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Kang DY, Bae SW, Jang KJ. Natural bioactive gallic acid shows potential anticancer effects by inhibiting the proliferation and invasiveness behavior in human embryonic carcinoma cells. Mol Med Rep 2025; 31:151. [PMID: 40211726 PMCID: PMC11997742 DOI: 10.3892/mmr.2025.13516] [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: 10/11/2024] [Accepted: 02/06/2025] [Indexed: 04/16/2025] Open
Abstract
Embryonic cancer stem cells (CSCs), referred to as self‑renewable cells, are commonly found in liquid and solid cancers and can also be attributed to tumor onset, resistance, expansion, recurrence and metastasis following treatment. Cancer therapy targeting CSCs using natural bioactive products is an optimal option for inhibiting cancer recurrence, thereby improving prognosis. Several natural compounds and extracts have been used to identify direct or indirect therapy effects that reduce the pathological activities of CSCs. Natural gallic acid (GA) is noted to have anticancer properties for oncogene expression, cycle arrest, apoptosis, angiogenesis, migration and metastasis in various cancers. The present study demonstrated that GA has various anticancer activities in NTERA‑2 and NCCIT human embryonic carcinoma cells. In two types of embryonic CSCs, GA effectively induced cell death via late apoptosis. Furthermore, GA showed the G0/G1 cell cycle arrest activity in embryonic CSCs by inducing the increase of p21, p27 and p53 expression and the decrease of CDK4, cyclin E and cyclin D1 expression. The present study showed that GA inhibited the expression levels of mRNA and protein for stem cell markers, such as SOX2, NANOG and OCT4, in NTERA‑2 and NCCIT cells. The induction of cellular and mitochondrial reactive oxygen species by GA also activated the cellular DNA damage response pathway by raising the phosphorylated‑BRCA1, ATM, Chk1, Chk2 and histone. Finally, GA inhibited CSCs invasion and migration by inhibiting the expression of matrix metalloproteinase by the downregulation of EGFR/JAK2/STAT5 signaling pathway. Thus, it is hypothesized that GA could be a potential inhibitor of cancer emergence by suppressing CSC properties.
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Affiliation(s)
- Dong Young Kang
- Department of Immunology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju. Chungcheong 27478, Republic of Korea
| | - Se Won Bae
- Department of Chemistry and Cosmetics, Jeju National University, Jeju, Jejudo 63243, Republic of Korea
| | - Kyoung-Jin Jang
- Department of Integrative Biological Sciences and Industry, College of Life Science, Sejong University, Seoul 05006, Republic of Korea
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Yi JR, Zeng B, Liu JF, Man QW. Network pharmacology and experimental validation reveals the potential therapeutic effects of Polygonum cuspidatum against odontogenic keratocyst. JOURNAL OF STOMATOLOGY, ORAL AND MAXILLOFACIAL SURGERY 2025; 126:102105. [PMID: 39362634 DOI: 10.1016/j.jormas.2024.102105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 08/27/2024] [Accepted: 10/01/2024] [Indexed: 10/05/2024]
Abstract
This study aimed to explore active ingredients in Polygonum cuspidatum with potential effects on odontogenic keratocysts (OKCs) using network pharmacological approach and bioinformatic gene analysis. The active ingredients and targets of P. cuspidatum were selected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and the ingredient-target network was constructed using Cytoscape software. Differentially expressed genes (DEGs) of OKC were selected and Gene Ontology (GO) enrichment analysis were performed through bioinformatic analysis using Gene Expression Omnibus (GEO) dataset GSE38494. The STRING database platform was used to draw protein-protein interaction network diagram, then the hub gene analysis was performed by Cytoscape software. AutoDock Vina software was used to perform molecular docking verification of the effects of the active ingredients on potential core targets. Finally, we use OKC nude animal model to testify the potential effects of P. cuspidatum. Ten active ingredients of P. cuspidatum were obtained. A total of 205 drug targets and 38 potential core targets of P. cuspidatum were confirmed in OKCs. The hub genes included PPARG, SPP1, COL3A1, MMP2, HMOX1, CCL2, CXCL10, VCAM1, RUNX2 and IRF1. Molecular docking showed that the key active ingredients including luteolin and quercetin which exhibited good docking activity with key target proteins (VCAM1, HMOX1 and MMP2). GO enrichment revealed that the pathways of P. cuspidatum acting on OKCs included the response to toxic substance, response to nutrient levels and response to xenobiotic stimulus. P. cuspidatum treatment in OKC could significantly down-regulate COL3A1 and MMP2 expressions in vivo and vitro. Our study indicated that P. cuspidatum is a potential therapeutic candidate for OKCs.
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Affiliation(s)
- Jing-Rui Yi
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Bang Zeng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jian-Feng Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Qi-Wen Man
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
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Hao JQ, Ran B, Hu SY, Zhuang ZX, Zhang JW, Xiong MR, Wang R, Zhuang W, Wang MJ. Exploring the link between Di-2-ethylhexyl phthalate (DEHP) exposure and muscle mass: A systematic investigation utilizing NHANES data analysis, network toxicology and molecular docking approaches. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 295:118132. [PMID: 40194361 DOI: 10.1016/j.ecoenv.2025.118132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/29/2025] [Accepted: 03/30/2025] [Indexed: 04/09/2025]
Abstract
Sarcopenia is a syndrome characterized by a progressive, widespread decline in muscle mass and strength. DEHP, a plasticizer involved in daily life and widely used, has been found in various everyday items and causes developmental dysregulation, reproductive impairments, tumorigenesis, and transgenerational disease. However, much remains to be discovered regarding the association between exposure to this environmental toxin and sarcopenia, as well as the toxic targets and molecular mechanisms. This research elucidated the relationship between contact with DEHP and the development of sarcopenia by integrating NHANES data analysis, network toxicology, and molecular docking. 3199 adults were enrolled, and multiple linear regressions were performed to reveal a significant negative correlation between lnDEHP and ALMBMI. Eighty-eight targets associated with DEHP and sarcopenia were identified. Subsequent STRING and Cytoscape screening stressed 20 key targets, including CASP3, BCL2, MMP9, BCL2L1, APP, and CTSS. GO and KEGG enrichment analyses revealed that these targets are involved in ligand-receptor interactions, apoptosis, and calcium signaling pathways. Molecular docking simulations using CB-dock confirmed the high-affinity binding interactions between DEHP and these key targets. This study validated the relationship between DEHP exposure and muscle mass. Further, it provided a theoretical basis for investigating the molecular mechanisms of DEHP exposure-induced skeletal muscle toxicity.
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Affiliation(s)
- Jia-Qi Hao
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Biao Ran
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Shu-Yue Hu
- Neonatology Department, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zi-Xuan Zhuang
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jia-Wan Zhang
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Meng-Rui Xiong
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wen Zhuang
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Mo-Jin Wang
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Rho SB, Kim BR, Lee SH, Lee CH. Translationally Controlled Tumor Protein Enhances Angiogenesis in Ovarian Tumors by Activating Vascular Endothelial Growth Factor Receptor 2 Signaling. Biomol Ther (Seoul) 2025; 33:193-202. [PMID: 39664017 PMCID: PMC11704413 DOI: 10.4062/biomolther.2024.206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024] Open
Abstract
Translationally controlled tumor protein (TCTP) is a regulatory protein that plays pivotal roles in cellular processes including the cell cycle, apoptosis, microtubule stabilization, embryo development, stress responses, and cancer. However, the molecular mechanism by which it promotes tumor angiogenesis is still unclear. In this study, we explored the mechanisms underlying stimulation of angiogenesis by a novel TCTP. Recombinant TCTP enhanced vascular endothelial growth factor (VEGF)-induced endothelial cell migration, capillary-like tubular structure formation, and cell proliferation by interacting with VEGF receptor 2 (VEGFR-2) in vitro. In contrast, we showed that TCTP knockdown (using short interfering [si]TCTP) led to a decrease in ovarian tumor cells. We also examined the expression of VEGF and hypoxia inducible factor 1 (HIF-1α), an important angiogenic factor. The expression of VEGF as well as HIF-1α was dramatically decreased by siTCTP. Mechanistically, siTCTP inhibited VEGFR-2 tyrosine phosphorylation and phosphorylation of its downstream targets PI3K, Akt, and mTOR. Collectively, these findings indicate that TCTP can promote proliferation and angiogenesis via the VEGFR-2/PI3K and mTOR signaling pathways in ovarian tumor cells, providing new insight into the mechanism behind the involvement of TCTP in tumor angiogenesis.
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Affiliation(s)
- Seung Bae Rho
- Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
| | - Boh-Ram Kim
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Seung-Hoon Lee
- Department of Life Science, Yong In University, Yongin 17092, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
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Files R, Cardoso C, Prada J, Silva F, Pires I. Syndecan-1 and E-Cadherin Expression in Canine Cutaneous Squamous Cell Carcinoma. Vet Sci 2024; 11:652. [PMID: 39728992 DOI: 10.3390/vetsci11120652] [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: 10/23/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) in dogs is a locally invasive tumor that typically occurs in areas of poorly pigmented skin due to sun exposure. Identifying new biomarkers, such as syndecan-1 (CD138) and E-cadherin, is fundamental for tumor diagnosis and prognosis. Dysregulation of syndecan-1, expressed in epithelial tissue, fibroblasts, and plasma cells, is associated with poor prognosis in several types of cancer. Similarly, E-cadherin, which plays a crucial role in cell adhesion and epithelial functionality, is also linked to adverse outcomes. This study evaluated the expression of syndecan-1 and E-cadherin in 47 cases of canine cutaneous squamous cell carcinoma. The results showed that the intensity of syndecan-1 decreased with increasing tumor aggressiveness, and its presence in the stroma was significantly associated with tumor grade. E-cadherin also demonstrated a decrease in intensity with increasing malignancy. However, the association between syndecan-1 and E-cadherin was not statistically significant. E-cadherin reduction and stromal syndecan-1 positivity seem to be associated with tumor aggressiveness in canine cutaneous squamous cell carcinoma. Further studies are needed to explore their roles in tumor progression.
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Affiliation(s)
- Rita Files
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Cláudia Cardoso
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Justina Prada
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Filipe Silva
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Isabel Pires
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
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Feng C, Chen X, Yin X, Jiang Y, Zhao C. Matrix Metalloproteinases on Skin Photoaging. J Cosmet Dermatol 2024; 23:3847-3862. [PMID: 39230065 PMCID: PMC11626319 DOI: 10.1111/jocd.16558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/31/2024] [Accepted: 08/20/2024] [Indexed: 09/05/2024]
Abstract
BACKGROUND Skin aging is characterized by an imbalance between the generation and degradation of extracellular matrix molecules (ECM). Matrix metalloproteinases (MMPs) are the primary enzymes responsible for ECM breakdown. Intrinsic and extrinsic stimuli can induce different MMPs. However, there is limited literature especially on the summary of skin MMPs and potential inhibitors. OBJECTIVE We aim to focus on the upregulation of MMP expression or activity in skin cells following exposure to UV radiation. We also would like to offer valuable insights into potential clinical applications of MMP inhibitors for mitigating skin aging. METHODS This article presents the summary of prior research, which involved an extensive literature search across diverse academic databases including Web of Science and PubMed. RESULTS Our findings offer a comprehensive insight into the effects of MMPs on skin aging after UV irradiation, including their substrate preferences and distinct roles in this process. Additionally, a comprehensive list of natural plant and animal extracts, proteins, polypeptides, amino acids, as well as natural and synthetic compounds that serve as inhibitors for MMPs is compiled. CONCLUSION Skin aging is a complex process influenced by environmental factors and MMPs. Research focuses on UV-induced skin damage and the formation of Advanced Glycosylation End Products (AGEs), leading to wrinkles and impaired functionality. Inhibiting MMPs is crucial for maintaining youthful skin. Natural sources of MMP inhibitor substances, such as extracts from plants and animals, offer a safer approach to obtain inhibitors through dietary supplements. Studying isolated active ingredients can contribute to developing targeted MMP inhibitors.
