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Kaufman-Szymczyk A, Jalmuzna J, Lubecka-Gajewska K. Soy-derived isoflavones as chemo-preventive agents targeting multiple signalling pathways for cancer prevention and therapy. Br J Pharmacol 2025; 182:2259-2286. [PMID: 38528688 DOI: 10.1111/bph.16353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/19/2024] [Accepted: 02/08/2024] [Indexed: 03/27/2024] Open
Abstract
The chemopreventive and chemotherapeutic properties of soy and soy-derived compounds, especially isoflavones, have been extensively studied in recent years. However, in contrast to their anticancer effects, such as cell growth inhibition, cell cycle arrest and apoptosis induction, isoflavones have also been found to promote the growth of cancer cells. Therefore, the aim of this comprehensive review article is to present the current state of knowledge regarding the molecular mechanisms by which soy-derived isoflavones target multiple cellular signalling pathways in cancer cells. Our findings indicate that soy-derived isoflavones act as, among other things, potent modulators of HOX transcript antisense RNA (HOTAIR)/SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), vascular endothelial growth factor (VEGF)/C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor type 4 (CXCR4), 17-β-oestradiol (E2)/oestrogen receptor-α (ERα)/neuroglobin (NGB) and sonic hedgehog signalling pathways, epigenetic modulatory agents (i.a. miR-155, miR-34a and miR-10a-5p) and cancer stem cells and epithelial-to-mesenchymal transition inhibitors. The paper also discusses the latest epidemiological studies and clinical trials and provides an insight into recent extensive research on the chemo-preventive and therapeutic potential of soy-derived isoflavones. LINKED ARTICLES: This article is part of a themed issue Natural Products and Cancer: From Drug Discovery to Prevention and Therapy. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.10/issuetoc.
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Affiliation(s)
- Agnieszka Kaufman-Szymczyk
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Łódź, Łódź, Poland
| | - Justyna Jalmuzna
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Łódź, Łódź, Poland
| | - Katarzyna Lubecka-Gajewska
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Łódź, Łódź, Poland
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Xie DM, Li ZY, Ren BK, Gong R, Yang D, Huang S. Tanshinone II A Facilitates Chemosensitivity of Osteosarcoma Cells to Cisplatin via Activation of p38 MAPK Pathway. Chin J Integr Med 2025; 31:326-335. [PMID: 39499413 DOI: 10.1007/s11655-024-4118-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2024] [Indexed: 11/07/2024]
Abstract
OBJECTIVE To examine the mechanism of action of tanshinone II A (Tan II A) in promoting chemosensitization of osteosarcoma cells to cisplatin (DDP). METHODS The effects of different concentrations of Tan II A (0-80 µ mol/L) and DDP (0-2 µ mol/L) on the proliferation of osteosarcoma cell lines (U2R, U2OS, 143B, and HOS) at different times were examined using the cell counting kit-8 and colony formation assays. Migration and invasion of U2R and U2OS cells were detected after 24 h treatment with 30 µ mol/L Tan II A, 0.5 µ mol/L DDP alone, and a combination of 10 µ mol/L Tan II A and 0.25 µ mol/L DDP using the transwell assay. After 48 h of treatment of U2R and U2OS cells with predetermined concentrations of each group of drugs, the cell cycle was analyzed using a cell cycle detection kit and flow cytometry. After 48 h treatment, apoptosis of U2R and U2OS cells was detected using annexin V-FITC apoptosis detection kit and flow cytometry. U2R cells were inoculated into the unilateral axilla of nude mice and then the mice were randomly divided into 4 groups of 6 nude mice each. The 4 groups were treated with equal volume of Tan II A (15 mg/kg), DDP (3 mg/kg), Tan II A (7.5 mg/kg) + DDP (1.5 mg/kg), and normal saline, respectively. The body weight of the nude mice was weighed, and the tumor volume and weight were measured. Cell-related gene and signaling pathway expression were detected by RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analysis. p38 MAPK signaling pathway proteins and apoptotic protein expressions were detected by Western blot. RESULTS In vitro studies have shown that Tan II A, DDP and the combination of Tan II A and DDP inhibit the proliferation, migration and invasion of osteosarcoma cells. The inhibitory effect was more pronounced in the Tan II A and DDP combined treatment group (P<0.05 or P<0.01). Osteosarcoma cells underwent significantly cell-cycle arrest and cell apoptosis by Tan II A-DDP combination treatment (P<0.05 or P<0.01). In vivo studies demonstrated that the Tan II A-DD combination treatment group significantly inhibited tumor growth compared to the Tan II A and DDP single drug group (P<0.01). Additionally, we found that the combination of Tan II A and DDP treatment enhanced the p38 MAPK signaling pathway. Western blot assays showed higher p-p38, cleaved caspase-3, and Bax and lower caspase-3, and Bcl-2 expressions with the combination of Tan II A and DDP treatment compared to the single drug treatment (P<0.01). CONCLUSION Tan II A synergizes with DDP by activating the p38/MAPK pathway to upregulate cleaved caspase-3 and Bax pro-apoptotic gene expressions, and downregulate caspase-3 and Bcl-2 inhibitory apoptotic gene expressions, thereby enhancing the chemosensitivity of osteosarcoma cells to DDP.
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Affiliation(s)
- Da-Ming Xie
- Department of Orthopaedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Nanchang, 330006, China
| | - Zhi-Yun Li
- Department of Orthopaedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Bing-Kai Ren
- Department of Orthopaedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Rui Gong
- Department of Clinical Medicine, Jiangxi Health Vocational College, Nanchang, 330052, China
| | - Dong Yang
- Department of Orthopaedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Nanchang, 330006, China
| | - Sheng Huang
- Department of Orthopaedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
- Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Nanchang, 330006, China.
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Niu C, Zhang J, Okolo PI, Daglilar E. Plant polyphenols in gastric cancer: Nature's healing touch. Semin Oncol 2025; 52:152333. [PMID: 40073717 DOI: 10.1053/j.seminoncol.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 03/14/2025]
Abstract
Globally, gastric cancer ranks as the fifth most common cancer and is the third most common cause of malignancy-associated mortality. Although surgery is the primary treatment option for gastric cancer, adjuvant chemotherapy improves survival in patients following surgery. Proverbially, plant polyphenols have many beneficial health effects, including anticancer properties. Extensive studies have shown that plant polyphenols exhibit potential anticancer effects against gastric cancer in vitro and in vivo, as well as very few human studies. However, this topic has not yet been reviewed. The present review shows that the potential anticancer effect of plant polyphenols on gastric cancer was preliminarily attributed to their antiproliferative, antimetastatic, and antiangiogenic effects and modulations of apoptosis, autophagy, and intracellular reactive oxygen species. Moreover, conventional therapeutics combined with plant polyphenols make gastric cancer cells more sensitive to conventional therapy. We also discuss challenges and opportunities in translating plant polyphenol-based therapy to clinical applications. The content provided in this review is of interest to pharmacologists, ethnobotanists, and oncologists who are involved in phytomedicine.
