China
| | - Yulu He
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Yue Yang
- Department of Thoracic Surgery, Organ Transplantation Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, China
| | - Tianyu Lu
- Department of Thoracic Surgery, Organ Transplantation Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, China
| | - Ze Tang
- Department of Thoracic Surgery, Organ Transplantation Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, China
| | - Youbin Cui
- Department of Thoracic Surgery, Organ Transplantation Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, China.
| | - Rui Wang
- Department of Thoracic Surgery, Organ Transplantation Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, China.
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Praveen A, Dougnon G, Matsui H. Exploring α-Syn's Functions Through Ablation Models: Physiological and Pathological Implications. Cell Mol Neurobiol 2025; 45:44. [PMID: 40389720 PMCID: PMC12089638 DOI: 10.1007/s10571-025-01560-2] [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: 02/18/2025] [Accepted: 05/07/2025] [Indexed: 05/21/2025]
Abstract
A significant advancement in neurodegenerative research was the discovery that α-synuclein (α-Syn/SNCA) plays a part in the pathophysiology of Parkinson's disease (PD). Decades later, the protein's significant impacts on various brain disorders are still being extensively explored. In disease conditions, α-Syn misfolds and forms abnormal aggregates that accumulate in neurons, thus triggering various organellar dysfunctions and ultimately neurodegeneration. These misfolded forms are highly heterogeneous and vary significantly among different synucleinopathies, such as PD, Multiple System Atrophy, or Dementia with Lewy bodies. Though initially believed to be exclusively localized in the brain, numerous pieces of evidence suggest that α-Syn functions transcend the central nervous system, with roles in peripheral functions, such as modulation of immune responses, hematopoiesis, and gastrointestinal regulation. Here, we aim to provide a detailed compilation of cellular functions and pathological phenotypes that are altered upon attenuation of α-Syn function in vitro and in vivo and explore the effects of SNCA gene silencing in healthy and disease states using cellular and animal models.
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Affiliation(s)
- Anjali Praveen
- Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan
| | - Godfried Dougnon
- Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan
| | - Hideaki Matsui
- Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
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12
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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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13
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Theivendren P, Pavadai P, Kunjiappan S, Ravi K, Kiruthiga N, Chidamabaram K, Alagarsamy S, Reddy NB. Emerging therapeutic strategies and opportunities in targeting protein pathways for breast cancer treatment: a critical review. NANOTECHNOLOGY 2025; 36:232001. [PMID: 40345214 DOI: 10.1088/1361-6528/add6ae] [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: 11/08/2024] [Accepted: 05/09/2025] [Indexed: 05/11/2025]
Abstract
Understanding breast cancer at a molecular level is essential for developing effective treatments due to its significant impact on women's mortality rates globally. Targeted medicines focus on specific proteins crucial to breast cancer progression, offering a promising treatment avenue. These proteins, often overexpressed or mutated in cancer cells, are vital for cell proliferation, division, and survival. Targeted drugs aim to inhibit these proteins, halting disease progression and sparing non-cancerous cells, which reduces side effects and improves patient quality of life. Key proteins in breast cancer treatment include HER2 (human epidermal growth factor receptor 2), ER (estrogen receptor), and PR (progesterone receptor). Drugs like Trastuzumab target HER2 to impede tumor growth in HER2-positive cancers, while hormone therapies targeting ER and PR improve outcomes for hormone receptor-positive cancers. Examining proteins such as EGFR, HER2/Neu, and ER reveals their roles in cancer pathways, with pathways like PI3K/Akt/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) and MAPK (mitogen-activated protein kinase) being crucial targets for therapies, potentially revolutionizing breast cancer treatment.
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Affiliation(s)
- Panneerselvam Theivendren
- Department of Pharmaceutical Chemistry & Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology & Advanced Studies, Pallavaram, Chennai, Tamil Nadu 600117, India
| | - Parasuraman Pavadai
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, M S R Nagar, Bengaluru, Karnataka 560054, India
| | - Selvaraj Kunjiappan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Tamil Nadu 626126, India
| | - Kaveena Ravi
- Department of Pharmaceutics, Swamy Vivekananda College of Pharmacy, Elayampalayam, Namakkal, Tamil Nadu 637205, India
| | - Natarajan Kiruthiga
- Department of Pharmaceutical Chemistry, KMCH College of Pharmacy, Kalappatti road, Coimbatore, Tamil Nadu 641048, India
| | - Kumarappan Chidamabaram
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Asir Province, Saudi Arabia
| | - Shanmugarathinam Alagarsamy
- Department of Pharmaceutical Technology, University College of Engineering, Bharathidasan Institute of Technology Campus, Anna University, Tiruchirappalli, Tamil Nadu 620024, India
| | - Nagireddy Bhuvan Reddy
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 602 105, India
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14
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Zhang HJ, Zhao Q, Zhang M, Yang LL, Abiti J, Han MM, Gao YP, Lu JT, Wang JN, Ji MY, Zhang X, Wang W, Qiu LL, Wang XY, Wang TY, Jia YL. Overexpression of Tgm2 in Chinese Hamster Ovary Cells Enhances Recombinant Monoclonal Antibody Expression and Promotes Cell Proliferation through Reduction of Apoptosis. ACS Synth Biol 2025; 14:1802-1812. [PMID: 40327404 DOI: 10.1021/acssynbio.5c00161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
Chinese hamster ovary (CHO) cells are the preferred host system for producing protein-based (antibody) therapeutics. However, recombinant CHO cells undergo substantial apoptosis during prolonged cultivation, impairing cell growth and ultimately compromising product yield and quality. Transglutaminase 2 (Tgm2), which mediates post-translational modifications of substrate proteins, regulates critical biological processes including cellular differentiation, apoptosis, cell cycle progression, and extracellular matrix assembly. In this study, we examined the effects of Tgm2 overexpression and knockdown on CHO cell growth and recombinant antibody production. Stable Tgm2 overexpression enhanced CHO cell proliferation while reducing apoptotic rates, resulting in significantly increased recombinant adalimumab expression (2.09 ± 0.08-fold) and specific productivity (1.88 ± 0.08-fold) compared to controls. In contrast, Tgm2 knockdown promoted apoptosis and induced cell cycle arrest. Mechanistically, elevated Tgm2 upregulated antiapoptotic genes (Bcl-2, Bcl-xL, and Mcl-1) while suppressing caspase-3 activity and BAX expression. These effects were associated with PI3K/AKT/mTOR pathway activation. Our findings demonstrate that Tgm2 overexpression enhances proliferation, bolsters antiapoptotic capacity, and improves monoclonal antibody production efficiency in CHO cells, establishing it as a viable strategy for increasing recombinant protein yields.
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Affiliation(s)
- Hui-Jie Zhang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Qi Zhao
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Miao Zhang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Lu Lu Yang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jumai Abiti
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Ming-Ming Han
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Yan-Ping Gao
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jiang-Tao Lu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jia-Ning Wang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Meng-Ying Ji
- School of Basic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Xi Zhang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Wen Wang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Le-Le Qiu
- School of Basic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Xiao-Yin Wang
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
- School of Basic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Tian-Yun Wang
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
- School of Basic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Yan-Long Jia
- School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China 453003
- International Joint Laboratory of Recombinant Drug Protein Expression System, Xinxiang, Henan China, 453003
- Henan Engineering Research Center for Biopharmaceutical Innovation, Xinxiang Medical University, Xinxiang, Henan 453003, China
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15
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Wang M, Pu N, Bo X, Chen F, Zhou Y, Cheng Q. Significance and mechanisms of perineural invasion in malignant tumors. Front Oncol 2025; 15:1572396. [PMID: 40421086 PMCID: PMC12104087 DOI: 10.3389/fonc.2025.1572396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/18/2025] [Indexed: 05/28/2025] Open
Abstract
Cancer remains the second leading cause of death worldwide. Tumor invasion and metastasis pose significant challenges for clinical management. In addition to the traditional pathways of metastasis such as hematologic or lymphatic transmission, perineural invasion (PNI) has become a unique mechanism of metastasis, which is closely associated with neuropathic pain, motor deficits, and poor prognosis. PNI is often observed in malignant tumors of the pancreas, head and neck, gastrointestinal tract, and lungs, and it reflects a unique neurotropic transfer behavior utilizing neural networks. Despite its clinical significance, targeted therapies for PNI are still lacking. This review synthesizes current evidences regarding PNI, elucidates the clinical significance of PNI in tumor metastasis, prognosis, and neurological dysfunction. By integrating the latest advances in multi-omics, we analyzed the potential key molecular pathways and tumor microenvironment drivers of PNI, and proposed future research directions for developing PNI-specific therapies to improve patient outcomes.
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Affiliation(s)
- Mengyao Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Niu Pu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xitong Bo
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Fuxiang Chen
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Yilong Zhou
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Qiong Cheng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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16
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Lan T, Wu G, Zuo B, Yang J, He P, Zhang Y. Regulation of the immune microenvironment and immunotherapy after liver transplantation. Front Immunol 2025; 16:1602877. [PMID: 40421010 PMCID: PMC12104065 DOI: 10.3389/fimmu.2025.1602877] [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: 03/30/2025] [Accepted: 04/22/2025] [Indexed: 05/28/2025] Open
Abstract
Liver transplantation (LT) is a primary treatment option for patients with end-stage liver disease. However, post-transplantation immune regulation is critical to graft survival and long-term patient outcomes. Following liver transplantation, the recipient's immune system mounts a response against the graft, while the graft promotes anti-rejection immune reactions and the establishment of immune tolerance. In recent years, advances in the study of the immune microenvironment have provided new insights into post-transplantation immune regulation. Meanwhile, immunotherapy strategies have opened new possibilities for improving transplantation success rates and long-term survival. This review summarizes recent progress in understanding the immune microenvironment and immunotherapy following liver transplantation, focusing on key components of the transplant immune microenvironment, their regulatory networks and mechanisms, major immunosuppressive strategies, emerging immunotherapeutic approaches, and current challenges. The aim was to provide a theoretical foundation for optimizing clinical practice.
