1
|
Albassam H, Almutairi O, Alnasser M, Altowairqi F, Almutairi F, Alobid S. Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy. J Enzyme Inhib Med Chem 2025; 40:2468852. [PMID: 39992303 PMCID: PMC11852364 DOI: 10.1080/14756366.2025.2468852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/24/2024] [Revised: 01/31/2025] [Accepted: 02/08/2025] [Indexed: 02/25/2025] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC50 of 12.14 µM, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019's binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment.
Collapse
Affiliation(s)
- Hussam Albassam
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Omar Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Majed Alnasser
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Faisal Altowairqi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Faris Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saad Alobid
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
2
|
Bao ZC, Liu ZD, Zhang Y, Dai HJ, Jia H, Ren F, Li N, Zhao L, Wang YW, Lv SY, Zhang Y. To investigate the effect and mechanism of tetrahydrocurcumin on hepatocellular carcinoma based on phosphoinositide 3-kinases/AKT signaling pathway. World J Gastrointest Oncol 2025; 17:102187. [DOI: 10.4251/wjgo.v17.i3.102187] [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] [Academic Contribution Register] [Received: 10/11/2024] [Revised: 11/20/2024] [Accepted: 01/02/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Liver cancer has a high incidence and mortality worldwide, especially in China. Herein, we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma (HCC), with a focus on the of phosphoinositide 3-kinases (PI3K)/AKT signaling pathway.
AIM To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.
METHODS Using Metascape, we analyzed the potential targets of tetrahydrocurcumin in HCC. Molecular docking validation was performed using SYBYL2.0. Cell Counting Kit-8, wound healing, and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration, invasion, and apoptosis. The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.
RESULTS Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells, promoted their apoptosis, and downregulated the expression of p-PI3K, p-AKT, and B cell leukemia/lymphoma 2, while upregulating caspase-3, p53, and B cell leukemia/lymphoma 2 associated X.
CONCLUSION In summary, tetrahydrocurcumin suppresses PI3K/AKT signaling, promotes apoptosis, and prevents the migration and invasion of liver cancer cells.
Collapse
Affiliation(s)
- Zhuo-Cong Bao
- Graduate School, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Zhao-Dong Liu
- Graduate School, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Ye Zhang
- Graduate School, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Hui-Jun Dai
- Guangxi Medical University Cancer Hospital, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hui Jia
- School of Traditional Chinese Medicine, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Fu Ren
- Key Laboratory of Human Ethnic Specificity and Phenomics of Critical Illness in Liaoning Province, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
- Key Laboratory of Phenomics in Shenyang, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Ning Li
- Key Laboratory of Human Ethnic Specificity and Phenomics of Critical Illness in Liaoning Province, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
- Key Laboratory of Phenomics in Shenyang, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
- Department of Biochemistry, School of Basic Medicine, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Lu Zhao
- Department of Biochemistry, School of Basic Medicine, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Yi-Wei Wang
- Key Laboratory of Human Ethnic Specificity and Phenomics of Critical Illness in Liaoning Province, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
- Molecular Morphology Laboratory, College of Basic Medical Sciences, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Shang-Yu Lv
- Batch 2022, Clinical Medicine, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| | - Yan Zhang
- Key Laboratory of Human Ethnic Specificity and Phenomics of Critical Illness in Liaoning Province, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
- Key Laboratory of Phenomics in Shenyang, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
- Department of Biochemistry, School of Basic Medicine, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
- International Education School, International Exchange and Cooperation Office, Shenyang Medical College, Shenyang 110034, Liaoning Province, China
| |
Collapse
|
3
|
Wen L, Rong F, Dai G, Liu Y, Lv Y, Luo Q, Liu DX, Chen R. Proteomic analysis of the nonstructural protein 2-host protein interactome reveals a novel regulatory role of SH3 domain-containing kinase-binding protein 1 in porcine reproductive and respiratory syndrome virus replication and apoptosis. Int J Biol Macromol 2025; 295:139218. [PMID: 39755310 DOI: 10.1016/j.ijbiomac.2024.139218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2024] [Revised: 12/24/2024] [Accepted: 12/24/2024] [Indexed: 01/06/2025]
Abstract
Virus-host protein interaction is critical for successful completion of viral replication cycles. As the largest nonstructural protein (NSP) of porcine reproductive and respiratory syndrome virus (PRRSV), NSP2 plays multiple and critical roles in viral replication, antiviral immunity, cellular tropism and virulence. An interactome of this protein with host proteins would be instrumental in full understanding of these multifunctional roles. In this study, we report the identification of 120 NSP2-interacting host proteins by co-immunoprecipitation coupled liquid chromatography mass spectrometry, via rescuing and utilizing a recombinant PRRSV expressing an HA-tagged NSP2. By comparing and subtracting with cells infected with parental virus, a comprehensive interactome was constructed. Bioinformatics analysis revealed that these host factors are mainly involved in translation regulation, metabolism, signal transduction and innate immunity signaling pathways. Selection of five host proteins (CtBP1, CtBP2, HSPA2, PPP1CA, SH3KBP1) for further verification and characterization confirmed their interactions with NSP2 and differential effects on PRRSV replication. Intriguingly, interaction of NSP2 and SH3KBP1 led to specific cleavage of SH3KBP1, antagonizing its pro-apoptotic activity. Taken together, this study provides overarching views on the NSP2-host interactome, paving a solid foundation for functional studies of host proteins in PRRSV biology and their potential as targets for novel therapeutics development.
Collapse
Affiliation(s)
- Lianghai Wen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Zhaoqing Branch Centre of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing 526238, China; Zhaoqing Institute of Biotechnology Co., Ltd., Zhaoqing 526238, China
| | - Fang Rong
- Zhaoqing Branch Centre of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing 526238, China
| | - Guo Dai
- Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou 510642, China
| | - Yufu Liu
- School of Life Sciences, Zhaoqing University, Zhaoqing 526061, China
| | - Yadi Lv
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Zhaoqing Branch Centre of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing 526238, China
| | - Qiong Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Wens Dahuanong Bio-Pharmaceutical Co., Ltd., Xinxing 527400, China
| | - Ding Xiang Liu
- Zhaoqing Branch Centre of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing 526238, China; Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou 510642, China.
| | - Ruiai Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Zhaoqing Branch Centre of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing 526238, China; Zhaoqing Institute of Biotechnology Co., Ltd., Zhaoqing 526238, China; Guangdong Wens Dahuanong Bio-Pharmaceutical Co., Ltd., Xinxing 527400, China.
| |
Collapse
|
4
|
Zhang HL, Lin Z, Zhang Y. Developments in research and commercialization of PI3K and AKT targets: a patent-based landscape. Pharm Pat Anal 2025:1-8. [PMID: 39993965 DOI: 10.1080/20468954.2025.2470102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/11/2024] [Accepted: 02/18/2025] [Indexed: 02/26/2025]
Abstract
PI3K and AKT signaling pathway has been linked to the pathophysiology of various diseases. This pathway has emerged as a crucial therapeutic strategy for cancer and other diseases. To better understand recent development of PI3K and AKT, a patent-based landscape study was performed. The results shows that both PI3K and AKT targets have shown prolific patent filings over the past 20 years. This study is the first to depict the therapeutic applications of both PI3K and AKT targets based on a patent big data analysis. Ten key therapeutic applications were identified, with over 77% of patents related to anti-cancer therapy for both PI3K and AKT targets. Additionally, our findings show that combination therapy is a distinguishing feature for drugs targeting both PI3K and AKT. The average time from patent application to drug approval for PI3K target drugs is 8.8 years. PI3K target drugs obtain market approval faster compared to AKT drugs. Approximately, 2 years of patent term extension could be obtained if the time from the patent application date to the drug approval date is less than 10 years.
Collapse
Affiliation(s)
- Hai-Long Zhang
- Central International Intellectual Property (Baotou) Co. Ltd, Baotou, China
| | - Zhaochen Lin
- Hydrogen Medicine Research Centre, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong, China
| | - Ying Zhang
- Pharmacy Intravenous Admixture Services, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong, China
| |
Collapse
|
5
|
Ding Z, Shao G, Li M. Targeting autophagy in premature ovarian failure: Therapeutic strategies from molecular pathways to clinical applications. Life Sci 2025; 366-367:123473. [PMID: 39971127 DOI: 10.1016/j.lfs.2025.123473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/11/2024] [Revised: 01/31/2025] [Accepted: 02/14/2025] [Indexed: 02/21/2025]
Abstract
Premature ovarian failure (POF) is a condition where the ovaries lose their function before the age of 40, leading to significant impacts on reproductive health and overall well-being. Current treatment options are limited and often ineffective at restoring ovarian function. This review explores the role of autophagy- a cellular process that helps maintain homeostasis by recycling damaged components-in the development and potential treatment of POF. Autophagy is crucial for the survival of follicle cells and can be disrupted by various stressors associated with POF, such as oxidative damage and mitochondrial dysfunction. We review several key molecular pathways involved in autophagy, including the PI3K/AKT/mTOR, PINK1-Parkin, JAK2/STAT3, MAPK and AMPK/FOXO3a pathways, which have been implicated in POF. Each pathway offers unique insights into how autophagy can be modulated to counteract POF-related damage. Additionally, we discuss emerging therapeutic strategies that target these pathways, including chemical compounds, peptides, hormones, RNA therapy, extracellular vesicles and traditional Chinese medicine. These approaches aim to restore autophagic balance, promote follicle survival and improve ovarian function. By targeting autophagy, new treatments may offer hope for better management and potential reversal of POF, thus improving the quality of life for affected individuals.
Collapse
Affiliation(s)
- Ziwen Ding
- Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Genbao Shao
- Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Mingyang Li
- Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
| |
Collapse
|
6
|
Zeng M, Hu Y, Zhao L, Duan C, Wu H, Xu Y, Liu X, Wang Y, Jiang D, Zeng S. Design, synthesis, and pharmacological evaluation of triazine-based PI3K/mTOR inhibitors for the potential treatment of non-small cell lung cancer. Eur J Med Chem 2025; 284:117200. [PMID: 39733482 DOI: 10.1016/j.ejmech.2024.117200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/14/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 12/31/2024]
Abstract
Dysregulated activation of the PI3K/AKT/mTOR pathway is crucial in the development of cancer, and disrupting it could potentially lead to cancer suppression, making it a viable strategy for cancer treatment. Here, as a consecutive work of our team, we described the identification and optimization of PI3K/mTOR inhibitors based on triazine scaffold, which exhibited potent PI3K/mTOR inhibitor activity. The systematically structure-activity relationship (SAR) results demonstrated that compound 5nh displayed high efficacy against PI3Kα and mTOR, with the IC50 values of 0.45 nM and 2.9 nM, respectively. Importantly, compared to the lead compound PKI-587, 5nh demonstrated significant inhibitory activity against non-small-cell lung cancer (NSCLC) cell lines, particularly HCC-827, with a 43-fold increase (3.5 nM vs 150 nM). Additionally, the compound showed effective inhibition against the EGFR-resistant variant HCC-827(GR) cell line. Mechanism validation demonstrated that 5nh significantly interfered with the PI3K/AKT/mTOR signaling pathway in HCC-827 cells. Furthermore, the oral pharmacokinetic properties of 5nh had been observably improved, with AUC0-t and Cmax increasing by 13-16 times at a dose of 10 mg/kg in mice. Importantly, the in vivo efficacy study demonstrated that orally treatment of 5nh led to significant tumor growth suppression, with a TGI value of 84.4 %. Collectively, our systematically medicinal chemistry campaigns suggested that 5nh, a novel oral available triazine derivative, held promise as a candidate for therapy of NSCLC by targeting the PI3K/AKT/mTOR cascade.