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Affiliation(s)
- Chengu Niu
- Internal medicine residency program, Rochester General Hospital, Rochester, NY, USA.
| | - Jing Zhang
- Rainier Springs Behavioral Health Hospital, Vancouver, WA, USA
| | - Patrick I Okolo
- Division of Gastroenterology, Carillion Clinic, Roanoke, VA, USA
| | - Ebubekir Daglilar
- Division of Gastroenterology, Charleston Area Medical Center/CAMC Institute for Academic Medicine Program, Charleston, WV, USA
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Wang Y, Sun X, Ren M, Ma F, Zhao R, Zhu X, Xu Y, Cao N, Chen Y, Pan Y, Zhao A. Integrative network pharmacology, transcriptomics, and proteomics reveal the material basis and mechanism of the Shen Qing Weichang Formula against gastric cancer. Chin Med 2025; 20:42. [PMID: 40155922 PMCID: PMC11954191 DOI: 10.1186/s13020-025-01091-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/05/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignancy with poor prognosis and lack of efficient therapeutic methods. Shen Qing Weichang Formula (SQWCF) is a patented traditional herbal prescription for GC, but its efficacy and underlying mechanism remains to be clarified. PURPOSE To explore the efficacy and potential mechanism of SQWCF in treating GC. METHODS A subcutaneous transplantation tumor model of human GC was established for assessing SQWCF's efficacy and safety. A comprehensive strategy integrating mass spectrometry, network pharmacology, omics analysis, and bioinformatic methods was adopted to explore the core components, key targets, and potential mechanism of SQWCF in treating GC. Molecular docking, immunohistochemistry, quantitative real-time PCR, and western blot were applied to validation. RESULTS In the mouse model of GC, SQWCF effectively suppressed the GC growth without evident toxicity and enhanced the therapeutic efficacy of paclitaxel. Network pharmacology and molecular docking based on mass spectrometry showed that key targets (CASP3, TP53, Bcl-2, and AKT1) and core active components (Calycosin, Glycitein, Liquiritigenin, Hesperetin, and Eriodictyol) involved in the anti-GC effect of SQWCF had stable binding affinity, of which AKT1 ranked the top in the affinity. Validation based on network pharmacology and omics analysis confirmed that PI3K-AKT and MAPK signaling pathways, as well as downstream apoptosis pathway, explained the therapeutic effects of SQWCF on GC. In addition, family with sequence similarity 81 member A (FAM81A) was identified as a novel biomarker of GC that was aberrantly highly expressed in GC and associated with poor prognosis by bioinformatic analysis, and was an effector target of SQWCF at both mRNA and protein levels. CONCLUSION This study uncovers a synergistic multi-component, multi-target, and multi-pathway regulatory mechanism of SQWCF in treating GC comprehensively, emphasizing its potential for therapeutic use and providing new insights into GC treatment.
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Affiliation(s)
- Yi Wang
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Xiaoyu Sun
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Mingming Ren
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Fangqi Ma
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Ruohan Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Xiaohong Zhu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Yan Xu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Nida Cao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Yuanyuan Chen
- Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Yongfu Pan
- Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China.
| | - Aiguang Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China.
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Madrid A, Calderón V, Silva V, Novoa P, Jara C, Möller AC, Villena J, Balada C, Guzmán L, Montenegro I. Characterization of Ultrasound-Extracted Pouteria splendens Fruit Extracts: Phytochemical Profiling and Evaluation of Antioxidant and Cytotoxic Effects. Foods 2025; 14:908. [PMID: 40231948 PMCID: PMC11941558 DOI: 10.3390/foods14060908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 04/16/2025] Open
Abstract
This study investigated the bioactive potential of Pouteria splendens fruit through ultrasound-assisted extraction, analyzing peel and pulp. The pulp exhibited a higher phytochemical content, with 179.67 mg GAE/g d.w. and 208.48 mg QE/g d.w., approximately 1.5 times more than in the peel. Fifty phenolic compounds were identified by HPLC-MS, including four types of phenolic acids, with hydroxybenzoic (52%) and hydroxycinnamic (42%) as the two predominant ones, and six types of flavonoids, with flavonols (26.67%) and flavones (23.33%) as the two most prevalent. The pulp demonstrated greater antioxidant activity than the peel and the commercial controls (BHA and BHT) in the DPPH assay (IC50 2.54 mg/mL); however, it showed lower activity in the FRAP assay. Cytotoxic activity was evaluated in cancerous (MCF-7, HT-29, and PC-3) and non-cancerous (CCD 841 CoN and HEK-293) cell lines. Notably, the pulp exhibited remarkable cytotoxic activity against colon cancer cells (HT-29), with an IC50 of 50 µg/mL, and possible selectivity by not showing significant activity in non-cancerous cells (CoN and HEK). These results suggest that P. splendens, and particularly its pulp, is a valuable source of bioactive polyphenols, with potential for the food and pharmaceutical industries.
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Affiliation(s)
- Alejandro Madrid
- Laboratorio de Productos Naturales y Síntesis Orgánica (LPNSO), Facultad de Ciencias Naturales y Exactas, Universidad de Playa Ancha, Avda. Leopoldo Carvallo 270, Playa Ancha, Valparaíso 2340000, Chile; (V.C.); (V.S.)
- Millennium Nucleus Bioproducts, Genomics and Environmental Microbiology (BioGEM), Avenida España 1680, Valparaíso 2390123, Chile;
| | - Valeska Calderón
- Laboratorio de Productos Naturales y Síntesis Orgánica (LPNSO), Facultad de Ciencias Naturales y Exactas, Universidad de Playa Ancha, Avda. Leopoldo Carvallo 270, Playa Ancha, Valparaíso 2340000, Chile; (V.C.); (V.S.)
| | - Valentina Silva
- Laboratorio de Productos Naturales y Síntesis Orgánica (LPNSO), Facultad de Ciencias Naturales y Exactas, Universidad de Playa Ancha, Avda. Leopoldo Carvallo 270, Playa Ancha, Valparaíso 2340000, Chile; (V.C.); (V.S.)
| | - Patricio Novoa
- Herbario del Jardín Botánico Nacional, Viña del Mar 2520000, Chile;
| | - Carlos Jara
- Centro Interdisciplinario de Investigación Biomédica e Ingeniería para la Salud (MEDING), Escuela de Kinesiología, Facultad de Medicina, Universidad de Valparaíso, Valparaíso 2340000, Chile;
| | - Alejandra Catalina Möller
- Escuela de Tecnología Médica, Facultad de Medicina, Universidad de Valparaíso, Angamos 655, Reñaca, Viña del Mar 2520000, Chile;
| | - Joan Villena
- Center of Interdisciplinary Biomedical and Engineering Research for Health (MEDING), Escuela de Medicina, Facultad de Medicina, Universidad de Valparaíso, Angamos 655, Reñaca, Viña del Mar 2520000, Chile;
| | - Cristóbal Balada
- Laboratorio de Química Biológica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340025, Chile; (C.B.); (L.G.)
| | - Leda Guzmán
- Laboratorio de Química Biológica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340025, Chile; (C.B.); (L.G.)
| | - Iván Montenegro
- Millennium Nucleus Bioproducts, Genomics and Environmental Microbiology (BioGEM), Avenida España 1680, Valparaíso 2390123, Chile;
- Center of Interdisciplinary Biomedical and Engineering Research for Health (MEDING), Escuela de Obstetricia y Puericultura, Facultad de Medicina, Universidad de Valparaíso, Angamos 655, Reñaca, Viña del Mar 2520000, Chile
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Won Y, Kim HH, Jeong SH, Bhosale PB, Abusaliya A, Heo JD, Seong JK, Ahn MJ, Kim HJ, Kim GS. The Effects of Iridin and Irigenin on Cancer: Comparison with Well-Known Isoflavones in Breast, Prostate, and Gastric Cancers. Int J Mol Sci 2025; 26:2390. [PMID: 40141034 PMCID: PMC11942201 DOI: 10.3390/ijms26062390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/28/2025] [Accepted: 02/28/2025] [Indexed: 03/28/2025] Open
Abstract
Cancer, a worldwide problem and one of the leading causes of death due to uncontrolled cell proliferation, can be caused by various factors, such as genetic and environmental factors. Apoptosis is a programmed cell death mechanism that eliminates abnormal cells or renews cells. There are two main apoptotic pathways: intrinsic and extrinsic pathways. These pathways can be affected by various signaling pathways in cancer, such as the PI3K/AKT, MAPK, Wnt, and JAK/STAT pathways. Numerous approaches to cancer treatment have been studied, and among them, natural compounds have been actively researched. Flavonoids are natural compounds from fruits and vegetables and have been studied for their anti-cancer effects. Isoflavones, one of the subclasses of flavonoids, are usually found in soy food or legumes and are effective in several bioactive functions. The well-known isoflavones are genistein, daidzein, and glycitein. Irigenin and iridin can be extracted from the Iris family. Both irigenin and iridin are currently being studied for anti-inflammation, antioxidant, and anti-cancer by inducing apoptosis. In this review, we summarized five isoflavones, genistein, daidzein, glycitein, irigenin, and iridin and their effects on three different cancers: breast cancer, prostate cancer, and gastric cancer.