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Affiliation(s)
- Tianyi Lan
- Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Gang Wu
- Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Bangyou Zuo
- Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jingming Yang
- Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Southwest Medical University, Luzhou, Sichuan, China
| | - Pan He
- Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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17
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Liu C, Zhang J, Ye Z, Luo J, Peng B, Wang Z. Research on the role and mechanism of the PI3K/Akt/mTOR signalling pathway in osteoporosis. Front Endocrinol (Lausanne) 2025; 16:1541714. [PMID: 40421249 PMCID: PMC12104071 DOI: 10.3389/fendo.2025.1541714] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 04/17/2025] [Indexed: 05/28/2025] Open
Abstract
Osteoporosis is a systemic metabolic bone disease characterised mainly by reduced bone mass, bone microstructure degradation, and loss of bone mechanical properties. As the world population ages, more than 200 million people worldwide suffer from the pain caused by osteoporosis every year, which severely affects their quality of life. Moreover, the prevalence of osteoporosis continues to increase. The pathogenesis of osteoporosis is highly complex and is closely related to apoptosis, autophagy, oxidative stress, the inflammatory response, and ferroptosis. The PI3K/Akt/mTOR signalling pathway is one of the most crucial intracellular signal transduction pathways. This pathway is not only involved in bone metabolism and bone remodelling but also closely related to the proliferation and differentiation of osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells. Abnormal activation or inhibition of the PI3K/Akt/mTOR signalling pathway can disrupt the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, ultimately leading to the development of osteoporosis. This review summarises the molecular mechanisms by which the PI3K/Akt/mTOR signalling pathway mediates five pathological mechanisms, namely, apoptosis, autophagy, oxidative stress, the inflammatory response, and ferroptosis, in the regulation of osteoporosis, aiming to provide a theoretical basis for the development of novel and effective therapeutic drugs and intervention measures for osteoporosis prevention and treatment.
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Affiliation(s)
- Chuanlong Liu
- Hunan Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, Hunan, China
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jianqiang Zhang
- Liuyang Traditional Chinese Medicine Hospital, Liuyang, Hunan, China
| | - Ziyu Ye
- Hunan Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, Hunan, China
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ji Luo
- Hunan Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, Hunan, China
| | - Bing Peng
- Hunan Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, Hunan, China
| | - Zhexiang Wang
- Hunan Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, Hunan, China
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18
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Hu D, Chen K. Construction of a circRNA-miRNA-mRNA regulatory network in glioblastoma multiforme based on bioinformatics analysis. Medicine (Baltimore) 2025; 104:e42392. [PMID: 40355207 PMCID: PMC12074040 DOI: 10.1097/md.0000000000042392] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 04/18/2025] [Indexed: 05/14/2025] Open
Abstract
This study aimed to investigate the functional roles and molecular regulatory mechanisms of circular RNAs in the development of glioblastoma multiforme. Differentially expressed circular RNAs were identified by integrating RNA sequencing data and circular RNA microarray data from the Gene Expression Omnibus database. CircAtlas and CircInteractome databases were used to predict microRNAs (miRNAs) interacting with these circular RNAs. Survival analysis of the miRNAs was performed using data from the Chinese Glioma Genome Atlas. The miRTarBase database was used to predict miRNA target genes, followed by the construction of a circular RNA-miRNA-messenger RNA regulatory network specific to glioblastoma multiforme. Functional enrichment analysis was carried out using the DAVID website, and protein-protein interaction networks were created using the Search Tool for the Retrieval of Interacting Genes/Proteins website and Cytoscape. Hub genes were identified, and their expression and prognostic relevance in glioblastoma multiforme were further examined. Four differentially expressed circRNAs and 10 associated miRNAs related to glioblastoma multiforme prognosis were identified. Functional enrichment showed the miRNAs target genes were mainly involved in apoptosis, cell cycle regulation and enriched in cancer-related pathways like mitogen-activated protein kinase and PI3K-Akt. Through the circRNA-miRNA-messenger RNA regulatory network and survival analysis, 3 core genes (core hub genes: catenin beta 1, BCL2, nuclear factor kappa B subunit 1) were identified as significantly downregulated in glioblastoma multiforme and associated with patient survival. This study highlights the potential regulatory roles of circular RNAs in glioblastoma multiforme pathogenesis and their involvement in key molecular pathways. The findings offer a theoretical foundation for understanding glioblastoma multiforme development and may facilitate the identification of novel biomarkers for this aggressive cancer.
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Affiliation(s)
- Dongpo Hu
- School of Medical Technology, Shangqiu Medical College, Shangqiu, Henan, China
| | - Kangjing Chen
- School of Medical Technology, Shangqiu Medical College, Shangqiu, Henan, China
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19
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Jin MY, Yu H, Deng Q, Wang Z, Wang JY, Li HL, Liang H. Virtual screening and molecular dynamics simulation study of ATP-competitive inhibitors targeting mTOR protein. PLoS One 2025; 20:e0319608. [PMID: 40324009 PMCID: PMC12052163 DOI: 10.1371/journal.pone.0319608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 02/04/2025] [Indexed: 05/07/2025] Open
Abstract
In order to explore efficient ATP-competitive mTOR inhibitors and aid the development of targeted anticancer drugs, this study focuses on virtual screening and molecular dynamics simulations. The compounds were sourced from the ChemDiv commercial compound library, and through virtual screening, 50 ligands with favorable binding modes and excellent docking scores were selected from 902,998 compounds. Molecular dynamics simulations, including RMSD (Root Mean Square Deviation) and RMSF (Root Mean Square Fluctuation), were used to further evaluate these 50 ligands. Structural stability, key residue interactions, hydrogen bonding, binding free energy, and other factors were quantitatively and qualitatively analyzed. Top1, top2, and top6, which exhibited outstanding performance, were identified. Simulations revealed that they bind stably in the active region of the mTOR protein, forming hydrogen bonds, π-π interactions, and hydrophobic interactions with key amino acid residues such as VAL-2240 and TRP-2239. This study provides a solid theoretical foundation for the development of mTOR inhibitors. Subsequent efforts will focus on optimizing these compounds, targeting structural adjustments to enhance their biological activity and specificity towards mTOR, thereby achieving more precise targeting and treatment of tumors.
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Affiliation(s)
- Mei-Yu Jin
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Hao Yu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Qiong Deng
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Zhu Wang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Jie-Yan Wang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Hao-Long Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Hui Liang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
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20
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Yu J, Deng X, Lin X, Xie L, Guo S, Lin X, Lin D. DST regulates cisplatin resistance in colorectal cancer via PI3K/Akt pathway. J Pharm Pharmacol 2025; 77:698-713. [PMID: 39419785 DOI: 10.1093/jpp/rgae104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 07/26/2024] [Indexed: 10/19/2024]
Abstract
OBJECTIVES Dystonin (DST), a potential tumor suppressor gene, plays a crucial role in regulating cancer cell proliferation and resistance to chemotherapy. However, DST's specific role in colorectal cancer (CRC) has not been thoroughly investigated, and this study aims to elucidate its molecular role in modulating cisplatin (DDP) resistance in CRC. METHODS DST expression was analyzed in CRC tumors, DDP-resistant CRC tissues, paracancer tissues, and normal tissues. Lentiviral overexpression and shRNA knockdown were conducted in advanced CRC and DDP-resistant cell lines to assess cell viability, apoptosis, invasion, migration, proliferation, and angiogenesis. Xenograft mouse models studied DST's impact on CRC tumor growth and DDP resistance in vivo. RESULTS DST expression was significantly reduced in CRC tumor and DDP-resistant CRC tissues compared to paracancer and normal tissues (P < .001). Upregulating DST inhibited CRC and DDP-resistant cell viability, proliferation, invasion, and migration while promoting apoptosis. DST overexpression also reduced angiogenesis and attenuated DDP-induced cytotoxicity in CRC cells. Mechanistically, DST upregulation suppressed DDP resistance in CRC cells via the PI3K/Akt signaling pathway. DST upregulation reduced CRC tumor growth and mitigated DDP resistance, in vivo. CONCLUSION DST plays a crucial role in limiting CRC progression and overcoming DDP resistance, suggesting potential for targeted CRC therapies.
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Affiliation(s)
- Jianwei Yu
- Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Xueqiong Deng
- Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Xueqin Lin
- Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Li Xie
- Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Sisi Guo
- Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Xiaoliang Lin
- Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Dong Lin
- Department of Gastroenterology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan 364000, Fujian Province, China
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Liao D, He Y, He B, Zeng S, Cui Y, Li C, Huang H. Inhibiting SNX10 induces autophagy to suppress invasion and EMT and inhibits the PI3K/AKT pathway in cervical cancer. Clin Transl Oncol 2025; 27:2084-2094. [PMID: 39367898 DOI: 10.1007/s12094-024-03715-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: 06/02/2024] [Accepted: 09/02/2024] [Indexed: 10/07/2024]
Abstract
PURPOSE Cervical cancer (CC) is a prevalent malignancy among women with high morbidity and poor prognosis. Sorting nexin 10 (SNX10) is a newly recognized cancer regulatory factor, while its action on CC progression remains elusive. Hence, this study studied the effect of SNX10 on CC development and investigated the mechanism. METHODS The SNX10 level in CC and the overall survival of CC cases with different SNX10 expressions were determined by bioinformatics analysis in GEPIA. The SNX10 expression in tumor tissues and clinical significance were studied in 64 CC cases. The overall survival was assessed using Kaplan-Meier analysis. The formation of LC3 was evaluated using immunofluorescence. Cell invasion was measured using the Transwell assay. Epithelial-to-mesenchymal transition (EMT) was determined by observing cell morphology and assessing EMT marker levels. A xenograft tumor was constructed to evaluate tumor growth. RESULTS SNX10 was elevated in CC tissues and cells, and the CC cases with high SNX10 levels exhibited poor overall survival. Besides, SNX10 correlated with the FIGO stage, lymph node invasion, and stromal invasion of CC. SNX10 silencing induced CC cell autophagy and suppressed CC cell invasion and EMT. Meanwhile, silenced SNX10 could suppress invasion and EMT via inducing autophagy. Furthermore, SNX10 inhibition suppressed the PI3K/AKT pathway. Moreover, silenced SNX10 restrained the tumor growth, autophagy, and EMT of CC in vivo. CONCLUSION SNX10 was enhanced in CC and correlated with poor prognosis. Silenced SNX10 induced autophagy to suppress invasion and EMT and inhibited the PI3K/AKT pathway in CC, making SNX10 a valuable molecule for CC therapy.
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Affiliation(s)
- Dan Liao
- Department of Gynaecology, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, No.1, Huangzhou Xianglong Road of Shilong Town, Dongguan, 523326, Guangdong, China.
| | - Yanxian He
- Department of Gynaecology, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, No.1, Huangzhou Xianglong Road of Shilong Town, Dongguan, 523326, Guangdong, China
| | - Bin He
- Clinical Translational Medical Center, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Saitian Zeng
- Department of Gynaecology, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, No.1, Huangzhou Xianglong Road of Shilong Town, Dongguan, 523326, Guangdong, China
| | - Yejia Cui
- Department of Clinical Laboratory, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Cuifen Li
- Department of Gynaecology, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, No.1, Huangzhou Xianglong Road of Shilong Town, Dongguan, 523326, Guangdong, China
| | - Haohai Huang
- Clinical Translational Medical Center, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong, China.
- Department of Clinical Pharmacy, Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, No.1, Huangzhou Xianglong Road of Shilong Town, Dongguan, 523326, Guangdong, China.
