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Hou YX, Ren W, He QQ, Huang LY, Gao TH, Li H. Tetramethylpyrazine induces reactive oxygen species-based mitochondria-mediated apoptosis in colon cancer cells. World J Gastrointest Oncol 2025; 17:104922. [DOI: 10.4251/wjgo.v17.i4.104922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer is one of the most common malignancies worldwide, and chemotherapy is a widely used strategy in colon cancer clinical therapy. Chemotherapy resistance is the main cause of recurrence and progression in colon cancer. Thus, novel drugs for treatment are urgently needed. Tetramethylpyrazine (TMP), a component of the traditional Chinese medicine Chuanxiong Hort, has been proven to exhibit a beneficial effect in tumors.
AIM To investigate the potential anticancer activity of TMP in colon cancer and the underlying mechanisms.
METHODS Colon cancer cells were incubated with different concentrations of TMP. Cell viability was evaluated by crystal violet staining assay, and cell apoptosis was assessed by flow cytometry. Apoptosis-associated protein expression was measured using Western blot analysis. Intracellular reactive oxygen species (ROS) levels were assessed by flow cytometry using DCF fluorescence intensity. Xenografts were established by the subcutaneous injection of colon cancer cells into nude mice; tumor growth was monitored and intracellular ROS was detected in tumors by malondialdehyde assay.
RESULTS TMP induced apoptosis of colon cancer cells via the activation of the mitochondrial pathway. TMP increased the generation of intracellular ROS and triggered mitochondria-mediated apoptosis in a caspase-dependent manner.
CONCLUSION Our study demonstrates that TMP induces the apoptosis of colon cancer cells and increases the generation of intracellular ROS. TMP triggers mitochondria-mediated apoptosis in a caspase-dependent manner. The accumulation of intracellular ROS is involved in TMP-induced apoptosis. Our findings suggest that TMP may be a potential therapeutic drug for the treatment of colon cancer.
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Affiliation(s)
- Yan-Xu Hou
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Wei Ren
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Qing-Qiang He
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Li-Yan Huang
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Tian-Hua Gao
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Hua Li
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
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Xu H, Chen X, Zhang Q, Yang Z, Tian J, Chen Q, Chen J. Effects of phenolic acids on tetramethylpyrazine formation via room temperature spontaneous ammoniation of acetoin. Food Chem X 2025; 25:102173. [PMID: 39897975 PMCID: PMC11783383 DOI: 10.1016/j.fochx.2025.102173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/08/2025] [Accepted: 01/11/2025] [Indexed: 02/04/2025] Open
Abstract
In this study, we aim to investigate the effects of phenolic acids on tetramethylpyrazine (TTMP) formation in low-temperature environments and discuss its possible mechanism. The results demonstrate that TTMP formation kinetics via acetoin (ACT) ammonification was determined to be pseudo-zero-order reaction, which transitions to a pseudo-first-order kinetic model upon high gallic acid concentrations. The TTMP formation in samples spiked with phenolic acids was significantly higher than the control group. The response surface results that the production of TTMP increases with the extension of time align with the TTMP content trend in vinegar aging. At pH 7.0, TTMP formation was 56 and 70 times higher than at pH 3.0 and pH 11.0, respectively. The findings indicate that phenolic acids can alter reactive imine intermediates associated with the formation of pyrazinyl radicals. This study provides valuable insights into enhancing the characteristic pyrazine flavor and improving quality control in fermented foods.
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Affiliation(s)
- Hui Xu
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, PR China
| | - Xuanrui Chen
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, PR China
| | - Qianqian Zhang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, PR China
| | - Zhizhi Yang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, PR China
| | - Jingjing Tian
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, PR China
| | - Qihe Chen
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou 310058, PR China
| | - Jicheng Chen
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, PR China
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Asghar A, Chohan TA, Khurshid U, Saleem H, Mustafa MW, Khursheed A, Alafnan A, Batul R, Bin Break MK, Almansour K, Anwar S. A systematic review on understanding the mechanistic pathways and clinical aspects of natural CDK inhibitors on cancer progression.: Unlocking cellular and biochemical mechanisms. Chem Biol Interact 2024; 393:110940. [PMID: 38467339 DOI: 10.1016/j.cbi.2024.110940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/03/2024] [Accepted: 03/04/2024] [Indexed: 03/13/2024]
Abstract
Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, focused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.