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Affiliation(s)
- Yaeram Won
- Department of Pharmacology, Institute of Medical Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; (Y.W.); (H.-J.K.)
- Department of Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea
| | - Hun-Hwan Kim
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (H.-H.K.); (S.-H.J.); (P.B.B.); (A.A.)
| | - Se-Hyo Jeong
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (H.-H.K.); (S.-H.J.); (P.B.B.); (A.A.)
| | - Pritam Bhagwan Bhosale
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (H.-H.K.); (S.-H.J.); (P.B.B.); (A.A.)
| | - Abuyaseer Abusaliya
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (H.-H.K.); (S.-H.J.); (P.B.B.); (A.A.)
| | - Jeong-Doo Heo
- Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology, 17 Jegok-gil, Jinju 52834, Republic of Korea;
| | - Je-Kyung Seong
- Laboratory of Developmental Biology and Goenomics, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea;
| | - Mee-Jung Ahn
- Department of Animal Science, College of Life Science, Sangji University, Wonju 26339, Republic of Korea;
| | - Hye-Jung Kim
- Department of Pharmacology, Institute of Medical Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; (Y.W.); (H.-J.K.)
- Department of Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea
| | - Gon-Sup Kim
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (H.-H.K.); (S.-H.J.); (P.B.B.); (A.A.)
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Hu Y, Zhang Y, Ding M, Xu R. HOXA10-AS Enhances Gastric Cancer Cell Proliferation, Migration, and Invasion via the p38 MAPK/STAT3 Signaling Pathway. J Biochem Mol Toxicol 2025; 39:e70187. [PMID: 39987516 DOI: 10.1002/jbt.70187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 01/11/2025] [Accepted: 02/08/2025] [Indexed: 02/25/2025]
Abstract
Gastric cancer (GC) represents a major global health concern, with over 1 million new cases diagnosed annually worldwide. Emerging studies have highlighted the significant correlation between long noncoding RNAs (lncRNAs) and the progression of GC. The objective of the current study is to investigate the roles and mechanism of lncRNA homeobox A10 antisense RNA (HOXA10-AS) in modulating malignant properties of GC cells. RT-qPCR was employed to detect HOXA10-AS expression in GC cells or human normal gastric epithelium cells. The cellular localization of HOXA10-AS and mRNA HOXA10 were detected using RNA fractionation assays. Colony forming assays and Transwell assays were performed to assess the proliferative, invasive, and migratory capabilities of GC cells. Western blot analysis was used to determine protein levels of epithelial mesenchymal transition (EMT) markers in GC cells. RNA immunoprecipitation, RNA pulldown assays and luciferase assays were conducted to explore gene interaction. As shown by experimental results, HOXA10-AS showed high expression in GC cells. The silencing of HOXA10-AS led to weakened proliferative, invasive, and migratory abilities of GC cells, as well as inhibition of the EMT process. Moreover, HOXA10-AS positively regulated HOXA10 expression by interacting with miR-29a/b/c-3p. Additionally, overexpression of HOXA10 counteracted the repressive impacts on malignant cellular process caused by the knockdown of HOXA10-AS. Furthermore, HOXA10-AS activated the p38 MAPK/STAT3 signaling pathway via upregulation of HOXA10. In conclusion, HOXA10-AS upregulates HOXA10 expression through interaction with miR-29a/b/c-3p. The resultant increase in HOXA10 expression activates the p38 MAPK/STAT3 signaling, thereby promoting GC cell growth, migration, invasion, and EMT process.
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Affiliation(s)
- Yu Hu
- Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ying Zhang
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meng Ding
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ruisi Xu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
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Wahyuni W, Fristiohady A, Sahidin I, Mahatva Yodha AW, Muh Julian Purnama LO, Idrus LS, Y MI, Alaydrus S, Sitti Musnina WO, Maulana S. Identification of Potential Anticancer Bioactive Compounds from Fractions of Alpinia monopleura Rhizome Extract. Pak J Biol Sci 2025; 28:253-266. [PMID: 40329755 DOI: 10.3923/pjbs.2025.253.266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
<b>Background and Objective:</b> Cancer is a malignant disease in body tissue where abnormal cells grow excessively and uncoordinated. Chemotherapy treatment still has weaknesses because apart from killing cancer cells, it also affects normal cells with fast proliferation rates, such as hair follicles, bone marrow and digestive tract cells, producing typical chemotherapy side effects. <i>Alpinia monopleura</i> has secondary metabolite content such as phenolic and flavonoid compounds as anticancer activity. This study aimed to investigate the cytotoxic activity of <i>A. monopleura</i> extract and its fractions and determine the phytoconstituents in the most active fraction against three distinct cancer-related protein targets. <b>Materials and Methods:</b> The <i>A. monopleura </i>extract and fractions were tested for cytotoxic against HeLa, MCF-7 and WiDr cell lines by using MTT assay. Then, the most active fraction was identified as its components by LC-HRMS and followed by molecular docking. <b>Results:</b> The most active cytotoxic effect was fraction 2 in HeLa cells, while fraction 4 in MCF-7 and WiDr. Several compounds have been successfully identified as contributing to their cytotoxic activity, proven by molecular docking investigation. It was found that compounds from fraction 2- Dehydroepiandrosterone, 5,7-dihydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one and 2-(3,4-dimethoxy phenyl)-5,7-dihydroxy-6-methoxy-4H-chromen-4-one-exhibited higher binding energies than Erlotinib, the native ligand with the cervical cancer target protein. <b>Conclusion:</b> Meanwhile, fraction 4 compounds had lower binding energy than the native ligands for each colon cancer and breast cancer protein target. Therefore, compounds from <i>A. monopleura </i>are promising for developing novel anticancer agents.
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Liu CY, Li Z, Cheng FE, Nan Y, Li WQ. Radix Codonopsis: a review of anticancer pharmacological activities. Front Pharmacol 2025; 15:1498707. [PMID: 39840099 PMCID: PMC11747557 DOI: 10.3389/fphar.2024.1498707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025] Open
Abstract
Radix Codonopsis (Dangshen), derived from the dried root of plants in the Campanulaceae family, is a widely used Chinese herbal medicine. It is renowned for its pharmacological effects, including tonifying the middle qi, invigorating the spleen, benefiting the lungs, enhancing immunity, and nourishing the blood. Codonopsis extract is frequently incorporated into health products such as tablets and capsules, making it accessible for daily health maintenance. Additionally, it is commonly used in dietary applications like soups, teas, and porridges to nourish qi, enrich blood, and promote overall vitality. In recent years, increasing attention has been given to the anti-cancer potential of Radix Codonopsis. Studies have identified key active components such as luteolin, stigmasterol, polyacetylenes, lobetyolin, and glycitein, which exhibit anti-tumor properties through mechanisms like inhibiting cancer cell growth and proliferation, suppressing epithelial-mesenchymal transition (EMT), and inducing apoptosis. This review highlights the research progress on Radix Codonopsis, including its active constituents, anti-cancer mechanisms, and its role in the convergence of medicine and food in modern life. By doing so, it aims to provide valuable insights and references for future scientific studies and clinical applications of Radix Codonopsis.