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22
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Zhao H, Wu Y, Kim SM. Enhancing doxorubicin's anticancer impact in colorectal cancer by targeting the Akt/Gsk3β/mTOR-SREBP1 signaling axis with an HDAC inhibitor. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2025; 29:321-335. [PMID: 40254556 PMCID: PMC12012316 DOI: 10.4196/kjpp.24.274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 11/05/2024] [Accepted: 11/19/2024] [Indexed: 04/22/2025]
Abstract
Colorectal cancer ranks third in global incidence and is the second leading cause of cancer-related mortality. Doxorubicin, an anthracycline chemotherapeutic drug, is integral to current cancer treatment protocols. However, toxicity and resistance to doxorubicin poses a significant challenge to effective therapy. Panobinostat has emerged as a critical agent in colorectal cancer treatment due to its potential to overcome doxorubicin resistance and enhance the efficacy of existing therapeutic protocols. This study aimed to evaluate the capability of panobinostat to surmount doxorubicin toxicity and resistance in colorectal cancer. Specifically, we assessed the efficacy of panobinostat in enhancing the therapeutic response to doxorubicin in colorectal cancer cells and explored the potential synergistic effects of their combined treatment. Our results demonstrate that the combination treatment significantly reduces cell viability and colony-forming ability in colorectal cancer cells compared to individual treatments. The combination induces significant apoptosis, as evidenced by increased levels of cleaved PARP and cleaved caspase-9, while also resulting in a greater reduction in p-Akt/p-GSK-3β/mTOR expression, along with substantial decreases in c-Myc and SREBP-1 levels, compared to monotherapies. Consistent with the in vitro experimental results, the combination treatment significantly inhibited tumor formation in colorectal cancer xenograft nude mice compared to the groups treated with either agent alone. In conclusion, our research suggests that the panobinostat effectively enhances the effect of doxorubicin and combination of two drugs significantly reduced colorectal cancer tumor growth by targeting the Akt/GSK-3β/mTOR signaling pathway, indicating a synergistic therapeutic potential of these two drugs in colorectal cancer treatment.
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Affiliation(s)
- Huaxin Zhao
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Yanling Wu
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Soo Mi Kim
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
- Research Institute of Clinical Medicine, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
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23
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Zwimpfer TA, Heidinger M, Coelho R, Stiegeler N, Schwab FD, Montavon C, Eller RS, Maggi N, Loesch JM, Vetter M, Lambertini M, Weber WP, Kurzeder C, Heinzelmann-Schwarz V. TP53 Mutations and Phosphatidylinositol 3-Kinase/AKT Pathway Alterations Are Key Determinants of Breast Cancer Outcome Independent of Subtype and Stage. JCO Precis Oncol 2025; 9:e2400767. [PMID: 40403210 PMCID: PMC12122097 DOI: 10.1200/po-24-00767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 02/22/2025] [Accepted: 04/04/2025] [Indexed: 05/24/2025] Open
Abstract
PURPOSE Breast cancer (BC) is a heterogeneous disease with genetic alterations influencing prognosis and treatment response. TP53 mutations (TP53muts) are present in approximately 30% of BC, but their prognostic impact remains controversial. In addition, the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (AKT) pathway is frequently altered and represents a promising therapeutic target for BC. Understanding the combined prognostic impact of TP53mut and PI3K/AKT pathway alterations across BC subtypes remains underexplored. METHODS This retrospective cohort study integrated clinical and genomic data from 4,265 patients with BC from the Molecular Taxonomy of Breast Cancer International Consortium (n = 2,509) and the Memorial Sloan Kettering Cancer Center (n = 1,756). Genetic profiling identified TP53mut and PI3K/AKT pathway alterations (AKT1, AKT2, AKT3, PIK3CA, PTEN, RICTOR). Survival outcomes were assessed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards models. RESULTS In 3,807 patients with available gene alteration status, TP53mut was associated with younger age, higher tumor grade, advanced stage, and aggressive subtypes (P < .001). TP53mut was associated with worse survival independent of subtype, stage, age, and grade (hazard ratio [HR], 1.43 [95% CI, 1.24 to 1.66]; P < .0001). The type of TP53mut has also been found to be prognostic in BC. PI3K/AKT pathway alterations were more frequent in TP53mut tumors and independently associated with worse survival (HR, 1.18 [95% CI, 1.03 to 1.35]; P = .0173). The combined presence of TP53mut and PI3K/AKT alterations resulted in the worst survival outcomes (HR, 1.61 [95% CI, 1.32 to 1.97]; P < .0001). CONCLUSION TP53mut status is a critical prognostic factor in BC, independent of subtypes and stage, and its adverse impact is amplified by PI3K/AKT pathway alterations. These findings emphasize the integration of genetic profiling into routine clinical practice to refine treatment strategies and identify potential therapeutic targets for this high-risk population.
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Affiliation(s)
- Tibor A. Zwimpfer
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Martin Heidinger
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
- Breast Centre, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Ricardo Coelho
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Nadja Stiegeler
- Department of Gynecology and Obstetrics, Bethesda Hospital Basel, Basel, Switzerland
| | - Fabienne D. Schwab
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
- Breast Centre, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Céline Montavon
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Ruth S. Eller
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Nadia Maggi
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
- Breast Centre, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Julie M. Loesch
- Breast Centre, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Marcus Vetter
- Medical Oncology, Cantonal Hospital Baselland, Medical University Clinic, Liestal, Switzerland
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Walter P. Weber
- Breast Centre, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Christian Kurzeder
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
- Breast Centre, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Viola Heinzelmann-Schwarz
- Gynecological Cancer Centre, University Hospital Basel and University of Basel, Basel, Switzerland
- Breast Centre, University Hospital Basel and University of Basel, Basel, Switzerland
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24
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Fang H, Chi X, Wang M, Liu J, Sun M, Zhang J, Zhang W. M2 macrophage-derived exosomes promote cell proliferation, migration and EMT of non-small cell lung cancer by secreting miR-155-5p. Mol Cell Biochem 2025; 480:3019-3032. [PMID: 39612105 DOI: 10.1007/s11010-024-05161-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 11/09/2024] [Indexed: 11/30/2024]
Abstract
Tumor-associated macrophages (TAMs) are a type of highly plastic immune cells in the tumor microenvironment (TME), which can be classified into two main phenotypes: classical activated M1 macrophages and alternatively activated M2 macrophages. As previously reported, M2-polarized TAMs play critical role in promoting the progression of non-small cell lung cancer (NSCLC) via secreting exosomes, but the detailed mechanisms are still largely unknown. In the present study, the THP-1 monocytes were sequentially induced into M0 and M2-polarized macrophages, and the exosomes were obtained from M0 (M0-exos) and M2 (M2-exos) polarized macrophages, respectively, and co-cultured with NSCLC cells (H1299 and A549) to establish the exosomes-cell co-culture system in vitro. As it was determined by MTT assay, RT-qPCR and Transwell assay, in contrast with the M0-exos, M2-exos significantly promoted cell proliferation, migration and epithelial-mesenchymal transition (EMT) process in NSCLC cells. Next, through screening the contents in the exosomes, it was verified that miR-155-5p was especially enriched in the M2-exos, and M2-exos enhanced cancer aggressiveness and tumorigenesis in in vitro NSCLC cells and in vivo xenograft tumor-bearing mice models via delivering miR-155-5p. The detailed molecular mechanisms were subsequently elucidated, and it was found that miR-155-5p bound with HuR to increase the stability and expression levels of VEGFR2, which further activated the tumor-promoting PI3K/Akt/mTOR signal pathway, and M2-exos-enhanced cancer progression in NSCLC cells were apparently suppressed by downregulating VEGFR2 and PI3K inhibitor LY294002 co-treatment. Taken together, M2-polarized TAMs secreted miR-155-5p-containing exosomes to enhanced cancer aggressiveness of NSCLC by activating the VEGFR2/PI3K/Akt/mTOR pathway in a HuR-dependent manner.
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Affiliation(s)
- Hua Fang
- Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, Post Street, Nangang District, Harbin, 150001, China
| | - Xiaowen Chi
- Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, Post Street, Nangang District, Harbin, 150001, China
| | - Mengyao Wang
- Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, Post Street, Nangang District, Harbin, 150001, China
| | - Jing Liu
- Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, Post Street, Nangang District, Harbin, 150001, China
| | - Meiqi Sun
- Respiratory and Critical Care Medicine, The Second Hospital of Heilongjiang Province, Harbin, 150028, China
| | - Jiashu Zhang
- Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, Post Street, Nangang District, Harbin, 150001, China
| | - Wei Zhang
- Respiratory and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, Post Street, Nangang District, Harbin, 150001, China.
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Asghar S, Iliescu R, Stiufiuc RI, Dragoi B. Co-Encapsulation of Multiple Antineoplastic Agents in Liposomes by Exploring Microfluidics. Int J Mol Sci 2025; 26:3820. [PMID: 40332493 PMCID: PMC12027889 DOI: 10.3390/ijms26083820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 05/08/2025] Open
Abstract
The inherent complexity of cancer proliferation and malignancy cannot be addressed by the conventional approach of relying on high doses of a single powerful anticancer agent, which is associated with poor efficacy, higher toxicity, and the development of drug resistance. Multiple drug therapy (MDT) rationally designed to target tumor heterogeneity, block alternative survival pathways, modulate the tumor microenvironment, and reduce toxicities would be a viable solution against cancer. Liposomes are the most suitable carrier for anticancer MDT due to their ability to encapsulate both hydrophilic and hydrophobic agents, biocompatibility, and controlled release properties; however, an adequate manufacturing method is important for effective co-encapsulation. Microfluidics involves the manipulation of fluids at the microscale for the controlled synthesis of liposomes with desirable properties. This work critically reviews the use of microfluidics for the synthesis of anticancer MDT liposomes. MDT success not only relies on the identification of synergistic dose combinations of the anticancer modalities but also warrants the loading of multiple therapeutic entities within liposomes in optimal ratios, the protection of the drugs by the nanocarrier during systemic circulation, and the synchronous release at the target site in the same pattern as confirmed in preliminary efficacy studies. Prospects have been identified for the bench-to-bedside translation of anticancer MDT liposomes using microfluidics.
