|
1
|
Zhang F, Wang T, Wang W, Lv Y, Qu Y, Liu D, Sun X, Kong X, Wang C, Shi J. ZnO colludes with C. acnes in healing delay and Scar hyperplasia by barrier destruction. J Nanobiotechnology 2025; 23:404. [PMID: 40450290 DOI: 10.1186/s12951-025-03414-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 04/23/2025] [Indexed: 06/03/2025] Open
Abstract
As an important component of sunscreen products for sensitive skin, the potential damage mechanism of ZnO nanoparticles on skin surface with barrier structure or function defect caused by Cutibacterium acnes (C. acnes) has not been elucidated, which poses a serious challenge for reasonable selection of sunscreen products for acne-infected skin. In this work, we demonstrated for the first time that C. acnes induced significant changes in the membrane permeability and intracellular pH of fibroblasts through lipase up-regulation and lipid peroxidation, promoting endocytosis and ionization of ZnO NPs. High amounts of Zn2 + further delayed acne wound healing and aggravated scar hyperplasia by intervening matrix metalloproteinase-9 (MMP-9) and TGF-β1/Smad pathway. MMP9 was confirmed to be the key target of ZnO in delaying acne wound healing by the wound regulatory effects of MMP9 agonist and MMP9 inhibitor. In summary, this work clarified the interaction mechanism between ZnO NPs and acne skins, providing guideline for the application of physical sunscreens for special skins.
Collapse
Affiliation(s)
- Fenglan Zhang
- Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, China
- College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266100, China
| | - Tianyi Wang
- College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266100, China
| | - Wenqiao Wang
- Department of Medicine, Qingdao University, Qingdao, 266071, China
| | - Yaqian Lv
- School of Veterinary Medicine, Qingdao Agricultural University, Qingdao, 266109, China
| | - Yingshan Qu
- School of Veterinary Medicine, Qingdao Agricultural University, Qingdao, 266109, China
| | - Danping Liu
- School of Veterinary Medicine, Qingdao Agricultural University, Qingdao, 266109, China
| | - Xiaoyue Sun
- Talent Beauty Biotech (Qingdao) Co., Ltd, 330 Songling Road, Laoshan District, Qingdao, 266061, China
| | - Xiaoying Kong
- Institute of Regenerative Medicine and Laboratory Technology Innovation, Qingdao University, Qingdao, 266071, China.
| | - Changyuan Wang
- Department of Dermatology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266071, China.
| | - Jinsheng Shi
- Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, China.
| |
Collapse
|
|
2
|
Otsuka T, Sato K, Kamiya T, Tanaka H, Hara H. Zinc treatment prevents IgE-mediated Ca 2+ influx and allergic response in RBL-2H3 cells. Eur J Pharmacol 2025; 994:177391. [PMID: 39971226 DOI: 10.1016/j.ejphar.2025.177391] [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: 10/17/2024] [Revised: 01/17/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
Zinc (Zn) is an essential metal in the body. It binds to many proteins and regulates their functions. In the immune system, it is known that administration of ZnSO4 suppresses T cell activation, but its effects on allergies are still unknown. In this study, we investigated the effects of ZnSO4 administration on allergic reactions using the rat basophilic leukemia cell line, RBL-2H3. ZnSO4 treatment inhibited cell degranulation induced by antigen and IgE stimulation, as well as by A23187, a Ca2+ ionophore. Antigen and IgE stimulation increased mRNA expression of IL-4, IL-13, and COX-2, and ZnSO4 treatment inhibited this expression. The elevation of intracellular Zn concentration and depletion of Zn did not affect degranulation. Phosphorylation of the proteins spleen tyrosine kinase, p38, ERK1/2, JNK, and Akt was increased by antigen stimulation, but ZnSO4 treatment did not inhibit this phosphorylation. ZnSO4 treatment inhibited the elevation of intracellular Ca2+ concentration induced by antigen and IgE stimulation, as well as by A23187. Additionally, ZnSO4 treatment inhibited thapsigargin, a store-operated Ca2+ entry stimulant, from inducing degranulation and increasing intracellular Ca2+ concentration. These data indicate that exogenous Zn2+ possesses a preventive effect on RBL-2H3 activation via inhibition of Ca2+ influx. The effect of Zn may involve Ca2+ release-activated channels. This study suggests that ZnSO4 treatment is valuable in suppressing allergic responses.
Collapse
Affiliation(s)
- Tomohiro Otsuka
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
| | - Kaho Sato
- Laboratory of Immunobiology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
| | - Tetsuro Kamiya
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
| | - Hiroyuki Tanaka
- Laboratory of Immunobiology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan; Medical Science Division, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; Center for One Medicine Innovation Translational Research (COMIT), Institute for Advanced Study, Gifu University, Gifu, Japan.
| | - Hirokazu Hara
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
| |
Collapse
|
|
3
|
Higuera M, Vargas-Accarino E, Torrens M, Bermúdez-Ramos M, Soriano-Varela A, Salcedo MT, Mínguez B. Impact of zinc on hepatocellular carcinoma cell behavior and metallothionein expression: Insights from preclinical models. Biomed Pharmacother 2025; 185:117918. [PMID: 40048869 DOI: 10.1016/j.biopha.2025.117918] [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: 10/03/2024] [Revised: 02/10/2025] [Accepted: 02/14/2025] [Indexed: 03/23/2025] Open
Abstract
BACKGROUND Zinc (Zn) is an essential trace element involved in a wide variety of cellular processes and is vital for optimal liver function. Our objective was to elucidate the potential therapeutic role of Zn in hepatocellular carcinoma (HCC), the third leading cause of cancer-related death and the first cause of death in patients with cirrhosis. METHODS The impact of Zn supplementation on proliferation, invasion, migration, cell cycle, and apoptosis was conducted on four HCC cell lines as well as in a xenograft mouse model of HCC from which tumor gene expression profiles were also analyzed. Gene deregulation and protein expression were validated in human HCC tissues. Finally, Zn and MT1 (Metallothionein 1) levels were quantified in plasma from patients with HCC. RESULTS Zn supplementation significantly modulated proliferation, invasion, and migration in HCC cell lines and induced apoptosis in a dose-dependent manner. Although Zn did not exhibit a significant increase in survival, Zn supplementation significantly altered the expression of MT genes. Specifically, MT1G and MT1H expression were notably suppressed in HCC tissues from mice and these results were validated in human HCC samples. Overall, gene and protein MTs expression was significantly lower in HCC areas compared to adjacent liver tissue and plasma Zn levels exhibited substantial variation across different stages of the liver disease. CONCLUSION Zn supplementation influences key cellular behaviors in a dose-dependent manner and upregulates the expression of MT family genes, which may have tumor-suppressive properties, in vitro an in vivo models. Future research should investigate the prognostic implications of Zn supplementation as part of a comprehensive therapeutic strategy for HCC patients.
Collapse
Affiliation(s)
- Mónica Higuera
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| | - Elena Vargas-Accarino
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - María Torrens
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Liver Unit, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| | - María Bermúdez-Ramos
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Agnès Soriano-Varela
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Liver Unit, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| | - María Teresa Salcedo
- Pathology Department, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Instituto de salud Carlos III, Madrid, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus de la UAB, Plaça Cívica, Bellaterra 08193, Spain.
| | - Beatriz Mínguez
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus de la UAB, Plaça Cívica, Bellaterra 08193, Spain.
| |
Collapse
|
|
4
|
GUJARAN TANVIVIJAY, EASWARAN VIGNESHBALAJI, SANKHE RUNALI, BAKTHAVATCHALAM PUGAZHANDHI, DSOUZA HERMANSUNIL, PAI KSREEDHARARANGANATH. Ketogenic diet with oxyresveratrol and zinc inhibits glioblastoma and restores memory function and motor coordination. Oncol Res 2025; 33:381-395. [PMID: 39866236 PMCID: PMC11753998 DOI: 10.32604/or.2024.049538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 06/13/2024] [Indexed: 01/28/2025] Open
Abstract
Background To date, there is no effective cure for the highly malignant brain tumor glioblastoma (GBM). GBM is the most common, aggressive central nervous system tumor (CNS). It commonly originates in glial cells such as microglia, oligodendroglia, astrocytes, or subpopulations of cancer stem cells (CSCs). Glucose plays an important role in the, which energy metabolism of normal and cancer cells, but cancer cells exhibit an increased demand for glucose is required for their differentiation and proliferation. The main aim of this study is to explore the anti-cancer efficacy of the ketogenic diet against GBM. Also, this research focuses on the identification of the catalytic action of zinc in epigenetic modulators such as oxyresveratrol and ensures the combinatorial effect in the treatment of GBM. Method In this study, we have evaluated various parameters to understand the therapeutic efficacy of the treatment groups through in vivo experiments against aggressive brain tumors. Intracerebroventricular experiments were performed to induce the tumor in the animals and estimate the tumor burden and proliferative index. Followed by the Morris water maze, an open field test, and rota rod was performed to evaluate the memory and motor coordination. To understand the glucose, and ketone level modification before and after treatment, the level of glucose and ketone was analyzed. Moreover, the zinc level is assessed using flame atomic absorption spectroscopy. Results The results suggested that the ketogenic diet has an anti-cancer efficacy against C6-induced GBM cell lines. Also, it exerts a synergistic effect with the epigenetic modulator, oxyresveratrol, and zinc against GBM cell lines. Moreover, the treatment groups improved memory and motor coordination and modified the glucose and ketone levels to reduce the tumor burden and Ki-67 proliferative index. Conclusion This study revealed the therapeutic effect of the ketogenic diet along with its combination such as oxyresveratrol and zinc against the C6-induced GBM in the Wistar rats. Also, it improved memory and motor coordination and reduced tumor growth. It also modified the glucose and ketone levels in the tumor-induced animal and supported to diminish the tumor burden.
Collapse
Affiliation(s)
- TANVI VIJAY GUJARAN
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - VIGNESH BALAJI EASWARAN
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - RUNALI SANKHE
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - PUGAZHANDHI BAKTHAVATCHALAM
- Division of Anatomy, Department of Basic Medical Science, Manipal Academy of Higher Education, Manipal, 576104, India
- Department of Anatomy and Physiology, American University of Antigua, University Park, Antigua, W1451, West Indies
| | - HERMAN SUNIL DSOUZA
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - K. SREEDHARA RANGANATH PAI
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| |
Collapse
|
|
5
|
Wang L, Ni C, Zhang K, Yang Y, Chen R, Lou X, Yan Y, Li K, Dong Y, Yao X, Wan J, Duan X, Wang F, Li Y, Qin Z. Chelating drug-induced labile Zn 2+ with nanoparticle-encapsulated TPEN at low dose enhances lung cancer chemotherapy through inhibiting ABCB1. iScience 2024; 27:111072. [PMID: 39507258 PMCID: PMC11539588 DOI: 10.1016/j.isci.2024.111072] [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: 04/28/2024] [Revised: 08/06/2024] [Accepted: 09/26/2024] [Indexed: 11/08/2024] Open
Abstract
Chemotherapy resistance is still a great challenge for clinical treatment of lung cancer. Here, we found that doxorubicin (DOX) induced an increase of labile Zn2+ in lung cancer cells, and these labile Zn2+ protected tumor cells against DOX cytotoxicity. Nanoparticles encapsulating N,N,N',N'-Tetrakis (2-pyridylmethyl)-ethylenediamine (TPEN) were then constructed to chelate labile Zn2+ for tumor therapy. Application of nanoparticle-encapsulated TPEN at low dose not only avoided severe side effects caused by removing physiological Zn2+ but also effectively chelated drug-induced labile Zn2+, and thereby enhanced DOX cytotoxicity. Mechanistically, nanosized TPEN inhibits ABCB1-mediated drug export potentiated by drug-induced labile Zn2+. Finally, the results unraveled that nanosized TPEN at low dose endowed DOX with the killing ability on resistant tumor cells. Taken together, our results demonstrate that chelating drug-induced labile Zn2+ by nanosized TPEN at low dose enhances lung cancer chemotherapy by inhibiting ABCB1, providing a feasible strategy to overcome chemoresistance in lung cancer.