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Affiliation(s)
- Cai-Yue Liu
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
| | - Zheng Li
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
| | - Fan-E. Cheng
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
| | - Yi Nan
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China
| | - Wei-Qiang Li
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China
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10
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Jeong SH, Kim HH, Park MY, Bhosale PB, Abusaliya A, Hwang KH, Moon YG, Heo JD, Seong JK, Ahn M, Park KI, Won CK, Kim GS. Potential Anticancer Effects of Isoflavone Prunetin and Prunetin Glycoside on Apoptosis Mechanisms. Int J Mol Sci 2024; 25:11713. [PMID: 39519265 PMCID: PMC11545868 DOI: 10.3390/ijms252111713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 10/24/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Cancer is a deadly disease caused by cells that deviate from the normal differentiation and proliferation behaviors and continue to multiply. There is still no definitive cure, and many side effects occur even after treatment. However, apoptosis, one of the programs imprinted on cells, is becoming an important concept in controlling cancer. Flavonoids are polyphenolic compounds found in plants, are naturally bioactive compounds, have been studied for their anticancer effects, and have fewer side effects than chemical treatments. Isoflavones are phytoestrogens belonging to the flavonoid family, and this review discusses in depth the potential anticancer effects of prunetin, one of the many flavonoid families, via the apoptotic mechanism. In addition, a glycoside called prunetin glucoside has been investigated for its anticancer effects through apoptotic mechanisms. The primary intention of this review is to identify the effects of prunetin and its glycoside, prunetin glucoside, on cell death signaling pathways in various cancers to enhance the potential anticancer effects of these natural compounds.
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Affiliation(s)
- Se Hyo Jeong
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
| | - Hun Hwan Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
| | - Min Yeong Park
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
| | - Pritam Bhangwan Bhosale
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
| | - Abuyaseer Abusaliya
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
| | - Kwang Hyun Hwang
- Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology, 17 Jegok-gil, Jinju 52834, Republic of Korea
| | - Yeon Gyu Moon
- Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology, 17 Jegok-gil, Jinju 52834, Republic of Korea
| | - Jeong Doo Heo
- Korea Institute of Toxicology, 141, Gajeong-ro, Yuseong-gu, Daejeon 35345, Republic of Korea
| | - Je Kyung Seong
- Laboratory of Developmental Biology and Genomics, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Meejung Ahn
- Department of Animal Science, College of Life Science, Sangji University, Wonju 26339, Republic of Korea
| | - Kwang Il Park
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
| | - Chung Kil Won
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
| | - Gon Sup Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (S.H.J.)
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11
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Li X, Chen X, Yu H, Huang R, Wu P, Gong Y, Chen X, Liu C. Knockdown and Overexpression Experiments to Investigate the Inhibitory Mechanism of Fuzheng Xiaozheng Prescription, an Effective Chinese Herbal Formula for the Clinical Treatment of Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2024; 17:1159. [PMID: 39338323 PMCID: PMC11434836 DOI: 10.3390/ph17091159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 09/30/2024] Open
Abstract
Fuzheng Xiaozheng prescription (FZXZP) is an effective formula for the treatment of different kinds of chronic liver diseases. However, its potential molecular mechanisms in treating hepatocellular carcinoma (HCC) have not been investigated thoroughly. The aim of this study is to elucidate the targets and intrinsic mechanisms of FZXZP and their active components for the treatment of HCC. The efficacy of FZXZP against HCC was clarified through a rat HCC model and HCC cell culture. Network pharmacology and molecular docking were utilized to predict the mechanism of action and effector components of FZXZP. The key mechanism and targets were verified by the construction of overexpression and knockout cell models. The results showed that FZXZP greatly delayed the development of HCC in vivo experiments, as evidenced by biochemical evaluations, H&E analyses and growth inhibition of HCC. FZXZP dramatically inhibited cell viability and proliferative capacity and induced the apoptosis of hepatoma cells in vitro. Moreover, network pharmacology analyses demonstrated that the EGFR family and apoptosis-related targets were found to be the most significant in bioinformatics analysis. Furthermore, the EGFR/STAT3 signal axis might be the most likely target of FZXZP in anti-HCC due to the fact that it could be down-regulated by FZXZP with an upward trend of Bax, Caspase-3, Caspase-8, Caspase-9 and an inverse trend of Bcl2. Importantly, the above targeted signal axis was finally validated by our knockdown and overexpression analyses. Meanwhile, flow cytometry and TUNEL staining also revealed that FZXZP significantly induced apoptosis in the EGFR-overexpressing HCC cell line. The molecular docking results revealed that the key effector components of FZXZP that exerted the above regulatory roles were wogonin and glycitein. All of these results suggest that FZXZP could significantly delay HCC development by inhibiting proliferation and promoting apoptosis of HCC cells, and the EGFR/STAT3 signal axis might be a critical signal axis of FZXZP in suppressing HCC progression.
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Affiliation(s)
- Xia Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaofeng Chen
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Han Yu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Renwei Huang
- Sichuan Provincial Key Laboratory for Development and Utilization of Characteristic Horticultural Biological Resources, College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu 611130, China
| | - Peijie Wu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanju Gong
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiping Chen
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Chao Liu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
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12
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Ma Z, Zhou F, Jin H, Wu X. Crosstalk between CXCL12/CXCR4/ACKR3 and the STAT3 Pathway. Cells 2024; 13:1027. [PMID: 38920657 PMCID: PMC11201928 DOI: 10.3390/cells13121027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/09/2024] [Accepted: 06/10/2024] [Indexed: 06/27/2024] Open
Abstract
The reciprocal modulation between the CXCL12/CXCR4/ACKR3 axis and the STAT3 signaling pathway plays a crucial role in the progression of various diseases and neoplasms. Activation of the CXCL12/CXCR4/ACKR3 axis triggers the STAT3 pathway through multiple mechanisms, while the STAT3 pathway also regulates the expression of CXCL12. This review offers a thorough and systematic analysis of the reciprocal regulatory mechanisms between the CXCL12/CXCR4/ACKR3 signaling axis and the STAT3 signaling pathway in the context of diseases, particularly tumors. It explores the potential clinical applications in tumor treatment, highlighting possible therapeutic targets and novel strategies for targeted tumor therapy.
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Affiliation(s)
| | | | | | - Xiaoming Wu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming 650500, China; (Z.M.); (F.Z.); (H.J.)
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13
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Morgos DT, Stefani C, Miricescu D, Greabu M, Stanciu S, Nica S, Stanescu-Spinu II, Balan DG, Balcangiu-Stroescu AE, Coculescu EC, Georgescu DE, Nica RI. Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer. Int J Mol Sci 2024; 25:1848. [PMID: 38339127 PMCID: PMC10856016 DOI: 10.3390/ijms25031848] [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: 12/21/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-PI3K/AKT/mTOR-and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors.
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Affiliation(s)
- Diana-Theodora Morgos
- Discipline of Anatomy, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Constantin Stefani
- Department I of Family Medicine and Clinical Base, “Dr. Carol Davila” Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Daniela Miricescu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Maria Greabu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Silviu Stanciu
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - Silvia Nica
- Emergency Discipline, University Hospital of Bucharest, 050098 Bucharest, Romania;
| | - Iulia-Ioana Stanescu-Spinu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Daniela Gabriela Balan
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Andra-Elena Balcangiu-Stroescu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Elena-Claudia Coculescu
- Discipline of Oral Pathology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Dragos-Eugen Georgescu
- Department of General Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 50474 Bucharest, Romania;
- Department of General Surgery, “Dr. Ion Cantacuzino” Clinical Hospital, 020475 Bucharest, Romania
| | - Remus Iulian Nica
- Central Military Emergency University Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania;
- Discipline of General Surgery, Faculty of Midwifery and Nursing, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Rezaul Islam M, Rauf A, Akash S, Kumer A, Hussain MS, Akter S, Gupta JK, Thameemul Ansari L, Mahfoj Islam Raj MM, Bin Emran T, Aljohani AS, Abdulmonem WA, Thiruvengadam R, Thiruvengadam M. Recent perspective on the potential role of phytocompounds in the prevention of gastric cancer. Process Biochem 2023; 135:83-101. [DOI: 10.1016/j.procbio.2023.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
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He M, Yasin K, Yu S, Li J, Xia L. Total Flavonoids in Artemisia absinthium L. and Evaluation of Its Anticancer Activity. Int J Mol Sci 2023; 24:16348. [PMID: 38003540 PMCID: PMC10671751 DOI: 10.3390/ijms242216348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/07/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
To overcome the shortcomings of traditional extraction methods, such as long extraction time and low efficiency, and considering the low content and high complexity of total flavonoids in Artemisia absinthium L., in this experiment, we adopted ultrasound-assisted enzymatic hydrolysis to improve the yield of total flavonoids, and combined this with molecular docking and network pharmacology to predict its core constituent targets, so as to evaluate its antitumor activity. The content of total flavonoids in Artemisia absinthium L. reached 3.80 ± 0.13%, and the main components included Astragalin, Cynaroside, Ononin, Rutin, Kaempferol-3-O-rutinoside, Diosmetin, Isorhamnetin, and Luteolin. Cynaroside and Astragalin exert their cervical cancer inhibitory functions by regulating several signaling proteins (e.g., EGFR, STAT3, CCND1, IGFIR, ESR1). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the anticancer activity of both compounds was associated with the ErbB signaling pathway and FoxO signaling pathway. MTT results showed that total flavonoids of Artemisia absinthium L. and its active components (Cynaroside and Astragalin) significantly inhibited the growth of HeLa cells in a concentration-dependent manner with IC50 of 396.0 ± 54.2 μg/mL and 449.0 ± 54.8 μg/mL, respectively. Furthermore, its active components can mediate apoptosis by inducing the accumulation of ROS.