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Affiliation(s)
- Chao Feng
- Beijing Qingyan Boshi Health Management Co., Ltd.BeijingChina
| | - Xianglong Chen
- Beijing Qingyan Boshi Health Management Co., Ltd.BeijingChina
| | - Xiuqing Yin
- Beijing Qingyan Boshi Health Management Co., Ltd.BeijingChina
| | - Yanfei Jiang
- Beijing Qingyan Boshi Health Management Co., Ltd.BeijingChina
| | - Chunyue Zhao
- Beijing Qingyan Boshi Health Management Co., Ltd.BeijingChina
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Rotenberg N, Feldman M, Shirian J, Hockla A, Radisky ES, Shifman JM. Engineered TIMP2 with narrow MMP-9 specificity is an effective inhibitor of invasion and proliferation of triple-negative breast cancer cells. J Biol Chem 2024; 300:107867. [PMID: 39419285 PMCID: PMC11609464 DOI: 10.1016/j.jbc.2024.107867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 09/19/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024] Open
Abstract
Matrix metalloproteinases (MMPs) are a family of endopeptidases that degrade extracellular matrix proteins, functioning in various physiological processes such as tissue remodeling, embryogenesis, and morphogenesis. Dysregulation of these enzymes is linked to multiple diseases. Specific inhibition of particular MMPs is crucial for anti-MMP drug development as some MMPs have shown antidisease properties. In this study, we aimed to design a highly specific inhibitor of MMP-9, that plays a crucial role in cell invasion and metastasis, using tissue inhibitor of metalloproteinases 2 (TIMP2s), an endogenous broad-family MMP inhibitor, as a prototype. In our earlier work, we were able to narrow down the specificity of the N-terminal domain of TIMP2 (N-TIMP2) toward MMP-9, yet at the expense of lowering its affinity to MMP-9. In this study, a library of N-TIMP2 mutants based on previous design with randomized additional positions was sorted for binding to MMP-9 using yeast surface display. Two selected N-TIMP2 mutants were expressed, purified, and their inhibitory activity against a panel of MMPs was measured. The best engineered N-TIMP2 mutant (REY) exhibited a 2-fold higher affinity to MMP-9 than that of the WT N-TIMP2, and 6- to 1.1 x 104-fold increase in binding specificity toward MMP-9 compared to five alternative MMPs. Moreover, REY demonstrated a significant increase in inhibition of cell invasion and proliferation compared to the WT N-TIMP2 in MDA-MB-231 breast cancer cells. Therefore, our engineered N-TIMP2 mutant emerges as a promising candidate for future therapeutic development, offering precise targeting of MMP-9 in MMP-9-driven diseases.
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Affiliation(s)
- Naama Rotenberg
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Mark Feldman
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Jason Shirian
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Alexandra Hockla
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA
| | - Evette S Radisky
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA
| | - Julia M Shifman
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
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Kadarwati LV, Lin IH, Huang YS, Lee YY, Chen SC, Chung CL, Chen IJ, Wang JY, Yougbaré S, Cheng TM, Kuo TR. Exploring Label-Free Imaging Techniques with Copper Sulfide Microspheres for Observing Breast Cancer Cells. ACS OMEGA 2024; 9:37882-37890. [PMID: 39281899 PMCID: PMC11391449 DOI: 10.1021/acsomega.4c04154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/18/2024]
Abstract
A single breast cancer is a prevalent form of cancer, affecting over 2.3 million women worldwide, as reported by the World Health Organization. Recently, researchers have extensively explored the utilization of biomaterials in breast cancer theranostics. One notable biomaterial being investigated is various structures of copper sulfide (CuS). In this work, a microsphere (MS) structure composed of CuS was employed for label-free imaging of MCF-7 breast cancer cells and normal Vero cells, respectively. Various label-free imaging techniques, such as bright field, dark field, phase contrast (PC), and differential interference contrast (DIC), were employed to capture images of CuS MSs, cell, and intact CuS MSs within a cell. The study compared the outcomes of each imaging technique and determined that DIC imaging provided the highest resolution for cells incubated with CuS MSs. Furthermore, the combination of PC and DIC techniques proved to be effective for imaging breast cancer cells in conjunction with CuS MSs. This research underscores the potential of CuS MSs for label-free cell detection and emphasizes the significance of selecting appropriate imaging techniques to attain high-quality images in the field of cell observation.
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Affiliation(s)
- Lutvi Vitria Kadarwati
- Graduate Institute of Biomedical Optomechatronics, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - I-Hsin Lin
- School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Shan Huang
- Graduate Institute of Nanomedicine and Medical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Yang Lee
- Southport Corporation, New Taipei City 22175, Taiwan
| | | | | | - I-Jan Chen
- Southport Corporation, New Taipei City 22175, Taiwan
| | - Jia-Yeh Wang
- Southport Corporation, New Taipei City 22175, Taiwan
| | - Sibidou Yougbaré
- Institut de Recherche en Sciences de La Santé/Direction Régionale du Centre Ouest (IRSS/DRCO), Nanoro BP 218, 11, Burkina Faso
| | - Tsai-Mu Cheng
- Graduate Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Cardiovascular Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Tsung-Rong Kuo
- Graduate Institute of Nanomedicine and Medical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
- Stanford Byers Center for Biodesign, Stanford University, Stanford, California 94305, United States
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Guo H, Mi P. Polymer-drug and polymer-protein conjugated nanocarriers: Design, drug delivery, imaging, therapy, and clinical applications. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1988. [PMID: 39109479 DOI: 10.1002/wnan.1988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 01/06/2025]
Abstract
Polymer-drug conjugates and polymer-protein conjugates have been pivotal in the realm of drug delivery systems for over half a century. These polymeric drugs are characterized by the conjugation of therapeutic molecules or functional moieties to polymers, enabling a range of benefits including extended circulation times, targeted delivery, controlled release, and decreased immunogenicity. This review delves into recent advancements and challenges in the clinical translations and preclinical studies of polymer-drug conjugates and polymer-protein conjugates. The design principles and functionalization strategies crucial for the development of these polymeric drugs were explored followed by the review of structural properties and characteristics of various polymer carriers. This review also identifies significant obstacles in the clinical translation of polymer-drug conjugates and provides insights into the directions for their future development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Haochen Guo
- Department of Radiology, Huaxi MR Research Center (HMRRC), and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kawasaki, Japan
| | - Peng Mi
- Department of Radiology, Huaxi MR Research Center (HMRRC), and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Liu H, Yu J, Hieawy A, Hu Z, Tay FR, Shen Y. Design and evaluation of an MMP-9-responsive hydrogel for vital pulp therapy. J Dent 2024; 146:105020. [PMID: 38670329 DOI: 10.1016/j.jdent.2024.105020] [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: 04/08/2024] [Revised: 04/21/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024] Open
Abstract
OBJECTIVE To design and evaluate a matrix metalloproteinase 9 (MMP-9)-responsive hydrogel for vital pulp therapy. METHODS A peptide linker with optimized sensitivity toward MMP-9 was crosslinked with 4-arm poly (ethylene glycol)-norbornene (PEG-NB) by thiol-norbornene photo-polymerization. This resulted in the formation of a hydrogel network in which the peptide IDR-1002 was incorporated. Hydrogel characterization and gelation kinetics were examined with Fourier-transform infrared spectroscopy, scanning electron microscopy, rheological testing, and swelling evaluation. Hydrogel degradation was examined through multiple exposure to pre-activated MMP-9, to simulate flare-ups of dental pulp inflammation. The IDR-1002 released from degraded hydrogels was measured with high-performance liquid chromatography. Effect of IDR-1002 released from hydrogels on one-week-old multispecies oral biofilms was evaluated using confocal laser scanning microscopy. RESULTS MMP-9-responsive, injectable, and photo-crosslinkable hydrogels were successfully synthesized. When hydrogel degradation and release of IDR-1002 were examined with exposure to pre-activated MMP-9, IDR-1002 release was significantly correlated with elevated levels of MMP-9 (p < 0.05). The effectiveness of IDR-1002 in killing bacteria in multispecies oral biofilms was significantly enhanced when the hydrogels were immersed in 10 nM or 20 nM pre-activated MMP-9, compared to immersion in phosphate-buffered saline (p < 0.05). CONCLUSIONS The MMP-9-responsive hydrogel is a promising candidate for on-demand delivery of bioactive agent in vital pulp therapy. CLINICAL SIGNIFICANCE MMP-9 is one of the most important diagnostic and prognostic biomarkers for pulpitis. An MMP-9-responsive hydrogel has potential to be used as an in-situ on-demand release system for the diagnosis and treatment of dental pulp inflammation.
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Affiliation(s)
- He Liu
- Division of Endodontics, Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada
| | - Jian Yu
- Division of Endodontics, Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada
| | - Ahmed Hieawy
- Division of Endodontics, Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada
| | - Ziqiu Hu
- Division of Endodontics, Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada
| | - Franklin R Tay
- Department of Endodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA.
| | - Ya Shen
- Division of Endodontics, Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada.
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Islam MR, Rauf A, Alash S, Fakir MNH, Thufa GK, Sowa MS, Mukherjee D, Kumar H, Hussain MS, Aljohani ASM, Imran M, Al Abdulmonem W, Thiruvengadam R, Thiruvengadam M. A comprehensive review of phytoconstituents in liver cancer prevention and treatment: targeting insights into molecular signaling pathways. Med Oncol 2024; 41:134. [PMID: 38703282 DOI: 10.1007/s12032-024-02333-5] [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] [Received: 12/08/2023] [Accepted: 02/13/2024] [Indexed: 05/06/2024]
Abstract
Primary liver cancer is a type of cancer that develops in the liver. Hepatocellular carcinoma is a primary liver cancer that usually affects adults. Liver cancer is a fatal global condition that affects millions of people worldwide. Despite advances in technology, the mortality rate remains alarming. There is growing interest in researching alternative medicines to prevent or reduce the effects of liver cancer. Recent studies have shown growing interest in herbal products, nutraceuticals, and Chinese medicines as potential treatments for liver cancer. These substances contain unique bioactive compounds with anticancer properties. The causes of liver cancer and potential treatments are discussed in this review. This study reviews natural compounds, such as curcumin, resveratrol, green tea catechins, grape seed extracts, vitamin D, and selenium. Preclinical and clinical studies have shown that these medications reduce the risk of liver cancer through their antiviral, anti-inflammatory, antioxidant, anti-angiogenic, and antimetastatic properties. This article discusses the therapeutic properties of natural products, nutraceuticals, and Chinese compounds for the prevention and treatment of liver cancer.
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Affiliation(s)
- Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar, 23561, Khyber Pakhtunkhwa, Pakistan.
| | - Shopnil Alash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Md Naeem Hossain Fakir
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Gazi Kaifeara Thufa
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Mahbuba Sharmin Sowa
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Dattatreya Mukherjee
- Raiganj Government Medical College and Hospital, Pranabananda Sarani, Raiganj, 733134, West Bengal, India
| | - Harendra Kumar
- Dow University of Health Sciences, Mission Rd, New Labour Colony Nanakwara, Karachi, 74200, Sindh, Pakistan
| | - Md Sadique Hussain
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, 302017, Rajasthan, India
| | - Abdullah S M Aljohani
- Department of Medical Biosciences, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Muhammad Imran
- Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, 61413, Abha, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Rekha Thiruvengadam
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, 600077, Tamil Nadu, India.
| | - Muthu Thiruvengadam
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul, 05029, South Korea
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12
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Zong L, Xu H, Zhang H, Tu Z, Zhang X, Wang S, Li M, Feng Y, Wang B, Li L, Xie X, He Z, Pu X. A review of matrix metalloproteinase-2-sensitive nanoparticles as a novel drug delivery for tumor therapy. Int J Biol Macromol 2024; 262:130043. [PMID: 38340921 DOI: 10.1016/j.ijbiomac.2024.130043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/12/2024]
Abstract
Matrix metalloproteinase-2 (MMP-2)-responsive nanodrug vehicles have garnered significant attention as antitumor drug delivery systems due to the extensive research on matrix metalloproteinases (MMPs) within the tumor extracellular matrix (ECM). These nanodrug vehicles exhibit stable circulation in the bloodstream and accumulate specifically in tumors through various mechanisms. Upon reaching tumor tissues, their structures are degraded in response to MMP-2 within the ECM, resulting in drug release. This controlled drug release significantly increases drug concentration within tumors, thereby enhancing its antitumor efficacy while minimizing side effects on normal organs. This review provides an overview of MMP-2 characteristics, enzyme-sensitive materials, and current research progress regarding their application as MMP-2-responsive nanodrug delivery system for anti-tumor drugs, as well as considering their future research prospects. In conclusion, MMP-2-sensitive drug delivery carriers have a broad application in all kinds of nanodrug delivery systems and are expected to become one of the main means for the clinical development and application of nanodrug delivery systems in the future.