Collapse
Affiliation(s)
- Linlin Wang
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Chen Ni
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Kaili Zhang
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yuanyuan Yang
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ruoyang Chen
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaohan Lou
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yan Yan
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Kexin Li
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ya Dong
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaohan Yao
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jiajia Wan
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xixi Duan
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Fazhan Wang
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - YongJuan Li
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
- The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Zhihai Qin
- Medical Research Center, Henan China–Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China
| |
Collapse
|
|
6
|
Liang F, Sun S, Zhou Y, Peng T, Xu X, Li B, Tan G. Escherichia coli alcohol dehydrogenase YahK is a protein that binds both iron and zinc. PeerJ 2024; 12:e18040. [PMID: 39282118 PMCID: PMC11397123 DOI: 10.7717/peerj.18040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 08/13/2024] [Indexed: 09/18/2024] Open
Abstract
Background Previous studies have highlighted the catalytic activity of Escherichia coli alcohol dehydrogenase YahK in the presence of coenzyme nicotinamide adenine dinucleotide (NAD) and metal zinc. Notably, competitive interaction between iron and zinc ligands has been shown to influence the catalytic efficiency of several key proteases. This study aims to unravel the intricate mechanisms underlying YahK's catalytic action, with a particular focus on the pivotal roles played by metal ions zinc and iron. Methods The purified YahK protein from E. coli cells cultivated in LB medium was utilized to investigate its metal-binding properties through UV-visible absorption measurements and determination of metal content. Subsequently, the effects of excess zinc and iron on the metal-binding ability and alcohol dehydrogenase activity of the YahK protein were explored using M9 minimal medium. Furthermore, site-directed mutagenesis technology was employed to determine the iron-binding site location within the YahK protein. Polyacrylamide gel electrophoresis was conducted to examine the relationship between iron and zinc with respect to the YahK protein. Results The study confirmed the presence of iron and zinc in the YahK protein, with the zinc-bound form exhibiting enhanced catalytic activity in alcohol dehydrogenation reactions. Conversely, the presence of iron appears to play a pivotal role in maintaining overall stability of the YahK protein. Furthermore, experimental findings indicate that excessive zinc within M9 minimal medium can competitively bind to iron-binding sites on YahK, thereby augmenting its alcohol dehydrogenase activity. Conclusion The dynamic binding of YahK to iron and zinc unveils its intricate regulatory mechanism as an alcohol dehydrogenase, thereby highlighting the possible physiological role of YahK in E. coli and its significance in governing cellular metabolic processes. This discovery provides a novel perspective for further investigating the specific impact of metal ion binding on YahK and E. coli cell metabolism.
Collapse
Affiliation(s)
- Feng Liang
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, Zhejiang, China
| | - Shujuan Sun
- Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Medicine, Linyi University, Linyi, Shandong, China
| | - YongGuang Zhou
- Laboratory of Molecular Medicine, Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tiantian Peng
- Laboratory of Molecular Medicine, Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xianxian Xu
- Laboratory of Molecular Medicine, Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Beibei Li
- Laboratory of Molecular Medicine, Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guoqiang Tan
- Laboratory of Molecular Medicine, Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| |
Collapse
|
|
7
|
Li D, Bao X, Lei S, Cao W, Zeng Z, Chen T. Identification of Clinical Value and Biological Effects of XIRP2 Mutation in Hepatocellular Carcinoma. BIOLOGY 2024; 13:633. [PMID: 39194571 DOI: 10.3390/biology13080633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/29/2024]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignant digestive tumor. Numerous genetic mutations have been documented in HCC, yet the clinical significance of these mutations remains largely unexplored. The objective of this study is to ascertain the clinical value and biological effects of xin actin binding repeat containing 2 (XIRP2) mutation in HCC. The gene mutation landscape of HCC was examined using data from the Cancer Genome Atlas and the International Cancer Genome Consortium databases. The prognostic significance of the XIRP2 mutation was assessed through KM plot analysis. The association between drug sensitivity and the XIRP2 mutation was investigated using the TIDE algorithm and CCK-8 experiments. The biological effects of the XIRP2 mutation were evaluated through qRT-PCR, protein stability experiments, and relevant biological experiments. The XIRP2 mutation is one of the high-frequency mutations in HCC, and is associated with poor prognosis. A total of 72 differentially expressed genes (DEGs) were observed in HCC tissues with the XIRP2 mutation as compared to those with the XIRP2 wildtype, and these DEGs were closely related to ion metabolic processes. The XIRP2 mutation was linked to alterations in the sensitivity of fludarabine, oxaliplatin, WEHI-539, and LCL-161. CCK-8 assays demonstrated that HCC cells carrying the XIRP2 mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the XIRP2 wildtype. The XIRP2 mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of XIRP2 resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the XIRP2 mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin.
Collapse
Affiliation(s)
- Dahuan Li
- Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang 550025, China
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China
| | - Xin Bao
- Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang 550025, China
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China
| | - Shan Lei
- Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang 550025, China
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China
| | - Wenpeng Cao
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China
| | - Zhirui Zeng
- Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang 550025, China
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China
| | - Tengxiang Chen
- Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang 550025, China
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China
| |
Collapse
|
|
8
|
Kubo Y, Igaue S, Utsunomiya D, Kubo K, Kurita D, Ishiyama K, Oguma J, Daiko H. Association between preoperative serum zinc level and prognosis in patients with advanced esophageal cancer in the neoadjuvant treatment era. Ann Gastroenterol Surg 2024; 8:595-603. [PMID: 38957556 PMCID: PMC11216781 DOI: 10.1002/ags3.12781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 07/04/2024] Open
Abstract
Background Zinc (Zn), an essential trace element, has an adverse influence on the prognosis of several cancers. However, the association between the preoperative serum Zn level and outcomes in patients with advanced esophageal cancer in the current neoadjuvant treatment era remains unclear. Methods This study involved 185 patients with esophageal cancer who underwent R0 surgery after neoadjuvant chemotherapy from August 2017 to February 2021. We retrospectively investigated the relationship between the preoperative serum Zn level and the patients' outcomes. Results The patients were divided into a low Zn group (<64 μg/dL) and a high Zn group (≤64 μg/dL) according to the mean preoperative serum Zn level. Low Zn had significantly worse overall survival (OS) (2-year OS rate: 76.2% vs. 83.3% in low vs. high Zn; p = 0.044). A low Zn in pathological non-responders (Grade ≤ 1a) was significantly associated with a shorter 2-year recurrence-free survival (RFS) rate (39.6% vs. 64.1% in low vs. high Zn; p = 0.032). The multivariate analysis identified low BMI and Zn level among preoperative nutritional status indices as an independent risk factor for worse RFS in non-responders. Compared with responders, pathological non-responders comprised significantly more males and a performance status of ≥1, and there was no difference in Zn level according to pathological response. Conclusion A preoperative low Zn level had a negative impact on early recurrence in esophageal cancer patients who underwent neoadjuvant chemotherapy. This suggests the need to administer Zn supplementation to patients with esophageal cancer who have preoperative Zn deficiency.
Collapse
Affiliation(s)
- Yuto Kubo
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Shota Igaue
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Daichi Utsunomiya
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Kentaro Kubo
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Daisuke Kurita
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Koshiro Ishiyama
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Junya Oguma
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Hiroyuki Daiko
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| |
Collapse
|
|
9
|
Vaghari-Tabari M, Jafari-Gharabaghlou D, Mohammadi M, Hashemzadeh MS. Zinc Oxide Nanoparticles and Cancer Chemotherapy: Helpful Tools for Enhancing Chemo-sensitivity and Reducing Side Effects? Biol Trace Elem Res 2024; 202:1878-1900. [PMID: 37639166 DOI: 10.1007/s12011-023-03803-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/05/2023] [Indexed: 08/29/2023]
Abstract
Cancer chemotherapy is still a serious challenge. Chemo-resistance and destructive side effects of chemotherapy drugs are the most critical limitations of chemotherapy. Chemo-resistance is the leading cause of chemotherapy failure. Chemo-resistance, which refers to the resistance of cancer cells to the anticancer effects of chemotherapy drugs, is caused by various reasons. Among the most important of these reasons is the increase in the efflux of chemotherapy drugs due to the rise in the expression and activity of ABC transporters, the weakening of apoptosis, and the strengthening of stemness. In the last decade, a significant number of studies focused on the application of nanotechnology in cancer treatment. Considering the anti-cancer properties of zinc, zinc oxide nanoparticles have received much attention in recent years. Some studies have indicated that zinc oxide nanoparticles can target the critical mechanisms of cancer chemo-resistance and enhance the effectiveness of chemotherapy drugs. These studies have shown that zinc oxide nanoparticles can reduce the activity of ABC transporters, increase DNA damage and apoptosis, and attenuate stemness in cancer cells, leading to enhanced chemo-sensitivity. Some other studies have also shown that zinc oxide nanoparticles in low doses can be helpful in minimizing the harmful side effects of chemotherapy drugs. In this article, after a brief overview of the mechanisms of chemo-resistance and anticancer effects of zinc, we will review all these studies in detail.
Collapse
Affiliation(s)
- Mostafa Vaghari-Tabari
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davoud Jafari-Gharabaghlou
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mozafar Mohammadi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
10
|
Luan M, Feng Z, Zhu W, Xing Y, Ma X, Zhu J, Wang Y, Jia Y. Mechanism of metal ion-induced cell death in gastrointestinal cancer. Biomed Pharmacother 2024; 174:116574. [PMID: 38593706 DOI: 10.1016/j.biopha.2024.116574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/26/2024] [Accepted: 04/05/2024] [Indexed: 04/11/2024] Open
Abstract
Gastrointestinal (GI) cancer is one of the most severe types of cancer, with a significant impact on human health worldwide. Due to the urgent demand for more effective therapeutic strategies against GI cancers, novel research on metal ions for treating GI cancers has attracted increasing attention. Currently, with accumulating research on the relationship between metal ions and cancer therapy, several metal ions have been discovered to induce cell death. In particular, the three novel modes of cell death, including ferroptosis, cuproptosis, and calcicoptosis, have become focal points of research in the field of cancer. Meanwhile, other metal ions have also been found to trigger cell death through various mechanisms. Accordingly, this review focuses on the mechanisms of metal ion-induced cell death in GI cancers, hoping to provide theoretical support for further GI cancer therapies.