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Affiliation(s)
| | | | | | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (M.H.); (K.Y.); (S.Y.)
| | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (M.H.); (K.Y.); (S.Y.)
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16
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Paudel P, Choi JS, Prajapati R, Seong SH, Park SE, Kang WC, Ryu JH, Jung HA. In Vitro Human Monoamine Oxidase Inhibition and Human Dopamine D 4 Receptor Antagonist Effect of Natural Flavonoids for Neuroprotection. Int J Mol Sci 2023; 24:15859. [PMID: 37958841 PMCID: PMC10650131 DOI: 10.3390/ijms242115859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Natural flavone and isoflavone analogs such as 3',4',7-trihydroxyflavone (1), 3',4',7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer's and Parkinson's disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC50 value: 7.57 ± 0.14 μM) and 3 as a competitive inhibitor of hMAO-B with an IC50 value of 7.19 ± 0.32 μM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD4R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD4R antagonist effect, respectively, for neuroprotection. The route of administration should be considered.
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Affiliation(s)
- Pradeep Paudel
- Invasive Insect Biocontrol and Behavior Laboratory, Beltsville Agricultural Research Center-West, USDA-ARS, Beltsville, MD 20705, USA
| | - Jae Sue Choi
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea; (J.S.C.); (R.P.); (S.H.S.); (S.E.P.)
| | - Ritu Prajapati
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea; (J.S.C.); (R.P.); (S.H.S.); (S.E.P.)
| | - Su Hui Seong
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea; (J.S.C.); (R.P.); (S.H.S.); (S.E.P.)
- Natural Products Research Division, Honam National Institute of Biological Resource, Mokpo 58762, Republic of Korea
| | - Se Eun Park
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea; (J.S.C.); (R.P.); (S.H.S.); (S.E.P.)
| | - Woo-Chang Kang
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; (W.-C.K.); (J.-H.R.)
| | - Jong-Hoon Ryu
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; (W.-C.K.); (J.-H.R.)
| | - Hyun Ah Jung
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
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17
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Hu Q, Li Z, Li Y, Deng X, Chen Y, Ma X, Zeng J, Zhao Y. Natural products targeting signaling pathways associated with regulated cell death in gastric cancer: Recent advances and perspectives. Phytother Res 2023. [PMID: 37157181 DOI: 10.1002/ptr.7866] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/17/2023] [Accepted: 04/25/2023] [Indexed: 05/10/2023]
Abstract
Gastric cancer (GC) is one of the most serious gastrointestinal malignancies with high morbidity and mortality. The complexity of GC process lies in the multi-phenotypic linkage regulation, in which regulatory cell death (RCD) is the core link, which largely dominates the fate of GC cells and becomes a key determinant of GC development and prognosis. In recent years, increasing evidence has been reported that natural products can prevent and inhibit the development of GC by regulating RCDs, showing great therapeutic potential. In order to further clarify its key regulatory characteristics, this review focused on specific expressions of RCDs, combined with a variety of signaling pathways and their crosstalk characteristics, sorted out the key targets and action rules of natural products targeting RCD. It is highlighted that a variety of core biological pathways and core targets are involved in the decision of GC cell fate, including the PI3K/Akt signaling pathway, MAPK-related signaling pathways, p53 signaling pathway, ER stress, Caspase-8, gasdermin D (GSDMD), and so on. Moreover, natural products target the crosstalk of different RCDs by modulating above signaling pathways. Taken together, these findings suggest that targeting various RCDs in GC with natural products is a promising strategy, providing a reference for further clarifying the molecular mechanism of natural products treating GC, which warrants further investigations in this area.
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Affiliation(s)
- Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Zhibei Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyu Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanling Zhao
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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Wani AK, Akhtar N, Sharma A, El-Zahaby SA. Fighting Carcinogenesis with Plant Metabolites by Weakening Proliferative Signaling and Disabling Replicative Immortality Networks of Rapidly Dividing and Invading Cancerous Cells. Curr Drug Deliv 2023; 20:371-386. [PMID: 35422214 DOI: 10.2174/1567201819666220414085606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/18/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cancer, an uncontrolled multistage disease causing swift division of cells, is a leading disease with the highest mortality rate. Cellular heterogeneity, evading growth suppressors, resisting cell death, and replicative immortality drive the tumor progression by resisting the therapeutic action of existing anticancer drugs through a series of intrinsic and extrinsic cellular interactions. The innate cellular mechanisms also regulate the replication process as a fence against proliferative signaling, enabling replicative immortality through telomere dysfunction. AREA COVERED The conventional genotoxic drugs have several off-target and collateral side effects associated with them. Thus, the need for the therapies targeting cyclin-dependent kinases or P13K signaling pathway to expose cancer cells to immune destruction, deactivation of invasion and metastasis, and maintaining cellular energetics is imperative. Compounds with anticancer attributes isolated from plants and rich in alkaloids, terpenes, and polyphenols have proven to be less toxic and highly targetspecific, making them biologically significant. This has opened a gateway for the exploration of more novel plant molecules by signifying their role as anticancer agents in synergy and alone, making them more effective than the existing cytotoxic regimens. EXPERT OPINION In this context, the current review presented recent data on cancer cases around the globe, along with discussing the fundamentals of proliferative signaling and replicative immortality of cancer cells. Recent findings were also highlighted, including antiproliferative and antireplicative action of plant-derived compounds, besides explaining the need for improving drug delivery systems.