Collapse
Affiliation(s)
- Ming Zeng
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China.
| | - Yingxuan Hu
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China
| | - Lan Zhao
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China
| | - Chengze Duan
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, China
| | - Haifeng Wu
- Zhejiang Research Institute of Chemical Industry, Hangzhou, 310023, China
| | - Yi Xu
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China
| | - Xiaoguang Liu
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China
| | - Yali Wang
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China
| | - Dengzhao Jiang
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China
| | - Shenxin Zeng
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, China; School of Pharmacy, Zhejiang University, Hangzhou, 310058, China.
| |
Collapse
|
7
|
Wei Y, Ma Z, Li Z, Kang J, Liao T, Jie L, Liu D, Shi L, Wang P, Mao J, Wu P. Gentiopicroside ameliorates synovial inflammation and fibrosis in KOA rats by modulating the HMGB1-mediated PI3K/AKT signaling axis. Int Immunopharmacol 2025; 147:113973. [PMID: 39764995 DOI: 10.1016/j.intimp.2024.113973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/24/2024] [Revised: 12/17/2024] [Accepted: 12/28/2024] [Indexed: 01/29/2025]
Abstract
BACKGROUND Knee osteoarthritis (KOA) is a degenerative joint disease characterized by synovial inflammation and fibrosis. Gentiopicroside (GPS), one of the main active ingredients of Gentiana macrophylla, is widely used in anti-inflammatory and anti-fibrotic therapies. However, the exact mechanism by which GPS treats synovial inflammation and fibrosis in KOA remains unclear. METHODS Fibroblast-like synoviocytes (FLSs) were stimulated with lipopolysaccharide (LPS) to induce inflammation and fibrosis, and CCK-8 was performed to determine the viability of GPS-treated FLSs, using immunofluorescence to examine the expression of P-PI3K and P-AKT, confocal microscopy was used to identify intracellular HMGB1 translocation. The KOA rat model was established by anterior cruciate ligament transection (ACLT) and subsequently subjected to GPS intervention. Inflammatory cytokines (TNF-α, IL-1β, and IL-6), fibrosis-related indicators (TGF-β, collagen I, TIMP1, and α-SMA), and HMGB1/PI3K/AKT signaling axis-related proteins and gene expression of fibroblast-like synoviocytes and synovial tissues were detected by Western blotting and real-time PCR. The histopathology of the synovium of the rats was assessed using Hematoxylin-eosin (HE), Sirius Red, and Masson staining. Immunohistochemistry was performed to detect the expression of HMGB1, P-PI3K, and P-AKT. RESULTS The present study revealed that GPS intervention significantly ameliorated inflammation and fibrosis in LPS-stimulated FLSs and KOA rat synovium. Immunofluorescence demonstrated that GPS inhibited the release of HMGB1 from the nucleus. Furthermore, GPS intervention down-regulates the levels of proteins and gene associated with the HMGB1/PI3K/AKT signaling pathway. CONCLUSION GPS ameliorated synovial inflammation and fibrosis in KOA rats, which may involve HMGB1-mediated activation of the PI3K/AKT signaling axis.
Collapse
Affiliation(s)
- Yibao Wei
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Zhenyuan Ma
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Zhenhui Li
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Junfeng Kang
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; The Affiliated Hospital of Shanxi University of Traditional Chinese Medicine, Taiyuan 030002, China
| | - Taiyang Liao
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lishi Jie
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Deren Liu
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lei Shi
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Peimin Wang
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Jun Mao
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China.
| | - Peng Wu
- Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China.
| |
Collapse
|
8
|
Wei L, Chen P, Shi L, Li G, Feng X, Zhao Y, Wang J, Chen ZS, Hu Z, Cui M, Zhou B. Composite Graphene for the Dimension- and Pore-Size-Mediated Stem Cell Differentiation to Bone Regenerative Medicine. ACS APPLIED MATERIALS & INTERFACES 2025; 17:7307-7323. [PMID: 39843162 DOI: 10.1021/acsami.4c17554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 01/24/2025]
Abstract
As one of the most promising means to repair diseased tissues, stem cell therapy with immense potential to differentiate into mature specialized cells has been rapidly developed. However, the clinical application of stem-cell-dominated regenerative medicine was heavily hindered by the loss of pluripotency during the long-term in vitro expansion. Here, a composite three-dimensional (3D) graphene-based biomaterial, denoted as GO-Por-CMP@CaP, with hierarchical pore structure (micro- to macropore), was developed to guide the directional differentiation of human umbilical cord MSCs (hucMSCs) into osteoblasts. GO-Por-CMP@CaP could act as a high-efficiency living composite material without a "dead space", effectively regulating the cellular response. The 3D topological structure generated via the two-step modification on two-dimensional graphene could effectively mimic the natural 3D microenvironment of cells, enhancing the stem cell attachment, which is not only conducive for the proliferation of stem cells but also beneficial for the osteogenic differentiation. Meanwhile, the wide existence of interconnected macropores was favorable for bone ingrowth, capillary formation, as well as the nutrients transportation. Furthermore, the concurrent existence of micro- and mesopores significantly promoted the extracellular matrix (ECM) adsorption, which ensured cellular attachment, leading to multiscale osteointegration. Both in vitro and in vivo assay demonstrated the above three factors collaborated mutually with nanosized calcium phosphate (CaP, with chemical similarities to the inorganic components of bone), which provided abundant adhesive sites to adequately induce osteogenic differentiation in the absence of any soluble growth factors. Proteomic analysis experiments confirmed that GO-Por-CMP@CaP promoted the differentiation of hucMSCs cells into osteoblasts by affecting the PI3K-Akt signaling pathway through the up-regulation of SPP1 protein. Our study offers a pure material-based stem cell differentiation regulating behavior via engineering the dimension and porosity of material, which provides insights into the design and development of substitutes to bone repair materials.
Collapse
Affiliation(s)
- Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong PR China
| | - Peilei Chen
- School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong PR China
| | - Lin Shi
- Weifang People's Hospital, Shandong Second Medical University, Weifang 261035, Shandong PR China
| | - Gentao Li
- School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong PR China
| | - Xiaozhe Feng
- School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong PR China
| | - Yao Zhao
- Affiliated Hospital of Shandong Second Medical University, Shandong Second Medical University, Weifang 261035, Shandong PR China
| | - Jiangyun Wang
- School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong PR China
| | - Zhe-Sheng Chen
- School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong PR China
| | - Zhenbo Hu
- Affiliated Hospital of Shandong Second Medical University, Shandong Second Medical University, Weifang 261035, Shandong PR China
| | - Min Cui
- Department of Pain Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong PR China
| | - Baolong Zhou
- School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong PR China
| |
Collapse
|
9
|
Fatima S, Kumar V, Kumar D. Molecular mechanism of genetic, epigenetic, and metabolic alteration in lung cancer. Med Oncol 2025; 42:61. [PMID: 39893601 DOI: 10.1007/s12032-025-02608-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/15/2024] [Accepted: 01/13/2025] [Indexed: 02/04/2025]
Abstract
Lung cancer, a leading cause of cancer-related deaths worldwide, is primarily linked to smoking, tobacco use, air pollution, and exposure to hazardous chemicals. Genetic alterations, particularly in oncogenes like RAS, EGFR, MYC, BRAF, HER, and P13K, can lead to metabolic changes in cancer cells. These cells often rely on glycolysis for energy production, even in the presence of oxygen, a phenomenon known as aerobic glycolysis. This metabolic shift, along with other alterations, contributes to cancer cell growth and survival. To develop effective therapies, it's crucial to understand the genetic and metabolic changes that drive lung cancer. This review aims to identify specific genes associated with these metabolic alterations and screen phytochemicals for their potential to target these genes. By targeting both genetic and metabolic pathways, we hope to develop innovative therapeutic approaches to combat lung cancer.
Collapse
Affiliation(s)
- Sheeri Fatima
- School of Health Science and Technology (SoHST), UPES, Dehradun, Uttarakhand, 248007, India
| | - Vineet Kumar
- Chemistry & Bioprospecting Division, Forest Research Institute, Dehradun, 248006, India
| | - Dhruv Kumar
- School of Health Science and Technology (SoHST), UPES, Dehradun, Uttarakhand, 248007, India.
| |
Collapse
|
10
|
Kao WH, Chiu KY, Tsai SCS, Teng CLJ, Oner M, Lai CH, Hsieh JT, Lin CC, Wang HY, Chen MC, Lin H. PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167568. [PMID: 39536992 DOI: 10.1016/j.bbadis.2024.167568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/01/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Aberrant PI3K/Akt activation is linked to prostate cancer (PCa) malignancy, while androgen receptor (AR) is critical in early-stage PCa development. Investigating the interaction between these pathways is crucial for PCa malignancy. Our previous study demonstrated that p35-CDK5 mediates post-translational modifications of AR, STAT3, and p21CIP1, eventually promoting PCa cell growth. This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the β-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.
Collapse
Affiliation(s)
- Wei-Hsiang Kao
- Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan; Translational Cell Therapy Center, China Medical University Hospital, Taichung 40447, Taiwan.
| | - Kun-Yuan Chiu
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan
| | - Stella Chin-Shaw Tsai
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan; Superintendent Office, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan; College of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan
| | - Chieh-Lin Jerry Teng
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan; Division of Hematology/Medical Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
| | - Muhammet Oner
- Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
| | - Chih-Ho Lai
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan 33302, Taiwan.
| | - Jer-Tsong Hsieh
- Department of Urology, University of Texas Southwestern Medical Center, TX75390, USA.
| | - Chi-Chien Lin
- Institute of Biomedical Science, National Chung Hsing University, Taichung 40227, Taiwan
| | - Hsin-Yi Wang
- Department of Nuclear Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
| | - Mei-Chih Chen
- Translational Cell Therapy Center, China Medical University Hospital, Taichung 40447, Taiwan.
| | - Ho Lin
- Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
| |
Collapse
|
11
|
Jain A, Das R, Giri M, Mane P, Shard A. Carbohydrate kinase inhibition: a promising strategy in cancer treatment. Drug Discov Today 2025; 30:104308. [PMID: 39912130 DOI: 10.1016/j.drudis.2025.104308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/09/2024] [Revised: 01/21/2025] [Accepted: 01/30/2025] [Indexed: 02/07/2025]
Abstract
Carbohydrate kinases (CKs) are pivotal in various biological processes, including energy consumption, cell signaling, and biosynthesis. They are a group of enzymes that facilitate the phosphorylation of carbohydrates, playing a crucial role in cellular metabolism. These enzymes facilitate the transfer of a phosphate group from a high-energy donor like ATP to a specified location on a carbohydrate substrate. Dysregulated kinase activity drives tumor growth and progression. Inhibitors targeting these enzymes have been developed and used in cancer therapy. The CK family encompasses three major types: hexokinases, ribokinases, and phosphatidylinositol kinases, with inhibitors of paramount importance in cancer treatment. This review explores the role of CKs in cancer and its inhibitors, providing insights into improving existing inhibitors and designing new ones.
Collapse
Affiliation(s)
- Archit Jain
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Rudradip Das
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Muskan Giri
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Pranita Mane
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Amit Shard
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India.
| |
Collapse
|
12
|
Jia Y, Sun J, Chen S, Bian Y, Jiang A, Liang H, Du X. Dedicator of cytokinesis protein 2 activates the epithelial-mesenchymal transition in renal fibrosis through the Rac1/PI3K/AKT pathway. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119894. [PMID: 39725220 DOI: 10.1016/j.bbamcr.2024.119894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 09/01/2024] [Revised: 11/28/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
Renal fibrosis is the most important feature of the progression of chronic kidney disease (CKD), and epithelial-mesenchymal transition (EMT) plays an important role in renal fibrosis. Dedicator of cytokinesis protein 2 (Dock2) is involved in the immune system and the development of a variety of fibrotic diseases. However, its specific role in renal fibrosis remains unclear. Therefore, in this study, we investigated the role and mechanism of Dock2 in renal fibrosis. We constructed an in vivo mouse model of unilateral ureteral obstruction (UUO) and an in vitro model of recombinant human transforming growth factor-β1 (TGF-β1)-induced HK-2 cells. The function and regulatory mechanism of Dock2 were studied via Western blotting, qRT-PCR, immunohistochemistry and immunofluorescence. First, Dock2 was more highly expressed in the kidneys of UUO mice than in those of sham-operated mice. A reduction in Dock2 can improve pathological changes in the kidney tissue of UUO mice, reduce the deposition of the extracellular matrix (ECM), and alleviate EMT. Silencing Dock2 reduced the activation of both the Rac1 pathway and the PI3K/AKT pathway. TGF-β1 promoted Dock2 expression in HK-2 cells in vitro. A decrease in Dock2 can inhibit the expression of Fibronectin, Collagen I, α-SMA and Vimentin and increase the level of E-cadherin. Treatment of HK-2 cells with the Rac1 activator 8-CPT or the PI3K/AKT pathway activator YS-49 inhibited the above changes induced by siDock2, indicating that Dock2 activates EMT in renal fibrosis through the Rac1/PI3K/AKT pathway. Our data suggest that Dock2 may be a potential target for renal fibrosis treatment.