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Affiliation(s)
- Andleeb Asghar
- Institute of Pharmaceutical Sciences (IPS), University of Veterinary and Animal Sciences (UVAS), Lahore, Pakistan
| | - Tahir Ali Chohan
- Institute of Pharmaceutical Sciences (IPS), University of Veterinary and Animal Sciences (UVAS), Lahore, Pakistan.
| | - Umair Khurshid
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The Islamia University of Bahawalpur, 63100 Bahawalpur, Pakistan
| | - Hammad Saleem
- Institute of Pharmaceutical Sciences (IPS), University of Veterinary and Animal Sciences (UVAS), Lahore, Pakistan.
| | - Mian Waqar Mustafa
- Department of Pharmacy, Forman Christian College University, Lahore, Pakistan
| | - Anjum Khursheed
- Department of Pharmacy, Grand Asian University, Sialkot, Pakistan
| | - Ahmed Alafnan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Ha'il, Saudi Arabia
| | - Rahila Batul
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Ha'il, Ha'il, Saudi Arabia
| | - Mohammed Khaled Bin Break
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Ha'il, Ha'il, Saudi Arabia
| | - Khaled Almansour
- Department of Pharmaceutics, College of Pharmacy, University of Ha'il, Ha'il, Saudi Arabia
| | - Sirajudheen Anwar
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Ha'il, Saudi Arabia
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Lin F, Zhang G, Yang X, Wang M, Wang R, Wan M, Wang J, Wu B, Yan T, Jia Y. A network pharmacology approach and experimental validation to investigate the anticancer mechanism and potential active targets of ethanol extract of Wei-Tong-Xin against colorectal cancer through induction of apoptosis via PI3K/AKT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:115933. [PMID: 36403742 DOI: 10.1016/j.jep.2022.115933] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Wei-Tong-Xin (WTX), derives from the Chinese herbal decoction (CHD) of Wan-Ying-Yuan in ancient China, has been shown to be effective therapeutic herbal decoction for treating gastrointestinal diseases. Present studies have demonstrated that WTX had potential to alleviate the symptoms of gastrointestinal inflammation, gastric ulcer and improve gastric motility. AIM OF THE STUDY The study primarily focused on exploring the therapeutic effect and possible pharmacological mechanism of WTX on colorectal cancer (CRC) based on network pharmacology, in vitro and in vivo experiments. MATERIALS AND METHODS Firstly, colorectal cancer and WTX associated with targets were searched from GeneCards database and TCM Systems Pharmacology Database and Analysis Platform (TCMSP) respectively. The protein-protein interaction (PPI) network also was constructed to screening key targets. In addition, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied to predict the underlying biological function and mechanism involving in the anti-colorectal cancer effect of WTX. Next, CCK-8, colony formation and transwell assays were performed to verify the influence of proliferation and metastasizing ability of HCT116 cells after treated with WTX. Cell cycle, apoptosis and reactive oxygen species (ROS) were analysis by flow cytometry. Hoechst 33258 staining was conducted to observe nuclear morphology changes. Protein expression of apoptosis and PI3K/AKT signaling as well as mRNA expression of ferroptosis and apoptosis were determined by Western Blotting and RT-qPCR. The effects of WTX and LY294002 combination on the PI3K/Akt/mTOR signaling pathway were measured by Western Blotting. Finally, the xenograft tumor mouse model was established by subcutaneous injection of CT26 cells to measure tumors volume and weight. Hematoxylin and eosin (HE) staining and immunohistochemical analysis were used to observe the pathological changes and the protein expression in tumor tissues. RESULTS There were 286 potential treatment targets from 130 bioactive compounds in WTX, 1349 CRC-related targets were identified. Eleven core targets (TP53, AKT1, STAT3, JUN, TNF, HSP90AA1, IL-6, MAPK3, CASP3, EGFR, MYC) were found by PPI network analysis constructed of 142 common targets. The results of KEGG enrichment displayed PI3K/AKT signaling pathway as core pathway. After the treatment of WTX, the inhibitory of viability, metastases and cell cycle arrest at G2/M phase were observed in HCT116 cells. Moreover, WTX induced an increase in the expression of apoptosis proteins (Bak, cytochrome c, cleaved caspase-9/caspase-9 and cleaved caspase-3/caspase-3) and the levels of ROS and MDA, a decrease in the expression of PI3K/AKT signaling related proteins (PI3K, p-PI3K, p-AKT/AKT and p-mTOR/mTOR) and the level of SOD. WTX treatment significantly reduced the tumor weight, increased cleaved caspase-3 positive area and decreased that of ki67 in xenograft mouse model. CONCLUSION Through a network pharmacology approach and in vitro experiments, we predicted and verified the effect of WTX on colorectal cancer cells mainly depended on the regulation of intrinsic apoptosis via PI3K/AKT signaling pathway, and further animal experiments proved that WTX has a good anti-colon cancer effect in vivo.
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Affiliation(s)
- Fei Lin
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Guanglin Zhang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Xihan Yang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Mengshi Wang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Ruixuan Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Meiqi Wan
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Jinyu Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Bo Wu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Tingxu Yan
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
| | - Ying Jia
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, China.
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