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Affiliation(s)
- Sajid Asghar
- Nanotechnology Laboratory, TRANSCEND Department, Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot, 700483 Iași, Romania;
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan
| | - Radu Iliescu
- Proteomics Laboratory, TRANSCEND Research Center, Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot Street, 700483 Iași, Romania
- Department of Pharmacology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Iași, Romania
| | - Rares-Ionut Stiufiuc
- Nanotechnology Laboratory, TRANSCEND Department, Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot, 700483 Iași, Romania;
- Department of NanoSciences, MEDFUTURE—Institute for Biomedical Research, “Iuliu Hatieganu” University of Medicine and Pharmacy, 4-6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Brindusa Dragoi
- Nanotechnology Laboratory, TRANSCEND Department, Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot, 700483 Iași, Romania;
- Faculty of Chemistry, Alexandru Ioan Cuza University of Iași, 11 Bd. Carol I, 700506 Iași, Romania
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Gebrehiwot NT, Liu Y, Li J, Liu HM. Molecular Alterations in Gastric Intestinal Metaplasia Shed Light on Alteration of Methionine Metabolism: Insight into New Diagnostic and Treatment Approaches. Biomedicines 2025; 13:964. [PMID: 40299656 PMCID: PMC12025106 DOI: 10.3390/biomedicines13040964] [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] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 05/01/2025] Open
Abstract
Gastric intestinal metaplasia (GIM) is a precancerous lesion and the key risk factor in the development of gastric cancer (GC), but early detection and treatment remain challenging. The traditional endoscopic diagnosis of metaplastic lesions is complicated by an increased rate of inappropriateness and false negativity. Although early interventions with H. pylori eradication, as well as endoscopic therapy results, were promising, there is still a significant unmet need to control GIM progression and recurrences. Molecular alterations, such as an increased DNA methylation index, have been identified as a crucial factor in the downregulation of tumor suppressor genes, such as the caudal-type homeobox (CDX2) gene, which regulates epithelial cell proliferation and GIM progression and is associated with treatment failure. CDX2 is downregulated by promoter hypermethylation in the colonic-type epithelium, in which the methylation was correlated with reduced intake of dietary folate sources. Tumor cells alter to dietary methionine sources in the biosynthesis of S-Adenosylmethionine, a universal methyl donor for transmethylation, under the conditions of limited folate and B12 availability. The gut microbiota also exhibited a shift in microbial composition, which could influence the host's dietary methionine metabolism. Meanwhile, activated oncogenic signaling via the PI3K/Akt/mTORC1/c-MYC pathway could promotes rewiring dietary methionine and cellular proliferation. Tumor methionine dependence is a metabolic phenotype that could be helpful in predictive screening of tumorigenesis and as a target for preventive therapy to enhance precision oncology. This review aimed to discuss the molecular alterations in GIM to shed light on the alteration of methionine metabolism, with insight into new diagnostic and treatment approaches and future research directions.
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Affiliation(s)
- Nigatu Tadesse Gebrehiwot
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
| | - Ying Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;
| | - Juan Li
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
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27
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Yuan Y, Chu G, Ma Q, Liang Z, Liang Y, Niu H. Multiscale screening and identifying specific targets for artesunate in suppressing bladder cancer. Front Pharmacol 2025; 16:1584502. [PMID: 40303931 PMCID: PMC12037512 DOI: 10.3389/fphar.2025.1584502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025] Open
Abstract
Background Bladder cancer (BLCA) is a highly aggressive urinary malignancy with high mortality in advanced stages, posing a significant health risk. Artesunate (ART), a derivative of artemisinin, has been demonstrated with potent anti-tumor activity in some studies, yet its specific targets for BLCA and the molecular mechanisms have not been fully elucidated. Purpose This study screened potential targets of ART against BLCA through network pharmacology, followed by molecular docking simulations and experimental validation in vitro and in vivo to elucidate the underlying mechanisms. Methods This study identified the critical targets of BLCA and ART by employing multiscale screening from public databases, and a protein-protein interaction (PPI) network was constructed. Molecular docking simulations confirmed the stable binding of ART to the identified tumor-related targets promoting BLCA progression. These computational findings were further validated through experiments in vivo and in vitro, ensuring robust and reliable results. Results Based on network pharmacology analysis, the effects of ART on BLCA were multifaceted. Molecular docking simulations confirmed the binding stability of ART with core targets. The experiments in vitro proved that ART could inhibit BLCA cell proliferation and migration by downregulating the expression of BCL-2, inducing Caspase 3-mediated apoptosis, resulting in cell cycle arrest and suppressing the PI3K/Akt/mTOR classical pathway involved in BLCA growth and metabolism. Studies in vivo also confirmed that ART had significant anti-tumor effects with minimal side effects. Conclusion This study identified the mechanism by which ART inhibited BLCA through multiple specific targets, revealing its potential anti-cancer pathways and laying the foundation for the clinical application of traditional Chinese medicine in BLCA therapy.
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Affiliation(s)
- Yi Yuan
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guangdi Chu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qingyue Ma
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhijuan Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ye Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haitao Niu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Popovici IA, Orasanu CI, Cozaru GC, Ionescu AC, Kajanto L, Cimpineanu B, Chisoi A, Mitroi AN, Poinareanu I, Voda RI, Ursica OA, Pundiche MB. An Overview of the Etiopathogenic Mechanisms Involved in the Expression of the Oral Microbiota. Clin Pract 2025; 15:80. [PMID: 40310312 PMCID: PMC12026067 DOI: 10.3390/clinpract15040080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/17/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025] Open
Abstract
Background/Objectives: The diversity of the oral microbiota exerts its effects in maintaining dental and overall health. The unique genetic profile of each individual influences the composition of the oral microbiota, determining susceptibility to certain diseases. The aim is to observe its role by highlighting the pathogenic mechanisms involved in oral dysbiosis and identify genetic determinism's influence in maintaining balance. Methods: This study was designed as a narrative review of the oral microbiota, utilizing some of the principles and guidelines of systematic review to increase methodological rigor. We examined 121 articles such as reviews, meta-analyses, editorials, and observational studies, which met the inclusion and exclusion criteria. The inclusion criteria for studies were as follows: (1) studies that evaluated the impact of the microbiota in oral or/and systemic diseases; (2) studies that observed pathogenic mechanisms in the oral microbiota; (3) studies that evaluated the interaction of the microbiota with the immune system (4); studies that evaluated genetic implications in the microbiota. Results: Host genes regulate inflammatory and immunological reactions that play a role in microbiological balance. This explains the increased resistance of some to diseases, including gingivitis or periodontitis. Also, the implications of oral dysbiosis are reflected not only locally, but also generally, being associated with various systemic conditions. Conclusions: Understanding the pathogenic mechanisms and genetic determinants involved in oral dysbiosis may help create individualized therapies for preventing and managing oral and systemic disorders. A healthy lifestyle and adequate oral hygiene can facilitate a diverse and balanced microbiome, crucial for overall health.
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Affiliation(s)
- Ion Alexandru Popovici
- Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 010221 Bucharest, Romania;
| | - Cristian Ionut Orasanu
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
| | - Georgeta-Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Anita-Cristina Ionescu
- Oncological Institute “Prof. Dr. Alexandru Trestioreanu”, 022328 Bucharest, Romania; (A.-C.I.); (L.K.)
| | - Lidia Kajanto
- Oncological Institute “Prof. Dr. Alexandru Trestioreanu”, 022328 Bucharest, Romania; (A.-C.I.); (L.K.)
| | - Bogdan Cimpineanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Adrian Nelutu Mitroi
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- Railway Clinical Hospital, 900123 Constanta, Romania
| | - Ionut Poinareanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
| | - Raluca Ioana Voda
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
| | - Oana Andreea Ursica
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Mihaela Butcaru Pundiche
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
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Mottaghi S, Abbaszadeh H, Valizadeh A, Hafezi K. The polyphenolic compound, α-conidendrin, exerts anti-colon cancer and anti-angiogenic effects by targeting several signaling molecules. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04090-2. [PMID: 40208320 DOI: 10.1007/s00210-025-04090-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 03/21/2025] [Indexed: 04/11/2025]
Abstract
Our previous study indicated that α-conidendrin had considerable anti-proliferative activities against breast cancer cell lines. The present study aimed to evaluate the anti-colon cancer and anti-angiogenic influences of α-conidendrin as well as its molecular mechanisms. The findings of the current study demonstrate that α-conidendrin possesses potent anti-colon cancer and anti-angiogenic effects. α-Conidendrin significantly inhibited the proliferation of colon cancer cells. This polyphenolic compound induced caspase-mediated apoptosis in HT-29 cells by modulating the PTEN/PI3K/Akt/mTOR signaling pathway. α-Conidendrin markedly upregulated the protein expression of PTEN and downregulated the protein expression of p-PI3K, p-AKt, and p-mTOR. The protein expression of caspase-3 and caspase-9 enhanced in colon cancer cells following treatment with α-conidendrin. This study also revealed the anti-angiogenic activities of α-conidendrin in the ex vivo and in vitro models. α-Conidendrin significantly downregulated the mRNA expression of HIF-1α, VEGF, MMP-2, and MMP-9 in endothelial cells. These data highlight that α-conidendrin can act as a novel and promising anti-cancer and anti-angiogenic agent for treatment of colon cancer.
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Affiliation(s)
- Sayeh Mottaghi
- Department of Pediatrics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hassan Abbaszadeh
- Department of Pharmacology, Faculty of Pharmacy, Medicinal Plants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Armita Valizadeh
- Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Katayoon Hafezi
- Department of Pharmacology, Faculty of Pharmacy, Medicinal Plants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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30
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Gergues M, Bari R, Koppisetti S, Gosiewska A, Kang L, Hariri RJ. Senescence, NK cells, and cancer: navigating the crossroads of aging and disease. Front Immunol 2025; 16:1565278. [PMID: 40255394 PMCID: PMC12006071 DOI: 10.3389/fimmu.2025.1565278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/18/2025] [Indexed: 04/22/2025] Open
Abstract
Cellular senescence, a state of stable cell cycle arrest, acts as a double-edged sword in cancer biology. In young organisms, it acts as a barrier against tumorigenesis, but in the aging population, it may facilitate tumor growth and metastasis through the senescence-associated secretory phenotype (SASP). Natural killer (NK) cells play a critical role in the immune system, particularly in the surveillance, targeting, and elimination of malignant and senescent cells. However, age-related immunosenescence is characterized by declining NK cell function resulting in diminished ability to fight infection, eliminate senescent cells and suppress tumor development. This implies that preserving or augmenting NK cell function may be central to defense against age-related degenerative and malignant diseases. This review explores the underlying mechanisms behind these interactions, focusing on how aging influences the battle between the immune system and cancer, the implications of senescent NK cells in disease progression, and the potential of adoptive NK cell therapy as a countermeasure to these age-related immunological challenges.
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Affiliation(s)
| | | | | | | | - Lin Kang
- Research and Development, Celularity Inc., Florham Park, NJ, United States
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31
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Haddadin L, Sun X. Stem Cells in Cancer: From Mechanisms to Therapeutic Strategies. Cells 2025; 14:538. [PMID: 40214491 PMCID: PMC11988674 DOI: 10.3390/cells14070538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 03/23/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer.