Collapse
Affiliation(s)
- Muhua Luan
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China; Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Zhaotian Feng
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China; Department of Medical Laboratory, Weifang Medical University, Weifang 261053, People's Republic of China
| | - Wenshuai Zhu
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Yuanxin Xing
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Xiaoli Ma
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Jingyu Zhu
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Yunshan Wang
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China; Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Yanfei Jia
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China; Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China; Department of Medical Laboratory, Weifang Medical University, Weifang 261053, People's Republic of China.
| |
Collapse
|
|
11
|
Yang P, Li H, Sun M, Guo X, Liao Y, Hu M, Ye P, Liu R. Zinc deficiency drives ferroptosis resistance by lactate production in esophageal squamous cell carcinoma. Free Radic Biol Med 2024; 213:512-522. [PMID: 38301975 DOI: 10.1016/j.freeradbiomed.2024.01.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/18/2024] [Accepted: 01/23/2024] [Indexed: 02/03/2024]
Abstract
Trace metal zinc is involved in key processes of solid tumors by its antioxidant properties, while the role of zinc at the onset of esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to determine whether zinc is associated with the ESCC and underlying molecular events involving malignant progression. Based on a case-control study, we found serum and urine zinc were decreased and correlated with ESCC progression. Thus, an in vitro model for zinc deficiency (ZD) was established, and we found that ZD contributed to the proliferation, migration, and invasion of EC109 cells. Untargeted metabolomics identified 59 upregulated metabolites and 6 downregulated metabolites, among which glycolysis and ferroptosis-related oxidation of chain fatty acids might play crucial steps in ZD-treated molecular events. Interestingly, ZD disrupted redox homeostasis and enhanced cytosolic Fe2+ of EC109 cells, while lipid peroxidation, the key marker of ferroptosis occurrence, was decreased after ZD treatment. The mechanism underlying these changes may involve ZD-enhanced ESCC glycolysis and lactate production, which confer ferroptosis resistance by inhibiting of p-AMPK and leading to the upregulation of SREBP1 and SCD1 to enhance the production of anti-ferroptosis monounsaturated fatty acids.
Collapse
Affiliation(s)
- Peiyan Yang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Hui Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Mingjun Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Xinxin Guo
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Yinghao Liao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Mohan Hu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Ping Ye
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China.
| |
Collapse
|
|
12
|
Mignen O, Vannier JP, Schneider P, Renaudineau Y, Abdoul-Azize S. Orai1 Ca 2+ channel modulators as therapeutic tools for treating cancer: Emerging evidence! Biochem Pharmacol 2024; 219:115955. [PMID: 38040093 DOI: 10.1016/j.bcp.2023.115955] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/25/2023] [Accepted: 11/28/2023] [Indexed: 12/03/2023]
Abstract
In non-excitable cells, Orai proteins represent the main channel for Store-Operated Calcium Entry (SOCE), and also mediate various store-independent Calcium Entry (SICE) pathways. Deregulation of these pathways contribute to increased tumor cell proliferation, migration, metastasis, and angiogenesis. Among Orais, Orai1 is an attractive therapeutic target explaining the development of specific modulators. Therapeutic trials using Orai1 channel inhibitors have been evaluated for treating diverse diseases such as psoriasis and acute pancreatitis, and emerging data suggest that Orai1 channel modulators may be beneficial for cancer treatment. This review discusses herein the importance of Orai1 channel modulators as potential therapeutic tools and the added value of these modulators for treating cancer.
Collapse
Affiliation(s)
| | | | | | - Yves Renaudineau
- Laboratory of Immunology, CHU Purpan Toulouse, INSERM U1291, CNRS U5051, University Toulouse III, 31062 Toulouse, France
| | - Souleymane Abdoul-Azize
- LBAI, UMR1227, Univ Brest, Inserm, Brest, France; Normandie Univ., UNIROUEN, INSERM, U1234, Rouen 76000, France.
| |
Collapse
|
|
13
|
Zhang L, Sunchen S, Lu C, Xu F, Dong H. Zinc-sensing receptor activation induces endothelium-dependent hyperpolarization-mediated vasorelaxation of arterioles. Biochem Pharmacol 2024; 219:115961. [PMID: 38049010 DOI: 10.1016/j.bcp.2023.115961] [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: 10/23/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/06/2023]
Abstract
BACKGROUND The micronutrient zinc (Zn2+) is critical for cell function as intracellular signaling and endogenous ligand for Zn2+ sensing receptor (ZnR). Although cytosolic Zn2+ (cyt) signaling in the vascular system was studied previously, role of the ZnR has not been explored in vascular physiology. METHODS ZnR-mediated relaxation response of human submucosal arterioles and the mesenteric arterioles from wide-type (WT), ZnR-/- and TRPV4-/- mice were determined by a Mulvany-style wire myograph. The perfused vessel density (PVD) of mouse mesenteric arterioles was also measured in in vivo study. The expression of ZnR in arterioles and vascular endothelial cells (VEC) were examined by immunofluorescence staining, and its function was characterized in VEC by Ca2+ imaging and patch clamp study. RESULTS ZnR expression was detected on human submucosal arterioles, murine mesenteric arterioles and VEC but not in ZnR-/- mice. ZnR activation predominately induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of arterioles in vitro and in vivo via Ca2+ signaling, which is totally different from endothelium-dependent vasorelaxation via Zn2+ (cyt) signaling reported previously. Furthermore, ZnR-induced vasorelaxation via EDH was significantly impaired in ZnR-/- and TRPV4-/- mice. Mechanistically, ZnR induced endothelium-dependent vasorelaxation predominately via PLC/IP3/IP3R and TRPV4/SOCE. The role of ZnR in regulating Ca2+ signaling and ion channels on VEC was verified by Ca2+ imaging and patch clamp techniques. CONCLUSION ZnR activation induces endothelium-dependent vasorelaxation of resistance vessels predominately via TRPV4/Ca2+/EDH pathway. We therefore not only provide new insights into physiological role of ZnR in vascular system but also may pave a potential pathway for developing Zn2+-based treatments for vascular disease.
Collapse
Affiliation(s)
- Luyun Zhang
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400037, China; Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Sijin Sunchen
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Cheng Lu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Feng Xu
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400037, China.
| | - Hui Dong
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400037, China; Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China.
| |
Collapse
|
|
14
|
Kirk H, Tufuor TA, Shaver AL, Nie J, Devarshi PP, Marshall K, Mitmesser SH, Noyes K. The association of the Affordable Care Act with nutrient consumption in adults in the United States. Front Public Health 2023; 11:1244042. [PMID: 38186698 PMCID: PMC10768893 DOI: 10.3389/fpubh.2023.1244042] [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: 06/21/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
The Patient Protection and Affordable Care Act, more commonly known as the ACA, was legislation passed in the United States in 2010 to expand access to health insurance coverage for millions of Americans with a key emphasis on preventive care. Nutrition plays a critical role in overall wellness, disease prevention and resilience to chronic illness but prior to the ACA many Americans did not have adequate health insurance coverage to ensure proper nutrition. With passage of the ACA, more individuals received access to nutritional counseling through their primary care physicians as well as prescription vitamins and supplements free of charge. The objective of this study was to evaluate the impact of a national health insurance reform on nutrient intake among general population, including more vulnerable low-income individuals and patients with chronic conditions. Using data from the National Health and Nutrition Examination Survey (NHANES), we identified 8,443 adults aged 21 years and older who participated in the survey before (2011-2012) and after the ACA (2015-2016) implementation and conducted a subgroup analysis of 952 respondents who identified as Medicaid beneficiaries and 719 patients with a history of cancer. Using pre-post study design and bivariate and multivariable logistic analyses, we compared nutrient intake from food and supplementation before and after the ACA and identified risk factors for inadequate intake. Our results suggest that intake of micronutrients found in nutrient-dense foods, mainly fruit and vegetables, has not changed significantly after the ACA. However, overall use of nutritional supplements increased after the ACA (p = 0.05), particularly magnesium (OR = 1.02), potassium (OR = 0.76), vitamin D (both D2, and D3, OR = 1.34), vitamin K (OR = 1.15) and zinc (OR = 0.83), for the general population as well as those in our subgroup analysis Cancer Survivors and Medicaid Recipients. Given the association of increased use of nutritional supplements and expansion of insurance access, particularly in our subgroup analysis, more research is necessary to understand the effect of increasing access to nutritional supplements on the overall intake of micro- and macronutrients to meet daily nutritional recommended allowances.
Collapse
Affiliation(s)
- Hilary Kirk
- Division of Health Services Policy and Practice, Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, United States
| | - Theresa A. Tufuor
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, United States
| | - Amy L. Shaver
- Division of Health Services Policy and Practice, Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, United States
| | - Jing Nie
- Division of Health Services Policy and Practice, Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, United States
| | | | | | | | - Katia Noyes
- Division of Health Services Policy and Practice, Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, United States
| |
Collapse
|
|
15
|
Terrell K, Choi S, Choi S. Calcium's Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions. Int J Mol Sci 2023; 24:17034. [PMID: 38069357 PMCID: PMC10706910 DOI: 10.3390/ijms242317034] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/16/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Calcium research, since its pivotal discovery in the early 1800s through the heating of limestone, has led to the identification of its multi-functional roles. These include its functions as a reducing agent in chemical processes, structural properties in shells and bones, and significant role in cells relating to this review: cellular signaling. Calcium signaling involves the movement of calcium ions within or between cells, which can affect the electrochemical gradients between intra- and extracellular membranes, ligand binding, enzyme activity, and other mechanisms that determine cell fate. Calcium signaling in muscle, as elucidated by the sliding filament model, plays a significant role in muscle contraction. However, as organisms age, alterations occur within muscle tissue. These changes include sarcopenia, loss of neuromuscular junctions, and changes in mineral concentration, all of which have implications for calcium's role. Additionally, a field of study that has gained recent attention, cellular senescence, is associated with aging and disturbed calcium homeostasis, and is thought to affect sarcopenia progression. Changes seen in calcium upon aging may also be influenced by its crosstalk with other minerals such as iron and zinc. This review investigates the role of calcium signaling in aging muscle and cellular senescence. We also aim to elucidate the interactions among calcium, iron, and zinc across various cells and conditions, ultimately deepening our understanding of calcium signaling in muscle aging.
Collapse
Affiliation(s)
| | | | - Sangyong Choi
- Department of Nutritional Sciences, College of Agriculture, Health, and Natural Resources, University of Connecticut, Storrs, CT 06269, USA
| |
Collapse
|
|
16
|
Lu G, Jia Z, Yu M, Zhang M, Xu C. A Ratiometric Fluorescent Sensor Based on Chelation-Enhanced Fluorescence of Carbon Dots for Zinc Ion Detection. Molecules 2023; 28:7818. [PMID: 38067546 PMCID: PMC10708225 DOI: 10.3390/molecules28237818] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/18/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Zinc ion, one of the most important transition metal ions in living organisms, plays a crucial role in the homeostasis of the organism. The disorder of zinc is associated with many major diseases. It is highly desirable to develop selective and sensitive methods for the real-time detection of zinc ions. In this work, double-emitting fluorescent carbon dots (CDs) are prepared by a solvothermal method using glutathione, L-aspartic acid, and formamide as the raw materials. The carbon dots specifically recognize zine ions and produce a decrease in fluorescence intensity at 684 nm and an increase at 649 nm, leading to a ratiometric fluorescent sensor for zinc detection. Through surface modification and spectral analysis, the surface groups including carboxyl, carbonyl, hydroxyl, and amino groups, and C=N in heterocycles of CDs are revealed to synergistically coordinate Zn2+, inducing the structural changes in the emission site. The CDs can afford a low limit of detection of ~5 nM for Zn2+ detection with good linearity in the range of 0.02-5 μM, showing good selectivity as well. The results from real samples including fetal bovine serum, milk powder, and zinc gluconate oral solution indicated the good applicability of the CDs in the determination of Zn2+.