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Affiliation(s)
- Lanlan Zong
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China; Huaihe Hospital of Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Hongliang Xu
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Huiqi Zhang
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Ziwei Tu
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Xiao Zhang
- Department of Pharmacy, Hebei Provincial Clinical Research Center for Eye Diseases, Hebei Provincial Key Laboratory of Ophthalmology, Hebei Provincial Eye Hospital, Xingtai City, Hebei Province 054001, China
| | - Shumin Wang
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Meigui Li
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Yu Feng
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Binke Wang
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China
| | - Luhui Li
- Medical School, Henan Technical Institute, Kaifeng, Henan 475004, China
| | - Xinmei Xie
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China.
| | - Zhonggui He
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Xiaohui Pu
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng 475004, China; Huaihe Hospital of Henan University, N. Jinming Ave., Kaifeng 475004, China.
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Xu K, Fu A, Li Z, Miao L, Lou Z, Jiang K, Lau C, Su T, Tong T, Bao J, Lyu A, Kwan HY. Elevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions. Nat Commun 2024; 15:1685. [PMID: 38402239 PMCID: PMC10894219 DOI: 10.1038/s41467-024-45995-5] [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: 03/24/2023] [Accepted: 02/06/2024] [Indexed: 02/26/2024] Open
Abstract
The cargo content in small extracellular vesicles (sEVs) changes under pathological conditions. Our data shows that in obesity, extracellular matrix protein 1 (ECM1) protein levels are significantly increased in circulating sEVs, which is dependent on integrin-β2. Knockdown of integrin-β2 does not affect cellular ECM1 protein levels but significantly reduces ECM1 protein levels in the sEVs released by these cells. In breast cancer (BC), overexpressing ECM1 increases matrix metalloproteinase 3 (MMP3) and S100A/B protein levels. Interestingly, sEVs purified from high-fat diet-induced obesity mice (D-sEVs) deliver more ECM1 protein to BC cells compared to sEVs from control diet-fed mice. Consequently, BC cells secrete more ECM1 protein, which promotes cancer cell invasion and migration. D-sEVs treatment also significantly enhances ECM1-mediated BC metastasis and growth in mouse models, as evidenced by the elevated tumor levels of MMP3 and S100A/B. Our study reveals a mechanism and suggests sEV-based strategies for treating obesity-associated BC.
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Affiliation(s)
- Keyang Xu
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Ai Fu
- Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhaoyi Li
- Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Liangbin Miao
- Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhonghan Lou
- Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Keying Jiang
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Condon Lau
- Department of Physics, City University of Hong Kong, Hong Kong, China
| | - Tao Su
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tiejun Tong
- Department of Mathematics, Hong Kong Baptist University, Hong Kong, China
| | - Jianfeng Bao
- Hangzhou Xixi Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Aiping Lyu
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
- Institute of Systems Medicine and Health Sciences, Hong Kong Baptist University, Hong Kong, China.
| | - Hiu Yee Kwan
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
- Institute of Systems Medicine and Health Sciences, Hong Kong Baptist University, Hong Kong, China.
- Institute of Research and Continuing Education, Hong Kong Baptist University, Shenzhen, China.
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Galadima M, Teles M, Pastor J, Hernández-Losa J, Rodríguez-Gil JE, Rivera del Alamo MM. Programmed Death-Ligand (PD-L1), Epidermal Growth Factor (EGF), Relaxin, and Matrix Metalloproteinase-3 (MMP3): Potential Biomarkers of Malignancy in Canine Mammary Neoplasia. Int J Mol Sci 2024; 25:1170. [PMID: 38256245 PMCID: PMC10816983 DOI: 10.3390/ijms25021170] [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: 12/11/2023] [Revised: 01/08/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
Gene expression has been suggested as a putative tool for prognosis and diagnosis in canine mammary neoplasia (CMNs). In the present study, 58 formalin-fixed paraffin-embedded (FFPE) paraffined canine mammary neoplasias from 27 different bitches were included. Thirty-seven tumours were classified as benign, whereas thirty-one were classified as different types of canine carcinoma. In addition, mammary samples from three healthy bitches were also included. The gene expression for vascular endothelial growth factor-α (VEGFα), CD20, progesterone receptor (PGR), hyaluronidase-1 (HYAL-1), programmed death-ligand 1 (PD-L1), epidermal growth factor (EGF), relaxin (RLN2), and matrix metalloproteinase-3 (MMP3) was assessed through RT-qPCR. All the assessed genes yielded a higher expression in neoplastic mammary tissue than in healthy tissue. All the evaluated genes were overexpressed in neoplastic mammary tissue, suggesting a role in the process of tumorigenesis. Moreover, PD-L1, EGF, relaxin, and MMP3 were significantly overexpressed in malignant CMNs compared to benign CMNs, suggesting they may be useful as malignancy biomarkers.
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Affiliation(s)
- Makchit Galadima
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; (M.G.); (J.P.); (J.E.R.-G.)
| | - Mariana Teles
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Josep Pastor
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; (M.G.); (J.P.); (J.E.R.-G.)
| | - Javier Hernández-Losa
- Department of Pathology, Hospital Universitari Vall d’Hebron, VHIR, 08035 Barcelona, Spain;
| | - Joan Enric Rodríguez-Gil
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; (M.G.); (J.P.); (J.E.R.-G.)
| | - Maria Montserrat Rivera del Alamo
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; (M.G.); (J.P.); (J.E.R.-G.)
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15
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Qulu W, Mtshali A, Osman F, Ndlela N, Ntuli L, Mzobe G, Naicker N, Garrett N, Rompalo A, Mindel A, Ngcapu S, Liebenberg L. High-risk human papillomavirus prevalence among South African women diagnosed with other STIs and BV. PLoS One 2023; 18:e0294698. [PMID: 38032961 PMCID: PMC10688634 DOI: 10.1371/journal.pone.0294698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 11/07/2023] [Indexed: 12/02/2023] Open
Abstract
INTRODUCTION Human papillomavirus (HPV) infection is a leading cause of cervical cancer. Although this relies on infection and persistence of HPV in epithelial cells, often occurring in the context of other sexually transmitted infections (STIs) and bacterial vaginosis (BV), data on the relationships between these and their relative effects on epithelial barrier integrity in women remain sparse. This study describes the epidemiology of HPV combined with STI and/or BV prevalence and the relative impact on matrix metalloproteinases (MMPs) among South African women. METHODS Roche Linear Array was used for HPV genotyping in menstrual cup pellets of 243 HIV-negative women participating in the CAPRISA 083 cohort study. Vulvovaginal swabs were tested for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis using Xpert® CT/NG assay and lateral flow assay, and Gram staining was performed to diagnose BV using Nugent scoring criteria. Concentrations of 5 MMPs were measured in menstrual cup supernatants by multiplexed ELISA. Fisher's exact tests, Mann-Whitney U tests, and multivariable regression models determined associations between HPV infection, STI and/or BV, and MMP concentrations. RESULTS HPV was prevalent in 34% of women (83/243; median 23 years, interquartile range (IQR) 21-27 years). Low-risk (lr) (71%, 59/83) and high-risk (hr)-HPV infections (54.2%, 45/83) were common. Hr-HPV was frequently detected in STI and/or BV-positive women compared to women without STIs or BV (p = 0.029). In multivariable analysis, BV was associated with increased odds of hr-HPV detection (OR: 2.64, 95%CI: 1.02-6.87, p = 0.046). Furthermore, Gardasil®9 vaccine-type strains were more frequently detected in women diagnosed with STI and/or BV (55.2%, 32/58 vs 24%, 6/25; p = 0.009). Among STI and/or BV-positive women, HPV detection was significantly associated with increased MMP-10 concentrations (b = 0.55, 95% CI 0.79-1.01; p = 0.022). CONCLUSION Most women with hr-HPV had another STI and/or BV, emphasizing an urgent need for STI and BV screening and intensive scale-up of cervical cancer screening and HPV vaccination programmes. Furthermore, the study highlights the need for more extensive research to confirm and understand the relationship between HPV infection and barrier integrity.
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Affiliation(s)
- Wenkosi Qulu
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Andile Mtshali
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Farzana Osman
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
| | - Nonsikelelo Ndlela
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Lungelo Ntuli
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Gugulethu Mzobe
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Nivashnee Naicker
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
| | - Nigel Garrett
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Nursing and Public Health, Discipline of Public Health Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Anne Rompalo
- Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Adrian Mindel
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
| | - Sinaye Ngcapu
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Lenine Liebenberg
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
- Centre for Epidemic Response and Innovation, Stellenbosch University, Cape Town, South Africa
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Nie Y, Xu L, Bai Z, Liu Y, Wang S, Zeng Q, Gao X, Xia X, Chang D. Prognostic utility of TME-associated genes in pancreatic cancer. Front Genet 2023; 14:1218774. [PMID: 37727377 PMCID: PMC10505756 DOI: 10.3389/fgene.2023.1218774] [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: 05/08/2023] [Accepted: 08/15/2023] [Indexed: 09/21/2023] Open
Abstract
Background: Pancreatic cancer (PC) is a deadly disease. The tumor microenvironment (TME) participates in PC oncogenesis. This study focuses on the assessment of the prognostic and treatment utility of TME-associated genes in PC. Methods: After obtaining the differentially expressed TME-related genes, univariate and multivariate Cox analyses and least absolute shrinkage and selection operator (LASSO) were performed to identify genes related to prognosis, and a risk model was established to evaluate risk scores, based on The Cancer Genome Atlas (TCGA) data set, and it was validated by external data sets from the Gene Expression Omnibus (GEO) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Multiomics analyses were adopted to explore the potential mechanisms, discover novel treatment targets, and assess the sensitivities of immunotherapy and chemotherapy. Results: Five TME-associated genes, namely, FERMT1, CARD9, IL20RB, MET, and MMP3, were identified and a risk score formula constructed. Next, their mRNA expressions were verified in cancer and normal pancreatic cells. Multiple algorithms confirmed that the risk model displayed a reliable ability of prognosis prediction and was an independent prognostic factor, indicating that high-risk patients had poor outcomes. Immunocyte infiltration, gene set enrichment analysis (GSEA), and single-cell analysis all showed a strong relationship between immune mechanism and low-risk samples. The risk score could predict the sensitivity of immunotherapy and some chemotherapy regimens, which included oxaliplatin and irinotecan. Various latent treatment targets (LAG3, TIGIT, and ARID1A) were addressed by mutation landscape based on the risk model. Conclusion: The risk model based on TME-related genes can reflect the prognosis of PC patients and functions as a novel set of biomarkers for PC therapy.
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Affiliation(s)
- Yuanhua Nie
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Longwen Xu
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Zilong Bai
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yaoyao Liu
- Geneplus-Beijing, Co., Ltd., Beijing, China
| | - Shilong Wang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Qingnuo Zeng
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xuan Gao
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- GenePlus- Shenzhen Clinical Laboratory, Shenzhen, China
| | | | - Dongmin Chang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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Oza PP, Kashfi K. The Triple Crown: NO, CO, and H 2S in cancer cell biology. Pharmacol Ther 2023; 249:108502. [PMID: 37517510 PMCID: PMC10529678 DOI: 10.1016/j.pharmthera.2023.108502] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/16/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023]
Abstract
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are three endogenously produced gases with important functions in the vasculature, immune defense, and inflammation. It is increasingly apparent that, far from working in isolation, these three exert many effects by modulating each other's activity. Each gas is produced by three enzymes, which have some tissue specificities and can also be non-enzymatically produced by redox reactions of various substrates. Both NO and CO share similar properties, such as activating soluble guanylate cyclase (sGC) to increase cyclic guanosine monophosphate (cGMP) levels. At the same time, H2S both inhibits phosphodiesterase 5A (PDE5A), an enzyme that metabolizes sGC and exerts redox regulation on sGC. The role of NO, CO, and H2S in the setting of cancer has been quite perplexing, as there is evidence for both tumor-promoting and pro-inflammatory effects and anti-tumor and anti-inflammatory activities. Each gasotransmitter has been found to have dual effects on different aspects of cancer biology, including cancer cell proliferation and apoptosis, invasion and metastasis, angiogenesis, and immunomodulation. These seemingly contradictory actions may relate to each gas having a dual effect dependent on its local flux. In this review, we discuss the major roles of NO, CO, and H2S in the context of cancer, with an effort to highlight the dual nature of each gas in different events occurring during cancer progression.