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Affiliation(s)
| | - Xueqin Sun
- Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
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32
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Zeng B, Shi H, Liu T, Tang J, Lin J, Lin X, Zeng T. The influence of homologous recombination repair on temozolomide chemosensitivity in gliomas. Carcinogenesis 2025; 46:bgaf017. [PMID: 40120126 DOI: 10.1093/carcin/bgaf017] [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: 11/18/2024] [Revised: 02/22/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025] Open
Abstract
Gliomas represent a prevalent form of primary brain tumors, with temozolomide (TMZ) serving as the established first-line therapeutic option. Nevertheless, the effectiveness of TMZ is hindered by the development of chemoresistance. Recent investigations have underscored the correlation of homologous recombination repair (HRR), a pivotal mechanism responsible for mending DNA double-strand breaks, with TMZ resistance in glioma treatment. This review centers on elucidating the significance of HRR in the management of gliomas, with a particular emphasis on pivotal molecules implicated in the HRR process, including RAD51, ATM, ATR, and newly identified small molecules that impact HRR. Modulating the expression of these genes can effectively restrain pathways such as ATM/CHK2, ATR/CHK1, and PI3K/AKT, subsequently augmenting the sensitivity of gliomas to TMZ. Noteworthy efforts have been directed towards exploring inhibitors of these pathways in recent research endeavors, culminating in encouraging outcomes. In conclusion, the involvement of HRR in glioma resistance unveils novel therapeutic avenues, with targeting crucial molecules in the HRR pathway, holding promise for enhancing the effectiveness of TMZ therapy.
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Affiliation(s)
- Biyun Zeng
- Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P. R. China
- School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong 523808, P. R. China
| | - Hansen Shi
- Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P. R. China
| | - Tiancai Liu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
| | - Jinjing Tang
- Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P. R. China
| | - Juncheng Lin
- School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong 523808, P. R. China
| | - Xiaocong Lin
- Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P. R. China
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, Guangdong 524023, P. R. China
| | - Tao Zeng
- Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P. R. China
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Srinivasan MK, Namasivayam N. Evaluating the in vitro and in vivo effects of carvacrol zinc oxide quantum dots in breast cancer. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2025; 36:796-815. [PMID: 39625392 DOI: 10.1080/09205063.2024.2429325] [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: 09/26/2024] [Accepted: 11/08/2024] [Indexed: 12/31/2024]
Abstract
The study investigates the molecular interactions and biological effects of carvacrol zinc oxide quantum dots (CVC-ZnO QDs) on breast cancer in vitro MCF-7 cell lines and in vivo mammary cancer models. Molecular docking using AutoDock Vina revealed binding energies of CVC with key proteins in the PI3K/AKT/mTOR pathway, including PI3K, AKT, PTEN, and mTOR. The results showed significant interaction with specific amino acids, indicating a strong binding affinity. In vitro studies demonstrated a dose-dependent cytotoxic effect of CVC-ZnO QDs on MCF-7 cells, with an IC50 of 20.02 µg/mL, while enhancing intracellular reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), indicative of apoptosis induction. Antioxidant activity, lipid peroxidation, and nuclear morphological changes were assessed, revealing decreased antioxidant status and increased lipid peroxidation in treated cells. In vivo, CVC-ZnO QDs modulated the PI3K/AKT/mTOR signaling in DMBA-induced mammary cancer in rats, decreasing p-PI3K, p-AKT, and p-mTOR expression while upregulating PTEN. Immunohistochemistry, qRT-PCR, and Western blot analyses confirmed these molecular alterations. The study concludes that CVC-ZnO QDs exert cytotoxic and pro-apoptotic effects on breast cancer cells by modulating the PI3K/Akt/mTOR pathway and promoting oxidative stress, presenting a potential therapeutic strategy for breast cancer management.
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Affiliation(s)
- Manoj Kumar Srinivasan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamilnadu, India
| | - Nalini Namasivayam
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamilnadu, India
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Lin W, Wang S, Liu R, Zhang D, Zhang J, Qi X, Li Z, Miao M, Cai X, Su G. Research progress of cPLA2 in cardiovascular diseases (Review). Mol Med Rep 2025; 31:103. [PMID: 39981923 PMCID: PMC11868774 DOI: 10.3892/mmr.2025.13468] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/28/2025] [Indexed: 02/22/2025] Open
Abstract
Cytoplasmic phospholipase A2 (cPLA2) is a vital member of the PLA2 family. Studies have demonstrated that cPLA2 plays a key role in various inflammatory‑related diseases and cancers. However, limited research has focused on cPLA2 in cardiovascular diseases. The present review discussed and summarized the research progress on cPLA2 in atherosclerosis, cardiomyopathy, myocardial ischemia‑reperfusion injury and other related conditions. It also highlighted the critical molecular mechanisms by which cPLA2 regulates the pathophysiological processes of vascular endothelial cells, platelets and myocardial cells in cardiovascular diseases. Current studies confirm that cPLA2 plays an important role in cardiovascular diseases and has the potential to become a therapeutic target for the diagnosis, treatment evaluation and prognosis of these conditions. The present review systematically explored the significant role of cPLA2 in cardiovascular diseases and elaborated on its underlying molecular mechanisms. The findings aimed to refine the theoretical understanding of cardiovascular disease pathogenesis and provide a foundation for developing novel treatment strategies.
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Affiliation(s)
- Wenyu Lin
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Shuya Wang
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Ronghan Liu
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Dan Zhang
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Jiaxing Zhang
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Xiaohan Qi
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Zheng Li
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Meng Miao
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
| | - Xiaojun Cai
- Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Guohai Su
- Department of Cardiovascular Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250013, P.R. China
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Liu S, Liu T, Li J, Hong J, Moosavi-Movahedi AA, Wei J. Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors. Neurosci Bull 2025; 41:676-690. [PMID: 39754628 PMCID: PMC11978575 DOI: 10.1007/s12264-024-01342-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 10/15/2024] [Indexed: 01/06/2025] Open
Abstract
Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
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Affiliation(s)
- Shufen Liu
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Tingting Liu
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Jingwen Li
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Jun Hong
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | | | - Jianshe Wei
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China.
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China.
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36
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Oliveira SB, Machado MQ, Sousa D, Pereira SS, Pignatelli D. The differential diagnosis of adrenocortical tumors: systematic review of Ki-67 and IGF2 and meta-analysis of Ki-67. Rev Endocr Metab Disord 2025; 26:261-278. [PMID: 39890749 PMCID: PMC11920293 DOI: 10.1007/s11154-025-09945-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2025] [Indexed: 02/03/2025]
Abstract
Distinguishing benign from malignant adrenocortical tumors (ACT) is not always easy, particularly for tumors with unclear malignant potential based on the histopathological features comprised of the Weiss score. Previous studies reported the potential utility of immunohistochemistry (IHC) markers to recognize malignancy, in particular the Insulin-like growth factor 2 (IGF2) and the proliferation marker, Ki-67. However, this information was not compiled before. Therefore, this review aimed to collect the evidence on the potential diagnosis utility of IGF2 and Ki-67 IHC staining. Additionally, a meta-analysis was performed to assess the Ki-67 accuracy to identify adrenocortical carcinoma. The systematic review and meta-analysis were conducted according to the PRISMA guidelines. From the 26 articles included in the systematic review, 21 articles provided individual data for IGF2 (n = 2) or for Ki-67 (n = 19), while 5 studies assessed both markers. IGF2 staining was positive in most carcinomas, in contrast to adenomas. However, the different immunostaining evaluation methods adopted among the studies impeded to perform a meta-analysis to assess IGF2 diagnostic accuracy. In contrast, for the most commonly used cut-off value of 5% stained cells, Ki-67 showed pooled specificity, sensitivity and log diagnostic odds ratio of 0.98 (95% CI 0.95 to 0.99), 0.82 (95% CI 0.65 to 0.92) and 4.26 (95% CI 3.40 to 5.12), respectively. At the 5% cut-off, Ki-67 demonstrated an excellent specificity to recognize malignant ACT. However. the moderate sensitivity observed indicates the need for further studies exploring alternative threshold values. Additionally, more studies using similar approaches are needed to assess the diagnostic accuracy of IGF2.Registration code in PROSPERO: CRD42022370389.
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Affiliation(s)
- Sofia B Oliveira
- UMIB - Unit for Multidisciplinary Research in Biomedicine; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- Department of Endocrinology, Unidade Local de Saúde de São João, Porto, Portugal
| | - Mariana Q Machado
- UMIB - Unit for Multidisciplinary Research in Biomedicine; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - Diana Sousa
- UMIB - Unit for Multidisciplinary Research in Biomedicine; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
- Faculdade de Medicina Dentária, UCP - Universidade Católica Portuguesa, Viseu, Portugal
| | - Sofia S Pereira
- UMIB - Unit for Multidisciplinary Research in Biomedicine; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.
| | - Duarte Pignatelli
- UMIB - Unit for Multidisciplinary Research in Biomedicine; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
- Department of Endocrinology, Unidade Local de Saúde de São João, Porto, Portugal
- Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
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Okuda K, Takagi A, Shimizu R, Nishi K, Hayano N, Takashima I, Konishi M. Total Synthesis of Antiausterity Agent Callistrilone O Reveals Promising Antitumor Activity in a Melanoma Homograft Mouse Model. ChemMedChem 2025; 20:e202400818. [PMID: 39812162 DOI: 10.1002/cmdc.202400818] [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: 10/17/2024] [Revised: 12/16/2024] [Accepted: 01/13/2025] [Indexed: 01/16/2025]
Abstract
The antiausterity strategy in anticancer drug discovery has attracted much attention as a way to exterminate cancer cells under nutrient deprived conditions which are commonly found in solid tumors. These tumors under low nutrient stress are known to be malignant and often resist conventional drug therapy. As a potential drug candidate, we focused on the meroterpenoid natural product callistrilone O which has demonstrated extremely potent antiausterity properties toward PANC-1 pancreatic carcinoma in vitro. Here, we report for the first time the total synthesis of callistrilone O in seven steps from phloroglucinol. A Friedel-Crafts-type Michael addition and an oxidative [3+2] cycloaddition with Fetizon's reagent were used to construct the molecular skeleton. The preferential cytotoxicity of callistrilone O was also evaluated with multiple starvation-resistant cancer cell lines under low nutrient conditions. Furthermore, callistrilone O was found to strongly suppress B16 melanoma tumor growth without critical toxicity in vivo. Overall, this study presents a novel anticancer agent candidate from natural products with a concise synthetic route which can be readily applied to the synthesis of derivatives.