Collapse
Affiliation(s)
- Yuanyuan Jia
- Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jing Sun
- Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Sha Chen
- Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yu Bian
- Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Anni Jiang
- Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Haihai Liang
- Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China.
| | - Xuanyi Du
- Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| |
Collapse
|
13
|
Gouda MA, Wei Z, Rodon J, Davies MA, Janku F, Gray RJ, Wang V, McShane LM, Rubinstein LV, Patton DR, Williams PM, Hamilton SR, Liu R, Bota DA, Swiecicki PL, Buchschacher GL, Tricoli JV, Conley BA, Arteaga CL, Harris LN, O'Dwyer PJ, Chen AP, Flaherty KT. Phase II Study of Copanlisib in Patients With PTEN Loss: Results From NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols Z1G and Z1H. JCO Precis Oncol 2025; 9:e2400451. [PMID: 39913886 DOI: 10.1200/po-24-00451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/10/2024] [Revised: 11/10/2024] [Accepted: 12/26/2024] [Indexed: 02/20/2025] Open
Abstract
PURPOSE Copanlisib, a pan-class phosphatidylinositol 3-kinase (PI3K) inhibitor with activity predominantly against the PI3K-delta and PI3K-alpha isoforms, has shown promising results in preclinical cancer models with PTEN loss. Herein, we report the activity and safety data from the Z1G and Z1H subprotocols, which included patients with PTEN loss, of the National Cancer Institute Molecular Analysis for Therapy Choice trial. METHODS Patients with complete loss of cytoplasmic and nuclear PTEN as determined by immunohistochemistry regardless of PTEN mutation or deletion status were included in subprotocol Z1G, and patients with a deleterious mutation in the PTEN gene and retained expression of PTEN were included in subprotocol Z1H. Copanlisib was given intravenously over 1 hour at a dose of 60 mg on days 1, 8, and 15 in a 21-day-on and 7-day-off schedule in 28-day cycles. Patients continued treatment until disease progression or unacceptable toxicity. RESULTS Overall, 49 patients (20 patients in Z1G and 29 in Z1H) were included in the primary efficacy analyses. The objective response rates in both cohorts were 0% (Z1G; 90% CI, 0 to 13.9) and 3.4% (Z1H; 90% CI, 0.2 to 15.3), respectively. The median progression-free and overall survival durations were 1.8 months (90% CI, 1.4 to 3.9 months) and 13.7 months (90% CI, 6.8 to 18.3 months) for the Z1G cohort and 1.8 months (90% CI, 1.8 to 2.1 months) and 9.0 months (90% CI, 5.4 to 13.3 months) for the Z1H cohort, respectively. CONCLUSION Our results do not support the antitumor activity of single-agent copanlisib in tumors with PTEN loss regardless of mutation or deletion status or PTEN deleterious mutations with PTEN expression.
Collapse
Affiliation(s)
- Mohamed A Gouda
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Zihan Wei
- Dana Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, MA
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael A Davies
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Robert J Gray
- Dana Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, MA
| | - Victoria Wang
- Dana Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, MA
| | - Lisa M McShane
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | - Larry V Rubinstein
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | - David R Patton
- Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD
| | | | - Stanley R Hamilton
- City of Hope National Medical Center and Comprehensive Cancer Center, Duarte, CA
| | - Raymond Liu
- Department of Hematology Oncology, The Permanente Medical Group, San Francisco, CA
| | - Daniela A Bota
- UCI Health Chao Family Comprehensive Cancer Center, Orange, CA
| | | | | | - James V Tricoli
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | | | | | - Lyndsay N Harris
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | | | - Alice P Chen
- Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
| | | |
Collapse
|
14
|
Hashemi M, Mohandesi Khosroshahi E, Asadi S, Tanha M, Ghatei Mohseni F, Abdolmohammad Sagha R, Taheri E, Vazayefi P, Shekarriz H, Habibi F, Mortazi S, Khorrami R, Nabavi N, Rashidi M, Taheriazam A, Rahimzadeh P, Entezari M. Emerging roles of non-coding RNAs in modulating the PI3K/Akt pathway in cancer. Noncoding RNA Res 2025; 10:1-15. [PMID: 39296640 PMCID: PMC11406677 DOI: 10.1016/j.ncrna.2024.08.002] [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] [Academic Contribution Register] [Received: 11/28/2023] [Revised: 07/25/2024] [Accepted: 08/08/2024] [Indexed: 09/21/2024] Open
Abstract
Cancer progression results from the dysregulation of molecular pathways, each with unique features that can either promote or inhibit tumor growth. The complexity of carcinogenesis makes it challenging for researchers to target all pathways in cancer therapy, emphasizing the importance of focusing on specific pathways for targeted treatment. One such pathway is the PI3K/Akt pathway, which is often overexpressed in cancer. As tumor cells progress, the expression of PI3K/Akt increases, further driving cancer advancement. This study aims to explore how ncRNAs regulate the expression of PI3K/Akt. NcRNAs are found in both the cytoplasm and nucleus, and their functions vary depending on their location. They can bind to the promoters of PI3K or Akt, either reducing or increasing their expression, thus influencing tumorigenesis. The ncRNA/PI3K/Akt axis plays a crucial role in determining cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and even chemoresistance and radioresistance in human cancers. Anti-tumor compounds can target ncRNAs to modulate the PI3K/Akt axis. Moreover, ncRNAs can regulate the PI3K/Akt pathway both directly and indirectly.
Collapse
Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahsa Tanha
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
| | - Forough Ghatei Mohseni
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramina Abdolmohammad Sagha
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Taheri
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Paria Vazayefi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Helya Shekarriz
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Habibi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shaghayegh Mortazi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Independent Researchers, Victoria, British Columbia, V8V 1P7, Canada
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| |
Collapse
|
15
|
Zhang Y, Zhou YL, Xu N, Meng T, Wang ZZ, Pan FM, Zhu LX. Chemokines and PI3K/AKT signaling pathway mediate the spontaneously ruptured hepatocellular carcinoma through the regulation of the cell cycle. Hepatobiliary Pancreat Dis Int 2025:S1499-3872(25)00029-3. [PMID: 39952875 DOI: 10.1016/j.hbpd.2025.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/25/2024] [Accepted: 11/26/2024] [Indexed: 02/17/2025]
Abstract
BACKGROUND The incidence of spontaneously ruptured hepatocellular carcinoma (srHCC) has been shown to significantly elevate mortality rates. However, the precise mechanisms underlying srHCC remain poorly understood. METHODS Analysis was conducted on the data of 198 hepatocellular carcinoma (HCC) patients to investigate the factors contributing to srHCC. The clinical data of 33 transcriptome HCC patients were served for verification. An in-depth transcriptome analysis was conducted to investigate the distinctions between 26 cases of srHCC and 35 cases of non-ruptured hepatocellular carcinoma (nrHCC). Weighted Gene Co-expression Network Analysis (WGCNA) tool was utilized to develop a gene co-expression network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways enrichment, and protein-protein interaction (PPI) network were carried out. The corresponding samples for spontaneously ruptured hepatocellular carcinoma tissue (srHCC-T) and ruptured hepatocellular carcinoma paracancerous tissue (srHCC-P) was selected for verification. Transcriptional data were validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Immunofluorescence (IF), immunohistochemistry (IHC) and Western blot were used to detect the protein expression. RESULTS Our results showed that white blood cell (WBC) and monocyte levels were significant independent risk factors for srHCC (P < 0.05). There was a strong association between the srHCC-T and the expression of cell cycle-related genes BUB1B and macrophage function-related gene MACRO. Furthermore, chemokines and the PI3K/AKT signaling pathway play a crucial role in regulating the cell cycle process through a complex network of interactions, ultimately impacting the occurrence of srHCC. CONCLUSIONS Our study confirms that chemokines and the PI3K/AKT signaling pathway mediate the occurrence of HCC rupture by regulating the cell cycle. We provide a theoretical basis for the clinical treatment of srHCC.
Collapse
Affiliation(s)
- Yan Zhang
- Department of General Surgery, the Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Yang-Liu Zhou
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Na Xu
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Tao Meng
- Department of General Surgery, Hefei First People's Hospital, Hefei 230000, China
| | - Zhen-Zhen Wang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Fa-Ming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei 230032, China.
| | - Li-Xin Zhu
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| |
Collapse
|
16
|
Lei J, Chen J, Yu W, Wu Q, Jing S, Tang Y, Lin L, Hu M. Portrait of WWP1: the current state in human cancer. Front Cell Dev Biol 2025; 12:1516613. [PMID: 39949609 PMCID: PMC11821962 DOI: 10.3389/fcell.2024.1516613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/24/2024] [Accepted: 12/31/2024] [Indexed: 02/16/2025] Open
Abstract
WWP1, a member of the C2-WW-HECT E3 ligase family, is an E3 ubiquitin-protein ligase containing WW domains. This enzyme plays a critical role in regulating diverse cellular processes. Its expression is modulated by various factors and non-coding RNAs, resulting in ubiquitination that affects substrate protein degradation. WWP1 demonstrates a dual function, acting predominantly as an oncogene in tumors but occasionally as a tumor suppressor. This review summarizes WWP1's biological roles, therapeutic potential in oncology, upstream regulatory factors, and downstream substrates. It aims to promote research on WWP1's antitumor effects, improve understanding of its role in tumorigenesis, and support the development of targeted therapies.
Collapse
Affiliation(s)
- Jiaming Lei
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Jun Chen
- The Central Hospital of Ezhou, Affiliated Hospital of Hubei University of Science and Technology, Ezhou, Hubei, China
| | - Wenwen Yu
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Qing Wu
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Shuang Jing
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Yuanguang Tang
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Li Lin
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Meichun Hu
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| |
Collapse
|
17
|
Zhang C, Zhang S, Wang G, Huang X, Xu S, Wang D, Guo C, Wang Y. Genomics and transcriptomics identify quantitative trait loci affecting growth-related traits in silver pomfret (Pampus argenteus). COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101414. [PMID: 39813916 DOI: 10.1016/j.cbd.2025.101414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 10/31/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/18/2025]
Abstract
Pampus argenteus, a species distributed throughout the Indo-West Pacific, plays a significant role in the yield of aquaculture species. However, cultured P. argenteus has always been characterised by unbalanced growth synchronisation among individuals, slow growth rate, and lack of excellent germplasm resources. Therefore, we conducted mass selection for fast-growing strain P. argenteus for several consecutive years. Various genetic improvement programs have modified its genome sequence through selective pressure, leaving nucleotide signals that can be detected at the genomic level. In the present study, we combined bulked segregant analysis and transcriptome sequencing to identify candidate single nucleotide polymorphisms (SNPs) and key genes for growth-related traits in P. argenteus. A total of 7,280,936 SNPs and 2,212,379 insertions/deletions were identified in the extreme phenotypes of the fast-growing and slow-growing groups. Based on the examination of SNP frequency differences and sliding-window analysis, 42 SNPs were identified as candidate markers. Moreover, 14 of the 42 SNPs linked to growth-related traits were confirmed to be credible SNPs, and eight growth-related genes were screened, namely myb-binding protein 1 A, insulin A/B chains, α-1B adrenoceptor, engulfment and cell motility protein 3, myosin light chain kinase family member 4, insulin receptor located, unconventional myosin-9b, and matrilin-1. An optimal three-factor model (SNP4&SNP12&SNP14) was constructed using the generalized multifactor dimensionality reduction method, and its accuracy was verified as 67.72 %. These results may benefit genetic studies and accelerate genetic improvement of fast-growing strains of P. argenteus.
Collapse
Affiliation(s)
- Cheng Zhang
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China; College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; Key Laboratory of Marine Biotechnology of Zhejiang Province, Ningbo University, Zhejiang, Ningbo 315211, China; Key Laboratory of Green Mariculture (Co-construction by Ministry and Province), Ministry of Agriculture and Rural, Ningbo University, Zhejiang, Ningbo 315211, China
| | - Shun Zhang
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China
| | - Guanlin Wang
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China
| | - Xiang Huang
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China
| | - Shanliang Xu
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China; Key Laboratory of Green Mariculture (Co-construction by Ministry and Province), Ministry of Agriculture and Rural, Ningbo University, Zhejiang, Ningbo 315211, China
| | - Danli Wang
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China; Key Laboratory of Marine Biotechnology of Zhejiang Province, Ningbo University, Zhejiang, Ningbo 315211, China; Key Laboratory of Green Mariculture (Co-construction by Ministry and Province), Ministry of Agriculture and Rural, Ningbo University, Zhejiang, Ningbo 315211, China
| | - Chunyang Guo
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China; Key Laboratory of Marine Biotechnology of Zhejiang Province, Ningbo University, Zhejiang, Ningbo 315211, China.
| | - Yajun Wang
- National Engineering Research Laboratory of marine biotechnology and Engineering, Ningbo University, Zhejiang, Ningbo 315211, China; Key Laboratory of Marine Biotechnology of Zhejiang Province, Ningbo University, Zhejiang, Ningbo 315211, China; Key Laboratory of Green Mariculture (Co-construction by Ministry and Province), Ministry of Agriculture and Rural, Ningbo University, Zhejiang, Ningbo 315211, China.
| |
Collapse
|
18
|
Mghwary AES, Hassan RA, Halim PA, Abdelhameid MK. Advances in structural identification of some thieno[2,3-d]pyrimidine scaffolds as antitumor molecules: Synthetic approaches and control programmed cancer cell death potential. Bioorg Chem 2025; 154:107985. [PMID: 39637483 DOI: 10.1016/j.bioorg.2024.107985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/04/2024] [Revised: 10/30/2024] [Accepted: 11/17/2024] [Indexed: 12/07/2024]
Abstract
Thieno[2,3-d]pyrimidine fragment is not only bioistostere to quinazoline ring but also to purines which exist in nucleic acids responsible for several key biological processes of the living cells, thus it is of a great interest for many researchers. Thieno[2,3-d]pyrimidine ring has become an important scaffold for different compounds with versatile pharmacological activities including anticancer. These compounds exert their anticancer activity through variant mechanisms of action; one of these is the induction of different programmed cell death types as apoptosis and necroptosis which is an effective approach for cancer treatment. This review highlights the different synthetic approaches of recent thieno[2,3-d]pyrimidine analogs along with their anticancer significance through induction of apoptotic or necroptotic cell death with illustration of the structure-activity relationship (SAR).