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Affiliation(s)
- Atif Khurshid Wani
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Punjab (144411), India
| | - Nahid Akhtar
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Punjab (144411), India
| | - Arun Sharma
- Department of Pharmacy, School of Pharmaceutical Sciences, Lovely Professional University, Punjab (144411), India
| | - Sally A El-Zahaby
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
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Multitarget and Multipathway Regulation of Zhenqi Fuzheng Granule against Non-Small Cell Lung Cancer Based On Network Pharmacology and Molecular Docking. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5967078. [DOI: 10.1155/2022/5967078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/31/2022] [Accepted: 10/17/2022] [Indexed: 11/18/2022]
Abstract
Background and Objective. The morbidity and mortality rates of non-small cell lung cancer (NSCLC) remain high. Zhenqi Fuzheng (ZQFZ) granule, which consists of Astragali Radix and Ligustri Lucidi Fructus, is commonly used to improve the immunity of cancer patients. However, the mechanism of ZQFZ granule against NSCLC is still unclear. In this study, the network pharmacology and molecular docking approaches were used to investigate the potential mechanism of ZQFZ granule on NSCLC. Methods. The ingredients in the ZQFZ granule were considered in one study based on UPLC, and the potential targets were predicted in the SwissTargetPrediction database. NSCLC targets were gathered from GeneCards, OMIM, and TTD databases. The ingredient-target-NSCLC network was drawn by Cytoscape. The protein–protein interaction was obtained from the STRING database, and the gene function and biological pathways were analyzed by Metascape. AutoDock Vina was used to verify the molecular docking between the key compounds and core targets, and PyMol visualized the results. Results. 244 targets were related to 13 candidate compounds and 1904 targets were related to NSCLC, of which a total of 106 anti-NSCLC targets were predicted. The compound-target-NSCLC network indicated that sinapinic acid, ferulic acid, asiatic acid, pratensein, and glycitein might be the key components for treating NSCLC. The 41 vital targets (out of 106 targets) above the median calculated by PPI degree were selected for bioinformatics analysis. The top 10 targets out of 41 ranked by MCC were IL-6, SRC, CTNNB1, STAT3, CASP3, TNF, EGFR, MAPK8, HSP90AA1, and PTGS2. ZQFZ granule treatment for NSCLC involved many pathways through KEGG analyses, which included pathways in cancer (hsa05200), proteoglycans in cancer (hsa05205), endocrine resistance (hsa01522), microRNAs in cancer (hsa05206), PI3K-Akt signaling pathway (hsa04151), and IL-17 signaling pathway (hsa04657). Molecular docking studies revealed that sinapinic acid, ferulic acid, asiatic acid, pratensein, and glycitein had good infinity with most core targets. Conclusions. This study indicated that ZQFZ granule with multicompounds could treat NSCLC through multitargets and multipathways.
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Xiang T, Jin W. Mechanism of Glycitein in the Treatment of Colon Cancer Based on Network Pharmacology and Molecular Docking. Lifestyle Genom 2022; 16:1-10. [PMID: 36183698 DOI: 10.1159/000527124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 09/12/2022] [Indexed: 12/22/2023] Open
Abstract
INTRODUCTION The prevalence of colon cancer remains high across the world. The early diagnosis of colon cancer is challenging. Moreover, patients with colon cancer frequently suffer from poor prognoses. METHODS Differentially expressed genes (DEGs) in colon cancer were acquired based on TCGA-COAD dataset screening. DEGs were input into the Connectivity Map (CMap) database to screen small molecule compounds with the potential to reverse colon cancer pathological function. Glycitein ranked first among the screened small-molecule compounds. We downloaded the main targets of glycitein from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database and constructed protein-protein interaction (PPI) networks of those which were closely related to targets by the Search Tool for the Retrieval of Interaction Gene/Proteins (STRING). Five potential targets of glycitein for treating colon cancer were identified (CCNA2, ESR1, ESR2, MAPK14, and PTGS2). These targets were used as seeds for random walk with restart (RWR) analysis of PPI networks. Then, the interaction network of glycitein-colon cancer-related genes was constructed based on the top 50 genes in affinity coefficients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the potential genes targeted by glycitein in colon cancer treatment and those that were closely bound up with targets. RESULTS GO analysis demonstrated that the enrichment of these genes was primarily discovered in biological functions including regulation of fibroblast proliferation, response to oxygen levels, and epithelial cell proliferation. The KEGG analysis results illustrated that the signaling pathways where these genes were mostly involved consisted of the mitogen-activated protein kinase signaling pathway, the phosphatidylinositol-3-kinase-Akt signaling pathway, and the p53 signaling pathway. Finally, stable binding of glycitein to five potential targets in colon cancer was verified by molecular docking. CONCLUSION This study elucidated the key targets and main pathways of glycitein on the basis of network pharmacology and preliminarily analyzed molecular mechanisms in the treatment of colon cancer. A scientific basis is provided for glycitein application in treating colon cancer.
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Affiliation(s)
- Tao Xiang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weibiao Jin
- Department of Tumor Thoracic Surgery, Pujiang Branch of the First Affiliated Hospital, Zhejiang University School of Medicine, Jinhua, China
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21
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Zhou W, Li P, Jin P. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway. Open Med (Wars) 2021; 16:1683-1695. [PMID: 34805531 PMCID: PMC8578810 DOI: 10.1515/med-2021-0369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/16/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Gastric carcinoma (GC) ranks the fifth most common cancer worldwide, with high incidence and mortality rates. Numerous microRNAs (miRNAs), including miR-654-5p, have been implicated in the pathophysiological processes of tumorigenesis. Nevertheless, the mechanism of miR-654-5p in GC is unclear. OBJECTIVES Our study is devoted to exploring the function and molecular mechanism of miR-654-5p on the malignant cell behaviors of GC. METHODS The gene expression was detected by reverse transcription quantitative polymerase chain reaction. GC cell proliferation and motion were assessed by colony formation assay and transwell assay. The binding capacity between miR-654-5p and G protein-regulated inducer of neurite outgrowth 1 (GPRIN1) was explored by luciferase reporter and RNA pulldown assays. The protein levels were detected by Western blotting. RESULTS miR-654-5p expression was higher in GC cells and tissues than control cells and tissues. miR-654-5p promoted GC cell growth and motion. Moreover, our findings showed that miR-654-5p was bound with GPRIN1. Importantly, downregulation of GPRIN1 rescued the inhibitory influence of miR-654-5p knockdown on GC cell malignant behaviors. Additionally, miR-654-5p activated the nuclear factor kappa-B (NF-κB) pathway by regulation of GPRIN1. CONCLUSIONS miR-654-5p facilitated cell proliferation, migration, and invasion in GC via targeting the GPRIN1 to activate the NF-κB pathway.
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Affiliation(s)
- Weidong Zhou
- Department of Gastroenterology, Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), 41Xibei Street, Ningbo 315010, Zhejiang, China
| | - Peifei Li
- Department of Gastroenterology, Ningbo First Hospital, Ningbo 315010, Zhejiang, China
| | - Peihua Jin
- Department of Gastroenterology, Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo 315010, Zhejiang, China
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22
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Diana EJ, Kanchana US, Mathew TV. Current developments in the synthesis of 4-chromanone-derived compounds. Org Biomol Chem 2021; 19:7995-8008. [PMID: 34494068 DOI: 10.1039/d1ob01352a] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The chroman-4-one framework is a significant structural entity that belongs to the class of oxygen-containing heterocycles. It acts as a major building block in a large class of medicinal compounds, and synthetic compounds exhibit a broad variety of remarkable biological and pharmaceutical activities. Several studies have been performed to improve the methodologies of 4-chromanone-derived compounds. This review focuses on the major synthetic methods of preparation reported on chroman-4-one derivatives from 2016 to 2021.
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Affiliation(s)
- Elizabeth J Diana
- Department of Chemistry, St. Thomas College Pala, Arunapuram P.O., Kottayam, Kerala, 686574, India. .,Department of Chemistry, Alphonsa College Pala, Arunapuram P.O., Kottayam, Kerala, 686574, India.
| | - U S Kanchana
- Department of Chemistry, St. Thomas College Pala, Arunapuram P.O., Kottayam, Kerala, 686574, India.
| | - Thomas V Mathew
- Department of Chemistry, St. Thomas College Pala, Arunapuram P.O., Kottayam, Kerala, 686574, India.