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Affiliation(s)
- Palak P Oza
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York 10091, USA.
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18
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Bocian-Jastrzębska A, Malczewska-Herman A, Kos-Kudła B. Role of Leptin and Adiponectin in Carcinogenesis. Cancers (Basel) 2023; 15:4250. [PMID: 37686525 PMCID: PMC10486522 DOI: 10.3390/cancers15174250] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Hormones produced by adipocytes, leptin and adiponectin, are associated with the process of carcinogenesis. Both of these adipokines have well-proven oncologic potential and can affect many aspects of tumorigenesis, from initiation and primary tumor growth to metastatic progression. Involvement in the formation of cancer includes interactions with the tumor microenvironment and its components, such as tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix and matrix metalloproteinases. Furthermore, these adipokines participate in the epithelial-mesenchymal transition and connect to angiogenesis, which is critical for cancer invasiveness and cancer cell migration. In addition, an enormous amount of evidence has demonstrated that altered concentrations of these adipocyte-derived hormones and the expression of their receptors in tumors are associated with poor prognosis in various types of cancer. Therefore, leptin and adiponectin dysfunction play a prominent role in cancer and impact tumor invasion and metastasis in different ways. This review clearly and comprehensively summarizes the recent findings and presents the role of leptin and adiponectin in cancer initiation, promotion and progression, focusing on associations with the tumor microenvironment and its components as well as roles in the epithelial-mesenchymal transition and angiogenesis.
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Affiliation(s)
- Agnes Bocian-Jastrzębska
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland; (A.M.-H.); (B.K.-K.)
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Almutairi S, Kalloush HM, Manoon NA, Bardaweel SK. Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013-2023). Molecules 2023; 28:5567. [PMID: 37513440 PMCID: PMC10384300 DOI: 10.3390/molecules28145567] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/09/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.
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Affiliation(s)
- Shriefa Almutairi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Hanin Moh'd Kalloush
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
- Department of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan
| | - Nour A Manoon
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
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Pietrzak J, Wosiak A, Szmajda-Krygier D, Świechowski R, Łochowski M, Pązik M, Balcerczak E. Correlation of TIMP1-MMP2/MMP9 Gene Expression Axis Changes with Treatment Efficacy and Survival of NSCLC Patients. Biomedicines 2023; 11:1777. [PMID: 37509417 PMCID: PMC10376864 DOI: 10.3390/biomedicines11071777] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/16/2023] [Accepted: 06/17/2023] [Indexed: 07/30/2023] Open
Abstract
In the course of lung cancer, normal cells are transformed into cancerous ones, and changes occur in the microenvironment, including the extracellular matrix (ECM), which is not only a scaffold for cells, but also a reservoir of cytokines, chemokines and growth factors. Metalloproteinases (MMPs) are among the elements that enable ECM remodeling. The publication focuses on the problem of changes in the gene expression of MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP1) in the blood of NSCLC patients during therapy (one year after surgical resection of the tumor). The paper also analyzes differences in the expression of the studied genes in the tumor tissue, as well as data collected in publicly available databases. The results of blood tests showed no differences in the expression of the tested genes during therapy; however, changes were observed in cancerous tissue, which was characterized by higher expression of MMP2 and MMP9, compared to non-cancerous tissue, and unchanged expression of TIMP1. Nevertheless, higher expression of each of the studied genes was associated with shorter patient survival. Interestingly, it was not only the increased expression of metalloproteinase genes, but also the increased expression of the metalloproteinase inhibitor (TIMP1) that was unfavorable for patients.
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Affiliation(s)
- Jacek Pietrzak
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Agnieszka Wosiak
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Dagmara Szmajda-Krygier
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Rafał Świechowski
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Mariusz Łochowski
- Department of Thoracic Surgery, Copernicus Memorial Hospital, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland
| | - Milena Pązik
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
| | - Ewa Balcerczak
- Laboratory of Molecular Diagnostics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, BRaIN Laboratories, Medical University of Lodz, Czechoslowacka 4, 92-216 Lodz, Poland
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Wang X, Tang G, Guo H, Ma J, Liu D, Wang Y, Jin R, Li Z, Tang Y. Research Progress on the Anti-Tumor Mechanism and Reversal of Multidrug Resistance of Zuojin Pill and its Main Components, Evodiamine and Berberine. Nat Prod Commun 2023; 18. [DOI: 10.1177/1934578x231161414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024] Open
Abstract
Background Cancer is one of the most serious diseases worldwide that threatens human health and leads to death. Chemotherapy is the main clinical method to treat tumors, but, despite the development of new chemotherapeutic drugs, the multidrug resistance (MDR) of cancer cells to conventional chemotherapeutic drugs remains a major cause of failure in cancer prevention and treatment. Therefore, overcoming this resistance has become a major challenge in cancer prevention and treatment. Method With the in-depth study of traditional Chinese medicines (TCMs) for the treatment of tumors, many such medicines have been found that can reverse MDR and enhance the sensitivity of chemotherapy. ZJW is a famous traditional medicine formula from China, recorded first in an ancient medicine book named Danxi Xinfa. It is composed of Huanglian and Wuzhuyu in a ratio of 6:1 by mass. Conclusion ZJW can inhibit proliferation, induce apoptosis, inhibit invasion and metastasis, and reverse MDR of tumor cells through multiple pathways and multiple targets. In this paper, we briefly review recent research on ZJW and its main components, evodiamine and berberine, in the anti-tumor mechanism and reversal of multidrug resistance.
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Affiliation(s)
- Xinyi Wang
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
| | - Gonghuan Tang
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
| | - Hui Guo
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
| | - Jingjing Ma
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
| | - Dongmei Liu
- No.988 Hospital of Joint Logistic Support Force, Zhengzhou, China
| | - Yuwei Wang
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
| | - Ruyi Jin
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
| | - Zhi Li
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
| | - Yuping Tang
- Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, XianYang, China
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Biological and Genetic Mechanisms of COPD, Its Diagnosis, Treatment, and Relationship with Lung Cancer. Biomedicines 2023; 11:biomedicines11020448. [PMID: 36830984 PMCID: PMC9953173 DOI: 10.3390/biomedicines11020448] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/09/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic adult diseases, with significant worldwide morbidity and mortality. Although long-term tobacco smoking is a critical risk factor for this global health problem, its molecular mechanisms remain unclear. Several phenomena are thought to be involved in the evolution of emphysema, including airway inflammation, proteinase/anti-proteinase imbalance, oxidative stress, and genetic/epigenetic modifications. Furthermore, COPD is one main risk for lung cancer (LC), the deadliest form of human tumor; formation and chronic inflammation accompanying COPD can be a potential driver of malignancy maturation (0.8-1.7% of COPD cases develop cancer/per year). Recently, the development of more research based on COPD and lung cancer molecular analysis has provided new light for understanding their pathogenesis, improving the diagnosis and treatments, and elucidating many connections between these diseases. Our review emphasizes the biological factors involved in COPD and lung cancer, the advances in their molecular mechanisms' research, and the state of the art of diagnosis and treatments. This work combines many biological and genetic elements into a single whole and strongly links COPD with lung tumor features.
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Matrix Metallopeptidase-Gene Signature Predicts Stage I Lung Adenocarcinoma Survival Outcomes. Int J Mol Sci 2023; 24:ijms24032382. [PMID: 36768704 PMCID: PMC9917043 DOI: 10.3390/ijms24032382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/16/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023] Open
Abstract
Tumor recurrence poses a significant challenge to the clinical management of stage I lung adenocarcinoma after curative surgical resection. Matrix metalloproteinases (MMPs) increase expression and correlate with recurrence and metastasis in surgically resected non-small cell lung cancer. However, the impact of MMPs on survival outcome varies, and their roles in patients with stage I lung adenocarcinoma remain unclear. In two discovery cohorts, we first analyzed 226 stage I-II lung adenocarcinoma cases in the GSE31210 cohort using a clustering-based method and identified a 150-gene MMP cluster with increased expression in tumors associated with worse survival outcomes. A similar analysis was performed on 517 lung adenocarcinoma cases in the Cancer Genome Atlas cohort. A 185-gene MMP cluster was identified, which also showed increased expression in tumors and correlated with poor survival outcomes. We further streamlined from the discovery cohorts a 36-gene MMP signature significantly associated with recurrence and worse overall survival in patients with stage I lung adenocarcinoma after surgical resection. After adjusting for covariates, the high MMP-gene signature expression remained an independent risk factor. In addition, the MMP-gene signature showed enrichment in epidermal growth factor receptor wild-type lung tumors, especially for those with Kirsten rat sarcoma virus mutations. Using an independent validation cohort, we further validated the MMP-gene signature in 70 stage I lung adenocarcinoma cases. In conclusion, MMP-gene signature is a potential predictive and prognostic biomarker to stratify patients with stage I lung adenocarcinoma into subgroups based on their risk of recurrence for aiding physicians in deciding the personalized adjuvant therapeutics.
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Żwierełło W, Maruszewska A, Skórka-Majewicz M, Gutowska I. Fluoride in the Central Nervous System and Its Potential Influence on the Development and Invasiveness of Brain Tumours-A Research Hypothesis. Int J Mol Sci 2023; 24:1558. [PMID: 36675073 PMCID: PMC9866357 DOI: 10.3390/ijms24021558] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
The purpose of this review is to attempt to outline the potential role of fluoride in the pathogenesis of brain tumours, including glioblastoma (GBM). In this paper, we show for the first time that fluoride can potentially affect the generally accepted signalling pathways implicated in the formation and clinical course of GBM. Fluorine compounds easily cross the blood-brain barrier. Enhanced oxidative stress, disruption of multiple cellular pathways, and microglial activation are just a few examples of recent reports on the role of fluoride in the central nervous system (CNS). We sought to present the key mechanisms underlying the development and invasiveness of GBM, as well as evidence on the current state of knowledge about the pleiotropic, direct, or indirect involvement of fluoride in the regulation of these mechanisms in various tissues, including neural and tumour tissue. The effects of fluoride on the human body are still a matter of controversy. However, given the growing incidence of brain tumours, especially in children, and numerous reports on the effects of fluoride on the CNS, it is worth taking a closer look at these mechanisms in the context of brain tumours, including gliomas.
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Affiliation(s)
- Wojciech Żwierełło
- Department of Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 71 St., 70-111 Szczecin, Poland
| | - Agnieszka Maruszewska
- Department of Physiology and Biochemistry, Institute of Biology, University of Szczecin, Felczaka 3c St., 71-412 Szczecin, Poland
- Molecular Biology and Biotechnology Centre, Institute of Biology, University of Szczecin, Wąska 13 St., 71-415 Szczecin, Poland
| | - Marta Skórka-Majewicz
- Department of Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 71 St., 70-111 Szczecin, Poland
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 71 St., 70-111 Szczecin, Poland
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IGFBP3 inhibits tumor growth and invasion of lung cancer cells and is associated with improved survival in lung cancer patients. Transl Oncol 2022; 27:101566. [PMID: 36257207 PMCID: PMC9583099 DOI: 10.1016/j.tranon.2022.101566] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/27/2022] [Accepted: 10/10/2022] [Indexed: 11/15/2022] Open
Abstract
The insulin-like growth factor (IGF)-pathway is involved in tumor cell proliferation, metastasis, and survival. We aimed to find out what effects IGF binding protein 3 (IGFBP3) exerted on H1299 lung cancer (LC) cells in terms of tumor growth and invasion and whether IGFBP3 was associated with clinical and pathological parameters in a prospective cohort of LC patients. H1299 cells were transfected with an IGFBP3-expressing vector. Its influence on apoptosis induction via flow cytometry annexin V FITC assay, cell proliferation in 2D and 3D cell culture, and invasion were examined. Expression of several matrix metalloproteinases (MMPs) and inhibitors (TIMP-1) were also investigated in IGFBP3-transfected LC cells. Further, data on LC patients (n = 131), tumor characteristics, and survival were prospectively collected and correlated with IGFBP3 plasma levels. IGFBP3 did not influence apoptosis induction and 2D cell proliferation. However, both spheroid growth (3D proliferation) and invasion of IGFBP3-transfected cells planted in an extracellular matrix-based gel were significantly inhibited. IGFBP3 inhibited MMP-1 release, and the total MMP activity. In LC patients, higher IGFBP3 plasma levels correlated with both lower clinical tumor stage, grading, Ki-67 staining, and the absence of necrosis (P < 0.05, respectively). Increased IGFBP3 plasma levels were associated with improved overall survival (hazard ratio 0.37, P = 0.01). In conclusion, overexpressed IGFBP3 in a LC cell line inhibited tumor growth and invasion. Translating from bench to bedside, investigation of clinicopathological parameters confirmed these experimental results showing that higher IGFBP3 plasma levels were associated with less aggressive tumor growth, reduced tumor spread, and improved survival of LC patients.