Collapse
Affiliation(s)
- Aml E-S Mghwary
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Rasha A Hassan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Peter A Halim
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Mohammed K Abdelhameid
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| |
Collapse
|
19
|
Yue L, Li N, Ye X, Xiu Y, Wang B. Polymethoxylated flavones for modulating signaling pathways in inflammation. Int Immunopharmacol 2024; 143:113522. [PMID: 39515044 DOI: 10.1016/j.intimp.2024.113522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/16/2024] [Revised: 09/18/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
Aberrant signaling pathways play a crucial role in the pathogenesis of various diseases, including inflammatory disorders and autoimmune conditions. Polymethoxylated flavones (PMFs), a class of natural compounds found in citrus fruits, have obtained increasing attention for their potential therapeutic effects in modulating inflammatory responses. Although significant progress has been made in the pharmacological research of PMFs, the mechanisms by which they modulate signaling pathways to treat inflammation have not been systematically reviewed or analyzed. To address this gap in the literature, this review explores the mechanisms underlying the anti-inflammatory properties of PMFs and their prospects as drugs for treating inflammatory diseases. We discuss the molecular targets and signaling pathways through which PMFs exert their anti-inflammatory effects, including NF-κB pathway, PI3K/Akt pathway, MAPK pathway, Nrf2 pathway, and regulation of inflammatory cytokine production. Furthermore, we highlight preclinical studies evaluating the efficacy of PMFs in various inflammatory conditions, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and osteoarthritis (OA). Despite promising findings, challenges remain in optimizing the pharmacokinetic properties and therapeutic efficacy of PMFs for clinical use. Future research directions include elucidating the structure-activity relationships of PMFs, developing novel delivery strategies, and conducting large-scale clinical trials to validate their efficacy and safety profiles. Overall, PMFs represent a promising class of natural compounds with potential applications as anti-inflammatory drugs, offering novel therapeutic opportunities for managing inflammatory diseases.
Collapse
Affiliation(s)
- Lixia Yue
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Ning Li
- Shenzhen Research Institute, the Hong Kong University of Science and Technology, Shenzhen 518054, China
| | - Xianglu Ye
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yanfeng Xiu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Bing Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
20
|
Liu L, Graff SL, Wang Y. New Emerging Therapies Targeting PI3K/AKT/mTOR/PTEN Pathway in Hormonal Receptor-Positive and HER2-Negative Breast Cancer-Current State and Molecular Pathology Perspective. Cancers (Basel) 2024; 17:16. [PMID: 39796647 PMCID: PMC11718791 DOI: 10.3390/cancers17010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/08/2024] [Revised: 12/17/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
In hormone receptor-positive and HER2-negative breast cancers, a growing number of revolutionary personalized therapies are in clinical use or trials, such as CDK4/6 inhibitors, immune checkpoint inhibitors, and PIK3CA inhibitors. Those treatment options are largely driven by the presence or absence of genomic alterations in the tumor. Therefore, molecular profiling is often performed during disease progression. The most encountered genomic alterations are in the PI3K/AKT/mTOR/PTEN pathway. This review discusses the genetic alterations associated with the PI3K/AKT/mTOR/PTEN pathway to help clinicians understand drug selection, resistance, or interaction from a molecular pathologist's perspective.
Collapse
Affiliation(s)
- Liu Liu
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Brown University Health, Providence, RI 02903, USA;
- Legorreta Cancer Center, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
| | - Stephanie L. Graff
- Legorreta Cancer Center, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
- Division of Medical Oncology, Rhode Island Hospital and Brown University Health, Providence, RI 02903, USA
| | - Yihong Wang
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Brown University Health, Providence, RI 02903, USA;
- Legorreta Cancer Center, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
| |
Collapse
|
21
|
Huete-Acevedo J, Mas-Bargues C, Arnal-Forné M, Atencia-Rabadán S, Sanz-Ros J, Borrás C. Role of Redox Homeostasis in the Communication Between Brain and Liver Through Extracellular Vesicles. Antioxidants (Basel) 2024; 13:1493. [PMID: 39765821 PMCID: PMC11672896 DOI: 10.3390/antiox13121493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/30/2024] [Revised: 11/21/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025] Open
Abstract
Extracellular vesicles (EVs) are small, membrane-bound particles secreted by cells into the extracellular environment, playing an increasingly recognized role in inter-organ communication and the regulation of various physiological processes. Regarding the redox homeostasis context, EVs play a pivotal role in propagating and mitigating oxidative stress signals across different organs. Cells under oxidative stress release EVs containing signaling molecules that can influence the redox status of distant cells and tissues. EVs are starting to be recognized as contributors to brain-liver communication. Therefore, in this review, we show how redox imbalance can affect the release of EVs in the brain and liver. We propose EVs as mediators of redox homeostasis in the brain-liver axis.
Collapse
Affiliation(s)
- Javier Huete-Acevedo
- MiniAging Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibáñez, 15, 46010 Valencia, Spain; (J.H.-A.); (C.M.-B.); (M.A.-F.); (S.A.-R.)
| | - Cristina Mas-Bargues
- MiniAging Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibáñez, 15, 46010 Valencia, Spain; (J.H.-A.); (C.M.-B.); (M.A.-F.); (S.A.-R.)
| | - Marta Arnal-Forné
- MiniAging Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibáñez, 15, 46010 Valencia, Spain; (J.H.-A.); (C.M.-B.); (M.A.-F.); (S.A.-R.)
| | - Sandra Atencia-Rabadán
- MiniAging Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibáñez, 15, 46010 Valencia, Spain; (J.H.-A.); (C.M.-B.); (M.A.-F.); (S.A.-R.)
| | - Jorge Sanz-Ros
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Consuelo Borrás
- MiniAging Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibáñez, 15, 46010 Valencia, Spain; (J.H.-A.); (C.M.-B.); (M.A.-F.); (S.A.-R.)
| |
Collapse
|
22
|
Xu L, Zhao X, Tang F, Zhang J, Peng C, Ao H. Ameliorative Effect of Ginsenoside Rc on 5-Fluorouracil-Induced Chemotherapeutic Intestinal Mucositis via the PI3K-AKT/NF-κB Signaling Pathway: In Vivo and In Vitro Evaluations. Int J Mol Sci 2024; 25:13085. [PMID: 39684797 DOI: 10.3390/ijms252313085] [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] [Academic Contribution Register] [Received: 11/05/2024] [Revised: 11/26/2024] [Accepted: 12/01/2024] [Indexed: 12/18/2024] Open
Abstract
5-Fluorouracil (5-Fu) is a chemotherapeutic agent widely used to treat various cancers, which causes intestinal mucositis as a common side effect. Ginsenoside Rc, an active compound with anti-inflammatory, antioxidant, immunomodulatory, and antitumor properties, has protective effects against chemotherapy-induced mucositis caused by 5-Fu. This study aims to evaluate the protective effects of Rc on 5-Fu-induced chemotherapy-related mucositis and to elucidate its underlying mechanisms. In vivo experiments were conducted to measure intestinal permeability and assess the effects of Rc on body weight loss, diarrhea, and intestinal pathology induced by 5-Fu. Network pharmacology was also employed to explore potential mechanisms. In vitro, IEC-6 cell models were used to validate the cytoprotective effects of Rc, including assessments of cell viability, apoptosis, lactate dehydrogenase (LDH) release, and changes in inflammatory cytokine levels. The results indicate that Rc significantly ameliorated body weight reduction, diarrhea, and intestinal damage in mice treated by 5-Fu. Rc significantly mitigated 5-Fu-induced cellular damage by reducing levels of inflammatory cytokines such as IL-1β, IL-6, and TNF-α and decreasing apoptosis and cell permeability. Western blot analysis revealed that Rc upregulated the expression of Bcl-2 and tight junction proteins and downregulated the expression of Bax. Furthermore, Rc exerts anti-inflammatory and anti-apoptotic effects through PI3K-AKT and NF-κB signaling pathways. In conclusion, ginsenoside Rc demonstrated significant protective effects against 5-Fu-induced intestinal mucositis via the PI3K-AKT/NF-κB signaling pathway, suggesting its potential as a therapeutic agent for chemotherapy-related mucositis.
Collapse
Affiliation(s)
- Liyue Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaolan Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Fei Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jingnan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Hui Ao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu, University of Traditional Chinese Medicine, Chengdu 611137, China
| |
Collapse
|
23
|
Khalafiyan A, Fadaie M, Khara F, Zarrabi A, Moghadam F, Khanahmad H, Cordani M, Boshtam M. Highlighting roles of autophagy in human diseases: a perspective from single-cell RNA sequencing analyses. Drug Discov Today 2024; 29:104224. [PMID: 39521332 DOI: 10.1016/j.drudis.2024.104224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/14/2024] [Revised: 09/24/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Autophagy, the lysosome-driven breakdown of intracellular components, is pivotal in regulating eukaryotic cellular processes and maintaining homeostasis, making it physiologically important even under normal conditions. Cellular mechanisms involving autophagy include the response to nutrient deprivation, intracellular quality control, early development, and cell differentiation. Despite its established health significance, the role of autophagy in cancer and other diseases remains complex and not fully understood. A comprehensive understanding of autophagy is crucial to facilitate the development of novel therapies and drugs that can protect and improve human health. High-throughput technologies, such as single-cell RNA sequencing (scRNA-seq), have enabled researchers to study transcriptional landscapes at single-cell resolution, significantly advancing our knowledge of autophagy pathways across diverse physiological and pathological contexts. This review discusses the latest advances in scRNA-seq for autophagy research and highlights its potential in the molecular characterization of various diseases.
Collapse
Affiliation(s)
- Anis Khalafiyan
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahmood Fadaie
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Khara
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan; Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Fariborz Moghadam
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Khanahmad
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Maryam Boshtam
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
| |
Collapse
|
24
|
Zhu S, Yu D, Wang X, Wang X. Predict the Drug-Drug Interaction of a Novel PI3Kα/δ Inhibitor, TQ-B3525, and Its Two Metabolites Using Physiologically Based Pharmacokinetic Modeling. J Clin Pharmacol 2024; 64:1517-1527. [PMID: 39105511 DOI: 10.1002/jcph.6111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/09/2024] [Accepted: 07/22/2024] [Indexed: 08/07/2024]
Abstract
A novel dual PI3K α/δ inhibitor, TQ-B3525, has been developed for the targeted treatment of lymphoma and solid tumors. TQ-B3525 is primarily metabolized by CYP3A4 and FOM3, while also serving as a substrate for the P-glycoprotein transporter. The aim of this study was to anticipate the drug-drug interaction (DDI) of TQ-B3525 and its two metabolites with CYP3A4 enzyme potent inducer (rifampicin) and CYP3A4/P-gp inhibitor (itraconazole) utilizing a physiologically based pharmacokinetic (PBPK) modeling approach. Clinical data from healthy and cancer patient adults were employed to construct and evaluate the PBPK model for TQ-B3525, M3, and M8-3. Models involving rifampicin combined with midazolam, itraconazole combined with midazolam or digoxin were utilized to showcase the robustness of evaluating DDI effects. The simulated drug exposure of TQ-B3525, M3, and M8-3 in healthy and patient adults were consistent with clinical data, and the mean fold error values were within the acceptable ranges. The simulated results of positive substrates correspond to those reported in the literature. Co-administration with rifampicin reduces Cmax and AUC of TQ-B3525 to 76.1% and 46.0%, while increasing the levels of M3 and M8-3. With itraconazole, Cmax and AUC of TQ-B3525 rise to 131% and 204%, but decrease substantially for M3 and M8-3. PBPK model simulation results showed that the systemic exposure of TQ-B3525 was significantly affected when co-administered with CYP3A4/P-gp inducers and inhibitors. This indicates that the combination with strong inducers and inhibitors should be carefully avoided or adjust the dosage of TQ-B3525 in clinic.
Collapse
Affiliation(s)
- Shixing Zhu
- Clinical Medicine Department, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, China
| | - Ding Yu
- Clinical Medicine Department, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, China
| | - Xunqiang Wang
- Clinical Medicine Department, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, China
| | - Xin Wang
- Clinical Medicine Department, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, China
| |
Collapse
|
25
|
Yuan HY, Liu WY, Feng G, Chen SD, Jin XZ, Chen LL, Song ZJ, Li K, Byrne CD, Targher G, Tian N, Li G, Zhang XL, George J, Zhou M, Wang F, Zheng MH. Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study. Diabetes Obes Metab 2024; 26:5757-5775. [PMID: 39285685 DOI: 10.1111/dom.15946] [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] [Academic Contribution Register] [Received: 06/22/2024] [Revised: 08/22/2024] [Accepted: 08/30/2024] [Indexed: 11/05/2024]
Abstract
AIMS To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). MATERIALS AND METHODS We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). RESULTS GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. CONCLUSIONS GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.