Collapse
Affiliation(s)
- Guangrong Lu
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, China;
| | - Zhenzhen Jia
- School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China; (Z.J.); (M.Y.)
| | - Mengdi Yu
- School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China; (Z.J.); (M.Y.)
| | - Mingzhen Zhang
- School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China; (Z.J.); (M.Y.)
| | - Changlong Xu
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, China;
| |
Collapse
|
|
17
|
Zhao H, Liu R, Wang L, Tang F, Chen W, Liu YN. Artificial Macrophage with Hierarchical Nanostructure for Biomimetic Reconstruction of Antitumor Immunity. NANO-MICRO LETTERS 2023; 15:216. [PMID: 37737506 PMCID: PMC10516848 DOI: 10.1007/s40820-023-01193-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 08/27/2023] [Indexed: 09/23/2023]
Abstract
Artificial cells are constructed from synthetic materials to imitate the biological functions of natural cells. By virtue of nanoengineering techniques, artificial cells with designed biomimetic functions provide alternatives to natural cells, showing vast potential for biomedical applications. Especially in cancer treatment, the deficiency of immunoactive macrophages results in tumor progression and immune resistance. To overcome the limitation, a BaSO4@ZIF-8/transferrin (TRF) nanomacrophage (NMΦ) is herein constructed as an alternative to immunoactive macrophages. Alike to natural immunoactive macrophages, NMΦ is stably retained in tumors through the specific affinity of TRF to tumor cells. Zn2+ as an "artificial cytokine" is then released from the ZIF-8 layer of NMΦ under tumor microenvironment. Similar as proinflammatory cytokines, Zn2+ can trigger cell anoikis to expose tumor antigens, which are selectively captured by the BaSO4 cavities. Therefore, the hierarchical nanostructure of NMΦs allows them to mediate immunogenic death of tumor cells and subsequent antigen capture for T cell activation to fabricate long-term antitumor immunity. As a proof-of-concept, the NMΦ mimics the biological functions of macrophage, including tumor residence, cytokine release, antigen capture and immune activation, which is hopeful to provide a paradigm for the design and biomedical applications of artificial cells.
Collapse
Affiliation(s)
- Henan Zhao
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, Hunan, People's Republic of China
| | - Renyu Liu
- Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Liqiang Wang
- Henan Province Industrial Technology Research Institute of Resources and Materials, School of Material Science and Engineering, Zhengzhou University, Zhengzhou, 450001, Henan, People's Republic of China
| | - Feiying Tang
- College of Chemical Engineering, Xiangtan University, Xiangtan, 411105, Hunan, People's Republic of China
| | - Wansong Chen
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, Hunan, People's Republic of China.
| | - You-Nian Liu
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, Hunan, People's Republic of China.
| |
Collapse
|
|
18
|
Wyrich M, Ohlig H, Wessolly M, Mairinger E, Steinborn J, Brcic L, Hegedus B, Hager T, Greimelmaier K, Wohlschlaeger J, Mairinger FD, Borchert S. Induction of metallothionein expression by supplementation of zinc induces resistance against platinum-based treatment in malignant pleural mesothelioma. Transl Cancer Res 2023; 12:1929-1936. [PMID: 37701096 PMCID: PMC10493783 DOI: 10.21037/tcr-22-2651] [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: 11/18/2022] [Accepted: 05/11/2023] [Indexed: 09/14/2023]
Abstract
Background Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Currently, multimodality treatment including chemotherapy with cisplatin or carboplatin in combination with pemetrexed offers the best options. Detoxification of heavy metals in the cell by metallothioneins (MT) is associated with early failure to platin-based chemotherapy. The induction of MTs gene expression or its enzyme results in saturation by exposure to metal ions such as zinc or cadmium. Its therapeutically effect is still not analyzed in depth. Methods In our study, we investigated three MPM cell lines and one fibroblast cell line in the course of cisplatin treatment and supplementation of zinc. Cell state analyses via an enzyme-activity based assay were performed. With this, we were able to analyze apoptosis, necrosis and viability of cells. Additionally, we tested treated cells for changes in metallothionein IIA (MT2A) expression by using quantitative realtime polymerase chain reaction. Results Zinc supplementation induces gene expression of MT2A. Overall, a zinc dose-dependent induction of apoptosis under platin-based treatment could be observed. This effect could be verified in all analyzed cell lines in varying intensity. Conclusions MT expression is induced by zinc in a dose-dependent manner and inhibits a successful cisplatin therapy. Therefore, heavy metal exposure during cisplatin therapy, e.g., via cigarette smoke, might be an important factor. This should be considered in further therapeutic approaches.
Collapse
Affiliation(s)
- Martine Wyrich
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Henning Ohlig
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michael Wessolly
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Elena Mairinger
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | | | - Luka Brcic
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Balazs Hegedus
- Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Thoracic Surgery and Thoracic Endoscopy, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Thomas Hager
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany
| | | | - Jeremias Wohlschlaeger
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany
| | - Fabian D. Mairinger
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Sabrina Borchert
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| |
Collapse
|
|
19
|
Li Y, Song R, Zhao J, Liu Y, Zhao J. Synthesis, structure, and properties of a novel naphthalene-derived fluorescent probe for the detection of Zn2+. Polyhedron 2023; 234:116336. [DOI: 10.1016/j.poly.2023.116336] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
|
|
20
|
Yang K, Wang X, Song C, He Z, Wang R, Xu Y, Jiang G, Wan Y, Mei J, Mao W. The role of lipid metabolic reprogramming in tumor microenvironment. Theranostics 2023; 13:1774-1808. [PMID: 37064872 PMCID: PMC10091885 DOI: 10.7150/thno.82920] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/07/2023] [Indexed: 04/18/2023] Open
Abstract
Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.
Collapse
Affiliation(s)
- Kai Yang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaokun Wang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Chenghu Song
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Zhao He
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Ruixin Wang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yongrui Xu
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Guanyu Jiang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yuan Wan
- The Pq Laboratory of BiomeDx/Rx, Department of Biomedical Engineering, Binghamton University, Binghamton 13850, USA
| | - Jie Mei
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Wenjun Mao
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| |
Collapse
|
|
21
|
Aziz MN, Nguyen L, Chang Y, Gout D, Pan Z, Lovely CJ. Novel thiazolidines of potential anti-proliferation properties against esophageal squamous cell carcinoma via ERK pathway. Eur J Med Chem 2023; 246:114909. [PMID: 36508971 DOI: 10.1016/j.ejmech.2022.114909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 11/25/2022]
Abstract
The discovery of a new class of extracellular-signal-regulated kinase (ERK) inhibitors has been achieved via developing novel 2-imino-5-arylidene-thiazolidine analogues. A novel synthetic method employing a solid support-mediated reaction was used to construct the targeted thiazolidines through a cascade reaction with good yields. The chemical and physical stability of the new thiazolidine library has successfully been achieved by blocking the labile C5-position to aerobic oxidation. A cell viability study was performed using esophageal squamous cell carcinoma cell lines (KYSE-30 and KYSE-150) and non-tumorous esophageal epithelial cell lines (HET-1A and NES-G4T) through utilization of an MTT assay, revealing that (Z)-5-((Z)-4-bromobenzylidene)-N-(4-methoxy-2-nitrophenyl)-4,4-dimethylthiazolidin-2-imine (6g) was the best compound among the synthesized library in terms of selectivity. DAPI staining experiments were performed to visualize the morphological changes and to investigate the apoptotic activity. Moreover, western blots were used to probe the mechanism/pathway behind the observed activity/selectivity of thiazolidine 6g which established selective inhibition of phosphorylation in the ERK pathway. Molecular modeling techniques have been utilized to confirm the observed activity. A molecular docking study revealed similar binding interactions between the synthesized thiazolidines and reported co-crystalized inhibitors with ERK proteins. Thus, the present study provides a starting point for the development of interesting bioactive 2-imino-5-arylidene-thiazolidines.
Collapse
Affiliation(s)
- Marian N Aziz
- Department of Chemistry and Biochemistry, 700 Planetarium Place, University of Texas at Arlington, TX, 76019, USA; Department of Pesticide Chemistry, National Research Centre, Dokki, Giza, 12622, Egypt
| | - Linh Nguyen
- Dept. of Biology, College of Science, University of Texas at Arlington, TX, 76019, USA; Department of Graduate Nursing, College of Nursing and Health Innovation, University of Texas at Arlington, TX, 76019, USA
| | - Yan Chang
- Department of Graduate Nursing, College of Nursing and Health Innovation, University of Texas at Arlington, TX, 76019, USA; Bone and Muscle Research Center, University of Texas at Arlington, TX, 76019, USA
| | - Delphine Gout
- Department of Chemistry and Biochemistry, 700 Planetarium Place, University of Texas at Arlington, TX, 76019, USA
| | - Zui Pan
- Department of Graduate Nursing, College of Nursing and Health Innovation, University of Texas at Arlington, TX, 76019, USA; Bone and Muscle Research Center, University of Texas at Arlington, TX, 76019, USA
| | - Carl J Lovely
- Department of Chemistry and Biochemistry, 700 Planetarium Place, University of Texas at Arlington, TX, 76019, USA.
| |
Collapse
|
|
22
|
Yang X, Tang Z, Li J, Jiang J. Esophagus cancer and essential trace elements. Front Public Health 2022; 10:1038153. [PMID: 36466456 PMCID: PMC9709130 DOI: 10.3389/fpubh.2022.1038153] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Numerous epidemiological and laboratory studies on essential trace elements have reported protective associations in developing various cancer types, including esophagus cancer (EC). However, the results are not always consistent. Some essential trace elements could play a vital role in preventing esophagus cancer. Some showed no association with esophageal cancer risk, while others harmed individuals. This article reviews the association between the intake or supplementation of essential trace elements (especially zinc, copper, iron, and selenium) and the risk of esophageal cancer. Generally, zinc intake may decrease the risk of esophageal cancer (EC), especially in high esophageal squamous cell carcinoma (ESCC) prevalence regions. The association between copper supplementation and EC remains uncertain. Total iron consumption is thought to be associated with lower EC risk, while heme iron intake may be associated with higher EC risk. Selenium intake showed a protective effect against EC, especially for those individuals with a low baseline selenium level. This review also prospects the research direction of the association between EC and essential trace elements.
Collapse
Affiliation(s)
- Xin Yang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhe Tang
- Department of Thoracic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Li
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizong Jiang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Jizong Jiang
| |
Collapse
|
|
23
|
Gao D, Asghar S, Hu R, Chen S, Niu R, Liu J, Chen Z, Xiao Y. Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy. Acta Pharm Sin B 2022; 13:1498-1521. [PMID: 37139410 PMCID: PMC10149905 DOI: 10.1016/j.apsb.2022.11.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/26/2022] [Accepted: 11/04/2022] [Indexed: 11/18/2022] Open
Abstract
Gas therapy has been proven to be a promising and advantageous treatment option for cancers. Studies have shown that nitric oxide (NO) is one of the smallest structurally significant gas molecules with great potential to suppress cancer. However, there is controversy and concern about its use as it exhibits the opposite physiological effects based on its levels in the tumor. Therefore, the anti-cancer mechanism of NO is the key to cancer treatment, and rationally designed NO delivery systems are crucial to the success of NO biomedical applications. This review summarizes the endogenous production of NO, its physiological mechanisms of action, the application of NO in cancer treatment, and nano-delivery systems for delivering NO donors. Moreover, it briefly reviews challenges in delivering NO from different nanoparticles and the issues associated with its combination treatment strategies. The advantages and challenges of various NO delivery platforms are recapitulated for possible transformation into clinical applications.