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Ding P, Peng B, Li G, Sun X, Wang G. Glucosamine-phosphate N-acetyltransferase 1 and its DNA methylation can be biomarkers for the diagnosis and prognosis of lung cancer. J Clin Lab Anal 2022; 36:e24628. [PMID: 35929347 PMCID: PMC9459321 DOI: 10.1002/jcla.24628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/04/2022] [Accepted: 07/16/2022] [Indexed: 12/05/2022] Open
Abstract
Objective Lung cancer ranking high in the cancer‐related list has long perplexed patients, in which glucosamine‐phosphate N‐acetyltransferase 1 (GNPNAT1) is found to be highly expressed. Besides, DNA methylation is perceived as a biomarker to assess the prognosis of patients with various cancers. However, the correlation between GNPNAT1 and DNA methylation and the role of GNPNAT1 in lung cancer remain vague. Methods Principal component analysis (PCA), heatmap, volcano map, Venn diagram, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to screen out the candidate genes. The viability, migration, and invasion of lung cancer cells were detected by CCK‐8 and Transwell assays. An xenograft tumor mouse model was established. The relative expressions of GNPNAT1, E‐cadherin, vimentin, Matrix metalloproteinase‐2 (MMP‐2), tissue inhibitor of metalloproteinase‐2 (TIMP‐2), E2F1, and cyclin D1 in cells or xenograft tumor tissues were quantified by Western blot, RT‐qPCR, or immunohistochemistry assay. Results GNPNAT1 was screened as the research object. GNPNAT1 methylation was downregulated, while GNPNAT1 expression was upregulated in lung cancer tissues. The methylation and mRNA levels of GNPNAT1 were correlated with the patient prognosis. GNPNAT1 increased cell viability, migration and invasion, and promoted the xenograft tumor volume and weight, whereas shGNPNAT1 acted oppositely. Moreover, expressions of Vimentin, MMP‐2, E2F1, and cyclin D1 were increased, but E‐cadherin and TIMP‐2 expressions were decreased by overexpressed GNPNAT1, whilst GNPNAT1 knockdown ran conversely. Conclusion GNPNAT1 and methylated GNPNAT1 coverage are biomarkers for the diagnosis and prognosis of lung cancer.
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Affiliation(s)
- Peikun Ding
- Department of Thoracic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University
| | - Bin Peng
- Department of Thoracic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University
| | - Guofeng Li
- Department of Thoracic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University
| | - Xuefeng Sun
- Department of Thoracic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University
| | - Guangsuo Wang
- Department of Thoracic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University
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de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L, Dufour A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol Rev 2022; 74:712-768. [PMID: 35738680 DOI: 10.1124/pharmrev.121.000349] [Citation(s) in RCA: 201] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
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Affiliation(s)
- Luiz G N de Almeida
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Hayley Thode
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Yekta Eslambolchi
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sameeksha Chopra
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Daniel Young
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Sean Gill
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Laurent Devel
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
| | - Antoine Dufour
- Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
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Jiao L, Dong Q, Zhai W, Zhao W, Shi P, Wu Y, Zhou X, Gao Y. A PD-L1 and VEGFR2 dual targeted peptide and its combination with irradiation for cancer immunotherapy. Pharmacol Res 2022; 182:106343. [DOI: 10.1016/j.phrs.2022.106343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 06/03/2022] [Accepted: 07/01/2022] [Indexed: 10/17/2022]
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Near-Infrared-Emissive AIE Bioconjugates: Recent Advances and Perspectives. Molecules 2022; 27:molecules27123914. [PMID: 35745035 PMCID: PMC9229065 DOI: 10.3390/molecules27123914] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/13/2022] [Accepted: 06/16/2022] [Indexed: 02/04/2023] Open
Abstract
Near-infrared (NIR) fluorescence materials have exhibited formidable power in the field of biomedicine, benefiting from their merits of low autofluorescence background, reduced photon scattering, and deeper penetration depth. Fluorophores possessing planar conformation may confront the shortcomings of aggregation-caused quenching effects at the aggregate level. Fortunately, the concept of aggregation-induced emission (AIE) thoroughly reverses this dilemma. AIE bioconjugates referring to the combination of luminogens showing an AIE nature with biomolecules possessing specific functionalities are generated via the covalent conjugation between AIEgens and functional biological species, covering carbohydrates, peptides, proteins, DNA, and so on. This perfect integration breeds unique superiorities containing high brightness, good water solubility, versatile functionalities, and prominent biosafety. In this review, we summarize the recent progresses of NIR-emissive AIE bioconjugates focusing on their design principles and biomedical applications. Furthermore, a brief prospect of the challenges and opportunities of AIE bioconjugates for a wide range of biomedical applications is presented.
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Tune BXJ, Sim MS, Poh CL, Guad RM, Woon CK, Hazarika I, Das A, Gopinath SCB, Rajan M, Sekar M, Subramaniyan V, Fuloria NK, Fuloria S, Batumalaie K, Wu YS. Matrix Metalloproteinases in Chemoresistance: Regulatory Roles, Molecular Interactions, and Potential Inhibitors. JOURNAL OF ONCOLOGY 2022; 2022:3249766. [PMID: 35586209 PMCID: PMC9110224 DOI: 10.1155/2022/3249766] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 04/11/2022] [Accepted: 04/19/2022] [Indexed: 02/08/2023]
Abstract
Cancer is one of the major causes of death worldwide. Its treatments usually fail when the tumor has become malignant and metastasized. Metastasis is a key source of cancer recurrence, which often leads to resistance towards chemotherapeutic agents. Hence, most cancer-related deaths are linked to the occurrence of chemoresistance. Although chemoresistance can emerge through a multitude of mechanisms, chemoresistance and metastasis share a similar pathway, which is an epithelial-to-mesenchymal transition (EMT). Matrix metalloproteinases (MMPs), a class of zinc and calcium-chelated enzymes, are found to be key players in driving cancer migration and metastasis through EMT induction. The aim of this review is to discuss the regulatory roles and associated molecular mechanisms of specific MMPs in regulating chemoresistance, particularly EMT initiation and resistance to apoptosis. A brief presentation on their potential diagnostic and prognostic values was also deciphered. It also aimed to describe existing MMP inhibitors and the potential of utilizing other strategies to inhibit MMPs to reduce chemoresistance, such as upstream inhibition of MMP expressions and MMP-responsive nanomaterials to deliver drugs as well as epigenetic regulations. Hence, manipulation of MMP expression can be a powerful tool to aid in treating patients with chemo-resistant cancers. However, much still needs to be done to bring the solution from bench to bedside.
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Affiliation(s)
- Bernadette Xin Jie Tune
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Maw Shin Sim
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
| | - Rhanye Mac Guad
- Department of Biomedical Science and Therapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu, 88400 Sabah, Malaysia
| | - Choy Ker Woon
- Department of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, 47000 Selangor, Malaysia
| | - Iswar Hazarika
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Science, Guwahati 781017, India
| | - Anju Das
- Department of Pharmacology, Royal School of Pharmacy, Royal Global University, Guwahati 781035, India
| | - Subash C. B. Gopinath
- Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, 02600 Perlis, Malaysia
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, 01000 Perlis, Malaysia
| | - Mariappan Rajan
- Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh 30450, Perak, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Pharmacology, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor 42610, Malaysia
| | | | - Shivkanya Fuloria
- Faculty of Pharmacy, AIMST University, Semeling, Bedong, Kedah 08100, Malaysia
| | - Kalaivani Batumalaie
- Department of Biomedical Sciences, Faculty of Health Sciences, Asia Metropolitan University, 81750 Johor Bahru, Malaysia
| | - Yuan Seng Wu
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
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Bonafé GA, Boschiero MN, Sodré AR, Ziegler JV, Rocha T, Ortega MM. Natural Plant Compounds: Does Caffeine, Dipotassium Glycyrrhizinate, Curcumin, and Euphol Play Roles as Antitumoral Compounds in Glioblastoma Cell Lines? Front Neurol 2022; 12:784330. [PMID: 35300350 PMCID: PMC8923017 DOI: 10.3389/fneur.2021.784330] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/29/2021] [Indexed: 12/21/2022] Open
Abstract
Many plant-derived compounds are shown to be promising antitumor therapeutic agents by enhancing apoptosis-related pathways and cell cycle impairment in tumor cells, including glioblastoma (GBM) cell lines. We aimed to review four natural plant compounds effective in GBM cell lines as caffeine, dipotassium glycyrrhizinate (DPG), curcumin, and euphol. Furthermore, antitumoral effect of these plant compounds on GBM cell lines through microRNAs (miRs) modulation was investigated. However, only DPG and curcumin were found as effective on miR modulation. Caffeine arrests GBM cell cycle in G0/G1 phase by cyclin-dependent kinases (CDK) complex inhibition and by decreasing BCL-2 and increasing FOXO1 expression levels causing greater apoptotic activity. Caffeine can also directly inhibit IP3R3, p38 phosphorylation, and rho-associated protein kinase (ROCK), decreasing cell invasion and migration capacity or indirectly by inhibiting the tissue inhibitor metalloproteinase-1 (TIMP-1) and integrins β1 and β3, leading to lower matrix metalloproteinases, MMP-2 and MMP-9. DPG presents antitumoral effect in GBM cells related to nuclear factor kappa B (NF-κB) pathway suppression by IRAK2 and TRAF6-mediating miR-16 and miR-146a, respectively. More recently, it was observed that DPG upregulated miR-4443 and miR-3620, responsible for post-transcriptional inhibition of the NF-κB pathway by CD209 and TNC modulation, respectively leading to lower MMP-9 and migration capacity. Curcumin is able to increase miR-223-3p, miR-133a-3p, miR-181a-5p, miR-34a-5p, miR-30c-5p, and miR-1290 expression leading to serine or threonine kinase (AKT) pathway impairment and also it decreases miR-27a-5p, miR-221-3p, miR-21-5p, miR-125b-5p, and miR-151-3p expression causing p53-BCL2 pathway inhibition and consequently, cellular apoptosis. Interestingly, lower expression of miR-27a by curcumin action enhanced the C/EBP homologous protein(CHOP) expression, leading to paraptosis. Curcumin can inhibit miR-21 expression and consequently activate apoptosis through caspase 3 and death receptor (DR) 4 and 5 activation. Autophagy is controlled by the LC-3 protein that interacts with Atg family for the LC3-II formation and autophagy activation. Euphol can enhance LC3-II levels directly in GBM cells or inhibits tumor invasion and migration through PDK1 modulation.