Collapse
Affiliation(s)
- Hai-Yang Yuan
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Yue Liu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gong Feng
- Xi'an Medical University, Xi'an, China
| | - Sui-Dan Chen
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xin-Zhe Jin
- Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li-Li Chen
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zi-Jun Song
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Ke Li
- School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Christopher D Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton and University of Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore-Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Na Tian
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Li
- Department of Infectious, Jining No.1 People's Hospital, Jining, China
| | - Xin-Lei Zhang
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jacob George
- Storr Liver Centre, Westmead Hospital and University of Sydney, Westmead, Australia
| | - Meng Zhou
- School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Fudi Wang
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| |
Collapse
|
26
|
Wang Z, Guo Y, Li K, Huo Y, Wang S, Dong S, Ma M. Targeting the PI3K/mTOR pathway in idiopathic pulmonary fibrosis: Advances and therapeutic potential. Bioorg Med Chem 2024; 115:117908. [PMID: 39471771 DOI: 10.1016/j.bmc.2024.117908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/18/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 11/01/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease characterized by irreversible tissue scarring, leading to severe respiratory dysfunction. Despite current treatments with the drugs Pirfenidone and Nintedanib, effective management of IPF remains inadequate due to limited therapeutic benefits and significant side effects. This review focuses on the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway, a critical regulator of cellular processes linked to fibrosis, such as fibroblast proliferation, inflammation, and epithelial-mesenchymal transition (EMT). We discuss recent advances in understanding the role of the PI3K/mTOR pathway in IPF pathogenesis and highlight emerging therapies targeting this pathway. The review compiles evidence from both preclinical and clinical studies, suggesting that PI3K/mTOR inhibitors may offer new hope for IPF treatment by modulating fibrosis and improving patient outcomes. Moreover, it outlines the potential for these inhibitors to be developed into effective, personalized treatment options, underscoring the importance of further research to explore their efficacy and safety profiles comprehensively.
Collapse
Affiliation(s)
- Zhengyang Wang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Yanzhi Guo
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Kaiyin Li
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Yan Huo
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
| | - Shuyan Wang
- Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Suzhen Dong
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
| | - Mingliang Ma
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China; Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China.
| |
Collapse
|
27
|
Liu M, Liu Q, Hu K, Dong Y, Sun X, Zou Z, Ji D, Liu T, Yu Y. Colorectal cancer with BRAF V600E mutation: Trends in immune checkpoint inhibitor treatment. Crit Rev Oncol Hematol 2024; 204:104497. [PMID: 39245296 DOI: 10.1016/j.critrevonc.2024.104497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/02/2024] [Revised: 08/29/2024] [Accepted: 08/31/2024] [Indexed: 09/10/2024] Open
Abstract
Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.
Collapse
Affiliation(s)
- Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qing Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Keshu Hu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yu Dong
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhiguo Zou
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Dingkun Ji
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| |
Collapse
|
28
|
Mallick S, Duttaroy AK, Dutta S. The PIK3CA gene and its pivotal role in tumor tropism of triple-negative breast cancer. Transl Oncol 2024; 50:102140. [PMID: 39369580 PMCID: PMC11491976 DOI: 10.1016/j.tranon.2024.102140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/24/2024] [Revised: 09/04/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024] Open
Abstract
The PIK3CA gene is a linchpin in the intricate molecular network governing triple-negative breast cancer (TNBC) tumor tropism, serving as a focal point for understanding this aggressive disease. Anchored within the PI3K/AKT/mTOR signaling axis, PIK3CA mutations exert substantial influence, driving cellular processes that highlight the unique biology of TNBC. This review meticulously highlights the association between PIK3CA mutations and distinct TNBC subtypes, elucidating the gene's multifaceted contributions to tumor tropism. Molecular dissection reveals how PIK3CA mutations dynamically modulate chemokine responses, growth factor signaling, and extracellular matrix interactions, orchestrating the complex migratory behaviour characteristic of TNBC cells. A detailed exploration of PIK3CA-targeted strategies in the therapeutic arena is presented, outlining the current landscape of clinical trials and precision medicine approaches. As the scientific narrative converges, this review underscores the critical role of PIK3CA in shaping the molecular intricacies of TNBC tumor tropism and illuminates pathways toward tailored interventions, promising a paradigm shift in the clinical management of TNBC.
Collapse
Affiliation(s)
- Sumit Mallick
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Mangalore, Karnataka, India
| | - Asim K Duttaroy
- Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Norway.
| | - Suman Dutta
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK; Dorothy Crowfoot Hodgkin Building, Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
| |
Collapse
|
29
|
Yang L, Sun J, Yang T, Zhang X, Xu C, Wei Y, Li Y, Zhao Y, Zhang S, Wu Q, Shi H, Fu Q, Xia L. Therapeutic effects and mechanisms of berberine on enteritis caused by Salmonella in poultry. Front Microbiol 2024; 15:1458579. [PMID: 39664055 PMCID: PMC11631916 DOI: 10.3389/fmicb.2024.1458579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/02/2024] [Accepted: 11/07/2024] [Indexed: 12/13/2024] Open
Abstract
The present study aimed to investigate the therapeutic effects of berberine (BBR) on Salmonella enteritis in broiler chickens and to elucidate its mechanisms of action preliminarily. Blood samples were collected from 21- to 35-day-old Sanhuang male chicks to measure immune and biochemical indicators and to calculate the organ coefficients for the liver, spleen, bursa of Fabricius, and thymus. The caecal microbiota was analysed through 16S ribosomal RNA (rRNA) gene sequencing, and transcriptome sequencing was conducted. Compared with the positive control group (S), the berberine-treated group (BS) presented increased serum immunoglobulin M (IgM) levels, serum IgG levels, and total antioxidant capacity; berberine ameliorated the increase in the thymus index caused by Salmonella administration. The addition of berberine to the diet increased the abundance of beneficial bacterial genera, including Bacteroides and Lactobacillus. It also decreased the abundance of harmful bacterial genera, including Faecalibacterium and Streptococcus. Transcriptome analysis revealed that gene expression in the S and BS groups was associated with T cell selection and B cell receptor signalling pathways, which are enriched primarily in multiple immune-related signalling pathways, including the B cell receptor signalling pathway, NF-κ B signalling pathway, intestinal immune network for IgA production, asthma, and African trypanosomiasis. The significantly expressed genes included ATAD5, ERP29, MGST2, PIK3CA, and HSP90AA1. The present study demonstrated that berberine has a good therapeutic effect on Salmonella infection in chicks, as it inhibits the occurrence and development of Salmonella-induced intestinal inflammation by regulating the balance of the gut microbiota and the expression of related genes, including ATAD5, ERP29, MGST2, PIK3CA, and HSP90AA1.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Lining Xia
- Xinjiang Key Laboratory of Herbivore Drug Research and Creation, College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, Xinjiang, China
| |
Collapse
|
30
|
Sami A, Raza A. Reprogramming the tumor microenvironment - macrophages emerge as key players in breast cancer immunotherapy. Front Immunol 2024; 15:1457491. [PMID: 39660126 PMCID: PMC11628348 DOI: 10.3389/fimmu.2024.1457491] [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] [Academic Contribution Register] [Received: 06/30/2024] [Accepted: 11/07/2024] [Indexed: 12/12/2024] Open
Abstract
Breast cancer has the highest global incidence among all cancers, affecting more than 2 million individuals annually. Despite the availability of new drugs and novel treatment combinations, it is postulated that the incidence and mortality of breast cancer will rise by 40.8% and 51.9% respectively by 2040. Such dire statistics are associated with the clonal evolution of cancer cells that leads to therapeutic resistance and consequent relapse in breast cancer patients. On the other hand, the tumor microenvironment (TME) comprising of tumor cells, cancer-associated immune cells, re-programmed stromal cells, and the extracellular matrix (ECM) creates an immunosuppressive niche facilitating immune evasion. This review focuses on a critical cellular component of the tumor microenvironment, the tumor-associated macrophages (TAMs) in breast cancer immunotherapy. Macrophages are inherently plastic and can convert from an anti-tumor M1 phenotype to a pro-tumor M2 phenotype based on microenvironmental cues. Cancer cells facilitate these cues, allowing the tumor-associated macrophages to gain M2 phenotype and mediate immune evasion. Therefore, knowledge of the distinct role of tumor-associated macrophages in immune evasion can help design therapeutics such as engineered macrophages, M2 targeting drugs, and novel macrophage-mediated drug delivery strategies for long-term survival in breast cancer.
Collapse
Affiliation(s)
- Ana Sami
- Department of Medicine and Dentistry, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Afsheen Raza
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| |
Collapse
|
31
|
Utpal BK, Dehbia Z, Zidan BMRM, Sweilam SH, Singh LP, Arunkumar MS, Sona M, Panigrahy UP, Keerthana R, Mandadi SR, Rab SO, Alshehri MA, Koula D, Suliman M, Nafady MH, Emran TB. Carotenoids as modulators of the PI3K/Akt/mTOR pathway: innovative strategies in cancer therapy. Med Oncol 2024; 42:4. [PMID: 39549201 DOI: 10.1007/s12032-024-02551-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/20/2024] [Accepted: 10/29/2024] [Indexed: 11/18/2024]
Abstract
Cancer progression is primarily driven by the uncontrolled activation of cellular signaling pathways, with the PI3K/Akt/mTOR (PAMT) pathway playing a central role. This pathway significantly contributes to the proliferation and survival of cancer cells, and its hyperactivity is a major challenge in managing several types of malignancies. This article delves into the promising potential of carotenoids, natural pigments found in abundance in fruits and vegetables, as a novel therapeutic strategy for cancer treatment. By specifically targeting and inhibiting the PAMT pathway, carotenoids may effectively disrupt the growth and survival of cancer cells. The article examines the complex mechanisms underlying these interactions and highlights the obstacles faced in cancer treatment. It proposes a compelling approach to developing therapies that leverage natural products to target this critical pathway, offering a fresh perspective on cancer treatment. Further research is essential to enhance the therapeutic efficacy of these compounds.
Collapse
Affiliation(s)
- Biswajit Kumar Utpal
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Zerrouki Dehbia
- Laboratory of AgroBiotechnology and Nutrition in Semi Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
| | - B M Redwan Matin Zidan
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Sherouk Hussein Sweilam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Egyptian Russian University, Cairo-Suez Road, Badr City, Cairo, 11829, Egypt
| | - Laliteshwar Pratap Singh
- Department of Pharmaceutical Chemistry, Narayan Institute of Pharmacy, Gopal Narayan Singh University, Sasaram (Rohtas) Bihar, Jamuhar, 821305, India
| | - M S Arunkumar
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - M Sona
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Uttam Prasad Panigrahy
- Faculty of Pharmaceutical Science, Assam Down Town University, Gandhi Nagar, Sankar Madhab Path, Panikhaiti, Guwahati, Assam, India
| | - R Keerthana
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India
| | - Sandhya Rani Mandadi
- Department of Pharmaceutics, Vishnu Institute of Pharmaceutical Education and Research, Tuljaraopet, Telangana , 502313, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Ali Alshehri
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk, 71491, Saudi Arabia
| | - Doukani Koula
- Laboratory of AgroBiotechnology and Nutrition in Semi Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
- Laboratory of Animal Production Sciences and Techniques, University of Abdelhamid Ibn Badis, Mostaganem, Algeria
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Mohamed H Nafady
- Faculty of Applied Health Science Technology, Misr University for Science and Technology, Giza, 12568, Egypt.
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| |
Collapse
|
32
|
Zhang H, Qi HZ, Li YJ, Shi XY, Hu ML, Chen XL, Li Y. Identification of novel inhibitors targeting PI3Kα via ensemble-based virtual screening method, biological evaluation and molecular dynamics simulation. J Comput Aided Mol Des 2024; 38:37. [PMID: 39528618 DOI: 10.1007/s10822-024-00580-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/17/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
PIK3CA gene encoding PI3K p110α is one of the most frequently mutated and overexpressed in majority of human cancers. Development of potent and selective novel inhibitors targeting PI3Kα was considered as the most promising approaches for cancer treatment. In this investigation, a virtual screening platform for PI3Kα inhibitors was established by employing machine learning methods, pharmacophore modeling, and molecular docking approaches. 28 potential PI3Kα inhibitors with different scaffolds were selected from the databases with 295,024 compounds. Among the 28 hits, hit15 exhibited the best inhibitory effect against PI3Kα with IC50 value less than 1.0 µM. The molecular dynamics simulation indicated that hit15 could stably bind to the active site of PI3Kα, interact with some residues by hydrophobic, electrostatic and hydrogen bonding interactions, and finally induced PI3Kα active pocket substantial conformation changes. Stable H-bond interactions were formed between hit15 and residues of Lys776, Asp810 and Asp933. The binding free energy of PI3Kα-hit15 was - 65.3 kJ/mol. The free energy decomposition indicated that key residues of Asp805, Ile848 and Ile932 contributed stronger energies to the binding free energy. The above results indicated that hit15 with novel scaffold was a potent PI3Kα inhibitor and considered as a promising candidate for further drug development to treat various cancers with PI3Kα over activated.