Collapse
Affiliation(s)
- Dan Gao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Sajid Asghar
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Rongfeng Hu
- Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei 230012, China
| | - Su Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Ruixin Niu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Jia Liu
- Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin 214499, China
- Corresponding authors. Tel./fax: +86 510 86700000 (Jia Liu); +86 25 85811050 (Zhipeng Chen); +86 25 83271079 (Yanyu Xiao).
| | - Zhipeng Chen
- Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Corresponding authors. Tel./fax: +86 510 86700000 (Jia Liu); +86 25 85811050 (Zhipeng Chen); +86 25 83271079 (Yanyu Xiao).
| | - Yanyu Xiao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 510 86700000 (Jia Liu); +86 25 85811050 (Zhipeng Chen); +86 25 83271079 (Yanyu Xiao).
| |
Collapse
|
|
24
|
Upper Gastrointestinal Cancer and Liver Cirrhosis. Cancers (Basel) 2022; 14:cancers14092269. [PMID: 35565397 PMCID: PMC9105927 DOI: 10.3390/cancers14092269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary There is a higher incidence rate of upper gastrointestinal cancer in those with liver cirrhosis. The contributing factors include gastric ulcers, congestive gastropathy, zinc deficiency, alcohol drinking, tobacco use and gut microbiota. Most of the de novo malignancies that develop after liver transplantation for cirrhotic patients are upper gastrointestinal cancers. The surgical risk of upper gastrointestinal cancers in cirrhotic patients with advanced liver cirrhosis is higher. Abstract The extended scope of upper gastrointestinal cancer can include esophageal cancer, gastric cancer and pancreatic cancer. A higher incidence rate of gastric cancer and esophageal cancer in patients with liver cirrhosis has been reported. It is attributable to four possible causes which exist in cirrhotic patients, including a higher prevalence of gastric ulcers and congestive gastropathy, zinc deficiency, alcohol drinking and tobacco use and coexisting gut microbiota. Helicobacter pylori infection enhances the development of gastric cancer. In addition, Helicobacter pylori, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans also contribute to the development of pancreatic cancer in cirrhotic patients. Cirrhotic patients (especially those with alcoholic liver cirrhosis) who undergo liver transplantation have a higher overall risk of developing de novo malignancies. Most de novo malignancies are upper gastrointestinal malignancies. The prognosis is usually poor. Considering the surgical risk of upper gastrointestinal cancer among those with liver cirrhosis, a radical gastrectomy with D1 or D2 lymph node dissection can be undertaken in Child class A patients. D1 lymph node dissection can be performed in Child class B patients. Endoscopic submucosal dissection for gastric cancer or esophageal cancer can be undertaken safely in selected cirrhotic patients. In Child class C patients, a radical gastrectomy is potentially fatal. Pancreatic radical surgery should be avoided in those with liver cirrhosis with Child class B or a MELD score over 15. The current review focuses on the recent reports on some factors in liver cirrhosis that contribute to the development of upper gastrointestinal cancer. Quitting alcohol drinking and tobacco use is important. How to decrease the risk of the development of gastrointestinal cancer in those with liver cirrhosis remains a challenging problem.
Collapse
|
|
25
|
Reddy SS, Addi UR, Pullakhandam R, Reddy GB. Dietary Zinc deficiency disrupts skeletal muscle proteostasis and mitochondrial biology in rats. Nutrition 2022; 98:111625. [DOI: 10.1016/j.nut.2022.111625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/30/2021] [Accepted: 01/27/2022] [Indexed: 10/19/2022]
|
|
26
|
Kang Y, Li Z, Lu F, Su Z, Ji X, Zhang S. Synthesis of red/black phosphorus-based composite nanosheets with a Z-scheme heterostructure for high-performance cancer phototherapy. NANOSCALE 2022; 14:766-779. [PMID: 34951432 DOI: 10.1039/d1nr07553e] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Two dimensional black phosphorus nanosheets (BP NSs) have attracted plenty of attention in the research field of cancer photonic therapy. However, the poor stability and relatively low efficiency of reactive oxygen species (ROS) generation of BP NSs limit their practical application. To address these drawbacks, herein we report a red/black phosphorus (RP/BP) composite nanosheet, M-RP/BP@ZnFe2O4, which was synthesized by (1) partially converting red phosphorus (RP) to black phosphorus (BP) followed by liquid-phase ultrasonic exfoliation to form RP/BP NSs, (2) in situ synthesis of ZnFe2O4 nanoparticles on the surface of RP/BP NSs, (3) and wrapping with the MCF-7 cell membrane. Due to the presence of RP, BP, ZnFe2O4 and the cell membrane, the M-RP/BP@ZnFe2O4 NSs exhibited high performance in cancer phototherapy with the following features: (i) a Z-scheme heterojunction structure was formed between RP/BP NSs thus enabling high separation efficiency of the photogenerated electrons and holes; (ii) the photoexcitation holes in the valence band of RP can break the tumor microenvironment by oxidizing glutathione; (iii) the NSs could decompose water to produce H2O2 and O2, which can be further converted to toxic ˙OH through the ZnFe2O4 catalyzed Fenton reaction and 1O2 through energy transfer, respectively; and (iv) the cell membrane wrapping improved the targeting of the composite NSs at the tumor site and photonic therapy can be finally triggered by a 660 nm laser to convert O2 to ˙O2- and 1O2. The in vitro cytotoxicity experiments showed that more than 90% cells were killed after photodynamic therapy (PDT) at 0.3 mg mL-1 M-RP/BP@ZnFe2O4 NSs, and the animal experiments with xenograft tumor model mice indicated that tumor growth was completely inhibited and the highest survival rate of 83.3% at 60 days post PDT was obtained.
Collapse
Affiliation(s)
- Yong Kang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
- University of Chinese Academy of Sciences, No. 19 Yuquan Road, Shijingshan District, Beijing, 100049, China
| | - Zhengjun Li
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
| | - Fengying Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
| | - Zhiguo Su
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
| | - Xiaoyuan Ji
- Academy of Medical Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, 300072, China
| | - Songping Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
| |
Collapse
|
|
27
|
Chen Y, Liu FX, Liu H. Effects of dietary zinc deficiency on esophageal squamous cell proliferation and the mechanisms involved. World J Gastrointest Oncol 2021; 13:1755-1765. [PMID: 34853648 PMCID: PMC8603456 DOI: 10.4251/wjgo.v13.i11.1755] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/30/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dietary zinc deficiency has been shown to be associated with the development of esophageal cancer in humans, but the exact mechanism of action is not known
AIM To observe the effects of dietary zinc deficiency on esophageal squamous cell proliferation.
METHODS Thirty C57BL/6 mice were randomly divided into three groups: A zinc-sufficient (ZS) group, zinc-deficient (ZD) group, and zinc-replenished (ZR) group. For weeks 1–10, zinc levels in the mice diets were 30.66–30.89 mg/kg in the ZS group and 0.66–0.89 mg/kg in the ZD and ZR groups. During weeks 10–12, the ZR group was switched to the ZS diet; the other two groups had no changes in their diets. Changes in body weight, serum, and esophageal tissue zinc concentrations were assessed as well as differences in the expression of proliferating cell nuclear antigen (PCNA), mitogen-activated protein kinase p38 (p38MAPK), nuclear factor kappa B (NF-κB) p105, NF-κB p65, and cyclooxygenase (COX)-2 proteins in the esophageal mucosa.
RESULTS The body weight and zinc concentration in the serum and esophageal mucosa were significantly lower in the ZD and ZR groups than in the ZS group (P < 0.05). In ZD mice, there was a marked proliferation of basal cells in the esophageal mucosa, resulting in a disturbance in the arrangement of basal cells in layers 2–4, a thickening of the squamous layer, and a significant increase in the expression of the above-mentioned five proteins involved in proliferation and inflammation in the esophageal mucosa. Two weeks after switching to the ZS diet, the serum zinc concentration in the ZR group increased, and the expression of PCNA, NF-κB p105, and COX-2 decreased, but the concentration of zinc in the esophageal mucosa and the structure of the esophageal mucosa did not display any significant changes
CONCLUSION The ZD diet decreased the growth rate and promoted the proliferation of esophageal squamous cells in mice. The mechanism of proliferation was related to the induced overexpression of COX-2, P38, PCNA, and NF-κB (p105 and p65), and the ZR diet reduced the expression of PCNA, NF-κB p105, and COX-2, thereby reversing this process.
Collapse
Affiliation(s)
- Yao Chen
- Department of Traditional Chinese Medicine, Peking University International Hospital, Beijing 102206, China
| | - Fang-Xun Liu
- International Medical Center, Peking University International Hospital, Beijing 102206, China
| | - Hong Liu
- Department of Gastroenterology, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China
| |
Collapse
|
|
28
|
Mansouri A, Keskas S, Azli T, Bouhila Z, Hamidatou L, Slamene H, Benamar MEA. Instrumental neutron activation analysis (INAA) of zinc concentrations in scalp hair and fingernails samples of Algerian females with breast cancer. RADIOCHIM ACTA 2021. [DOI: 10.1515/ract-2021-1069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Abstract
In the present work, zinc levels were measured in scalp hair and fingernails in order to identify potential risk factors for breast cancer. The samples were collected from 40 Algerian breast cancer female patients and from 20 normal subjects matching the same age range. The concentration of zinc was analyzed using Instrumental neutron activation analysis technique (INAA). In scalp hair samples it was found in the range 119–792 μg/g for the normal subjects and in the range 82–806 μg/g for the patients, with an increase rate of 10.9%. The range of concentration of zinc in fingernails was found between 89 and 247 μg/g for normal subjects and between 75 and 276 μg/g for the patients with an increase rate of 2.5%. The influence of age on zinc concentration was also investigated. The obtained results show some consistency with those obtained by other groups.
Collapse
Affiliation(s)
- Ammar Mansouri
- Nuclear Research Centre of Algiers , 2, Frantz Fanon Street, P.O. Box 399 , Algiers 16000 , Algeria
| | - Sabiha Keskas
- Department of Cellular Biology and Physiology , Saad Dahlab University , Blida 09000 , Algeria
| | - Tarek Azli
- Nuclear Research Centre of Draria , P.O. Box 43, Sebala, Draria , Algiers , Algeria
| | - Zohra Bouhila
- Nuclear Research Centre of Draria , P.O. Box 43, Sebala, Draria , Algiers , Algeria
| | - Lylia Hamidatou
- Nuclear Research Centre of Birine , P.O. Box 180 Ain Oussara , Djelfa 17200 , Algeria
| | - Hocine Slamene
- Nuclear Research Centre of Birine , P.O. Box 180 Ain Oussara , Djelfa 17200 , Algeria
| | - Mohammed El-Amine Benamar
- University Centre Amine El-Okkal El-Hadj Moussa Eg-Akhamouk , P.O. Box 10034 Sersouf , Tamenghast 11000 , Algeria
| |
Collapse
|
|
29
|
Chandra A, Dutta B, Pal K, Jana K, Sinha C. Designing of an Adipic acid bridged Zn(II) coordination polymer: Synthesis and biological study. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.130923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
30
|
Choi S, Sathe A, Mathé E, Xing C, Pan Z. Identification of a Putative Enhancer RNA for EGFR in Hyper-Accessible Regions in Esophageal Squamous Cell Carcinoma Cells by Analysis of Chromatin Accessibility Landscapes. Front Oncol 2021; 11:724687. [PMID: 34722266 PMCID: PMC8554337 DOI: 10.3389/fonc.2021.724687] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/20/2021] [Indexed: 01/22/2023] Open
Abstract
Abnormal genetic and epigenetic modifications play a key role in esophageal cancer. By Assay for Transposase-Accessible Chromatin by sequencing (ATAC-seq), this study compared chromatin accessibility landscapes among two esophageal squamous cell carcinoma (ESCC) cell lines, KYSE-30 and KYSE-150, and a non-cancerous esophageal epithelial cell line, HET-1A. Data showed that hyper-accessible regions in ESCC cells contained genes related with cancer hallmarks, such as epidermal growth factor receptor (EGFR). Multi-omics analysis and digital-droplet PCR results demonstrated that several non-coding RNAs in EGFR upstream were upregulated in ESCC cells. Among them, one appeared to act as an enhancer RNA responsible for EGFR overexpression. Further motif analysis and pharmacological data suggested that AP-1 family transcription factors were able to bind the hyper-accessible regions and thus to regulate cancer cell proliferation and migration. This study discovered a putative enhancer RNA for EGFR gene and the reliance of ESCC on AP-1 transcription factor.