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Affiliation(s)
- Kensuke Okuda
- Laboratory of Bioorganic & Natural Products Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan
| | - Akira Takagi
- Laboratory of Bioorganic & Natural Products Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan
| | - Ryohei Shimizu
- Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan
- Department of Molecular Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo, 142-8501, Japan
| | - Kensuke Nishi
- Laboratory of Bioorganic & Natural Products Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan
| | - Narumi Hayano
- Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan
| | - Ippei Takashima
- Laboratory of Bioorganic & Natural Products Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba, Sendai, Miyagi, 980-8577, Japan
| | - Morichika Konishi
- Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan
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Li Y, Niu J, Sun Z, Liu J. FTO-mediated m6A Methylation of KCNAB2 Inhibits Tumor Property of Non-Small Cell Lung Cancer Cells and M2 Macrophage Polarization by Inactivating the PI3K/AKT Pathway. J Biochem Mol Toxicol 2025; 39:e70232. [PMID: 40114527 DOI: 10.1002/jbt.70232] [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: 04/01/2024] [Revised: 01/11/2025] [Accepted: 03/09/2025] [Indexed: 03/22/2025]
Abstract
Potassium voltage-gated channel subfamily A regulatory beta subunit 2 (KCNAB2) is a potassium voltage-gated channel subfamily A member that plays a role in non-small cell lung cancer (NSCLC). However, its functional impact and mechanism in NSCLC are not fully understood. Here, we analyzed its effects on NSCLC cell behaviors and the underlying mechanism.mRNA expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR),(qRT-PCR), while protein expression was quantified by western blotting blot analysis or immunohistochemistry assay. NSCLC cell proliferation, migration, invasion, macrophage polarization, and apoptosis were evaluated through cell-based assays including cell counting kit-8 (CCK-8)(CCK-8) assay, flow cytometry, Tunel assay, wound-healing assay, and transwell invasion assay. The role of FTO alpha-ketoglutarate dependent dioxygenase (FTO)-mediated(FTO)-mediated m6A methylation in the regulation of KCNAB2 expression and their impacts on NSCLC cell behavior and M2 macrophage polarization were assessed through m6A RNA immunoprecipitation assay and rescue experiments. Xenograft mouse model assay was used to determine the effect of KCNAB2 on tumor formation in vivo.in vivo.KCNAB2 expression was downregulated and FTO expression was upregulated in NSCLC tissues and cells when compared with controls. Moreover, the expression of KCNAB2 was found to be lower in stage III NSCLC patients compared to those at stages I and II, and it was also lower in patients with positive lymph node metastasis compared to those with negative lymph node metastasis. Overexpression of KCNAB2 inhibited NSCLC cell proliferation, migration, invasion, and M2 macrophage polarization, while inducing cell apoptosis. These effects were mediated, at least partially, by inactivating the phosphoinositide 3-kinase (PI3K)/AKT(PI3K)/AKT pathway. Moreover, ectopic expression of KCNAB2 delayed tumor formation in vivo. FTOin vivo. FTO was found to mediate m6A methylation of KCNAB2, and knockdown of FTO resulted in the upregulation of KCNAB2 expression, leading to inhibition of NSCLC cell behavior and M2 macrophage polarization.KCNAB2 overexpression inhibited NSCLC cell behavior and M2 macrophage polarization by inactivating the PI3KPI3K/AKT/AKT pathway. Furthermore, FTOFTO-mediated-mediated m6A methylation was involved in the regulation of KCNAB2 expression in NSCLC. These results enhance our understanding of the role of KCNAB2 in NSCLC and suggest its potential as a therapeutic target.
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Affiliation(s)
- Yanguang Li
- Department of thoracic surgery, Cangzhou Central Hospital, Cangzhou City, Hebei Province, China
| | - Jieting Niu
- Department of geriatric internal medicine, Cangzhou Central Hospital, Cangzhou City, Hebei Province, China
| | - Zhiguang Sun
- Department of thoracic surgery, Cangzhou Hospital of Integrated TCM-WM, Cangzhou City, Hebei Province, China
| | - Junfeng Liu
- Department 3 of thoracic, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
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Xuan W, Liang C, Yang S, Zheng L, Wu X, Zhang X. FABP4 expression in neutrophils as a predictor of sepsis and SI-ARDS based on BALF transcriptome and peripheral blood validation. Chin Med J (Engl) 2025:00029330-990000000-01499. [PMID: 40169352 DOI: 10.1097/cm9.0000000000003447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND The objective of this study is to delineate the differential gene expression patterns of neutrophils in bronchoalveolar lavage fluid (BALF) from patients with sepsis and those experiencing progression to sepsis-induced acute respiratory distress syndrome (SI-ARDS). Additionally, we aim to comprehensively profile the transcriptomic landscape of neutrophils in BALF from patients with sepsis and SI-ARDS, particularly focusing on cases caused by specific bacterial pathogens. METHODS Patients with confirmed sepsis (n = 14) or SI-ARDS (n = 11) were recruited. Besides, a control group consisting of patients with unrelated diseases (n = 7) who required bronchoscopy was also included (cohort 1). We collected the neutrophils in BALF from participants in cohort 1. To validate the identified differentially expressed genes (DEGs) and evaluate neutrophil apoptosis, an additional cohort (cohort 2) was recruited, consisting of 5 healthy controls, 10 patients with sepsis, and 10 patients with SI-ARDS. Peripheral blood neutrophils were collected from participants in cohort 2 for further analysis. DEGs between SI-ARDS patients and controls, sepsis patients and controls, as well as SI-ARDS patients and sepsis patients were identified. And, publicly available datasets were downloaded to compare with local results. Additionally, the DEGs were also identified between patients infected with drug-resistant Klebsiella pneumoniae and those infected with other bacterial pathogens. Furthermore, a third cohort (cohort 3) consisting of 57 sepsis patients and 46 SI-ARDS patients was recruited for investigating the prognostic significance of neutrophils in SI-ARDS. RESULTS In cohort 1, 8/14 of the septic patients and 6/11 of the SI-ARDS patients were affected by drug-resistant Klebsiella pneumonia. There were 9921 DEGs between sepsis patients and controls, 10,252 DEGs between SI-ARDS patients and controls, and 24 DEGs between SI-ARDS and sepsis patients in neutrophils from BALF. Notably, fatty acid-binding pro-tein 4 (FABP4) exhibited significant downregulation in SI-ARDS patients. In cohort 2, peripheral blood analysis confirmed consistent trends, demonstrating that FABP4 expression was decreased, which contributed to the attenuation of neutrophil apoptosis. And FABP4 inhibitor-induced apoptosis resistance was reversed by a phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) inhibitor. Furthermore, survival analysis revealed that SI-ARDS patients with low levels of neutrophil FABP4 expression exhibited poor survival. Additionally, 520 overlapping DEGs were identified between the sepsis and control group comparisons and the SI-ARDS and sepsis group comparisons. Among these overlapping DEGs, 85% were downregulated, predominantly targeting immune-related pathways, whereas a smaller subset was upregulated, mainly associated with metabolism. DEGs in neutrophils in BALF of SI-ARDS and controls notably overlapped with those in neutrophils in peripheral blood. Importantly, DEGs in sepsis/SI-ARDS caused by drug-resistant Klebsiella pneumoniae differed from DEGs in sepsis/SI-ARDS caused by other bacteria. Additionally, FABP4 expression consistently decreased, attenuating neutrophil apoptosis. CONCLUSIONS The downregulation of FABP4 in neutrophils was found to inhibit apoptosis through the activation of the PI3K/AKT signaling pathway. Importantly, the expression level of FABP4 in neutrophil emerged as a prognostic indicator for sepsis and SI-ARDS patients, suggesting its potential utility in clinical decision-making to address the challenges posed by this condition.
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Affiliation(s)
- Weixia Xuan
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing 100000, China
- Department of Pulmonary and Critical Care Medicine, National Center for Respiratory Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing 100000, China
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Chaofan Liang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Shenying Yang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Longcheng Zheng
- Department of Respiratory and Critical Care Medicine, People's Hospital of Henan University, People's Hospital of Henan Province, Zhengzhou, Henan 450003, China
| | - Xu Wu
- Department of Scientific Research, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 41000, China
| | - Xiaoju Zhang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
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Sun W, Chao G, Wu Q, Xia Y, Shang M, Wei Q, Zhou J, Liao L. Astragaloside IV improves the survival rates of retinal ganglion cells in traumatic optic neuropathy by regulating autophagy mediated by the AMPK-MTOR-ULK signaling pathway. Mol Vis 2025; 31:99-112. [PMID: 40384763 PMCID: PMC12085218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 03/26/2025] [Indexed: 05/20/2025] Open
Abstract
Purpose Autophagy is involved in the pathological changes of traumatic optic neuropathy (TON), and the regulation of autophagy mediated by the AMPK-mTOR-ULK pathway is a potential therapeutic approach. Astragaloside IV (AS-IV) can regulate autophagy and play a therapeutic role in various diseases. This study aimed to observe the therapeutic effect of astragaloside on TON and the role of AMPK-MTOR-ULK pathway-mediated autophagy in this process. Methods After the TON model was established, varying doses of AS-IV were administered as an intervention. Additionally, compound C (an AMPK inhibitor) or 3-methyladenine (an autophagy inhibitor) was administered intraperitoneally in conjunction with AS-IV. Samples were collected following a 7-day intervention period. Western blot analysis was conducted to measure the protein and phosphorylation levels of AMPK, mTOR, and ULK proteins. Moreover, western blot and quantitative reverse transcription PCR assays were used to quantify LC3 levels in retinal tissue. LC3 immunofluorescence was performed to examine autophagy levels in the ganglion cell layer (GCL), while transmission electron microscopy was employed to observe autophagosomes. Additionally, BRN3A immunofluorescence was used to label retinal ganglion cells (RGCs) in the GCL, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used to assess apoptosis within the GCL. Finally, optic nerve conduction function was evaluated using flash visual evoked potentials. Results After 7 days, the phosphorylation levels of AMPK, mTOR, and ULK proteins in retinal tissue exhibited significant changes following TON. AS-IV treatment enhanced LC3 messenger RNA and protein levels in TON model rats, and the autophagy-promoting effect of AS-IV was reversed by 3-methyladenine. Moreover, AS-IV elevated P-AMPK and P-ULK levels while decreasing P-mTOR levels. AS-IV also improved the survival rate of RGCs and reduced the P2 peak latency of flash visual evoked potentials. These effects were attenuated by the AMPK inhibitor compound C. Additionally, AS-IV increased the levels of AKT1 and P-AKT1 while decreasing P-S6RP levels in the retinal tissue of TON model rats. Conclusions AS-IV can increase the survival rate of RGCs and improve visual function after TON, which may be related to the improvement of autophagy by regulating the AMPK-MTORC1-ULK pathway.