Collapse
Affiliation(s)
- Hui Zhang
- College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People's Republic of China.
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
| | - Hua-Zhao Qi
- College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People's Republic of China
| | - Ya-Juan Li
- College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People's Republic of China
| | - Xiu-Yun Shi
- College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People's Republic of China
| | - Mei-Ling Hu
- College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People's Republic of China
| | - Xiang-Long Chen
- College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People's Republic of China
| | - Yuan Li
- College of Life Science, Northwest Normal University, Lanzhou, 730070, Gansu, People's Republic of China
| |
Collapse
|
33
|
Pasula MB, Sapkota S, Sylvester PW, Briski KP. Sex-dimorphic effects of glucose transporter-2 gene knockdown on hypothalamic primary astrocyte phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of rapamycin (mTOR) cascade protein expression and phosphorylation. Mol Cell Endocrinol 2024; 593:112341. [PMID: 39128492 PMCID: PMC11401769 DOI: 10.1016/j.mce.2024.112341] [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] [Academic Contribution Register] [Received: 06/22/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 08/13/2024]
Abstract
Glucose transporter-2 (GLUT2), a unique high capacity/low affinity, highly efficient membrane transporter and sensor, regulates hypothalamic astrocyte glucose phosphorylation and glycogen metabolism. The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway participates in glucose homeostasis, but its sensitivity to glucose-sensory cues is unknown. Current research used a hypothalamic astrocyte primary culture model to investigate whether glucoprivation causes PI3K/Akt/mTOR pathway activation in one or both sexes by GLUT2-dependent mechanisms. Glucoprivation did not alter astrocyte PI3K levels, yet up-regulated both phosphorylated derivatives in female and down-regulated male p60 phosphoprotein expression. GLUT2 siRNA pretreatment diminished glucoprivic patterns of PI3K and phospho-PI3K expression in each sex. Astrocyte Akt and phospho-Akt/Thr308 proteins exhibited divergent, sex-contingent responses to GLUT2 gene knockdown or glucoprivation. GLUT2 siRNA pretreatment exacerbated glucoprivic-associated Akt diminution in the female, and either amplified (male) or reversed (female) glucoprivic regulation of phospho-Akt/Thr308 expression. GLUT2 gene silencing down- (male) or up-(female) regulated mTOR protein, and phospho-mTOR protein in male. Male astrocyte mTOR and phospho-mTOR profile were refractory to glucoprivation, but glucose-deprived females showed GLUT2-independent mTOR inhibition and GLUT2-dependent phospho-mTOR up-augmentation. Results identify a larger number of glucoprivic-sensitive PI3K/Akt/mTOR pathway proteins in female versus male astrocytes, and document divergent responses of common glucose-sensitive targets. GLUT2 stimulates phosphoPI3K protein expression in each sex, but imposes differential control of PI3K, Akt, phospho-Akt/Thr308, mTOR, and phospho-mTOR profiles in male versus female. Data implicate GLUT2 as a driver of distinctive pathway protein responses to glucoprivation in female, but not male.
Collapse
Affiliation(s)
- Madhu Babu Pasula
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, USA
| | - Subash Sapkota
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, USA
| | - Paul W Sylvester
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, USA
| | - Karen P Briski
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, USA.
| |
Collapse
|
34
|
Gao Y, Yu Y, Zhang M, Yu W, Kang L. Mechanisms of endocrine resistance in hormone receptor-positive breast cancer. Front Oncol 2024; 14:1448687. [PMID: 39544302 PMCID: PMC11560879 DOI: 10.3389/fonc.2024.1448687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/14/2024] [Accepted: 10/09/2024] [Indexed: 11/17/2024] Open
Abstract
Hormone receptor-positive breast cancer may recur or metastasize years or decades after its diagnosis. Furthermore, hormone receptor expression may persist in relapsed or metastatic cancer cells. Endocrine therapy is one of the most efficacious treatments for hormone receptor-positive breast cancers. Nevertheless, a considerable proportion of patients develop resistance to endocrine therapy. Previous studies have identified numerous mechanisms underlying drug resistance, such as epigenetic abnormalities in the estrogen receptor (ER) genome, activation of ER-independent ligands, and alterations in signaling pathways including PI3K/AKT/mTOR, Notch, NF-κB, FGFR, and IRE1-XBP1. This article reviews the mechanisms of endocrine resistance in hormone receptor-positive advanced breast cancer, drawing from previous studies, and discusses the latest research advancements and prospects.
Collapse
Affiliation(s)
| | | | | | | | - Lihua Kang
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
| |
Collapse
|
35
|
Zheng S, Qi W, Xue T, Zao X, Xie J, Zhang P, Li X, Ye Y, Liu A. Chinese medicine in the treatment of chronic hepatitis B: The mechanisms of signal pathway regulation. Heliyon 2024; 10:e39176. [PMID: 39640799 PMCID: PMC11620126 DOI: 10.1016/j.heliyon.2024.e39176] [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] [Academic Contribution Register] [Received: 10/06/2024] [Accepted: 10/08/2024] [Indexed: 12/07/2024] Open
Abstract
Chronic hepatitis B (CHB) is a chronic inflammatory disease of the liver caused by infection with the hepatitis B virus (HBV), which in later stages can lead to the development of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma in severe cases, jeopardizing long-term quality of life, with a poor prognosis, and placing a serious financial burden on many families around the world. The pathogenesis of the disease is complex and closely related to the immune function of the body, which has not yet been fully elucidated. The development of chronic hepatitis B is closely related to the involvement of various signaling pathways, such as JAK/STAT, PI3K/Akt, Toll-like receptor, NF-κB and MAPK signaling pathways. A large number of studies have shown that Chinese medicine has obvious advantages in anti-hepatitis B virus, and it can effectively treat the disease by modulating relevant signaling pathways, strengthening immune resistance and defense, and inhibiting inflammatory responses, and certain research progress has been made, but there is still a lack of a comprehensive review on the modulation of relevant signaling pathways in Chinese medicine for the treatment of CHB. Therefore, this article systematically combed and elaborated the relevant literature on the modulation of relevant signaling pathways by traditional Chinese medicine in recent years, with a view to providing new ideas for the treatment of CHB and further drug development.
Collapse
Affiliation(s)
- Shihao Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Wenying Qi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Tianyu Xue
- Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang, 050000, China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
| | - Jinchi Xie
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Peng Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yongan Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100007, China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Aimin Liu
- Shangzhuang Township Community Health Service Center, Beijing, 100094, China
| |
Collapse
|
36
|
Wright B, King S, Suphioglu C. The Importance of Phosphoinositide 3-Kinase in Neuroinflammation. Int J Mol Sci 2024; 25:11638. [PMID: 39519189 PMCID: PMC11546674 DOI: 10.3390/ijms252111638] [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] [Academic Contribution Register] [Received: 10/02/2024] [Revised: 10/23/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis (MS). This review explores the role of phosphoinositide 3-kinase (PI3K), a key enzyme involved in cellular survival, proliferation, and inflammatory responses, within the context of neuroinflammation. Two PI3K isoforms of interest, PI3Kγ and PI3Kδ, are specific to the regulation of CNS cells, such as microglia, astrocytes, neurons, and oligodendrocytes, influencing pathways, such as Akt, mTOR, and NF-κB, that control cytokine production, immune cell activation, and neuroprotection. The dysregulation of PI3K signalling is implicated in chronic neuroinflammation, contributing to the exacerbation of neurodegenerative diseases. Preclinical studies show promise in targeting neuronal disorders using PI3K inhibitors, such as AS605240 (PI3Kγ) and idelalisib (PI3Kδ), which have reduced inflammation, microglial activation, and neuronal death in in vivo models of AD. However, the clinical translation of these inhibitors faces challenges, including blood-brain barrier (BBB) permeability, isoform specificity, and long-term safety concerns. This review highlights the therapeutic potential of PI3K modulation in neuroinflammatory diseases, identifying key gaps in the current research, particularly in the need for brain-penetrating and isoform-specific inhibitors. These findings underscore the importance of future research to develop targeted therapies that can effectively modulate PI3K activity and provide neuroprotection in chronic neurodegenerative disorders.
Collapse
Affiliation(s)
- Brock Wright
- NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia; (B.W.); (S.K.)
- Centre for Sustainable Bioproducts, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
| | - Samuel King
- NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia; (B.W.); (S.K.)
- Centre for Sustainable Bioproducts, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
| | - Cenk Suphioglu
- NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia; (B.W.); (S.K.)
- Centre for Sustainable Bioproducts, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
| |
Collapse
|
37
|
Alsereidi FR, Khashim Z, Marzook H, Al-Rawi AM, Salomon T, Almansoori MK, Madkour MM, Hamam AM, Ramadan MM, Peterson QP, Saleh MA. Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells. Cardiovasc Diabetol 2024; 23:388. [PMID: 39472869 PMCID: PMC11520772 DOI: 10.1186/s12933-024-02481-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] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/28/2024] [Accepted: 10/21/2024] [Indexed: 11/02/2024] Open
Abstract
Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is well-recognized for its therapeutic benefits in type 2 diabetes (T2D) and cardiovascular diseases. In this comprehensive in vitro study, we investigated DAPA's effects on cardiomyocytes, aortic endothelial cells (AECs), and stem cell-derived beta cells (SC-β), focusing on its impact on hypertrophy, inflammation, and cellular stress. Our results demonstrate that DAPA effectively attenuates isoproterenol (ISO)-induced hypertrophy in cardiomyocytes, reducing cell size and improving cellular structure. Mechanistically, DAPA mitigates reactive oxygen species (ROS) production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation. Additionally, DAPA's modulation of SGLT2, the Na+/H + exchanger 1 (NHE1), and glucose transporter (GLUT 1) type 1 highlights its critical role in maintaining cellular ion balance and glucose metabolism, providing insights into its cardioprotective mechanisms. In aortic endothelial cells (AECs), DAPA exhibited notable anti-inflammatory properties by restoring AKT and phosphoinositide 3-kinase (PI3K) expression, enhancing mitogen-activated protein kinase (MAPK) activation, and downregulating inflammatory cytokines at both the gene and protein levels. Furthermore, DAPA alleviated tumor necrosis factor (TNFα)-induced inflammation and stress responses while enhancing endothelial nitric oxide synthase (eNOS) expression, suggesting its potential to preserve vascular function and improve endothelial health. Investigating SC-β cells, we found that DAPA enhances insulin functionality without altering cell identity, indicating potential benefits for diabetes management. DAPA also upregulated MAFA, PI3K, and NRF2 expression, positively influencing β-cell function and stress response. Additionally, it attenuated NLRP3 activation in inflammation and reduced NHE1 and glucose-regulated protein GRP78 expression, offering novel insights into its anti-inflammatory and stress-modulating effects. Overall, our findings elucidate the multifaceted therapeutic potential of DAPA across various cellular models, emphasizing its role in mitigating hypertrophy, inflammation, and cellular stress through the activation of the AKT pathway and other signaling cascades. These mechanisms may not only contribute to enhanced cardiac and endothelial function but also underscore DAPA's potential to address metabolic dysregulation in T2D.
Collapse
Affiliation(s)
- Fatmah R Alsereidi
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Emirates Health Services (EHS), Dubai, United Arab Emirates
| | - Zenith Khashim
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Hezlin Marzook
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Ahmed M Al-Rawi
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Tiana Salomon
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Mahra K Almansoori
- College of Medicine and Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates
| | - Moustafa M Madkour
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Ahmed Mohamed Hamam
- Endocrinology and Metabolism Department, Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud M Ramadan
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Department of Cardiology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Quinn P Peterson
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mohamed A Saleh
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| |
Collapse
|
38
|
El-Shoura EAM, Abdelzaher LA, Mahmoud NI, Farghaly OA, Sabry M, Girgis Shahataa M, Salem EA, Saad HM, Elhussieny O, Kozman MR, Atwa AM. Combined sulforaphane and β-sitosterol mitigate olanzapine-induced metabolic disorders in rats: Insights on FOXO, PI3K/AKT, JAK/STAT3, and MAPK signaling pathways. Int Immunopharmacol 2024; 140:112904. [PMID: 39116489 DOI: 10.1016/j.intimp.2024.112904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/25/2024] [Revised: 07/27/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
One of the best antipsychotics for treating schizophrenia and bipolar disorders is olanzapine (OLA). However, its use is restricted owing to unfavorable adverse effects as liver damage, dyslipidemia, and weight gain. The primary objective of the present investigation was to examine the signaling mechanisms that underlie the metabolic disruption generated by OLA. Besides, the potential protective effect of sulforaphane (SFN) and β-sitosterol (βSS) against obesity and metabolic toxicity induced by OLA were inspected as well. A total of five groups of male Wistar rats were established, including the control, OLA, SFN+OLA, βSS+OLA, and the combination + OLA groups. Hepatic histopathology, biochemical analyses, ultimate body weights, liver function, oxidative stress, and pro-inflammatory cytokines were evaluated. In addition to the relative expression of FOXO, the signaling pathways for PI3K/AKT, JAK/STAT3, and MAPK were assessed as well. All biochemical and hepatic histopathological abnormalities caused by OLA were alleviated by SFN and/or βSS. A substantial decrease in systolic blood pressure (SBP), proinflammatory cytokines, serum lipid profile parameters, hepatic MDA, TBIL, AST, and ALT were reduced through SFN or/and βSS. To sum up, the detrimental effects of OLA are mediated by alterations in the Akt/FOXO3a/ATG12, Ras/SOS2/Raf-1/MEK/ERK1/2, and Smad3,4/TGF-β signaling pathways. The administration of SFN and/or βSS has the potential to mitigate the metabolic deficit, biochemical imbalances, hepatic histological abnormalities, and the overall unfavorable consequences induced by OLA by modulating the abovementioned signaling pathways.