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Affiliation(s)
- Gabriel Alves Bonafé
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University Medical School, São Paulo, Brazil
| | - Matheus Negri Boschiero
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University Medical School, São Paulo, Brazil
| | - André Rodrigues Sodré
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University Medical School, São Paulo, Brazil
| | | | - Thalita Rocha
- Postgraduate Program in Biomaterials and Regenerative Medicine, Faculty of Medical Sciences and Health, Pontifical Catholic University of São Paulo, São Paulo, Brazil
| | - Manoela Marques Ortega
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University Medical School, São Paulo, Brazil
- *Correspondence: Manoela Marques Ortega
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Zheng Y, Zhang W, Xu L, Zhou H, Yuan M, Xu H. Recent Progress in Understanding the Action of Natural Compounds at Novel Therapeutic Drug Targets for the Treatment of Liver Cancer. Front Oncol 2022; 11:795548. [PMID: 35155196 PMCID: PMC8825370 DOI: 10.3389/fonc.2021.795548] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/27/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the third most common cause of cancer-related death following lung and stomach cancers. As a highly lethal disease, liver cancer is diagnosed frequently in less developed countries. Natural compounds extracted from herbs, animals and natural materials have been adopted by traditional Chinese medicine (TCM) practices and reported to be effective in the development of new medications for the treatment of diseases. It is important to focus on the mechanisms of action of natural compounds against hepatocellular carcinoma (HCC), particularly in terms of cell cycle regulation, apoptosis induction, autophagy mediation and cell migration and invasion. In this review, we characterize novel representative natural compounds according to their pharmacologic effects based on recently published studies. The aim of this review is to summarize and explore novel therapeutic drug targets of natural compounds, which could accelerate the discovery of new anticancer drugs.
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Affiliation(s)
- Yannan Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Engineering Research Center of Shanghai Colleges for Traditional Chinese Medicine (TCM) New Drug Discovery, Shanghai, China
| | - Wenhui Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Engineering Research Center of Shanghai Colleges for Traditional Chinese Medicine (TCM) New Drug Discovery, Shanghai, China
| | - Lin Xu
- Engineering Research Center of Shanghai Colleges for Traditional Chinese Medicine (TCM) New Drug Discovery, Shanghai, China.,School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Hua Zhou
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Man Yuan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Engineering Research Center of Shanghai Colleges for Traditional Chinese Medicine (TCM) New Drug Discovery, Shanghai, China
| | - Hongxi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Cristi F, Gutiérrez T, Hitt MM, Shmulevitz M. Genetic Modifications That Expand Oncolytic Virus Potency. Front Mol Biosci 2022; 9:831091. [PMID: 35155581 PMCID: PMC8826539 DOI: 10.3389/fmolb.2022.831091] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/06/2022] [Indexed: 12/20/2022] Open
Abstract
Oncolytic viruses (OVs) are a promising type of cancer therapy since they selectively replicate in tumor cells without damaging healthy cells. Many oncolytic viruses have progressed to human clinical trials, however, their performance as monotherapy has not been as successful as expected. Importantly, recent literature suggests that the oncolytic potential of these viruses can be further increased by genetically modifying the viruses. In this review, we describe genetic modifications to OVs that improve their ability to kill tumor cells directly, to dismantle the tumor microenvironment, or to alter tumor cell signaling and enhance anti-tumor immunity. These advances are particularly important to increase virus spread and reduce metastasis, as demonstrated in animal models. Since metastasis is the principal cause of mortality in cancer patients, having OVs designed to target metastases could transform cancer therapy. The genetic alterations reported to date are only the beginning of all possible improvements to OVs. Modifications described here could be combined together, targeting multiple processes, or with other non-viral therapies with potential to provide a strong and lasting anti-tumor response in cancer patients.
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Affiliation(s)
- Francisca Cristi
- Shmulevitz Laboratory, Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Tomás Gutiérrez
- Goping Laboratory, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Mary M. Hitt
- Hitt Laboratory, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Mary M. Hitt, ; Maya Shmulevitz,
| | - Maya Shmulevitz
- Shmulevitz Laboratory, Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Mary M. Hitt, ; Maya Shmulevitz,
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Metformin as a Potential Treatment Option for Endometriosis. Cancers (Basel) 2022; 14:cancers14030577. [PMID: 35158846 PMCID: PMC8833654 DOI: 10.3390/cancers14030577] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/07/2022] [Accepted: 01/21/2022] [Indexed: 02/07/2023] Open
Abstract
Endometriosis is a common disease in women of reproductive age, and its pathogenesis seems to be largely affected by hormone imbalance, inflammation, oxidative stress, and autophagy dysregulation. These pathophysiological disturbances interact with one another through mechanisms that are still awaiting elucidation. The aim of this article is to present current knowledge regarding the possibilities of using metformin in the pharmacological treatment of endometriosis. Metformin is an insulin sensitizer widely used for the treatment of type 2 diabetes mellitus. The pleiotropic effects of metformin are mainly exerted through the activation of AMP-activated protein kinase, which is the key cellular energy homeostasis regulator that inhibits mTOR, a major autophagy suppressor. Metformin regresses endometriotic implants by increasing the activity of superoxide dismutase. It is also an inhibitor of metalloproteinase-2, decreasing the levels of the vascular endothelial growth factor and matrix metalloproteinase-9 in animal studies. In endometriosis, metformin might modify the stroma-epithelium communication via Wnt2/β-catenin. With its unique therapeutic mechanisms and no serious side effects, metformin seems to be a helpful anti-inflammatory and anti-proliferative agent in the treatment of endometriosis. It could be a missing link for the successful treatment of this chronic disease.
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Ratajczak-Wielgomas K, Kmiecik A, Dziegiel P. Role of Periostin Expression in Non-Small Cell Lung Cancer: Periostin Silencing Inhibits the Migration and Invasion of Lung Cancer Cells via Regulation of MMP-2 Expression. Int J Mol Sci 2022; 23:ijms23031240. [PMID: 35163164 PMCID: PMC8835752 DOI: 10.3390/ijms23031240] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 01/08/2023] Open
Abstract
The involvement of periostin (POSTN) in non-small-cell lung cancer (NSCLC) migration, invasion, and its underlying mechanisms has not been well established. The present study aims to determine epithelial POSTN expression in NSCLC and to assess associations with clinicopathological factors and prognosis as well as to explore the effects of POSTN knockdown on tumor microenvironment and the migration and invasion of lung cancer cells. Immunohistochemistry was used to evaluate epithelial POSTN expression in NSCLC. POSTN mRNA expression in the dissected lung cancer cells was confirmed by laser capture microdissection and real-time PCR. A549 cells were used for transfecting shRNA-POSTN lentiviral particles. Wound healing and Transwell invasion assays were used to assess the migratory and invasive abilities of A549 cells transfected with POSTN-specific short hairpin (sh)RNA. The results demonstrated significantly higher cytoplasmic POSTN expression in the whole NSCLC group compared to non-malignant lung tissue (NMLT). POSTN expression in cancer cells may be considered to be an independent prognostic factor for survival in NSCLC. POSTN knockdown significantly inhibited A549 cell migration and invasion capabilities in vitro. The activity and the expression level of matrix metalloproteinase-2 (MMP-2) were significantly decreased in A549.shRNA compared to control cells. In summary, POSTN may regulate lung cancer cell invasiveness by modulating the expression of MMP-2 and may represent a potential target for novel therapeutic intervention for NSCLC.
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Affiliation(s)
- Katarzyna Ratajczak-Wielgomas
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.K.); (P.D.)
- Correspondence: ; Tel.: +48-7-1784-1365; Fax: +48-7-1784-0082
| | - Alicja Kmiecik
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.K.); (P.D.)
| | - Piotr Dziegiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.K.); (P.D.)
- Department of Human Biology, Faculty of Physiotherapy, University School of Physical Education, 51-612 Wroclaw, Poland
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Fang P, Zhou J, Xia Z, Lu Y, Liu X. Effects of Propofol Versus Sevoflurane on Postoperative Breast Cancer Prognosis: A Narrative Review. Front Oncol 2022; 11:793093. [PMID: 35127500 PMCID: PMC8811129 DOI: 10.3389/fonc.2021.793093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 12/30/2021] [Indexed: 12/24/2022] Open
Abstract
Perioperative interventions produce substantial biologic perturbations which are associated with the risk of recurrence after cancer surgery. The changes of tumor microenvironment caused by anesthetic drugs received increasing attention. Till now, it’s still unclear whether or not anesthetic drugs may exert positive or negative impact on cancer outcomes after surgery. Breast cancer is the most common tumor and the leading cause of cancer deaths in women. Propofol and sevoflurane are respectively the most commonly used intravenous and inhaled anesthetics. Debates regarding which of the two most commonly used anesthetics may relatively contribute to the recurrence and metastasis vulnerability of breast cancer postoperatively remain. This review aimed to provide a comprehensive view about the effect of propofol versus sevoflurane on the prognosis of breast cancer obtained from pre-clinical studies and clinical studies. Laboratory and animal studies have demonstrated that sevoflurane may enhance the recurrence and metastasis of breast cancer, while propofol is more likely to reduce the activity of breast cancer cells by attenuating the suppression of the immune system, promoting tumor cells apoptosis, and through other direct anti-tumor effects. However, retrospective clinical studies have shown contradictory results about the effects of propofol and sevoflurane on long-term survival in breast cancer patients. Furthermore, recent prospective studies did not identify significant differences between propofol and sevoflurane in breast cancer metastasis and recurrence. Therefore, more preclinical studies and randomized controlled studies are needed to guide the choice of anesthetics for breast cancer patients.
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Affiliation(s)
- Panpan Fang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiaqi Zhou
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhengyuan Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Yao Lu, ; Zhengyuan Xia,
| | - Yao Lu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yao Lu, ; Zhengyuan Xia,
| | - Xuesheng Liu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Zhang X, Zheng Q, Wang Z, Xu C, Han H, Li A, Ma G, Li J, Lu C, Chen H, Zhang Z. Qualitative and Quantitative Analysis of Tumor Cell Invasion Using Au Clusters. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 12:145. [PMID: 35010094 PMCID: PMC8746878 DOI: 10.3390/nano12010145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/20/2021] [Accepted: 12/24/2021] [Indexed: 12/11/2022]
Abstract
Tumor invasion/metastasis is still the major cause of death in cancer patients. Membrane type-1 matrix metalloproteinase (MT1-MMP) is directly related to tumor invasion/metastasis. To accurately and quickly distinguish the risk of invasion/metastasis of primary tumor cells, it is urgent to develop a simple and precise quantitative method to distinguish the expression level of MT1-MMP. In this work, we have constructed red fluorescent Au clusters with peroxidase-like properties that could specifically bind to MT1-MMP on human cervical cancer cells. After MT1-MMP was labelled with Au clusters, we could visually see red fluorescence of MT1-MMP on cervical cancer cells via fluorescence microscopy and catalytic color imaging using an ordinary optical microscope. The constructed Au clusters contained 26 Au atoms; thus, the amount of MT1-MMP on cervical cancer cells could be accurately quantified using inductively coupled plasma mass spectrometry (ICP-MS). More importantly, the invasion/metastasis capabilities of the cervical cancer Siha, Caski and Hela cells with different MT1-MMP amounts could be accurately distinguished by fluorescence/catalysis qualitative imaging and ICP-MS quantitative analysis. This method of qualitative/quantitative analysis of tumor-associated proteins on cancer cells has great potential for accurately diagnosing aggressive tumor cells and assessment of their invasion/metastasis risk.
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Affiliation(s)
- Xiangchun Zhang
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Qinqin Zheng
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Ziqi Wang
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Chao Xu
- College of Chemistry and Material Science, Shandong Agricultural University, Taian 271018, China;
| | - Haolei Han
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Aiping Li
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Guicen Ma
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Jiaojiao Li
- Department of Chemistry and Biology, Faculty of Environment and Life Science, Beijing University of Technology, Beijing 100124, China;
| | - Chengyin Lu
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Hongping Chen
- Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China; (X.Z.); (Q.Z.); (Z.W.); (H.H.); (A.L.); (G.M.); (C.L.)
| | - Zhichao Zhang
- Department of Musculoskeletal Tumor, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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Tsai MT, Sun YS, Keerthi M, Panda AK, Dhawan U, Chang YH, Lai CF, Hsiao M, Wang HY, Chung RJ. Oral Cancer Theranostic Application of FeAu Bimetallic Nanoparticles Conjugated with MMP-1 Antibody. NANOMATERIALS 2021; 12:nano12010061. [PMID: 35010011 PMCID: PMC8746455 DOI: 10.3390/nano12010061] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 12/27/2022]
Abstract
Metastatic oral squamous cell carcinoma (SCC) displays a poor disease prognosis with a 5-year survival rate of 39%. Chemotherapy has emerged as the mainstream treatment against small clusters of cancer cells but poses more risks than benefits for metastatic cells due to the non-specificity and cytotoxicity. To overcome these obstacles, we conjugated antibodies specific for matrix metalloproteinase-1 (MMP-1), a prognostic biomarker of SCC, to iron–gold bimetallic nanoparticles (FeAu NPs) and explored the capability of this complex to target and limit SSC cell growth via magnetic field-induced hyperthermia. Our results showed that 4.32 ± 0.79 nm sized FeAu NPs were superparamagnetic in nature with a saturation magnetization (Ms) of 5.8 emu/g and elevated the media temperature to 45 °C, confirming the prospect to deliver hyperthermia. Furthermore, conjugation with MMP-1 antibodies resulted in a 3.07-fold higher uptake in HSC-3 (human tongue squamous cell carcinoma) cells as compared to L929 (fibroblast) cells, which translated to a 5-fold decrease in cell viability, confirming SCC targeting. Finally, upon magnetic stimulation, MMP-1-FeAu NPs conjugate triggered 89% HSC-3 cellular death, confirming the efficacy of antibody-conjugated nanoparticles in limiting SCC growth. The synergistic effect of biomarker-specific antibodies and magnetic nanoparticle-induced hyperthermia may open new doors towards SCC targeting for improved disease prognosis.