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In Vitro Antibacterial Effect of the Methanolic Extract of the Korean Soybean Fermented Product Doenjang against Staphylococcus aureus. Animals (Basel) 2021; 11:ani11082319. [PMID: 34438775 PMCID: PMC8388408 DOI: 10.3390/ani11082319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The emergence of bacterial antibiotic resistance is a negative phenomenon occurring worldwide in both animals and humans. The EU banned the use of antibiotic growth promoters in animal production, as their administration to livestock is assumed to substantially contribute to the spread of bacterial resistance. Therefore, alternatives to antibiotic substances are needed to maintain the quality and quantity of animal products. Certain plant materials, such as fermented soybean products, can serve as a source of substances with potential to decrease the growth of resistant bacteria, such as Staphylococcus aureus. Fermented soybean products, including doenjang, are known to contain natural phytoestrogens called isoflavones, which are especially interesting due to their antimicrobial activity; these products can also be utilized in animal feed. Thus, the antibacterial activity of the methanolic extract of the Korean soybean fermented product doenjang was evaluated using standardized microbiological methods against nine strains of resistant and sensitive S. aureus, including those occurring in animals. The extract has been shown to be active at a concentration range of 2048–4096 µg/mL against all tested S. aureus strains and can therefore serve as a promising alternative to antibiotics in animal feed after additional testing in the laboratory and on living animals. Abstract Ultra-high performance liquid chromatography/mass spectrometry showed soyasaponin I and the isoflavones daidzein, genistein, and glycitein to be the main components of the methanolic extract of the Korean soybean fermented product doenjang, which is known to be a rich source of naturally occurring bioactive substances, at average contents of 515.40, 236.30, 131.23, and 29.00 ng/mg, respectively. The antimicrobial activity of the methanolic extract of doenjang against nine Staphylococcusaureus strains was determined in vitro by the broth microdilution method to investigate its potential to serve as an alternative antibacterial compound. The results suggest that the extract is an effective antistaphylococcal agent at concentrations of 2048–4096 µg/mL. Moreover, the tested extract also showed the ability to inhibit the growth of both methicillin-sensitive and methicillin-resistant animal and clinical S. aureus isolates. The growth kinetics of the chosen strains of S. aureus at the minimum inhibitory concentration of the methanolic extract of doenjang support the idea that the tested extract acts as an antibacterial compound. To the best of our knowledge, this is the first report on the antistaphylococcal action of the methanolic extract of doenjang thus, additional studies including in vivo testing are necessary to confirm this hypothesis.
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Network Pharmacology/Metabolomics-Based Validation of AMPK and PI3K/AKT Signaling Pathway as a Central Role of Shengqi Fuzheng Injection Regulation of Mitochondrial Dysfunction in Cancer-Related Fatigue. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5556212. [PMID: 34326918 PMCID: PMC8302405 DOI: 10.1155/2021/5556212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/06/2021] [Accepted: 06/12/2021] [Indexed: 12/17/2022]
Abstract
Chinese herbal medicines have multiple targets and properties, and their use in multidisciplinary cancer therapies has consequently received increasing attention. Here, we have investigated the possible active ingredients associated with cancer-related fatigue (CRF) in the Shengqi Fuzheng Injection (SFI). In vitro cell models were used to measure the regulation effects of SFI on CRF. Metabolomic analysis was used to identify the potential genes and pathways in C2C12 mouse myoblasts treated with SFI, and the interaction of compounds and CRF targets was predicted using network pharmacology and molecular docking analyses. The putative pathways were further verified using immuno-blotting assays. The results showed that SFI significantly inhibited muscle cell apoptosis and increased the mitochondrial membrane potential of muscle cells. The network pharmacology analysis results identified 36 candidate compounds, and 244 potential targets were yielded by SFI, and they shared 10 key targets associated with cancer-related fatigue. According to the enrichment analysis and experimental validation, SFI might ameliorate muscle cell mitochondrial function by activating AMPK and inhibiting the PI3K/Akt signaling pathways, and the expression changes of mitochondrial metabolic enzymes MnSOD and apoptosis-associated proteins Bax and Bcl-2 were also triggered. The functions and mechanisms of SFI in anticancer-related fatigue were found here to be at least partly due to the targeting of the AMPK and PI3K/Akt signaling pathways, and this has highlighted new potential applications for network pharmacology when researching Chinese Medicines.
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Bragagnolo FS, Funari CS, Ibáñez E, Cifuentes A. Metabolomics as a Tool to Study Underused Soy Parts: In Search of Bioactive Compounds. Foods 2021; 10:foods10061308. [PMID: 34200265 PMCID: PMC8230045 DOI: 10.3390/foods10061308] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 12/19/2022] Open
Abstract
The valorization of agri-food by-products is essential from both economic and sustainability perspectives. The large quantity of such materials causes problems for the environment; however, they can also generate new valuable ingredients and products which promote beneficial effects on human health. It is estimated that soybean production, the major oilseed crop worldwide, will leave about 597 million metric tons of branches, leaves, pods, and roots on the ground post-harvesting in 2020/21. An alternative for the use of soy-related by-products arises from the several bioactive compounds found in this plant. Metabolomics studies have already identified isoflavonoids, saponins, and organic and fatty acids, among other metabolites, in all soy organs. The present review aims to show the application of metabolomics for identifying high-added-value compounds in underused parts of the soy plant, listing the main bioactive metabolites identified up to now, as well as the factors affecting their production.
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Affiliation(s)
- Felipe Sanchez Bragagnolo
- School of Agricultural Sciences, São Paulo State University (UNESP), Botucatu 18610-034, SP, Brazil; (F.S.B.); (C.S.F.)
- Laboratory of Foodomics, Institute of Food Science Research (CIAL-CSIC), 28049 Madrid, Spain;
| | - Cristiano Soleo Funari
- School of Agricultural Sciences, São Paulo State University (UNESP), Botucatu 18610-034, SP, Brazil; (F.S.B.); (C.S.F.)
| | - Elena Ibáñez
- Laboratory of Foodomics, Institute of Food Science Research (CIAL-CSIC), 28049 Madrid, Spain;
| | - Alejandro Cifuentes
- Laboratory of Foodomics, Institute of Food Science Research (CIAL-CSIC), 28049 Madrid, Spain;
- Correspondence:
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10-HDA Induces ROS-Mediated Apoptosis in A549 Human Lung Cancer Cells by Regulating the MAPK, STAT3, NF- κB, and TGF- β1 Signaling Pathways. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3042636. [PMID: 33376719 PMCID: PMC7744184 DOI: 10.1155/2020/3042636] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/18/2020] [Accepted: 11/22/2020] [Indexed: 01/19/2023]
Abstract
10-Hydroxy-2-decenoic acid (10-HDA), also known as royal jelly acid, has a variety of physiological functions, and recent studies have shown that it also has anticancer effects. However, its anticancer mechanisms have not been clearly defined. In this study, we investigated the underlying mechanisms of 10-HDA in A549 human lung cancer cells. We used Cell Counting Kit-8 assay, scratch wound healing assay, flow cytometry, and western blot analysis to investigate its apoptotic effects and underlying mechanism. Our results showed that 10-HDA inhibited the proliferation of three types of human lung cancer cells and had no significant toxic effects on normal cells. Accompanying reactive oxygen species (ROS), 10-HDA induced A549 cell apoptosis by regulating mitochondrial-associated apoptosis, and caused cell cycle arrest at the G0/G1 phase in a time-dependent manner. Meanwhile, 10-HDA also regulated mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) signaling pathways by increasing the expression levels of phosphorylated c-Jun N-terminal kinase, p-p38, and I-κB, and additionally, by decreasing the expression levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, and NF-κB. These effects were blocked by MAPK inhibitors and N-acetyl-L-cysteine. Furthermore, 10-HDA inhibited cell migration by regulating transforming growth factor beta 1 (TGF-β1), SNAI1, GSK-3β, E-cadherin, N-cadherin, and vimentin. Taken together, the results of this study showed that 10-HDA induced cell cycle arrest and apoptosis in A549 human lung cancer cells through ROS-mediated MAPK, STAT3, NF-κB, and TGF-β1 signaling pathways. Therefore, 10-HDA may be a potential therapy for human lung cancer.