Collapse
Affiliation(s)
- Ehab A M El-Shoura
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | - Lobna A Abdelzaher
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nesreen I Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Omar A Farghaly
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Egypt
| | - Mostafa Sabry
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Egypt
| | - Mary Girgis Shahataa
- Department of Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Esraa A Salem
- Department of Medical Physiology, Faculty of Medicine, Menoufia University, Shebeen ElKom, 32511, Egypt
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh 51744, Egypt
| | - Omnya Elhussieny
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh 51744, Egypt
| | - Magy R Kozman
- Clinical Pharmacy Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza 12563, Egypt
| | - Ahmed M Atwa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt; Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Ayen Iraqi University, Thi-Qar 64001, Iraq
| |
Collapse
|
39
|
Cutshaw G, Joshi N, Wen X, Quam E, Hassan N, Uthaman S, Waite J, Sarkar S, Singh B, Bardhan R. Metabolic Response to Small Molecule Therapy in Colorectal Cancer Tracked with Raman Spectroscopy and Metabolomics. Angew Chem Int Ed Engl 2024; 63:e202410919. [PMID: 38995663 PMCID: PMC11473224 DOI: 10.1002/anie.202410919] [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] [Academic Contribution Register] [Received: 06/10/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/13/2024]
Abstract
Despite numerous screening tools for colorectal cancer (CRC), 25 % of patients are diagnosed with advanced disease. Novel diagnostic technologies that are early, accurate, and rapid are imperative to assess the therapeutic efficacy of clinical drugs and identify new biomarkers of treatment response. Here Raman spectroscopy (RS) was used to track metabolic reprogramming in KRAS-mutant HCT116 and SW837 cells, and KRAS wild-type CC cells. RS combined with multivariate analysis methods distinguished nonresponsive, partially responsive, and responsive cells treated with cetuximab, a monoclonal antibody for EGFR inhibition, sotorasib, a clinically approved KRAS inhibitor, and various doses of trametinib, an inhibitor of the MAPK pathway. Cells treated with a combination of subtoxic doses of trametinib and BKM120, an inhibitor of the PI3K pathway, showed a synergistic response between the two pathways. Using a supervised machine learning regression model, we established a scoring methodology trained to a priori predict therapeutic response to new treatment combinations. RS metabolites were verified with mass spectrometry, and enrichment pathways were identified, including amino acid, purine, and nicotinate and nicotinamide metabolism that differentiated monotherapy from combination therapy. Our approach may ultimately be applicable to patient-derived primary cells and cultures of patient tumors to predict effective drugs for individualized care.
Collapse
Affiliation(s)
- Gabriel Cutshaw
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Neeraj Joshi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Xiaona Wen
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Elizabeth Quam
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Nora Hassan
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Saji Uthaman
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Joshua Waite
- Department of Mechanical Engineering, Iowa State University, Ames, IA 50012, USA
| | - Soumik Sarkar
- Department of Mechanical Engineering, Iowa State University, Ames, IA 50012, USA
| | - Bhuminder Singh
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Rizia Bardhan
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| |
Collapse
|
40
|
Zhou Z, Xie Y, Wei Q, Zhang X, Xu Z. Revisiting the role of MicroRNAs in the pathogenesis of idiopathic pulmonary fibrosis. Front Cell Dev Biol 2024; 12:1470875. [PMID: 39479511 PMCID: PMC11521927 DOI: 10.3389/fcell.2024.1470875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/26/2024] [Accepted: 09/30/2024] [Indexed: 11/02/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.
Collapse
Affiliation(s)
| | | | | | | | - Zhihao Xu
- The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| |
Collapse
|
41
|
Liu J, Wang Y, Tian M, Xia M, Zheng Y, Hao M, Qian Y, Shu H, Zhang W, Peng P, Zhao Z, Dong K, Peng W, Gao T, Li Z, Jin X, Wei M, Feng Y. O-GlcNAcylation of ATP-citrate lyase couples glucose supply to lipogenesis for rapid tumor cell proliferation. Proc Natl Acad Sci U S A 2024; 121:e2402674121. [PMID: 39388261 PMCID: PMC11494317 DOI: 10.1073/pnas.2402674121] [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] [Academic Contribution Register] [Received: 02/15/2024] [Accepted: 08/26/2024] [Indexed: 10/12/2024] Open
Abstract
Elevated lipid synthesis is one of the best-characterized metabolic alterations in cancer and crucial for membrane expansion. As a key rate-limiting enzyme in de novo fatty acid synthesis, ATP-citrate lyase (ACLY) is frequently up-regulated in tumors and regulated by posttranslational modifications (PTMs). Despite emerging evidence showing O-GlcNAcylation on ACLY, its biological function still remains unknown. Here, we observed a significant upregulation of ACLY O-GlcNAcylation in various types of human tumor cells and tissues and identified S979 as a major O-GlcNAcylation site. Importantly, S979 O-GlcNAcylation is required for substrate CoA binding and crucial for ACLY enzymatic activity. Moreover, it is sensitive to glucose fluctuation and decisive for fatty acid synthesis as well as tumor cell proliferation. In response to EGF stimulation, both S979 O-GlcNAcylation and previously characterized S455 phosphorylation played indispensable role in the regulation of ACLY activity and cell proliferation; however, they functioned independently from each other. In vivo, streptozocin treatment- and EGFR overexpression-induced growth of xenograft tumors was mitigated once S979 was mutated. Collectively, this work helps comprehend how cells interrogate the nutrient enrichment for proliferation and suggests that although mammalian cell proliferation is controlled by mitogen signaling, the ancient nutrition-sensing mechanism is conserved and still efficacious in the cells of multicellular organisms.
Collapse
Affiliation(s)
- Jia Liu
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Yang Wang
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Miaomiao Tian
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Mingjie Xia
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Yi Zheng
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Miao Hao
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin130033, People’s Republic Of China
| | - Yuqiang Qian
- 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, Changchun130062, China
| | - Hengyao Shu
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Wenxia Zhang
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Pinghui Peng
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Zhexuan Zhao
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Kejian Dong
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Wanting Peng
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Tian Gao
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Zhanjun Li
- 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, Changchun130062, China
| | - Xin Jin
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Min Wei
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| | - Yunpeng Feng
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin130024, People’s Republic Of China
| |
Collapse
|
42
|
Gao Y, Li J, Cheng W, Diao T, Liu H, Bo Y, Liu C, Zhou W, Chen M, Zhang Y, Liu Z, Han W, Chen R, Peng J, Zhu L, Hou W, Zhang Z. Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation. Cancer Cell 2024; 42:1764-1783.e10. [PMID: 39303725 DOI: 10.1016/j.ccell.2024.08.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/28/2023] [Revised: 07/28/2024] [Accepted: 08/28/2024] [Indexed: 09/22/2024]
Abstract
Fibroblasts, known for their functional diversity, play crucial roles in inflammation and cancer. In this study, we conduct comprehensive single-cell RNA sequencing analyses on fibroblast cells from 517 human samples, spanning 11 tissue types and diverse pathological states. We identify distinct fibroblast subpopulations with universal and tissue-specific characteristics. Pathological conditions lead to significant shifts in fibroblast compositions, including the expansion of immune-modulating fibroblasts during inflammation and tissue-remodeling myofibroblasts in cancer. Within the myofibroblast category, we identify four transcriptionally distinct subpopulations originating from different developmental origins, with LRRC15+ myofibroblasts displaying terminally differentiated features. Both LRRC15+ and MMP1+ myofibroblasts demonstrate pro-tumor potential that contribute to the immune-excluded and immune-suppressive tumor microenvironments (TMEs), whereas PI16+ fibroblasts show potential anti-tumor functions in adjacent non-cancerous regions. Fibroblast-subtype compositions define patient subtypes with distinct clinical outcomes. This study advances our understanding of fibroblast biology and suggests potential therapeutic strategies for targeting specific fibroblast subsets in cancer treatment.
Collapse
Affiliation(s)
- Yang Gao
- School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Jianan Li
- Changping Laboratory, Beijing 102206, China
| | - Wenfeng Cheng
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Tian Diao
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Huilan Liu
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Yufei Bo
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Chang Liu
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Wei Zhou
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Minmin Chen
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Yuanyuan Zhang
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Weidong Han
- Department of Bio-therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Rufu Chen
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510180, China
| | - Jirun Peng
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Linnan Zhu
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Wenhong Hou
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
| | - Zemin Zhang
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China.
| |
Collapse
|
43
|
Ouissam AJ, Hind C, Sami Aziz B, Said A. Inhibition of the PI3K/AKT/mTOR pathway in pancreatic cancer: is it a worthwhile endeavor? Ther Adv Med Oncol 2024; 16:17588359241284911. [PMID: 39399412 PMCID: PMC11468005 DOI: 10.1177/17588359241284911] [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] [Academic Contribution Register] [Received: 04/19/2024] [Accepted: 09/03/2024] [Indexed: 10/15/2024] Open
Abstract
Pancreatic cancer (PC) is an aggressive disease that is challenging to treat and is associated with a high mortality rate. The most common type of PC is pancreatic ductal adenocarcinoma (PDAC), and the existing treatment options are insufficient for PDAC patients. Due to the complexity and heterogeneity of PDAC, personalized medicine is necessary for effectively treating this illness. To achieve this, it is essential to understand the mechanism of PDAC carcinogenesis. Targeted therapies are a promising strategy to improve patient outcomes. Aberrant activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a crucial role in PC pathogenesis, from initiation to progression. This review provides a comprehensive overview of the current state of knowledge regarding the PI3K pathway in PDAC, summarizes clinical data on PI3K pathway inhibition in PDAC, and explores potential effective combinations that are a promising direction requiring further investigation in PDAC.
Collapse
Affiliation(s)
- Al Jarroudi Ouissam
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Chibani Hind
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Brahmi Sami Aziz
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Afqir Said
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| |
Collapse
|
44
|
Li L, Liu N, Zhou T, Qin X, Song X, Wang S, Pang J, Ou Q, Wang Y, Zhang D, Li J, Xu F, Shi S, Yu J, Yuan S. A biomarker exploration in small-cell lung cancer for brain metastases risk and prophylactic cranial irradiation therapy efficacy. Lung Cancer 2024; 196:107959. [PMID: 39340898 DOI: 10.1016/j.lungcan.2024.107959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/07/2024] [Revised: 08/20/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Small-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies. MATERIALS AND METHODS We analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model. RESULTS Alterations in the cell cycle pathway, particularly RB1 mutations, were more common in patients with BM, while FLT4 mutations were more frequent in those without BM (P=0.002 and P=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11-2.70; P=0.016), RB1 mutations (SHR: 2.19; 95 % CI: 1.27-3.81; P=0.005), and BCL3 amplification (SHR: 2.27; 95 % CI: 1.09-4.71; P=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25-1.60; P<0.001), FLT4 mutations (SHR: 0.26; 95 % CI: 0.07-0.98; P=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43-1.00; P=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline RB1 mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months. CONCLUSION Our study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.