Collapse
Affiliation(s)
- Sangyong Choi
- College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX, United States
- Department of Nutritional Sciences, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT, United States
| | - Adwait Sathe
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Ewy Mathé
- Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD, United States
| | - Chao Xing
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, United States
- Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, United States
- Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Zui Pan
- College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX, United States
| |
Collapse
|
|
31
|
Evaluation of the Anticancer and DNA-Binding Characteristics of Dichloro(diimine)zinc(II) Complexes. CHEMISTRY 2021. [DOI: 10.3390/chemistry3040086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Several metal diimine complexes have been reported to possess anticancer properties. To evaluate the anticancer properties of tetrahedral zinc(II) diimine complexes, six complexes were synthesized with the general formula M(N^N)Cl2 {where M = Zn, Pt and N^N = 2,2’-biquinoline (1), 2,2’-dipyridylketone (2) and 4-((pyridine-2-ylmethylene)amino)phenol (3)}. In general, the intrinsic DNA-binding constants for the different compounds exhibited values within close proximity; the changes in the viscosity of the CT-DNA upon binding to the compounds suggest intercalation-binding mode. Molecular docking study predicted that complexes containing the highly planar ligand 2,2’-biquinoline are capable to establish π–π interactions with nucleobases of the DNA; the other four complexes engaged in donor–acceptor interactions with DNA nucleobases. The six complexes and two reference drugs (cisplatin and sunitinib) were tested against two cancer cell lines (COLO 205 and RCC-PR) and one normal cell line (LLC-MK2), highlighting the better performance of the zinc(II) complexes compared to their platinum(II) analogues. Moreover, zinc(II) complexes have higher selectivity index values than the reference drugs, with promising anticancer properties.
Collapse
|
|
32
|
Liu Y, Wang Y, Song S, Zhang H. Cancer therapeutic strategies based on metal ions. Chem Sci 2021; 12:12234-12247. [PMID: 34603654 PMCID: PMC8480331 DOI: 10.1039/d1sc03516a] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 09/01/2021] [Indexed: 02/06/2023] Open
Abstract
As a necessary substance to maintain the body's normal life activities, metal ions are ubiquitous in organisms and play a major role in various complex physiological and biochemical processes, such as material transportation, energy conversion, information transmission, metabolic regulation, etc. Their abnormal distribution/accumulation in cells can interfere with these processes, causing irreversible physical damage to cells or activating biochemical reactions to induce cell death. Therefore, metal ions can be exploited against a wide spectrum of cancers with high efficiency and without drug resistance, which can effectively inhibit the growth of cancer cells by triggering biocatalysis, breaking the osmotic balance, affecting metabolism, interfering with signal transduction, damaging DNA, etc. This perspective systematically summarizes the latest research progress of metal ion-based anti-tumor therapy, and emphasizes the challenges and development directions of this type of therapeutic strategy, hoping to provide a general implication for future research.
Collapse
Affiliation(s)
- Yang Liu
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 P. R. China
- University of Science and Technology of China Hefei Anhui 230026 P. R. China
| | - Yinghui Wang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 P. R. China
| | - Shuyan Song
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 P. R. China
- University of Science and Technology of China Hefei Anhui 230026 P. R. China
| | - Hongjie Zhang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 P. R. China
- University of Science and Technology of China Hefei Anhui 230026 P. R. China
- Department of Chemistry, Tsinghua University Beijing 100084 P. R. China
| |
Collapse
|
|
33
|
Story MJ. Essential sufficiency of zinc, ω-3 polyunsaturated fatty acids, vitamin D and magnesium for prevention and treatment of COVID-19, diabetes, cardiovascular diseases, lung diseases and cancer. Biochimie 2021; 187:94-109. [PMID: 34082041 PMCID: PMC8166046 DOI: 10.1016/j.biochi.2021.05.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023]
Abstract
Despite the development of a number of vaccines for COVID-19, there remains a need for prevention and treatment of the virus SARS-CoV-2 and the ensuing disease COVID-19. This report discusses the key elements of SARS-CoV-2 and COVID-19 that can be readily treated: viral entry, the immune system and inflammation, and the cytokine storm. It is shown that the essential nutrients zinc, ω-3 polyunsaturated fatty acids (PUFAs), vitamin D and magnesium provide the ideal combination for prevention and treatment of COVID-19: prevention of SARS-CoV-2 entry to host cells, prevention of proliferation of SARS-CoV-2, inhibition of excessive inflammation, improved control of the regulation of the immune system, inhibition of the cytokine storm, and reduction in the effects of acute respiratory distress syndrome (ARDS) and associated non-communicable diseases. It is emphasized that the non-communicable diseases associated with COVID-19 are inherently more prevalent in the elderly than the young, and that the maintenance of sufficiency of zinc, ω-3 PUFAs, vitamin D and magnesium is essential for the elderly to prevent the occurrence of non-communicable diseases such as diabetes, cardiovascular diseases, lung diseases and cancer. Annual checking of levels of these essential nutrients is recommended for those over 65 years of age, together with appropriate adjustments in their intake, with these services and supplies being at government cost. The cost:benefit ratio would be huge as the cost of the nutrients and the testing of their levels would be very small compared with the cost savings of specialists and hospitalization.
Collapse
Affiliation(s)
- Michael J Story
- Story Pharmaceutics Pty Ltd, PO Box 6086, Linden Park, South Australia, 5065, Australia.
| |
Collapse
|
|
34
|
Cui C, Zhang Y, Liu G, Zhang S, Zhang J, Wang X. Advances in the study of cancer metastasis and calcium signaling as potential therapeutic targets. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:266-291. [PMID: 36046433 PMCID: PMC9400724 DOI: 10.37349/etat.2021.00046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/21/2021] [Indexed: 11/19/2022] Open
Abstract
Metastasis is still the primary cause of cancer-related mortality. However, the underlying mechanisms of cancer metastasis are not yet fully understood. Currently, the epithelial-mesenchymal transition, metabolic remodeling, cancer cell intercommunication and the tumor microenvironment including diverse stromal cells, are reported to affect the metastatic process of cancer cells. Calcium ions (Ca2+) are ubiquitous second messengers that manipulate cancer metastasis by affecting signaling pathways. Diverse transporter/pump/channel-mediated Ca2+ currents form Ca2+ oscillations that can be decoded by Ca2+-binding proteins, which are promising prognostic biomarkers and therapeutic targets of cancer metastasis. This paper presents a review of the advances in research on the mechanisms underlying cancer metastasis and the roles of Ca2+-related signals in these events.
Collapse
Affiliation(s)
- Chaochu Cui
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Yongxi Zhang
- Department of Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Gang Liu
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Shuhong Zhang
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Jinghang Zhang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, China
| | - Xianwei Wang
- Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, China
| |
Collapse
|
|
35
|
Chang Y, Roy S, Pan Z. Store-Operated Calcium Channels as Drug Target in Gastroesophageal Cancers. Front Pharmacol 2021; 12:668730. [PMID: 34012400 PMCID: PMC8126661 DOI: 10.3389/fphar.2021.668730] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
Gastroesophageal cancers, including tumors occurring in esophagus and stomach, usually have poor prognosis and lack effective chemotherapeutic drugs for treatment. The association between dysregulated store-operated calcium entry (SOCE), a key intracellular Ca2+ signaling pathway and gastroesophageal cancers are emerging. This review summarizes the recent advances in understanding the contribution of SOCE-mediated intracellular Ca2+ signaling to gastroesophageal cancers. It assesses the pathophysiological role of each component in SOCE machinery, such as Orais and STIMs in the cancer cell proliferation, migration, and invasion as well as stemness maintenance. Lastly, it discusses efforts towards development of more specific and potent SOCE inhibitors, which may be a new set of chemotherapeutic drugs appearing at the horizon, to provide either targeted therapy or adjuvant treatment to overcome drug resistance for gastroesophageal cancers.
Collapse
Affiliation(s)
- Yan Chang
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| | - Souvik Roy
- Department of Mathematics, The University of Texas at Arlington, Arlington, TX, United States
| | - Zui Pan
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| |
Collapse
|
|
36
|
Liu L, Hou Y, Hu J, Zhou L, Chen K, Yang X, Song Z. SLC39A8/Zinc Suppresses the Progression of Clear Cell Renal Cell Carcinoma. Front Oncol 2021; 11:651921. [PMID: 33869056 PMCID: PMC8045709 DOI: 10.3389/fonc.2021.651921] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/05/2021] [Indexed: 12/19/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most frequent and lethal subtype, which has high risk of metastasis or recurrence, accounting for 75–83% of renal cell carcinoma (RCC). Zrt‐ and Irt‐like proteins (ZIP) family members (SLC39A1-14) function to pass zinc into the cytoplasm for many critical biological processes when cellular zinc is depleted. However, the functional analysis of individual ZIP family genes in ccRCC is not clarified. This study aimed to investigate whether ZIP family genes are related to the clinicopathological features and survival of ccRCC patients, and to identify the function of key gene of ZIP family in ccRCC in vitro. Through bioinformatics analysis of tumor databases, SLC39A8 was identified as a key gene of ZIP family in ccRCC, which could be used as an effective indicator for diagnosing ccRCC and judging its prognosis. With the progression of tumor, the expression of SLC39A8 decreased progressively. The prognosis of patients with low expression of SLC39A8 is significantly worse. Furthermore, we found that overexpression of SLC39A8 or treatment with low concentration of zinc chloride could effectively inhibit the proliferation, migration and invasion of ccRCC cells. Moreover, the inhibition effect of SLC39A8 overexpression could be enhanced by low concentration zinc supplement. Therefore, this study provides a novel understanding for the role of SLC39A8/zinc in the regulation of ccRCC progression. These findings provide a new direction and target for progressive ccRCC drug development and combination therapy strategies.
Collapse
Affiliation(s)
- Lilong Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaxin Hou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junyi Hu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lijie Zhou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiong Yang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhengshuai Song
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
37
|
Jankovic-Karasoulos T, McAninch D, Dixon C, Leemaqz SYL, François M, Leifert WR, McCullough D, Ricciardelli C, Roberts CT, Bianco-Miotto T. The effect of zinc on human trophoblast proliferation and oxidative stress. J Nutr Biochem 2020; 90:108574. [PMID: 33388345 DOI: 10.1016/j.jnutbio.2020.108574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 10/26/2020] [Accepted: 12/24/2020] [Indexed: 10/22/2022]
Abstract
Adequate Zinc (Zn) intake is required to prevent multiple teratogenic effects however deviations from adequate Zn intake, including high maternal Zn status, have been linked to increased incidence of pregnancy complications, including those associated with inadequate placentation. Using placental trophoblast HTR8/SVneo cells and first trimester human placental explants (n = 12), we assessed the effects of varying Zn concentrations on trophoblast proliferation, viability, apoptosis and oxidative stress. Compared to physiologically normal Zn levels (20 µM), HTR-8/SVneo cell proliferation index was significantly lower in the presence of physiologically elevated (40 µM; P = .020) and supra-physiological (80 µM; P = .007) Zn. The latter was also associated with reduced proliferation (P = .004) and viability (P < .0001) in cultured placental explants, but not apoptosis. Reactive oxygen species production in HTR8/SVneo cultures was significantly higher in the presence of 80 µM Zn compared to all physiologically relevant levels. Oxidative stress, induced by an oxidizing agent menadione, was further exacerbated by high (80 µM) Zn. Zn did not affect lipid peroxidation in either HTR8/SVneo cells or placental explants or antioxidant defense mechanisms that included glutathione reductase and superoxide dismutase. Further study should focus on elucidating mechanisms behind impaired trophoblast proliferation and increased oxidative stress as a result of elevated Zn levels.