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Affiliation(s)
- Wu Sun
- Department of Ophthalmology, Xiyuan Hospital China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Guojun Chao
- Eye Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Qiong Wu
- Beijing Tongren Hospital, Beijing, China
| | - Yanting Xia
- Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mengqiu Shang
- Eye Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China
- Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qiping Wei
- Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jian Zhou
- Beijing University of Chinese Medicine, Beijing, China
- Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Liang Liao
- Beijing University of Chinese Medicine, Beijing, China
- Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
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Tripathi KL, Dwivedi VD, Badoni H. Pharmacophore modeling and molecular dynamics simulations to study the conformational stability of natural HER2 inhibitors in breast cancer therapy. Mol Divers 2025:10.1007/s11030-025-11165-y. [PMID: 40126740 DOI: 10.1007/s11030-025-11165-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 03/07/2025] [Indexed: 03/26/2025]
Abstract
HER2-positive breast cancer remains a significant clinical challenge, often exhibiting resistance to standard therapies. This study applies a comprehensive in silico approach to identify the natural compounds with potential inhibitory effects on HER2, focusing on pharmacophore modeling, virtual screening, molecular dynamics (MD) simulations, and binding affinity estimation. Initially, 24 known HER2 inhibitors from the BindingDB database were analyzed using Schrödinger's Phase module to generate a pharmacophore model, highlighting one hydrophobic (H) and three aromatic rings (RRR) features essential for HER2 binding. Screening against the Coconut Database, comprising 406,076 natural compounds, yielded 60,581 hits that matched the HRRR pharmacophore. These hits underwent a rigorous docking workflow with Glide (HTVS, SP, and XP modes), narrowing the candidates to 757 compounds with high binding affinity. Further refinement using Lipinski's rule of five produced a final set of 12 compounds exhibiting drug-like properties. 500-ns MD simulations evaluated these complexes' stability and dynamic behavior, while MM-GBSA calculations confirmed strong binding affinities dominated by van der Waals and electrostatic interactions. Compounds CNP0116178, CNP0356942, and CNP0136985 demonstrated superior binding profiles compared to the reference, marking them as lead candidates for HER2 inhibition. This study underscores the efficacy of computational methods in early-stage drug discovery and highlights promising candidates for further experimental validation and optimization. These findings offer a basis for developing targeted HER2 therapies and demonstrate the potential of natural compounds in advancing breast cancer treatment.
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Affiliation(s)
- Kanchan Lata Tripathi
- Department of Biotechnology, School of Applied and Life Sciences, Uttaranchal University, Premnagar, Dehradun, 248006, India
| | - Vivek Dhar Dwivedi
- Saveetha Institute of Medical and Technical Sciences, Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha University, Chennai, India.
- Bioinformatics Research Division, Quanta Calculus, Greater Noida, India.
| | - Himani Badoni
- Department of Biotechnology, School of Applied and Life Sciences, Uttaranchal University, Premnagar, Dehradun, 248006, India.
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Qin L, Lu J, Qian Q, Tang M, Liu M. PNO1 enhances ovarian cancer cell growth, invasion, and stemness via activating the AKT/Wnt/β-catenin pathway. Sci Rep 2025; 15:9656. [PMID: 40113869 PMCID: PMC11926344 DOI: 10.1038/s41598-025-93519-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 03/07/2025] [Indexed: 03/22/2025] Open
Abstract
PNO1, a key promoter of oncogenesis, is often characterized by its aberrant expression in both colorectal and esophageal cancers, markedly accelerating their progression. Nonetheless, the role of PNO1 in ovarian cancer and its underlying mechanisms remain unexplored comprehensively. In addition to the abnormal PNO1 expression in ovarian cancer tissues by The Cancer Genome Atlas (TCGA) database, the clinical data examinations indicated its strong association with lower survival rates among ovarian cancer patients. Considering the crucial role of the AKT signaling pathway, we hypothesized that PNO1 might drive the progression of ovarian cancer by modulating the AKT pathway. To validate this hypothesis, experiments were conducted to silence PNO1 in ovarian cancer cells. These findings demonstrated that PNO1 silencing markedly reduced the proliferation and invasion capabilities of ovarian cancer cell lines, triggering their apoptosis. Moreover, the PNO1 suppression significantly decreased the expression levels of p-AKT, GSK-3β, and active β-catenin proteins, further confirming the regulatory correlation between PNO1 and the AKT/Wnt/β-catenin pathway. The oncogenic effects mediated by the PNO1-activated Wnt/β-catenin pathway were counteracted by inhibitors of the AKT signaling pathway. Further, the subcutaneous xenograft tumor assays in vivo validated that PNO1 silencing decreased the tumorigenic potential of ovarian cancer cells. In summary, this study has elucidated that the upregulation of PNO1 modulated the tumorigenic role of the AKT/Wnt/β-catenin pathway in ovarian cancer, offering new insights into its oncogenic function.
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Affiliation(s)
- Lu Qin
- Department of Pathology, Jingjiang Traditional Chinese Medicine Hospital of Jiangsu Province, 29 Kangning Road, Jingjiang, 214500, Jiangsu, China
| | - Jiao Lu
- Department of Pathology, Jingjiang Traditional Chinese Medicine Hospital of Jiangsu Province, 29 Kangning Road, Jingjiang, 214500, Jiangsu, China
| | - Qiaohong Qian
- Department of Integrative Medicine, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, 200011, Shanghai, China
| | - Minjie Tang
- Department of Integrative Medicine, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, 200011, Shanghai, China
| | - Min Liu
- Department of Integrative Medicine, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, 200011, Shanghai, China.
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Tan Y, Ouyang Y, Ma Z, Huang J, Tan C, Qiu J, Wu F. Mitochondrial Quality Control Systems in Septic AKI: Molecular Mechanisms and Therapeutic Implications. Int J Med Sci 2025; 22:1852-1864. [PMID: 40225865 PMCID: PMC11983313 DOI: 10.7150/ijms.107012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 03/05/2025] [Indexed: 04/15/2025] Open
Abstract
Objectives: Despite significant advancements in medical treatments, the creation of a successful treatment strategy for acute kidney injury (AKI) remains a pressing concern. Given the well-documented clinical benefits of canagliflozin in renal protection, our research focused on exploring the possible therapeutic benefits of canagliflozin in treating AKI, with a focus on its underlying mechanisms of action. Methods: To induce AKI, we utilized lipopolysaccharide (LPS) in the presence of canagliflozin, allowing us to assess the drug's effects on kidney function and structure. Results: Our results indicate that canagliflozin lowered blood urea nitrogen and serum creatinine concentrations while enhancing tubular architecture in rodents with LPS-triggered septic AKI. It additionally diminished inflammation, oxidative damage, and tubular cell apoptosis. In vitro, canagliflozin maintained mitochondrial functionality in LPS-exposed HK-2 cells by stabilizing membrane potential, reducing ROS generation, and normalizing respiratory chain activity. Its benefits were facilitated through the AMPKα1/PGC1α/NRF1 axis, promoting mitochondrial regeneration. Importantly, blocking this pathway or employing AMPKα1-deficient animals negated canagliflozin's protective effects, highlighting the essential role of AMPKα1 in its kidney-protective mechanisms. Conclusion: Our investigation implies that canagliflozin might represent a viable treatment strategy for septic AKI, operating through the stimulation of the AMPKα1/PGC1α/NRF1 axis to preserve kidney performance and structural integrity. These findings warrant further investigation into the clinical potential of canagliflozin in this context.
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Affiliation(s)
- Ying Tan
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yue Ouyang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Zisheng Ma
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jianming Huang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Chuhong Tan
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Junxiong Qiu
- Department of Cardiovascular Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Feng Wu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
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Cho YB, Park KS. The Effect and Treatment of PIK3CA Mutations in Breast Cancer: Current Understanding and Future Directions. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:518. [PMID: 40142329 PMCID: PMC11944057 DOI: 10.3390/medicina61030518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025]
Abstract
Gene mutations in PIK3CA, the catalytic subunit of phosphoinositide 3-kinases, are significantly associated with prognosis in breast cancer. This association suggests that breast cancer patients with PIK3CA mutations should receive PIK3CA mutant-specific treatment. This review aimed to investigate novel treatments for PIK3CA-mutant breast cancer. This study investigated the effects of PIK3CA mutations in breast cancer with respect to gene ontology and the PI3K/AKT/mTOR pathway. Subsequently, we comprehensively examined all clinical trials that targeted breast cancer patients with PIK3CA mutations. Finally, this review explored the potential of a new treatment for noncoding RNA.
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Affiliation(s)
- Young-Bin Cho
- Department of Medicine, Graduate School of Konkuk University, Seoul 05029, Republic of Korea
| | - Kyoung-Sik Park
- Department of Surgery, Konkuk University Medical Center, Seoul 05029, Republic of Korea
- Department of Surgery, Konkuk University School of Medicine, Seoul 05029, Republic of Korea
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Xiang S, Luo Y, Liu W, Tang C, Zhu T, Tian L, Zheng T, Ling L, Jia M, Li X, Cao Y. Calycosin alleviates ovariectomy-induced osteoporosis by promoting BMSCs autophagy via the PI3K/Akt/mTOR pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04009-x. [PMID: 40087184 DOI: 10.1007/s00210-025-04009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 03/03/2025] [Indexed: 03/17/2025]
Abstract
Calycosin, the main extract from the traditional Chinese medicine (TCM) Astragalus membranaceus, has demonstrated anti-osteoporotic properties in ovariectomized (OVX) mice. However, the specific pathways through which it prevents osteoporosis remain unexplored. This study aimed to investigate the pathways by which calycosin promotes autophagy in bone marrow mesenchymal stem cells (BMSCs) and alleviates ovariectomy-induced osteoporosis. Mice were divided into three groups: sham, OVX, and OVX + calycosin. Following a 12-week intervention period, assessments included analysis of bone microstructure, serum concentrations of LC3II and ALP, and evaluation of Trap expression in femoral tissue. Immunohistochemical staining was used to assess the expression levels of PI3K, Runx2, and Beclin-1 in bone tissue. Additionally, levels of Runx2, ALP, p-PI3K, PI3K, mTOR, p-mTOR, Beclin-1, and ULK1 were analyzed. Osteogenic differentiation of BMSCs was evaluated using ALP and Alizarin red staining. OVX significantly impaired BMSCs osteogenic differentiation, resulting in bone loss. In contrast, calycosin increased bone mass, promoted osteogenesis, and reduced cancellous bone loss. Parameters, such as BMD, BV/TV, Tb.N, and Tb.Th, were significantly higher in the OVX + calycosin group compared to the OVX group. Additionally, Tb.Sp was notably reduced in the OVX + calycosin group. Calycosin also upregulated levels of Runx2, ALP, p-PI3K, p-mTOR, ULK1, and Beclin-1. In cellular studies, calycosin promoted BMSCs osteogenesis under OVX conditions; however, this effect was inhibited by LY294002. Calycosin effectively combats bone loss and improves bone structure. Its mechanism likely involves the promotion of autophagy in osteoblasts, thereby stimulating BMSC osteogenic differentiation. This effect may be mediated through the PI3K/Akt/mTOR pathway. These findings suggest that calycosin has the potential to serve as an alternative therapy for treating osteoporosis.