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Affiliation(s)
- Meng-Tsan Tsai
- Department of Electrical Engineering, Chang Gung University, 259, Wenhua 1st Rd., Taoyuan City 33302, Taiwan;
- Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou Branch, 5, Fuxing St., Guishan Dist., Taoyuan City 33305, Taiwan
| | - Ying-Sui Sun
- School of Dental Technology, College of Oral Medicine, Taipei Medical University, 250, Wu-Hsing St., Taipei 11031, Taiwan;
| | - Murugan Keerthi
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), 1, Sec. 3, Zhongxiao E. Rd., Taipei 10608, Taiwan; (M.K.); (A.K.P.); (Y.-H.C.)
| | - Asit Kumar Panda
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), 1, Sec. 3, Zhongxiao E. Rd., Taipei 10608, Taiwan; (M.K.); (A.K.P.); (Y.-H.C.)
| | - Udesh Dhawan
- Centre for the Cellular Microenvironment, University of Glasgow, Glasgow G12 8QQ, UK
- Correspondence: (U.D.); (H.-Y.W.); (R.-J.C.); Tel.: +886-2-8772-8701 or +886-2-2771-2171 (ext. 2547) (R.-J.C.); Fax: +886-2-2731-7117 (R.-J.C.)
| | - Yung-Hsiang Chang
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), 1, Sec. 3, Zhongxiao E. Rd., Taipei 10608, Taiwan; (M.K.); (A.K.P.); (Y.-H.C.)
| | - Chih-Fang Lai
- DFON Biomedical Technology Inc., 1, Sec. 3, Zhongxiao E. Rd., Taipei 10608, Taiwan;
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, 128, Sec. 2, Academia Rd., Nankang, Taipei 115, Taiwan;
- Department of Biochemistry, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Rd., Sanmin Dist., Kaohsiung City 80708, Taiwan
| | - Huey-Yuan Wang
- Department of Stomatology, MacKay Memorial Hospital, 92, Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan
- Correspondence: (U.D.); (H.-Y.W.); (R.-J.C.); Tel.: +886-2-8772-8701 or +886-2-2771-2171 (ext. 2547) (R.-J.C.); Fax: +886-2-2731-7117 (R.-J.C.)
| | - Ren-Jei Chung
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), 1, Sec. 3, Zhongxiao E. Rd., Taipei 10608, Taiwan; (M.K.); (A.K.P.); (Y.-H.C.)
- Correspondence: (U.D.); (H.-Y.W.); (R.-J.C.); Tel.: +886-2-8772-8701 or +886-2-2771-2171 (ext. 2547) (R.-J.C.); Fax: +886-2-2731-7117 (R.-J.C.)
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Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression. Int J Mol Sci 2021; 23:ijms23010146. [PMID: 35008569 PMCID: PMC8745566 DOI: 10.3390/ijms23010146] [Citation(s) in RCA: 223] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell-matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.
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Li CH, Ko JL, Hsiao YP, Tsai MH, Lai YC, Hsin IL, Kang YT, Sheu GT, Lin WL, Wu MF. Plasma Endoglin is Associated with Favorable Outcome for Pemetrexed-Based Therapy in Advanced Non-Small Cell Lung Cancer. Cancer Manag Res 2021; 13:9305-9318. [PMID: 35221721 PMCID: PMC8866988 DOI: 10.2147/cmar.s338957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 11/25/2021] [Indexed: 11/29/2022] Open
Abstract
Purpose Pemetrexed-based chemotherapy (Pem-C) is the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, limited tumor-associated proteins in blood are available to predict pemetrexed response and/or survival. Patients and Methods Plasma samples from three responders and three nonresponders with stage IIIB–IV NSCLC were collected prior to Pem-C and analyzed using Proteome ProfilerTM Human XL Oncology Array to detect 84 oncology-related proteins. The plasma concentrations of cathepsin S, endoglin (ENG), and matrix metalloproteinases 3 and 9 in 71 patients with advanced NSCLC treated with Pem-C were further measured using enzyme-linked immunosorbent assay based on the remarkable differences in the four proteins between responders and nonresponders in the array results. Results Pem-C responders had significantly higher ENG levels but not the other three markers than nonresponders (mean ENG level: 27.1 ± 7.4 vs 22.3 ± 6.9, p < 0.01). High ENG concentration was correlated with improved progression-free survival (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.31–0.86, p < 0.01) and overall survival (HR: 0.55, 95% CI: 0.32–0.94, p < 0.05) in patients treated with Pem-C, and the ENG level was an independent factor in our cohort (HR: 0.54, 95% CI: 0.33–0.89, p < 0.05). ENG concentration in Pem-C responders also significantly increased at the time of best response (p < 0.05). Conclusion Cumulatively, this study reveals that ENG is correlated with Pem-C responsiveness in patients, which indicates the potential use of plasma ENG levels as a non-invasive biomarker for pemetrexed-based treatment in patients with non-squamous NSCLC.
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Affiliation(s)
- Che-Hsing Li
- Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
- Graduate Program in Immunology & Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jiunn-Liang Ko
- Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
- CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 402, Taiwan
| | - Yu-Ping Hsiao
- Division of Dermatology, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
| | - Ming-Hung Tsai
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, 40447, Taiwan
| | - Yen-Chein Lai
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, 402, Taiwan
| | - I-Lun Hsin
- Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
- CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 402, Taiwan
| | - Yu-Ting Kang
- Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
- CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 402, Taiwan
| | - Gwo-Tarng Sheu
- Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
- CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 402, Taiwan
| | - Wea-Lung Lin
- School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
- Department of Pathology, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
| | - Ming-Fang Wu
- Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
- CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
- Correspondence: Ming-Fang Wu Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, 110, Sec. 1, Jianguo N. Road, Taichung, 40201, TaiwanTel +886-4-24739595#34711 Email
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Asif PJ, Longobardi C, Hahne M, Medema JP. The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis. Cancers (Basel) 2021; 13:4720. [PMID: 34572947 PMCID: PMC8472587 DOI: 10.3390/cancers13184720] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/13/2021] [Accepted: 09/18/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is crucial to understand the role of CAFs in this process. Colorectal cancer (CRC) is a heterogeneous disease and lethality is especially common in a subtype of CRC with high stromal infiltration. A key component of stroma is cancer-associated fibroblasts (CAFs). To provide new perspectives for research on CAFs and CAF-targeted therapeutics, especially in CRC, we discuss the mechanisms, crosstalk, and functions involved in CAF-mediated cancer invasion, metastasis, and protection. This summary can serve as a framework for future studies elucidating these roles of CAFs.
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Affiliation(s)
- Paris Jabeen Asif
- Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (P.J.A.); (C.L.)
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Ciro Longobardi
- Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (P.J.A.); (C.L.)
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Michael Hahne
- Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, 34090 Montpellier, France;
| | - Jan Paul Medema
- Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (P.J.A.); (C.L.)
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Targeting matrix metalloproteinase MMP3 greatly enhances oncolytic virus mediated tumor therapy. Transl Oncol 2021; 14:101221. [PMID: 34530193 PMCID: PMC8450250 DOI: 10.1016/j.tranon.2021.101221] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022] Open
Abstract
In cancer, the extracellular matrix is extensively remodeled during chronic inflammation, thus affecting cell transcription, differentiation, migration and cell-cell interactions. Matrix metalloproteinases can degrade the extracellular matrix of tumor tissues and take important roles in disease progression. Numerous efforts to develop cancer treatments targeting matrix metalloproteinases have failed in clinical trials owing to the ineffectiveness and toxicity of the applied inhibitors. In this study, we investigated the potential of targeting matrix metalloproteinases and oncolytic virus combination in cancer therapy. We found that MMP3 expression was upregulated in various cancers and MMP3 expression in the tumor cells, but not in other tissues, was important for tumor growth and metastasis. Single treatment of colon cancer with multiple MMP3 inhibitors was not effective in mice. Nevertheless, the therapeutic effect of MMP3 was greatly improved by combination with an oncolytic virus. A potential mechanism of MMP3 in regulating tumor cell proliferation and invasion was mediated via Erk1/2 an NF-κB signaling. This study reveals that MMP3 is a promising target and the combined treatment with oncolytic virus is a potential strategy for cancer therapy.
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Rahman F, Nguyen TM, Adekoya OA, Campestre C, Tortorella P, Sylte I, Winberg JO. Inhibition of bacterial and human zinc-metalloproteases by bisphosphonate- and catechol-containing compounds. J Enzyme Inhib Med Chem 2021; 36:819-830. [PMID: 33757387 PMCID: PMC7993378 DOI: 10.1080/14756366.2021.1901088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Compounds containg catechol or bisphosphonate were tested as inhibitors of the zinc metalloproteases, thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) which are bacterial virulence factors, and the human matrix metalloproteases MMP-9 and -14. Inhibition of virulence is a putative strategy in the development of antibacterial drugs, but the inhibitors should not interfere with human enzymes. Docking indicated that the inhibitors bound MMP-9 and MMP-14 with the phenyl, biphenyl, chlorophenyl, nitrophenyl or methoxyphenyl ringsystem in the S1'-subpocket, while these ringsystems entered the S2'- or S1 -subpockets or a region involving amino acids in the S1'- and S2'-subpockets of the bacterial enzymes. An arginine conserved among the bacterial enzymes seemed to hinder entrance deeply into the S1'-subpocket. Only the bisphosphonate containing compound RC2 bound stronger to PLN and TLN than to MMP-9 and MMP-14. Docking indicated that the reason was that the conserved arginine (R203 in TLN and R198 in PLN) interacts with phosphate groups of RC2.
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Affiliation(s)
- Fatema Rahman
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Tra-Mi Nguyen
- Department of Pharmacy, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Olayiwola A Adekoya
- Department of Pharmacy, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Cristina Campestre
- Department of Pharmacy, University of "G. d'Annunzio" Chieti, Chieti, Italy
| | - Paolo Tortorella
- Department of Pharmacy, Science of Pharmacy, University "A. Moro" Bari, Bari, Italy
| | - Ingebrigt Sylte
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Jan-Olof Winberg
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
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Ngema LM, Adeyemi SA, Marimuthu T, Choonara YE. A review on engineered magnetic nanoparticles in Non-Small-Cell lung carcinoma targeted therapy. Int J Pharm 2021; 606:120870. [PMID: 34245844 DOI: 10.1016/j.ijpharm.2021.120870] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023]
Abstract
There are growing appeals forthe design of efficacious treatment options for non-small-cell lung carcinoma (NSCLC) as it accrues to ~ 85% cases of lung cancer. Although platinum-based doublet chemotherapy has been the main therapeutic intervention in NSCLC management, this leads to myriad of problems including intolerability to the doublet regimens and detrimental side effects due to high doses. A new approach is therefore needed and warrants the design of targeted drug delivery systems that can halt tumor proliferation and metastasis by targeting key molecules, while exhibiting minimal side effects and toxicity. This review aims to explore the rational design of magnetic nanoparticles for the development of tumor-targeting systems for NSCLC. In the review, we explore the anticancer merits of conjugated linoleic acid (CLA) and provide a concise incursion into its application for the invention of functionalized magnetic nanoparticles in the targeted treatment of NSCLC. Recent nanoparticle-based targeted chemotherapies for targeting angiogenesis biomarkers in NSCLC will also be reviewed to further highlight versatility of magnetic nanoparticles. These developments through molecular tuning at the nanoscale and supported by comprehensive pre-clinical studies could lead to the establishment of precise nanosystems for tumor-homing cancer therapy.