Collapse
Affiliation(s)
- Li Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Ning Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Tao Zhou
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Xueting Qin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Xiaoyu Song
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Song Wang
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing 210000, Jiangsu, PR China
| | - Jiaohui Pang
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing 210000, Jiangsu, PR China
| | - Qiuxiang Ou
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing 210000, Jiangsu, PR China
| | - Yong Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Dexian Zhang
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Jiaran Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Fuhao Xu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Shuming Shi
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China
| | - Shuanghu Yuan
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China; Department Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, PR China; Department of Radiation Oncology, Anhui Provincial Cancer Hospital, Hefei 230031, Anhui, PR China.
| |
Collapse
|
45
|
Fang H, Wang X, Wang Z, Ma X, Zhang L, Yang L. Modulation of PI3K/AKT/mTOR signaling pathway in the ovine liver and duodenum during early pregnancy. Domest Anim Endocrinol 2024; 89:106870. [PMID: 38954983 DOI: 10.1016/j.domaniend.2024.106870] [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] [Academic Contribution Register] [Received: 03/16/2024] [Revised: 06/22/2024] [Accepted: 06/26/2024] [Indexed: 07/04/2024]
Abstract
The liver and intestine play a critical role in nutrient absorption, storage, and metabolism. The aim of this study was to evaluate expression pattern of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) signaling pathway that included PI3K, AKT1, mTOR, FoxO1, SREBP-1, PPARα, PTEN and FXR in the maternal liver and duodenum. Ovine livers and duodenums were sampled at day 16 of the estrous cycle, and at days 13, 16 and 25 of gestation, and RT-qPCR, western blot and immunohistochemistry analysis were used to detect mRNA and protein expression. The results showed that expression of PI3K, AKT1, p-mTOR, FoxO1, SREBP-1 and PTEN upregulated in the maternal liver, and PPARα upregulated in the duodenum. However, expression of FoxO1, SREBP-1 and PTEN in the duodenum downregulated during early pregnancy. In addition, expression levels of SREBP-1, PTEN and PPARα in the maternal liver, and PI3K in the duodenum peaked at day 13 of pregnancy. In addition, expression levels of PI3K, p-mTOR and FoxO1 in the liver, and AKT1 and p-mTOR in the duodenum peaked at day 16 of pregnancy. Nevertheless, expression levels of FXR both in the maternal liver duodenum downregulated at days 13 and 16 of pregnancy. In conclusion, early pregnancy regulated expression pattern of PI3K/AKT/mTOR signaling pathway in the ovine liver and duodenum in a pregnancy stage-specific and tissue-specific manner, which may be necessary for the adaptations in maternal hepatic nutrient metabolism and intestinal nutrient absorption early pregnancy.
Collapse
Affiliation(s)
- Hongxu Fang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, No. 19 Taiji Road, Handan 056038, PR China
| | - Xinxin Wang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, No. 19 Taiji Road, Handan 056038, PR China
| | - Zhongyue Wang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, No. 19 Taiji Road, Handan 056038, PR China
| | - Xiaoxin Ma
- School of Life Sciences and Food Engineering, Hebei University of Engineering, No. 19 Taiji Road, Handan 056038, PR China
| | - Leying Zhang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, No. 19 Taiji Road, Handan 056038, PR China
| | - Ling Yang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, No. 19 Taiji Road, Handan 056038, PR China.
| |
Collapse
|
46
|
Deng Z, Qing Q, Huang B. A bibliometric analysis of the application of the PI3K-AKT-mTOR signaling pathway in cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7255-7272. [PMID: 38709265 DOI: 10.1007/s00210-024-03112-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 01/23/2024] [Accepted: 04/18/2024] [Indexed: 05/07/2024]
Abstract
PI3K-AKT-mTOR plays as important role in the growth, metabolism, proliferation, and migration of cancer cells, and in apoptosis, autophagy, inflammation, and angiogenesis in cancer. In this study, the aim was to comprehensively review the current research landscape regarding the PI3K-AKT-mTOR pathway in cancer, using bibliometrics to analyze research hotspots, and provide ideas for future research directions. Literature published on the topic between January 2006 and May 2023 was retrieved from the Web of Science core database, and key information and a visualization map were analyzed using CiteSpace and VOSviewer. A total of 5800 articles from 95 countries/regions were collected, including from China and the USA. The number of publications on the topic increased year on year. The major research institution was the University of Texas MD Anderson Cancer Center. Oncotarget and Clinical Cancer Research were the most prevalent journals in the field. Of 26,621 authors, R Kurzrock published the most articles, and J Engelman was cited most frequently. "A549 cell," "first line treatment," "first in human phase I," and "inhibitor" were the keywords of emerging research hotspots. Inhibitors of the PI3K-AKT-mTOR pathway and their use in clinical therapeutic strategies for cancer were the main topics in the field, and future research should also focus on PI3K-AKT-mTOR pathway inhibitors. This study is the first to comprehensively summarize trends and development s in research into the PI3K-AKT-mTOR pathway in cancer. The information that was obtained clarified recent research frontiers and directions, providing references for scholars of cancer management.
Collapse
Affiliation(s)
- Zhengzheng Deng
- School of Public Health, University of South China, Hengyang, 421001, Hunan Province, China
| | - Qiancheng Qing
- School of Public Health, University of South China, Hengyang, 421001, Hunan Province, China
| | - Bo Huang
- School of Public Health, University of South China, Hengyang, 421001, Hunan Province, China.
| |
Collapse
|
47
|
Calabrese EJ, Pressman P, Hayes AW, Dhawan G, Kapoor R, Agathokleous E, Calabrese V. Oocyte maturation, blastocyst and embryonic development are mediated and enhanced via hormesis. Food Chem Toxicol 2024; 192:114941. [PMID: 39153727 DOI: 10.1016/j.fct.2024.114941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/19/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
The present paper provides the first integrative assessment of the capacity of dietary, endogenous and other agents to induce hormetic dose responses in oocytes, their supportive cells such as granulosa cells, blastocyst formation and early stage embryo development with the goal of improving fertility and reproductive success. The analysis showed that numerous agents enhance oocyte maturation and blastocyst/embryonic development in an hormetic fashion. These findings indicate that numerous agents improve oocyte-related biological functioning under normal conditions as well as enhancing its capacity to prevent damage from numerous chemical toxins and related stressor agents, including heat and age-related processes in pre-post conditioning and concurrent exposures. The present assessment suggests that hormetic-based lifestyles and dietary interventions may offer the potential to enhance healthy reproductive performance with applications to animal husbandry and human biology. The present findings also significantly extend the generality of the hormesis dose response concept to multiple fundamental biological processes (i.e., oocyte maturation, fertilization and blastocyst/embryo development).
Collapse
Affiliation(s)
| | - Peter Pressman
- University of Maine, 5728 Fernald Hall, Room 201, Orono, ME, 04469, USA.
| | - A Wallace Hayes
- Center for Environmental Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, USA.
| | - Gaurav Dhawan
- Sri Guru Ram Das (SGRD), University of Health Sciences, Amritsar, India.
| | - Rachna Kapoor
- Saint Francis Hospital and Medical Center, Hartford, CT, USA.
| | - Evgenios Agathokleous
- School of Ecology and Applied Meteorology, Nanjing University of Information Science & Technology, Nanjing, 210044, China.
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, School of Medicine University of Catania, Via Santa Sofia 97, Catania, 95123, Italy.
| |
Collapse
|
48
|
Salphati L, Pang J, Plise EG, Cheong J, Braun MG, Friedman LS, Hong Thibodeau R, Jaochico A, Johnson R, Liu N, Nannini M, Sampath D, Song K, Hannan EJ, Staben ST. Preclinical assessment of the PI3Kα selective inhibitor inavolisib and prediction of its pharmacokinetics and efficacious dose in human. Xenobiotica 2024; 54:808-820. [PMID: 39387185 DOI: 10.1080/00498254.2024.2415103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/30/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024]
Abstract
1. Small molecule inhibitors of the PI3K pathway have been extensively investigated as potential anticancer agents. Among the effectors in this pathway, PI3Kα is the kinase most frequently associated with the development of tumours, through mutations and amplifications of the PIK3CA gene encoding the p110α catalytic subunit.2. Inavolisib (GDC-0077) is a potent and PI3Kα-selective inhibitor that also specifically triggers the degradation of the mutant p110α protein.3. We characterised inavolisib ADME properties in preclinical in vitro and in vivo studies, assessed its efficacy in the PIK3CA mutant KPL-4 breast cancer xenograft model, and predicted its pharmacokinetics and efficacious dose in humans.4. Inavolisib had a moderate permeability (1.9•10-6 cm/s) in MDCK cells and was a P-gp and Bcrp1 substrate. It appeared metabolically stable in hepatocytes incubations from human and preclinical species. The systemic clearance was low in mouse, monkey and dog and high in rat. Oral bioavailability ranged from 57.5% to 100%. Inavolisib was efficacious in the KPL-4 sub-cutaneous xenograft model.5. The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.
Collapse
Affiliation(s)
- Laurent Salphati
- Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Jodie Pang
- Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Emile G Plise
- Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Jonathan Cheong
- Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | | | - Lori S Friedman
- Cancer Signaling, Genentech, Inc., South San Francisco, CA, USA
| | | | - Allan Jaochico
- Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Ryan Johnson
- Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Ning Liu
- Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Michelle Nannini
- Translational Oncology, Genentech, Inc., South San Francisco, CA, USA
| | - Deepak Sampath
- Translational Oncology, Genentech, Inc., South San Francisco, CA, USA
| | - Kyung Song
- Cancer Signaling, Genentech, Inc., South San Francisco, CA, USA
| | - Emily J Hannan
- Chemistry, Genentech, Inc., South San Francisco, CA, USA
| | | |
Collapse
|
49
|
Zheng T, Jiang T, Ma H, Zhu Y, Wang M. Targeting PI3K/Akt in Cerebral Ischemia Reperfusion Injury Alleviation: From Signaling Networks to Targeted Therapy. Mol Neurobiol 2024; 61:7930-7949. [PMID: 38441860 DOI: 10.1007/s12035-024-04039-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/01/2023] [Accepted: 02/09/2024] [Indexed: 09/21/2024]
Abstract
Ischemia/reperfusion (I/R) injury is a pathological event that results in reperfusion due to low blood flow to an organ. Cerebral ischemia is a common cerebrovascular disease with high mortality, and reperfusion is the current standard intervention. However, reperfusion may further induce cellular damage and dysfunction known as cerebral ischemia/reperfusion injury (CIRI). Currently, strategies for the clinical management of CIRI are limited, necessitating the exploration of novel and efficacious treatment modalities for the benefit of patients. PI3K/Akt signaling pathway is an important cellular process associated with the disease. Stimulation of the PI3K/Akt pathway enhances I/R injury in multiple organs such as heart, brain, lung, and liver. It stands as a pivotal signaling pathway crucial for diminishing cerebral infarction size and safeguarding the functionality of brain tissue after CIRI. During CIRI, activation of the PI3K/Akt pathway exhibits a protective effect on CIRI. Furthermore, activation of the PI3K/Akt pathway has the potential to augment the activity of antioxidant enzymes, resulting in a decrease in reactive oxygen species (ROS) and the associated oxidative stress. Meanwhile, PI3K/Akt plays a neuroprotective role by inhibiting inflammatory responses and apoptosis. For example, PI3K/Akt interacts with NF-κB, Nrf2, and MAPK signaling pathways to mitigate CIRI. This article is aimed to explore the pivotal role and underlying mechanism of PI3K/Akt in ameliorating CIRI and investigate the influence of ischemic preconditioning and post-processing, as well as the impact of pertinent drugs or activators targeting the PI3K/Akt pathway on CIRI. The primary objective is to furnish compelling evidence supporting the activation of PI3K/Akt in the context of CIRI, elucidating its mechanistic intricacies. By doing so, the paper aims to underscore the critical contribution of PI3K/Akt in mitigating CIRI, providing a theoretical foundation for considering the PI3K/Akt pathway as a viable target for CIRI treatment.
Collapse
Affiliation(s)
- Ting Zheng
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Neurology, The Second Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Taotao Jiang
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Neurology, The Second Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Hongxiang Ma
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Neurology, The Second Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Yanping Zhu
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Neurology, The Second Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Manxia Wang
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Department of Neurology, The Second Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
| |
Collapse
|
50
|
Tolue Ghasaban F, Taghehchian N, Zangouei AS, Keivany MR, Moghbeli M. MicroRNA-135b mainly functions as an oncogene during tumor progression. Pathol Res Pract 2024; 262:155547. [PMID: 39151250 DOI: 10.1016/j.prp.2024.155547] [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] [Academic Contribution Register] [Received: 06/04/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
Late diagnosis is considered one of the main reasons of high mortality rate among cancer patients that results in therapeutic failure and tumor relapse. Therefore, it is needed to evaluate the molecular mechanisms associated with tumor progression to introduce efficient markers for the early tumor detection among cancer patients. The remarkable stability of microRNAs (miRNAs) in body fluids makes them potential candidates to use as the non-invasive tumor biomarkers in cancer screening programs. MiR-135b has key roles in prognosis and survival of cancer patients by either stimulating or inhibiting cell proliferation, invasion, and angiogenesis. Therefore, in the present review we assessed the molecular biology of miR-135b during tumor progression to introduce that as a novel tumor marker in cancer patients. It has been reported that miR-135b mainly acts as an oncogene by regulation of transcription factors, signaling pathways, drug response, cellular metabolism, and autophagy. This review paves the way to suggest miR-135b as a tumor marker and therapeutic target in cancer patients following the further clinical trials and animal studies.
Collapse
Affiliation(s)
- Faezeh Tolue Ghasaban
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Keivany
- Department of Radiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|