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Affiliation(s)
- Shouyu Xiang
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, People's Republic of China
| | - Yinji Luo
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, People's Republic of China
| | - Wei Liu
- Department of Orthopedics, Guilin People's Hospital, Guilin, China
| | - Cheng Tang
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, People's Republic of China
| | - Tianyu Zhu
- Department of Burns and Plastic Surgery, Shenzhen University General Hospital, Shenzhen, China
| | - Lai Tian
- The Zhushan People's Hospital, ShiYan, China
| | - Tiansheng Zheng
- Department of Endocrinology, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Long Ling
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, People's Republic of China
| | - Mingyang Jia
- Operating Room, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xing Li
- State Key Laboratory of Dampness, Syndrome of Chinese Medicine, Department of Orthopedic Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.
| | - Yanming Cao
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, People's Republic of China.
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Greenzaid JD, Thakker S, Ruley AJ, Eichinger JM, Strowd LC. Management of Mycosis Fungoides and Sézary Syndrome With Oral Systemic Therapies. J Cutan Med Surg 2025:12034754251322881. [PMID: 40072489 DOI: 10.1177/12034754251322881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes of cutaneous T-cell lymphoma with numerous topical and systemic therapies. Early-stage MF can be managed with topical corticosteroids, mechlorethamine, and phototherapy. However, patients are often non-responsive to topical therapies, thus requiring systemic therapies. There are few studies summarizing oral (PO) therapies for MF and SS. We aim to discuss the efficacy and safety of FDA-approved, off-label, and investigational oral therapies for MF and SS. FDA-approved oral therapies include bexarotene and vorinostat, both of which are effective in patients who are recalcitrant to prior topical therapies. Off-label oral therapies include methotrexate, acitretin, and chlorambucil. Methotrexate improves MF lesions in both early-stage and late-stage MF and is effective in erythrodermic MF. A combination of acitretin with phototherapy may lead to better response rates compared to acitretin monotherapy. Chlorambucil is mainly used to treat erythrodermic MF. Investigational oral therapies for MF include tenalisib, duvelisib, cerdulatinib, lenalidomide, bortezomib, and azacytidine, and direct comparison studies between these investigational agents and FDA-approved therapies should be undertaken to better understand their role in the management of MF and SS.
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Affiliation(s)
- Jonathan D Greenzaid
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sach Thakker
- Georgetown University School of Medicine, Washington, DC, USA
| | - Ainsley J Ruley
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | | | - Lindsay C Strowd
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
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Xu H, Zhu J, Lin X, Chen C, Tao J. A Comprehensive Review of Traditional Chinese Medicine in the Management of Ulcerative Colitis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2025; 53:435-473. [PMID: 40066486 DOI: 10.1142/s0192415x2550017x] [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: 04/08/2025]
Abstract
Ulcerative colitis (UC) is a chronic, nonspecific inflammatory disorder characterized by symptoms such as abdominal pain, diarrhea, hematochezia, and urgency during defecation. While the primary site of involvement is the colon, UC can extend to encompass the entire rectum and colon. The causes and development mechanisms of UC are still not well understood; nonetheless, it is currently held that factors including environmental influences, genetic predispositions, intestinal mucosal integrity, gut microbiota composition, and immune dysregulation contribute to its development. Dysregulated immune responses are pivotal in the pathophysiology of UC, and these aberrant responses are considered key contributors to the disease onset. In patients with UC, immune cells become hyperactive and erroneously target normal intestinal tissue, resulting in inflammatory cascades and damage to the intestinal mucosa. The therapeutic strategies currently employed for UC include immunosuppressive agents such as aminosalicylates and corticosteroids. However, these treatments often prove costly and carry significant adverse effects - imposing a considerable burden on patients. Traditional Chinese Medicine (TCM) has attracted worldwide attention because of its multi-target approach, minimal side effects, cost-effectiveness, and favorable efficacy profiles. In this review, the ways in which TCM modulates inflammatory responses in the treatment of ulcerative colitis have been outlined. Research into TCM modalities for modulating inflammatory pathways in the treatment of UC, which has yielded promising advancements, including individual herbs, herbal formulations, and their derivatives, has been summarized. TCM has been utilized to treat UC and the immune system plays a key role in regulating intestinal homeostasis. It is imperative to facilitate large-scale evidence-based medical research and promote the clinical application of TCM in the management of UC.
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Affiliation(s)
- Huate Xu
- School of Public Health, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
| | - Jinhui Zhu
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
| | - Xiangyun Lin
- School of Public Health, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
- Nantong Key Laboratory of Environmental Toxicology, Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
| | - Chao Chen
- School of Public Health, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
- Nantong Key Laboratory of Environmental Toxicology, Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
| | - Jinhua Tao
- School of Public Health, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
- Nantong Key Laboratory of Environmental Toxicology, Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, P. R. China
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Xiong M, Liu D, Wang X, Ren H, Chi W, Xiu B, Zhang Q, Zhang J, Zhang L, Wang Z, Chen M, Xue J, Chi Y, Wu J. PPARG Activation of Fatty Acid Metabolism Drives Resistance to Anti-HER2 Therapies in HER2-Positive Breast Cancer. Int J Biol Sci 2025; 21:2396-2414. [PMID: 40303293 PMCID: PMC12035890 DOI: 10.7150/ijbs.99275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/21/2025] [Indexed: 05/02/2025] Open
Abstract
HER2-positive breast cancer, which accounts for approximately 15-20% of all breast cancers, is characterized by its aggressive recurrence, metastasis and reduced survival. Despite advances in anti-HER2 therapies, many patients continue to face treatment resistance, either initially or after an initial positive response, resulting in relapse or disease progression. The primary focus of this research was to identify the peroxisome proliferator-activated receptor gamma (PPARG) as a contributing factor to decreased drug sensitivity by establishing anti-HER2 drug-resistant cell lines of HER2-positive breast cancer. We found that PPARG promotes fatty acid metabolism and activates the PI3K/Akt/mTOR signaling pathway. Inhibition of fatty acid synthesis (FASN) after overexpression of PPARG, effectively blocking the activation of the PI3K/Akt/mTOR pathway and enhancing cellular anti-HER2 drug sensitivity. Co-administration of the PPARG inhibitor GW9662 has emerged as a promising strategy to augment the efficacy of anti-HER2 therapies, offering potential for clinical applications.
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Affiliation(s)
- Min Xiong
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Douwaner Liu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xuliren Wang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Hengyu Ren
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Weiru Chi
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Bingqiu Xiu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Qi Zhang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jiayu Zhang
- Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Liyi Zhang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zehao Wang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ming Chen
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jingyan Xue
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yayun Chi
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiong Wu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
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Bithi SA, Al Hasan MS, Bhuia MS, Mia E, Yana NT, Hasan AMW, Uddin MB, Sayeed MA, Emon Y, Hasan R, Chowdhury R, Islam MT. Botanical sources, biopharmaceutical profile, anticancer effects with mechanistic insight, toxicological and clinical evidence of prunetin: a literature review. Med Oncol 2025; 42:87. [PMID: 40029540 DOI: 10.1007/s12032-025-02646-z] [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: 01/13/2025] [Accepted: 02/24/2025] [Indexed: 03/05/2025]
Abstract
Prunetin (PRU), a naturally occurring flavonoid, has gained recognition for its wide-ranging therapeutic benefits, though its anticancer properties have yet to be extensively reviewed. This study explores the potential of PRU in targeting critical molecular pathways involved in tumor progression, including oxidative stress, apoptosis, cell cycle regulation, and metastasis. Data were compiled from reputable sources, including PubMed, Springer Link, Scopus, Wiley Online, Web of Science, ScienceDirect, and Google Scholar. The findings emphasize PRU's ability to mitigate oxidative stress, promote apoptosis, and regulate the cell cycle in cancer cells. Its anti-inflammatory and anti-angiogenic properties further enhance its effectiveness against cancer. Mechanistic studies reveal that PRU suppresses oncogenic pathways such as PI3K/Akt/mTOR (Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin) while activating tumor-suppressor mechanisms. Experimental models show that PRU effectively inhibits cancer cell proliferation and metastasis. Additionally, PRU exhibits favorable pharmacokinetics, demonstrating high intestinal absorption (95.5%), good Caco-2 permeability, and metabolism via CYP1A2, CYP2C19, CYP2C9, and CYP3A4, though it has poor blood-brain barrier (BBB) permeability and limited aqueous solubility, posing challenges for systemic bioavailability. Beyond its anticancer properties, PRU displays broad pharmacological relevance, including anti-inflammatory, cardioprotective, neuroprotective, anti-obesity, and osteoprotective effects, mediated through pathways, such as NF-κB, MAPK, and AMPK. Toxicological studies indicate a favorable safety profile, with low cytotoxicity in normal cells and no significant toxicity at high doses in preclinical models. While clinical evidence on PRU remains limited, studies on structurally related isoflavones suggest promising therapeutic potential, necessitating further clinical trials to establish its efficacy and safety in humans.
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Affiliation(s)
- Sumaya Akter Bithi
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh
| | - Md Sakib Al Hasan
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh.
| | - Md Shimul Bhuia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh
| | - Emon Mia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh
| | - Noshin Tasnim Yana
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh
| | - Ali Mohamod Wasaf Hasan
- Department of Pharmacy, Mawlana Bhashani Science and Technology University, Santosh, Tangail, Bangladesh
| | | | - Md Abu Sayeed
- Department of Pharmacy, Mawlana Bhashani Science and Technology University, Santosh, Tangail, Bangladesh
| | - Yasin Emon
- Department of Pharmacy, Islamic University, Kushtia, 7003, Bangladesh
| | - Rubel Hasan
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh
| | - Raihan Chowdhury
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh
| | - Muhammad Torequl Islam
- Pharmacy Discipline, Khulna University, Khulna, 9208, Bangladesh.
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center Ltd, Gopalganj, 8100, Bangladesh.
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50
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Zhang X, Zhang Z. Insulin receptor tyrosine kinase substrate in health and disease (Review). Mol Med Rep 2025; 31:72. [PMID: 39930824 PMCID: PMC11795247 DOI: 10.3892/mmr.2025.13437] [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: 09/17/2024] [Accepted: 12/19/2024] [Indexed: 02/14/2025] Open
Abstract
Insulin receptor (IR) tyrosine kinase substrate (IRTKS) was first identified >20 years ago as a tyrosine‑phosphorylated IR substrate and subsequently characterized as a protein containing an inverse‑Bin‑amphiphysin‑Rvs domain. Subsequent research has shown that IRTKS functions as a scaffold protein with multiple domains, which results in diverse functions in a variety of cell activities. For example, IRTKS plays roles in regulating the formation of membrane protrusions; triggering pathogen‑driven actin assembly; modulating insulin signaling, antiviral immunity and embryonic development; and promoting tumor occurrence and progression. It is also a candidate forensic biomarker of hypothermia. Nevertheless, a systematic summary of the biological functions of IRTKS and its underlying molecular mechanism is lacking. Therefore, the present review provides a comprehensive summary of the latest advancements in IRTKS research, thereby establishing a framework for understanding the contribution of IRTKS to diverse cell processes.
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Affiliation(s)
- Xueyan Zhang
- Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Zhewen Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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