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Affiliation(s)
- Lindokuhle M Ngema
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Samson A Adeyemi
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Thashree Marimuthu
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Yahya E Choonara
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa.
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Nano-Strategies Targeting the Integrin αvβ3 Network for Cancer Therapy. Cells 2021; 10:cells10071684. [PMID: 34359854 PMCID: PMC8307885 DOI: 10.3390/cells10071684] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Integrin αvβ3, a cell surface receptor, participates in signaling transduction pathways in cancer cell proliferation and metastasis. Several ligands bind to integrin αvβ3 to regulate proliferation and metastasis in cancer cells. Crosstalk between the integrin and other signal transduction pathways also plays an important role in modulating cancer proliferation. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) activates the downstream integrin FAK to stimulate biological activities including cancer proliferation and metastasis. Blockage of signals related to integrin αvβ3 was shown to be a promising target for cancer therapies. 3,3′,5,5′-tetraiodothyroacetic acid (tetrac) completely binds to the integrin with the thyroid hormone to suppress cancer proliferation. The (E)-stilbene analog, resveratrol, also binds to integrin αvβ3 to inhibit cancer growth. Recently, nanotechnologies have been used in the biomedical field for detection and therapeutic purposes. In the current review, we show and evaluate the potentiation of the nanomaterial carrier RGD peptide, derivatives of PLGA-tetrac (NDAT), and nanoresveratrol targeting integrin αvβ3 in cancer therapies.
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Mir MA, Mehraj U, Sheikh BA. Recent Advances in Chemotherapeutic Implications of Deguelin: A Plant-Derived Retinoid. ACTA ACUST UNITED AC 2021. [DOI: 10.2174/2210315510666200128125950] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Deguelin, a plant retinoid has emerged to be a promising therapeutic agent in the treatment
of different cancers. Recent studies demonstrate that deguelin has potential as an angiogenesis
antagonist in malignant and endothelial cells by specifically targeting HGF-c-Met and VEGFVEGFR
pathways. It is reported to have profound therapeutic effects in pancreatic cancer by inactivation
of the hedgehog (Hh) signalling pathway and suppresses the expression of matrix metalloproteinases
such as MMP-2 and MMP-9. The basic underlying mechanisms for deguelin mediated anti-
NSCLC effects were uncovered through its induction of elevated intracellular Reactive Oxygen Species
(ROS) levels and suppression of the PI3K /Akt-HK2 signalling pathway. Deguelin induces cell
apoptosis by targeting various pathways most notably regulating the expression of galectin-1 and
binding directly to anti-apoptotic Bcl-2 (B-cell lymphoma 2), Bcl-xl (B-cell lymphoma-extralarge)
and Mcl-1 (Myeloid Cell Leukemia Sequence 1) in the hydrophobic grooves thereby liberating BAD
and BAX from binding with these proteins. These results derived from the effect of Deguelin on various
cancer cell lines have further elucidated its role as a novel anti-tumorigenic agent targeting angiogenesis,
apoptosis, cell proliferation and migration for cancer chemoprevention. In this review, an
attempt has been made to highlight the potential therapeutic effects of Deguelin in destroying the
cancer cells by inhibiting various tumour promoting pathways and its uses as a therapeutic agent
alone or in combination.
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Affiliation(s)
- Manzoor A. Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Umar Mehraj
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Bashir A. Sheikh
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
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Vallée A, Vallée JN, Le Blanche A, Lecarpentier Y. PPARγ Agonists: Emergent Therapy in Endometriosis. Pharmaceuticals (Basel) 2021; 14:ph14060543. [PMID: 34204039 PMCID: PMC8229142 DOI: 10.3390/ph14060543] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/31/2021] [Accepted: 06/04/2021] [Indexed: 01/01/2023] Open
Abstract
Endometriosis is one of the major gynecological diseases of reproductive-age women. This disease is characterized by the presence of glands and stroma outside the uterine cavity. Several studies have shown the major role of inflammation, angiogenesis, adhesion and invasion, and apoptosis in endometriotic lesions. Nevertheless, the mechanisms underlying endometriotic mechanisms still remain unclear and therapies are not currently efficient. The introduction of new agents can be effective by improving the condition of patients. PPARγ ligands can directly modulate these pathways in endometriosis. However, data in humans remain low. Thus, the purpose of this review is to summarize the potential actions of PPARγ agonists in endometriosis by acting on inflammation, angiogenesis, invasion, adhesion, and apoptosis.
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Affiliation(s)
- Alexandre Vallée
- Department of Clinical Research and Innovation (DRCI), Foch Hospital, 92150 Suresnes, France
- Correspondence:
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, Université Picardie Jules Verne (UPJV), 80000 Amiens, France;
- DACTIM-Mis, Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, 86000 Poitiers, France
| | - Alain Le Blanche
- Laboratoire CeRSM (EA-2931), UPL, Université Paris Nanterre, F92000 Nanterre, France;
- Hôpital René-Dubos de Pontoise and Université de Versailles-Saint-Quentin, Simone Veil UFR des Sciences de la Santé, 78180 Montigny-le-Bretonneux, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l’Est Francilien (GHEF), 77100 Meaux, France;
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Lorenzo-Gómez R, Miranda-Castro R, de-Los-Santos-Álvarez N, Lobo-Castañón MJ. Bioanalytical methods for circulating extracellular matrix-related proteins: new opportunities in cancer diagnosis. Anal Bioanal Chem 2021; 414:147-165. [PMID: 34091712 DOI: 10.1007/s00216-021-03416-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/15/2021] [Accepted: 05/18/2021] [Indexed: 01/16/2023]
Abstract
The role of the extracellular matrix (ECM) remodeling in tumorigenesis and metastasis is becoming increasingly clear. Cancer development requires that tumor cells recruit a tumor microenvironment permissive for further tumor growth. This is a dynamic process that takes place by a cross-talk between tumor cells and ECM. As a consequence, molecules derived from the ECM changes associated to cancer are released into the bloodstream, representing potential biomarkers of tumor development. This article highlights the importance of developing and improving bioanalytical methods for the detection of ECM remodeling-derived components, as a step forward to translate the basic knowledge about cancer progression into the clinical practice.
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Affiliation(s)
- Ramón Lorenzo-Gómez
- Departamento de Química Física y Analítica, Universidad de Oviedo, Av. Julián Clavería 8, 33006, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, Avenida de Roma, 33011, Oviedo, Spain
| | - Rebeca Miranda-Castro
- Departamento de Química Física y Analítica, Universidad de Oviedo, Av. Julián Clavería 8, 33006, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, Avenida de Roma, 33011, Oviedo, Spain
| | - Noemí de-Los-Santos-Álvarez
- Departamento de Química Física y Analítica, Universidad de Oviedo, Av. Julián Clavería 8, 33006, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, Avenida de Roma, 33011, Oviedo, Spain
| | - María Jesús Lobo-Castañón
- Departamento de Química Física y Analítica, Universidad de Oviedo, Av. Julián Clavería 8, 33006, Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias, Avenida de Roma, 33011, Oviedo, Spain.
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Soheilifar MH, Masoudi-Khoram N, Madadi S, Nobari S, Maadi H, Keshmiri Neghab H, Amini R, Pishnamazi M. Angioregulatory microRNAs in breast cancer: Molecular mechanistic basis and implications for therapeutic strategies. J Adv Res 2021; 37:235-253. [PMID: 35499045 PMCID: PMC9039675 DOI: 10.1016/j.jare.2021.06.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/13/2021] [Accepted: 06/23/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer-associated angiogenesis is a fundamental process in tumor growth and metastasis. Angioregulatory miRNA–target gene interaction is not only involved in sprouting vessels of breast tumors but also, trans-differentiation of breast cancer cells to endothelial cells in a process termed vasculogenic mimicry. Successful targeting of tumor angiogenesis is still a missing link in the treatment of Breast cancer (BC) due to the low effectiveness of anti-angiogenic therapies in this cancer. Response to anti-angiogenic therapeutics are controlled by a miRNAs, so the identification of interaction networks of miRNAs–targets can be applicable in determining anti-angiogeneic therapy and new biomarkers in BC. Angioregulatory miRNAs in breast cancer cells and their microenvironment have therapeutic potential in cancer treatment. Background Cancer-associated angiogenesis is a fundamental process in tumor growth and metastasis. A variety of signaling regulators and pathways contribute to establish neovascularization, among them as small endogenous non-coding RNAs, microRNAs (miRNAs) play prominent dual regulatory function in breast cancer (BC) angiogenesis. Aim of Review This review aims at describing the current state-of-the-art in BC angiogenesis-mediated by angioregulatory miRNAs, and an overview of miRNAs dysregulation association with the anti-angiogenic response in addition to potential clinical application of miRNAs-based therapeutics. Key Scientific Concepts of Review Angioregulatory miRNA–target gene interaction is not only involved in sprouting vessels of breast tumors but also, trans-differentiation of BC cells to endothelial cells (ECs) in a process termed vasculogenic mimicry. Using canonical and non-canonical angiogenesis pathways, the tumor cell employs the oncogenic characteristics such as miRNAs dysregulation to increase survival, proliferation, oxygen and nutrient supply, and treatment resistance. Angioregulatory miRNAs in BC cells and their microenvironment have therapeutic potential in cancer treatment. Although, miRNAs dysregulation can serve as tumor biomarker nevertheless, due to the association of miRNAs dysregulation with anti-angiogenic resistant phenotype, clinical benefits of anti-angiogenic therapy might be challenging in BC. Hence, unveiling the molecular mechanism underlying angioregulatory miRNAs sparked a booming interest in finding new treatment strategies such as miRNA-based therapies in BC.
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Affiliation(s)
- Mohammad Hasan Soheilifar
- Department of Medical Laser, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Corresponding authorsat: Yara Institute, Academic Center for Education, Culture and Research (ACECR), Enghelab St, Tehran 1315795613, Iran (Mohammad Hasan Soheilifar). University of Limerick, Limerick V94 T9PX, Ireland (Mahboubeh Pishnamazi).
| | - Nastaran Masoudi-Khoram
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Soheil Madadi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sima Nobari
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Maadi
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Hoda Keshmiri Neghab
- Department of Photo Healing and Regeneration, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran
| | - Razieh Amini
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahboubeh Pishnamazi
- Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland
- Corresponding authorsat: Yara Institute, Academic Center for Education, Culture and Research (ACECR), Enghelab St, Tehran 1315795613, Iran (Mohammad Hasan Soheilifar). University of Limerick, Limerick V94 T9PX, Ireland (Mahboubeh Pishnamazi).
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Estaras M, Gonzalez-Portillo MR, Fernandez-Bermejo M, Mateos JM, Vara D, Blanco-Fernandez G, Lopez-Guerra D, Roncero V, Salido GM, González A. Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia. Int J Mol Sci 2021; 22:5555. [PMID: 34074034 PMCID: PMC8197391 DOI: 10.3390/ijms22115555] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 02/06/2023] Open
Abstract
In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM-1 µM) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2α and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of α-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.
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Affiliation(s)
- Matias Estaras
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
| | - Manuel R. Gonzalez-Portillo
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
| | - Miguel Fernandez-Bermejo
- Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain; (M.F.-B.); (J.M.M.); (D.V.)
| | - Jose M. Mateos
- Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain; (M.F.-B.); (J.M.M.); (D.V.)
| | - Daniel Vara
- Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain; (M.F.-B.); (J.M.M.); (D.V.)
| | - Gerardo Blanco-Fernandez
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, University Hospital, 06080 Badajoz, Spain; (G.B.-F.); (D.L.-G.)
| | - Diego Lopez-Guerra
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, University Hospital, 06080 Badajoz, Spain; (G.B.-F.); (D.L.-G.)
| | - Vicente Roncero
- Unit of Histology and Pathological Anatomy, Veterinary Faculty, University of Extremadura, 10003 Caceres, Spain;
| | - Gines M. Salido
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
| | - Antonio González
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
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