Collapse
Affiliation(s)
- Tanja Jankovic-Karasoulos
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia; Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Dale McAninch
- Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Clare Dixon
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia; School of Agriculture, Food and Wine, Waite Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - Shalem Y-L Leemaqz
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia; Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Maxime François
- School of Agriculture, Food and Wine, Waite Research Institute, University of Adelaide, Adelaide, SA, Australia; CSIRO Health and Biosecurity, Future Science Platforms Probing Biosystems, Adelaide, SA, Australia
| | - Wayne R Leifert
- CSIRO Health and Biosecurity, Future Science Platforms Probing Biosystems, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Dylan McCullough
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia; Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Carmela Ricciardelli
- Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Claire T Roberts
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia; Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
| | - Tina Bianco-Miotto
- Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; School of Agriculture, Food and Wine, Waite Research Institute, University of Adelaide, Adelaide, SA, Australia.
| |
Collapse
|
|
38
|
Story MJ. Zinc, ω-3 polyunsaturated fatty acids and vitamin D: An essential combination for prevention and treatment of cancers. Biochimie 2020; 181:100-122. [PMID: 33307154 DOI: 10.1016/j.biochi.2020.11.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 11/14/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
Zinc, ω-3 polyunsaturated fatty acids (PUFAs) and vitamin D are essential nutrients for health, maturation and general wellbeing. Extensive literature searches have revealed the widespread similarity in molecular biological properties of zinc, ω-3 PUFAs and vitamin D, and their similar anti-cancer properties, even though they have different modes of action. These three nutrients are separately essential for good health, especially in the aged. Zinc, ω-3 PUFAs and vitamin D are inexpensive and safe as they are fundamentally natural and have the properties of correcting and inhibiting undesirable actions without disturbing the normal functions of cells or their extracellular environment. This review of the anticancer properties of zinc, ω-3 PUFAs and vitamin D is made in the context of the hallmarks of cancer. The anticancer properties of zinc, ω-3 PUFAs and vitamin D can therefore be used beneficially through combined treatment or supplementation. It is proposed that sufficiency of zinc, ω-3 PUFAs and vitamin D is a necessary requirement during chemotherapy treatment and that clinical trials can have questionable integrity if this sufficiency is not checked and maintained during efficacy trials.
Collapse
Affiliation(s)
- Michael J Story
- Story Pharmaceutics Pty Ltd, PO Box 6086, Linden Park, South Australia, 5065, Australia.
| |
Collapse
|
|
39
|
Zhu M, Lv B, Ge W, Cui Z, Zhao K, Feng Y, Yang X. Suppression of store-operated Ca 2+ entry regulated by silencing Orai1 inhibits C6 glioma cell motility via decreasing Pyk2 activity and promoting focal adhesion. Cell Cycle 2020; 19:3468-3479. [PMID: 33269647 DOI: 10.1080/15384101.2020.1843814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Store-operated Ca2+ entry (SOCE) plays an important role in regulating Ca2+ influx, which participates in tumor cell survival and motility. We aim to elucidate the role of SOCE in the behavior of C6 glioma cells. Lentiviral vector inserted with the Orai1-targeting shRNA was used to inhibit SOCE in C6 glioma cells. The down-regulation of Orai1 was confirmed by western blot. The ability of shOrai1 or SOCE inhibitor (SKF96365) in regulating SOCE inhibition was evaluated by measuring Ca2+ concentration. Additionally, its effect on cell behavior was assessed using methyl thiazolyl tetrazolium (MTT) assay, wound healing assay, transwell assay, and adhesion assay. Focal adhesions were visualized by immunofluorescence assay. Further, the expression of proline-rich tyrosine kinase 2 (Pyk2) and phosphorylated Pyk2 (p-Pyk2) was analyzed using western blot. Both, SKF96365 treatment and the Orai1 down-regulation inhibited SOCE by perturbing Ca2+ influx. The inhibitory effects of shOrai1 on C6 cell proliferation, migration, and invasion were similar to that of SKF96365. Moreover, Orai1 inhibition enhanced C6 cell adhesion by increasing the size of focal adhesion plaques. The down-regulation of Pyk2 was observed in both SKF96365-treated and Orai1-silenced C6 cells. Additionally, Orai1 inhibition blocked AKT/mTOR, NFAT, and NF-κB pathways. The silencing of Orai1 inhibited the C6 glioma cell migration, invasion and contributed to focal adhesion.
Collapse
Affiliation(s)
- Meng Zhu
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University , Qingdao, China.,Department of Neurosurgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Bingke Lv
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University , Qingdao, China
| | - Wenjing Ge
- Department of Radiology, Qingdao Municipal Hospital , Qingdao, China
| | - Zhenwen Cui
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University , Qingdao, China
| | - Kai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University , Qingdao, China
| | - Yugong Feng
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University , Qingdao, China
| | - Xuejun Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital , Tianjin, China
| |
Collapse
|
|
40
|
Zhang R, Zhao G, Shi H, Zhao X, Wang B, Dong P, Watari H, Pfeffer LM, Yue J. Zinc regulates primary ovarian tumor growth and metastasis through the epithelial to mesenchymal transition. Free Radic Biol Med 2020; 160:775-783. [PMID: 32927017 PMCID: PMC7704937 DOI: 10.1016/j.freeradbiomed.2020.09.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/29/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The trace element zinc plays an indispensable role in human health and diseases including cancer due to its antioxidant properties. While zinc supplements have been used for cancer prevention, zinc is also a risk factor for cancer development. It is still unclear how zinc plays a role in ovarian cancer. METHODS To understand how zinc contributes to ovarian tumor growth and metastasis, we examined whether zinc contributes to tumor metastasis by regulating epithelial to mesenchymal transition (EMT) using ovarian cancer cells in vitro. Cell migration and invasion were examined using transwell plates and EMT markers were examined using Western blot. Primary ovarian tumor growth and metastasis were assessed using orthotopic ovarian cancer mouse models in vivo. RESULTS Zinc promoted EMT, while TPEN (N, N, N', N'-tetrakis-(2-pyridylmethyl)-ethylenediamine), a membrane-permeable selective zinc chelator, inhibited EMT in a dose dependent manner in ovarian cancer cells. Moreover, zinc promoted ovarian cancer cell migration and invasion, while TPEN inhibited cell migration and invasion. Zinc activated expression of the metal response transcriptional factor-1 (MTF-1), while TPEN inhibited MTF-1 expression in a dose dependent manner. Knockout of MTF-1 inhibited zinc-induced cell migration, invasion and augmented the inhibitory effect of TPEN on cell migration and invasion. Loss of MTF-1 attenuated zinc-induced ERK1/2 and AKT activation and augmented the effect of TPEN in attenuating the ERK1/2 and AKT pathways. TPEN effectively inhibited primary ovarian tumor growth and metastasis in an orthotopic ovarian cancer mouse model by suppressing EMT. CONCLUSION zinc contributes to ovarian tumor metastasis by promoting EMT through a MTF-1 dependent pathway. Zinc depletion by TPEN may be a novel approach for ovarian cancer therapy by inhibiting EMT and attenuating the ERK1/2 and AKT pathways.
Collapse
Affiliation(s)
- Ruitao Zhang
- Department of Gynecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China; Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
| | - Guannan Zhao
- Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
| | - Huirong Shi
- Department of Gynecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
| | - Xinxin Zhao
- Department of Gynecology and Obstetrics, Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
| | - Baojin Wang
- Department of Gynecology and Obstetrics, Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
| | - Peixin Dong
- Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Hidemichi Watari
- Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Lawrence M Pfeffer
- Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
| |
Collapse
|
|
41
|
Wang M, Phadke M, Packard D, Yadav D, Gorelick F. Zinc: Roles in pancreatic physiology and disease. Pancreatology 2020; 20:1413-1420. [PMID: 32917512 PMCID: PMC7572834 DOI: 10.1016/j.pan.2020.08.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022]
Abstract
Zinc is an essential trace element. Deficiencies are frequently seen with gastrointestinal diseases, including chronic pancreatitis, nutritional deficiency, and reduced intestinal absorption. Additionally, reduced zinc levels have been linked to cellular changes associated with acute pancreatitis such as enhanced inflammation with increased macrophage activation and production of inflammatory cytokines such as IL-1β, impaired autophagy, and modulation of calcium homeostasis. Preliminary data suggest that zinc deficiency may lead to pancreatic injury in animal models. The purpose of this review is to explore the biologic effects of zinc deficiency that could impact pancreatic disease. MESH KEYWORDS: Malnutrition, inflammation, trace element.
Collapse
Affiliation(s)
- Melinda Wang
- Yale School of Medicine, Department of Internal Medicine and VA HealthCare System, CT, USA
| | - Madhura Phadke
- Yale School of Medicine, Department of Internal Medicine and VA HealthCare System, CT, USA
| | - Daniel Packard
- Yale School of Medicine, Department of Internal Medicine and VA HealthCare System, CT, USA
| | - Dhiraj Yadav
- University of Pittsburgh, Department of Medicine, USA
| | - Fred Gorelick
- Yale School of Medicine, Department of Internal Medicine and VA HealthCare System, CT, USA.
| |
Collapse
|
|
42
|
Balaji E V, Kumar N, Satarker S, Nampoothiri M. Zinc as a plausible epigenetic modulator of glioblastoma multiforme. Eur J Pharmacol 2020; 887:173549. [PMID: 32926916 DOI: 10.1016/j.ejphar.2020.173549] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/26/2020] [Accepted: 09/09/2020] [Indexed: 01/04/2023]
Abstract
Glioblastoma Multiforme (GBM) is an aggressive brain tumor (WHO grade 4 astrocytoma) with unknown causes and is associated with a reduced life expectancy. The available treatment options namely radiotherapy, surgery and chemotherapy have failed to improve life expectancy. Out of the various therapeutic approaches, epigenetic therapy is one of the most studied. Epigenetic therapy is involved in the effective treatment of GBM by inhibiting DNA methyltransferase, histone deacetylation and non-coding RNA. It also promotes the expression of the tumor suppressor gene and is involved in the suppression of the oncogene. Various targets are being studied to implement proper epigenetic regulation to control GBM effectively. Zinc is one of the micronutrients which is considered to maintain epigenetic regulation by promoting the proper DNA folding, protecting genetic material from the oxidative damage and controlling the enzyme activation involved in the epigenetic regulation. Here, we are discussing the importance of zinc in regulating the epigenetic modifications and assessing its role in glioblastoma research. The discussion also highlights the importance of artificial intelligence using epigenetics for envisaging the glioma progression, diagnosis and its management.
Collapse
Affiliation(s)
- Vignesh Balaji E
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Nitesh Kumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
| |
Collapse
|
|
43
|
How Dysregulated Ion Channels and Transporters Take a Hand in Esophageal, Liver, and Colorectal Cancer. Rev Physiol Biochem Pharmacol 2020; 181:129-222. [PMID: 32875386 DOI: 10.1007/112_2020_41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Over the last two decades, the understanding of how dysregulated ion channels and transporters are involved in carcinogenesis and tumor growth and progression, including invasiveness and metastasis, has been increasing exponentially. The present review specifies virtually all ion channels and transporters whose faulty expression or regulation contributes to esophageal, hepatocellular, and colorectal cancer. The variety reaches from Ca2+, K+, Na+, and Cl- channels over divalent metal transporters, Na+ or Cl- coupled Ca2+, HCO3- and H+ exchangers to monocarboxylate carriers and organic anion and cation transporters. In several cases, the underlying mechanisms by which these ion channels/transporters are interwoven with malignancies have been fully or at least partially unveiled. Ca2+, Akt/NF-κB, and Ca2+- or pH-dependent Wnt/β-catenin signaling emerge as cross points through which ion channels/transporters interfere with gene expression, modulate cell proliferation, trigger epithelial-to-mesenchymal transition, and promote cell motility and metastasis. Also miRs, lncRNAs, and DNA methylation represent potential links between the misexpression of genes encoding for ion channels/transporters, their malfunctioning, and cancer. The knowledge of all these molecular interactions has provided the basis for therapeutic strategies and approaches, some of which will be broached in this review.