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Sheng YN, Luo YH, Liu SB, Xu WT, Zhang Y, Zhang T, Xue H, Zuo WB, Li YN, Wang CY, Jin CH. Zeaxanthin Induces Apoptosis via ROS-Regulated MAPK and AKT Signaling Pathway in Human Gastric Cancer Cells. Onco Targets Ther 2020; 13:10995-11006. [PMID: 33149614 PMCID: PMC7605660 DOI: 10.2147/ott.s272514] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/23/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Zeaxanthin, a carotenoid commonly found in plants, has a variety of biological functions including anti-cancer activity. PURPOSE This study aimed to investigate the potential mechanisms of zeaxanthin in human gastric cancer cells. METHODS CCK-8 assay was used to examine the cytotoxic effect of zeaxanthin on human gastric cancer cells. Flow cytometry was used to analyse AGS cell cycle distribution and apoptosis status. Western blot analysis was used to detect the expression levels of cycle-related proteins (Cyclin A, Cyclin B1, CDK1/2, p21, and p27), apoptosis-related proteins (Bcl-2, Bad, caspase-3, PARP), MAPK, AKT, STAT3, and NF-κB. RESULTS CCK-8 assay showed that zeaxanthin has obvious cytotoxic effects on 12 types of human gastric cancer cells, but no obvious toxic effect on normal cells. In addition, flow cytometry and Western blotting results showed that zeaxanthin induces apoptosis by reducing mitochondrial membrane potential; increasing Cytochrome C, Bax, cleaved-caspase-3 (cle-cas-3), and cleaved-PARP (cle-PARP) expression levels; and decreasing Bcl-2, pro-caspase-3 (pro-cas-3), and pro-PARP expression levels. Additionally, zeaxanthin caused cell cycle arrest at the G2/M phase by increasing the levels of p21 and p27 and reduced the levels of AKT, Cyclin A, Cyclin B1, and Cyclin-dependent kinase 1/2 (CDK1/2). Furthermore, after zeaxanthin treatment, the expression levels of reactive oxygen species (ROS), p-JNK, p-p38, and I-κB increased, and the expression levels of p-ERK, p-AKT, STAT3, and NF-κB decreased. However, the ROS scavenger N-acetylcysteine (NAC) and MAPK inhibitors inhibited zeaxanthin-induced apoptosis, and under the action of zeaxanthin, MAPK regulated NF-κB and STAT3, and reduced their protein expression levels. CONCLUSION Zeaxanthin has a potential effect against gastric cancer cells through the ROS-mediated MAPK, AKT, NF-κB, and STAT3 signaling pathways, and it is expected to become a new drug for the treatment of human gastric cancer.
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Affiliation(s)
- Ya-Nan Sheng
- Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Ying-Hua Luo
- Department of Grass Science, College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Shao-Bin Liu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Wan-Ting Xu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Yu Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Tong Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Hui Xue
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Wen-Bo Zuo
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Yan-Nan Li
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
| | - Chang-Yuan Wang
- Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
- National Coarse Cereals Engineering Research Center, Daqing163319, People’s Republic of China
| | - Cheng-Hao Jin
- Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing163319, People’s Republic of China
- National Coarse Cereals Engineering Research Center, Daqing163319, People’s Republic of China
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Lu Y, Sun J, Hu M, Kong X, Zhong W, Li C. Network Pharmacology Analysis to Uncover the Potential Mechanisms of Lycium barbarum on Colorectal Cancer. Interdiscip Sci 2020; 12:515-525. [PMID: 33048277 DOI: 10.1007/s12539-020-00397-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 09/01/2020] [Accepted: 09/14/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Studies have shown that extracts from Lycium barbarum exerted protective effects against colorectal cancer (CRC) cells. We used the network pharmacology method to determine the effects of L. barbarum on CRC and to predict core targets, biological functions, pathways, and mechanisms of action. METHOD We obtained the active compounds and their targets in L. barbarum via use of the Traditional Chinese Medicine System Pharmacology Database (TCMSP), gathered the CRC targets from Malacards, TTD, GeneCards, and DisGeNET, and chosen the overlapped targets as the candidate targets. After protein-protein interaction (PPI) network analysis, 20 with the highest node degree were selected as the core targets, and their enrichment and pathways were analyzed. Furthermore, we employed iGEMDOCK to validate the compound-target relation. RESULT Eventually, 103 overlapped targets were chosen as the candidate targets. Targets with the top 20 highest node degree were selected as the core targets. Gene Ontology (GO) enrichment analysis indicated that the core targets were enriched in cell proliferation regulation, extracellular space, cytokine receptor binding, and so on. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis proved that the core targets were significantly enriched in bladder cancer, pathways in cancer. The docking results demonstrated that beta-sitosterol, glycitein, and quercetin had good binding activity to CRC putative targets. CONCLUSION Our work successfully predicted the functioning ingredients and potential targets of L. barbarum in CRC and illustrated the potential pathways and mechanisms comprehensively. Nevertheless, these results still call for in vitro and in vivo experiments to validate.
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Affiliation(s)
- Yi Lu
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People's Republic of China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jiachen Sun
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People's Republic of China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Minhui Hu
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People's Republic of China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Xianhe Kong
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People's Republic of China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Weijie Zhong
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People's Republic of China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chujun Li
- Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People's Republic of China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
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STAT3 Pathway in Gastric Cancer: Signaling, Therapeutic Targeting and Future Prospects. BIOLOGY 2020; 9:biology9060126. [PMID: 32545648 PMCID: PMC7345582 DOI: 10.3390/biology9060126] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 12/11/2022]
Abstract
Molecular signaling pathways play a significant role in the regulation of biological mechanisms, and their abnormal expression can provide the conditions for cancer development. The signal transducer and activator of transcription 3 (STAT3) is a key member of the STAT proteins and its oncogene role in cancer has been shown. STAT3 is able to promote the proliferation and invasion of cancer cells and induces chemoresistance. Different downstream targets of STAT3 have been identified in cancer and it has also been shown that microRNA (miR), long non-coding RNA (lncRNA) and other molecular pathways are able to function as upstream mediators of STAT3 in cancer. In the present review, we focus on the role and regulation of STAT3 in gastric cancer (GC). miRs and lncRNAs are considered as potential upstream mediators of STAT3 and they are able to affect STAT3 expression in exerting their oncogene or onco-suppressor role in GC cells. Anti-tumor compounds suppress the STAT3 signaling pathway to restrict the proliferation and malignant behavior of GC cells. Other molecular pathways, such as sirtuin, stathmin and so on, can act as upstream mediators of STAT3 in GC. Notably, the components of the tumor microenvironment that are capable of targeting STAT3 in GC, such as fibroblasts and macrophages, are discussed in this review. Finally, we demonstrate that STAT3 can target oncogene factors to enhance the proliferation and metastasis of GC cells.
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Li Q, Xi J, Li B, Li N. MiR‐16, as a potential NF‐κB‐related miRNA, exerts anti‐inflammatory effects on LPS‐induced myocarditis via mediating CD40 expression: A preliminary study. J Biochem Mol Toxicol 2019; 34:e22426. [PMID: 31777165 DOI: 10.1002/jbt.22426] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 09/10/2019] [Accepted: 11/14/2019] [Indexed: 12/26/2022]
Affiliation(s)
- Qiang‐Qiang Li
- Department of Cardiology of Integrated Traditional Chinese and Western MedicineAnqiu People's Hospital Weifang Shandong China
| | - Jing Xi
- Department of CardiologyAnqiu People's Hospital Weifang Shandong China
| | - Bing‐Qiang Li
- Department of CardiologyAnqiu People's Hospital Weifang Shandong China
| | - Ning Li
- Department of CardiologyAnqiu People's Hospital Weifang Shandong China
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Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells. Biomolecules 2019; 9:biom9080302. [PMID: 31349651 PMCID: PMC6723681 DOI: 10.3390/biom9080302] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 01/09/2023] Open
Abstract
The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties. The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells. We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells. Further investigation showed that CBD significantly upregulated ataxia telangiectasia-mutated gene (ATM) and p53 protein expression and downregulated p21 protein expression in SGC-7901 cells, which subsequently inhibited the levels of CDK2 and cyclin E, thereby resulting in cell cycle arrest at the G0–G1 phase. In addition, CBD significantly increased Bax expression levels, decreased Bcl-2 expression levels and mitochondrial membrane potential, and then upregulated the levels of cleaved caspase-3 and cleaved caspase-9, thereby inducing apoptosis in SGC-7901 cells. Finally, we found that intracellular reactive oxygen species (ROS) increased after CBD treatment. These results indicated that CBD could induce G0–G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.
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