Collapse
|
|
44
|
Becskeházi E, Korsós MM, Erőss B, Hegyi P, Venglovecz V. OEsophageal Ion Transport Mechanisms and Significance Under Pathological Conditions. Front Physiol 2020; 11:855. [PMID: 32765303 PMCID: PMC7379034 DOI: 10.3389/fphys.2020.00855] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 06/25/2020] [Indexed: 12/20/2022] Open
Abstract
Ion transporters play an important role in several physiological functions, such as cell volume regulation, pH homeostasis and secretion. In the oesophagus, ion transport proteins are part of the epithelial resistance, a mechanism which protects the oesophagus against reflux-induced damage. A change in the function or expression of ion transporters has significance in the development or neoplastic progression of Barrett's oesophagus (BO). In this review, we discuss the physiological and pathophysiological roles of ion transporters in the oesophagus, highlighting transport proteins which serve as therapeutic targets or prognostic markers in eosinophilic oesophagitis, BO and esophageal cancer. We believe that this review highlights important relationships which might contribute to a better understanding of the pathomechanisms of esophageal diseases.
Collapse
Affiliation(s)
- Eszter Becskeházi
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | | | - Bálint Erőss
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| |
Collapse
|
|
45
|
Tran PHL, Tran TTD. Developmental Strategies of Curcumin Solid Dispersions for Enhancing Bioavailability. Anticancer Agents Med Chem 2020; 20:1874-1882. [PMID: 32640962 DOI: 10.2174/1871520620666200708103845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 03/28/2020] [Accepted: 04/26/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Although curcumin has been demonstrated to be beneficial in treating various diseases, its low solubility, chemical stability and bioavailability limit its application, especially in cancer therapy. METHODS Solid dispersions have been utilized in the last few decades to improve the bioavailability and stability of curcumin. RESULTS However, there is a lack of summaries and classifications of the methods for preparing curcumin with this technology. The current review aims to overview the strategies used to develop solid dispersions containing curcumin for improving drug delivery. The classification of techniques for creating solid dispersions for curcumin was summarized, including systems for protecting curcumin degradation despite its chemical stability. The applications of advanced nanotechnologies in recent studies of solid dispersions were also discussed to explain the roles of nanoparticles in formulations. CONCLUSION This overview of recent developments in formulating solid dispersions for improving curcumin bioavailability will contribute to future studies of curcumin for clinical development.
Collapse
Affiliation(s)
- Phuong H L Tran
- Deakin University, Geelong Australia, School of Medicine, Melbourne, Vic, Australia
| | - Thao T D Tran
- Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam,Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| |
Collapse
|
|
46
|
Zhang X, Pan Z. Influence of microbiota on immunity and immunotherapy for gastric and esophageal cancers. Gastroenterol Rep (Oxf) 2020; 8:206-214. [PMID: 32665852 PMCID: PMC7333930 DOI: 10.1093/gastro/goaa014] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 03/05/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric and esophageal cancers are multifactorial and multistage-involved malignancy. While the impact of gut microbiota on overall human health and diseases has been well documented, the influence of gastric and esophageal microbiota on gastric and esophageal cancers remains unclear. This review will discuss the reported alteration in the composition of gastric and esophageal microbiota in normal and disease conditions, and the potential role of dysbiosis in carcinogenesis and tumorigenesis. This review will also discuss how dysbiosis stimulates local and systemic immunity, which may impact on the immunotherapy for cancer.
Collapse
Affiliation(s)
- Xiaoli Zhang
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
| | - Zui Pan
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, USA
| |
Collapse
|
|
47
|
Serra M, Columbano A, Ammarah U, Mazzone M, Menga A. Understanding Metal Dynamics Between Cancer Cells and Macrophages: Competition or Synergism? Front Oncol 2020; 10:646. [PMID: 32426284 PMCID: PMC7203474 DOI: 10.3389/fonc.2020.00646] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/07/2020] [Indexed: 12/13/2022] Open
Abstract
Metal ions, such as selenium, copper, zinc, and iron are naturally present in the environment (air, drinking water, and food) and are vital for cellular functions at chemical, molecular, and biological levels. These trace elements are involved in various biochemical reactions by acting as cofactors for many enzymes and control important biological processes by binding to the receptors and transcription factors. Moreover, they are essential for the stabilization of the cellular structures and for the maintenance of genome stability. A body of preclinical and clinical evidence indicates that dysregulation of metal homeostasis, both at intracellular and tissue level, contributes to the pathogenesis of many different types of cancer. These trace minerals play a crucial role in preventing or accelerating neoplastic cell transformation and in modulating the inflammatory and pro-tumorigenic response in immune cells, such as macrophages, by controlling a plethora of metabolic reactions. In this context, macrophages and cancer cells interact in different manners and some of these interactions are modulated by availability of metals. The current review discusses the new findings and focuses on the involvement of these micronutrients in metabolic and cellular signaling mechanisms that influence macrophage functions, onset of cancer and its progression. An improved understanding of "metallic" cross-talk between macrophages and cancer cells may pave the way for innovative pharmaceutical or dietary interventions in order to restore the balance of these trace elements and also strengthen the chemotherapeutic treatment.
Collapse
Affiliation(s)
- Marina Serra
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
| | - Amedeo Columbano
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Ummi Ammarah
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center – MBC, University of Torino, Turin, Italy
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center – MBC, University of Torino, Turin, Italy
| | - Alessio Menga
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center – MBC, University of Torino, Turin, Italy
| |
Collapse
|
|
48
|
Ding J, Jin Z, Yang X, Lou J, Shan W, Hu Y, Du Q, Liao Q, Xu J, Xie R. Plasma membrane Ca 2+-permeable channels and sodium/calcium exchangers in tumorigenesis and tumor development of the upper gastrointestinal tract. Cancer Lett 2020; 475:14-21. [PMID: 32004573 DOI: 10.1016/j.canlet.2020.01.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/30/2019] [Accepted: 01/23/2020] [Indexed: 12/17/2022]
Abstract
The upper gastrointestinal (GI) tumors are multifactorial diseases associated with a combination of oncogenes and environmental factors. Currently, surgery, chemotherapy, radiotherapy and immunotherapy are relatively effective treatment options for the patients with these tumors. However, the asymptomatic phenotype of these tumors during the early stages poses as a significant limiting factor to diagnosis and often renders treatments ineffective. Therefore, new early diagnosis and effective therapy for upper GI tumors are urgently needed. Ca2+ is a pivotal intracellular second messenger and plays a crucial role in living cells by regulating several processes from cell division to death. The aberrant Ca2+ homeostasis is related to many human pathological conditions and diseases, including cancer, and thus the changes in the expression and function of plasma membrane Ca2+ permeable channels and sodium/calcium exchangers are frequently described in tumorigenesis and tumor development of the upper GI tract, including voltage-gated Ca2+ channels (VGCC), transient receptor potential (TRP) channels, store-operated channels (SOC) and Na+/Ca2+ exchanger (NCX). This review will summarize the current knowledge about plasma membrane Ca2+ permeable channels and sodium/calcium exchangers in the upper GI tumors and provide a synopsis of recent advancements on the role and involvement of these channels in upper GI tumors as well as a discussion of the possible strategies to target these channels and exchangers for diagnosis and therapy of the upper GI tumors.
Collapse
Affiliation(s)
- JianHong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Xiaoxu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Weixi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Yanxia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Qiushi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China
| | - Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China.
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, PR China.
| |
Collapse
|
|
49
|
El-Desouky MA, Fahmi AA, Abdelkader IY, Nasraldin KM. Anticancer Effect of Amygdalin (Vitamin B-17) on Hepatocellular Carcinoma Cell Line (HepG2) in the Presence and Absence of Zinc. Anticancer Agents Med Chem 2020; 20:486-494. [PMID: 31958042 DOI: 10.2174/1871520620666200120095525] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/28/2019] [Accepted: 11/21/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Amygdalin (Vitamin B-17) is a naturally occurring vitamin found in the seeds of the fruits of Prunus Rosacea family including apricot, bitter almond, cherry, and peach. OBJECTIVE The purpose of this study was to examine the effect of amygdalin with and without zinc on hepatocellular carcinoma (HepG2) cell line. METHODS MTT assay was used to evaluate the cytotoxicity of amygdalin without zinc, amygdalin + 20μmol zinc, and amygdalin + 800μmol zinc on HepG2 cell lines. The cell cycle distribution assay was determined by flow cytometry. Apoptosis was confirmed by Annexin V-FITC/PI staining assay. Moreover, the pathway of apoptosis was determined by the percentage of change in the mean levels of P53, Bcl2, Bax, cytochrome c, and caspase-3. RESULTS Amygdalin without zinc showed strong anti-HepG2 activity. Furthermore, HepG2 cell lines treatment with amygdalin + 20μmol zinc and amygdalin + 800μmol zinc showed a highly significant apoptotic effect than the effect of amygdalin without zinc. Amygdalin treatment induced cell cycle arrest at G2/M and increased the levels of P53, Bax, cytochrome c, and caspase-3 significantly, while it decreased the level of anti-apoptotic Bcl2. CONCLUSION Amygdalin is a natural anti-cancer agent, which can be used for the treatment of hepatocellular carcinoma. It promotes apoptosis via the intrinsic cell death pathway (the mitochondria-initiated pathway) and cell cycle arrest at G/M. The potency of amygdalin in HepG2 treatment increased significantly by the addition of zinc.
Collapse
Affiliation(s)
| | - Abdelgawad A Fahmi
- Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt
| | - Ibrahim Y Abdelkader
- Department of Medical Sciences, Faculty of Dentistry, The British University in Egypt (BUE), El-Shorouk, Egypt
| | - Karima M Nasraldin
- Department of Medical Sciences, Faculty of Dentistry, The British University in Egypt (BUE), El-Shorouk, Egypt
| |
Collapse
|
|
50
|
Kaya B, Yılmaz ZK, Şahin O, Aslim B, Ülküseven B. Structural characterization of new zinc(ii) complexes with N2O2 chelating thiosemicarbazidato ligands; investigation of the relationship between their DNA interaction and in vitro antiproliferative activity towards human cancer cells. NEW J CHEM 2020. [DOI: 10.1039/d0nj02149k] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
New candidates to become DNA-targeting antiproliferative agents: Zinc(ii) complexes bearing N2O2-thiosemicarbazidato ligands.
Collapse
Affiliation(s)
- Büşra Kaya
- Department of Chemistry, Engineering Faculty
- Istanbul University-Cerrahpasa
- 34320 Avcilar
- Turkey
| | | | - Onur Şahin
- Sinop University
- Scientific and Technological Research Application and Research Center
- 57000 Sinop
- Turkey
| | - Belma Aslim
- Faculty of Science
- Department of Biology
- Gazi University
- Ankara
- Turkey
| | - Bahri Ülküseven
- Department of Chemistry, Engineering Faculty
- Istanbul University-Cerrahpasa
- 34320 Avcilar
- Turkey
| |
Collapse
|